Background

Medulloblastoma in adults is a rare entity. Data addressing this disease in adults are scarce. We reviewed the clinicopathological, molecular characteristics and treatment outcomes of patients treated at our center.

Methods

Patients with medulloblastoma were retrospectively analyzed from our database from 2007-2019. Data included were age at diagnosis, gender, and risk stratification including the status of metastasis, type of surgery, radiotherapy, and chemotherapy status. Overall survival (OS) and progression-free survival (PFS) were calculated using Kaplan Meier Method. Log-rank test and Cox proportional hazard models were performed to identify predictors of OS and PFS. In addition, molecular sub-grouping was conducted on 29 patients.

Results

A total of 54 patients were eligible for the study. Median age at diagnosis was 26 years. Most (77.8%) patients were non-metastatic at presentation (M0 Chang stage). Complete resection was achieved in 81.5% of patients and all received adjuvant radiation. Chemotherapy was administered at the time of progression or recurrence. 59.3% were standard risk. The most common molecular subtype, Sonic hedgehog (SHH), was identified in 79.3% (23/29) of patients, followed by WNT and Group 4 each account for 10.3%. With a median follow-up of 53 months, 15 patients (27.8%) developed relapses, seven relapses were distant, three were local and five had both local and distant relapses. Five-year OS and PFS were 68.4%, and 70.0%, respectively. Patients in SHH subgroup had 5-year OS (61.4%) and PFS (59.0%), whereas 5-year OS and PFS were 100% for both Group 4 and WNT subgroups. 66.7% of distant and combined relapses were from the high-risk cohort. On univariate analysis, high-risk group and the presence of metastases conferred poor OS (p=0.007, p=0.008) and PFS (p=0.03, p=0.03). However, on multivariate analysis, none of the variables retained significance.

Conclusions

Our study is among the largest reports on adult medulloblastoma. Distant relapse is the predominant pattern in high-risk patients supporting the need for treatment intensification. SHH is the most common molecular subtype in adults and their survival outcome appears to be worse compared to pediatrics with the same molecular subgroup.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

CAN008 (Asunercept) is a recombinant glycosylated CD95-Fc fusion protein that disrupts the CD95/CD95L signaling pathway that promotes the growth and metastasis of tumor cells in glioblastoma multiforme (GBM). In 2016, a phase I/II open-label, dose-escalation trial of CAN008 as an add-on treatment to standard temozolomide/radiotherapy (TMZ/RT) treatment in newly-diagnosed GBM patients indicated that it was well-tolerated and showed promising efficacy. We now report long-term follow-up results from this study at our center.

Methods

Adults with newly diagnosed GBM were administered CAN008 (200 mg or 400 mg IV weekly) plus TMZ/RT for 6 weeks after tumor excision, followed by maintenance CAN008 plus TMZ until confirmed tumor recurrence or 24 months after surgery. Tumor samples were analyzed using next-generation whole exome sequencing.

Results

Between August 2016 and September 2017, 10 newly diagnosed GBM patients were enrolled and underwent surgical resection followed by standard TMZ/RT treatment. Of the 9 patients treated at Chang-Gung Memorial Hospital, 3 received low-dose (200 mg/week), and 6 received high-dose (400 mg/week) CAN008 treatment. 4 (high-dose group) of these 9 patients were alive at 5-year follow-up. The overall survival rate of the high-dose CAN008 group was 83% (95% CI 58.3-100) at 2 years, and it remained at 67% (37.9-100) at 3, 4, and 5 years, compared to an institutional database (N=218) that showed a declining rate of 34.3% (27.4-42.9), 19.5% (13.5-28.3), 16.1% (10.5-24.8), and 8.2% (3.9-17.1), respectively, at the same time points, and median progression-free survival was 17.95 months (3.7-NA), PFS was defined as the time from the date of the first diagnosis of GBM to the date of the first radiologically documented disease progression. DNA analysis revealed that a higher tumor mutation burden and a higher frequency of DNAH family gene mutations were associated with a favorable response to CAN008 treatment.

Conclusions

CAN008 400 mg IV weekly administered in conjunction with standard TMZ/RT treatment significantly improved the long-term outcomes of patients with newly-diagnosed GBM. Higher tumor mutation burden and a higher frequency of DNAH family gene mutations may be predictors of a favorable response to CAN008 treatment.

Clinical trial identification

NCT02853565.

Legal entity responsible for the study

Hong-Chieh Tsai, Department of Neurosurgery, Chang Gung Memorial Hospital Linkou Branch, Taoyuan, Taiwan.

Funding

CANbridge Pharmaceuticals Inc., Shanghai, China.

Disclosure

G.F. Cox, F-M. Huang: Financial Interests, Personal, Full or part-time Employment: CANbridge Pharmaceuticals Inc. All other authors have declared no conflicts of interest.

Background

Glioblastoma (GBM) is the most common primary malignant brain tumor of adults, with an aggressive behavior and a poor prognosis associated. 90% of patients develop recurrence/progression after the first-line standard treatment with Stupp protocol. Evidence for second-line treatment remains controversial and no standard of care is established. The aim of this study was to provide real-word evidence on the use of bevacizumab plus irinotecan (BEV+IRI) as second-line treatment of GBM.

Methods

Retrospective study on adult patients with a first recurrence of a GBM, after treatment with Stupp protocol. Of these, we selected patients treated with BEV+IRI at second-line (10 mg/kg and 125 mg/m², respectively, every 2 weeks), between 2011 and 2020, at our institution. Data were obtained from medical records. Progression-free survival (PFS) and overall survival (OS) were analyzed by the Kaplan-Meier method.

Results

42 patients were enrolled. 62% (n=26) were men and the median age was 53 years (35-78). Frontal localization of GBM was the most common (n=17, 40%). In the second-line all patients received BEV+IRI, with a mean of 19 cycles. A 20% dose reduction of IRI was necessary in 4 patients (2 cases due to severe thrombocytopenia; 2 cases due to deterioration of ECOG-PS). Response evaluation by magnetic resonance imaging revealed an objective response rate of 37% and 7%, at 3 and 6 months of treatment, respectively. There were no cases of complete response with this combination. The median PFS (mPFS) was 7 months (95% confidence interval [CI]=2.966-11.034), with a 6-month PFS of 81%. The median OS (mOS) was 8.5 months (95% CI=6.766-15.234), with a 6-month OS of 59.5%, 1-year OS of 43% and 2-year OS of 21%. The most frequent toxicities (any grade) were fatigue (n=35, 83%), diarrhea (n=26, 62%), anemia (n=23, 55%) and thrombocytopenia (n=19, 45%).

Conclusions

In this analysis mPFS and mOS were longer than the historical control group- mPFS: 7 versus 4 months (RTOG 0625); mOS: 8.5 versus 7.7 months (RTOG 0625). Toxicity profile was consistent with previously published data, but not insignificant. However, BEV+IRI is a regimen with activity in recurrent GBM and its toxicity is considered acceptable given the extremely unfavorable prognosis associated with this tumor.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Glioblastoma, lethal brain tumor arising from glial cells. Our lab, have identified the oncogenic role of FAT1 gene in glioblastoma, regulating inflammatory, hypoxic microenvironment and migratory/invasive properties of the tumor cells. The elimination of cancer cells may also be mediated by autophagic cell death. Here we have established the effect of FAT1 on cellular autophagy and cancer cell death.

Methods

Glioblastoma cells U87MG and LN229 were cultured under normoxia & hypoxia. FAT1 was knocked out by CRISPR Cas9. Cell death were analyzed by MTT assay. Expression of autophagy markers were analyzed by qPCR & Westernblot. Modulation of autophagy was done by EBSS and Bafilomycin. Subcellular expression of autophagy marker was analyzed using confocal microscopy. Expression correlation was done in Glioblastoma patient tumor samples (n=30) collected from Neurosurgery OT, AIIMS, by qPCR and IHC.

Results

FAT1 (∼500kDa protien) was knocked out successfully with ∼95% efficiency in U87MG and LN229 cells. We observed significant cell death with deprived serum condition in FAT1 knockout cells. Expression of autophagy markers (Beclin1, LC3b, ULK1, ATG13, ATG7 and ATG5) found significantly increased at mRNA and protein level in FAT1 knockout cells. On autophagy modulation we found further increased in expression of autophagy markers at mRNA and protein level in FAT1 knockout cells, as well as significantly increased subcellular expression of LC3b was observed. There was significant negative correlation between the expression of FAT1 and autophagy markers were observed in Glioblastoma patient tumor samples.

Conclusions

On FAT1 knockout, under tumor mimic conditions (serum-deprivation & hypoxia) glioblastoma cells were led to autophagic cell death. Significantly increased expression of autophagy markers on FAT1 knockout and its combination with autophagic modulation substantiates the autophagic cell death in glioblastoma cells. Increased subcellular localization of LC3 validates the accumulation of autophagic vacuoles on FAT1 knockout in glioblastoma cells. Conclusively, our glioblastoma tumor data and in-vitro findings strongly suggest the role of FAT1 in negative regulating the expression of autophagy markers, thereby protecting the tumor cells from autophagic cell death.

Legal entity responsible for the study

Governance by Kunzang Chosdol, AIIMS, New Delhi, ICMR, New Delhi.

Funding

AIIMS, New Delhi, ICMR, New Delhi.

Disclosure

All authors have declared no conflicts of interest.

Background

Vertebral hemangiomas are benign, highly vascular lesions of the vertebra. Asymptomatic hemangiomas are common, but they rarely enlarge in size and present with myelopathy. The aim of this study was to analyze the long-term outcome of patients of vertebral hemangioma presenting with myelopathy who were managed in a resource-constrained environment, the majority of whom were treated by our novel three-pronged strategy of alcohol injection, posterior decompression, and short segment fixation.

Methods

All patients of symptomatic vertebral hemangioma with myelopathy treated at our hospital from 2001 to 2015 with follow up till January 2018, with at least 2 years follow up were included. The operative procedure, blood loss and complications were recorded. Clinical outcomes were measured using ASIA score.

Results

Out of 60 patients operated, 44 (26 males, 18 females) fulfilled the inclusion criteria. 41 hemangiomas were located in the thoracic spine two in lumbar spine and one in cervical spine. Upper thoracic spine involvement was more common than lower thoracic spine involvement. Mean age was 29.34 years (range 10 - 68 years). Mean follow up was 74.63 months (range 24 - 180 months). All patients had improvement in motor strength postoperatively. Local pain, which was present in two patients resolved, bladder symptoms present in 13 patients also resolved.

Conclusions

Our experience in treating symptomatic vertebral hemangiomas, along with the long term follow up data suggests that good postoperative results can be achieved with minimal complications, in carefully selected patients.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The glioblastoma multiforme (GBM) is the most common and aggressive malignant primary brain tumor. Surgery followed of temozolomide administered concurrently with radiation therapy (RT) and followed by adjuvant temozolomide for six cycles significantly improved survival compared with radiation therapy alone. Real-world evidence is scarce in Latin America.

Methods

A retrospective study was conducted at the Hospital de Oncología, Centro Médico Nacional Siglo XXI, a referral center in Mexico. We included histologically confirmed patients with GBM treated in a period from January 2015 to January 2021. Descriptive statistics and Kaplan-Meier method with log-rank were used for analysis. Cox regression was used for multivariate analysis.

Results

A total of 184 patients were included, 96 were men (52,2%) and 88 were women (47.8%); median age was 56 years (range 18 - 87). ECOG performance status scale 0-1, and ≥ 2 represented 34.2% and 65.8% of the cohort, respectively. Maximal surgical resection was performed in 172 patients (93%). After surgery or biopsy, 12 patients (6.5%) did not receive any subsequent treatment. Treatment with concomitant RT with TMZ was offered to 156 patients (84.4%) and RT alone to 16 patients (8.7%). The most common RT modality was conventional fractionation (60 Gy in 30 fractions) in 75% of cases. After concurrent therapy, 135 (86.5%) received adjuvant TMZ, of which 53.4% received ≤ 5 cycles and 46.6% received ≥ 6 cycles. The median overall survival of the entire cohort was 20.1 months (95% CI 13.3 - 26.9 months). Survival in patients with adjuvant TMZ was superior versus patients who did not receive complete multimodal treatment (26.3 months vs 10.5 months, p<0.001). In the multivariate analysis, adjuvant chemotherapy was the only independent factor with statistical significance HR 0.18 (95% CI, 0.08 to 0.41 [p<0.001]). Table: 6P

Conclusions

In this retrospective study, we confirmed the benefit adjuvant treatment with TMZ in patients with GBM.

Legal entity responsible for the study

Raul Rogelio Trejo Rosales.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Εxtraneural metastases (ENM) do not occur often with central nervous system (CNS) tumors (only 7% of cases) due to the existing blood- brain barrier (BBB) and lack of classic lymph drainage. They are usually found in cases of a prior surgery or biopsy. In 1955 the minimal criteria that had to be met in order for a metastasizing CNS tumor to be accepted as such, were proposed by Weiss. Tumors of the posterior fossa are usually associated with higher operative mortality compared to supratentorial tumors, due to increased intracranial pressure and Abraham and Chandy in 1963 proposed the use of a ventriculoperitoneal shunt (VPS) to surpass this danger. Medulloblastomas in particular often render a VPS necessary for symptom relief.

Methods

We searched electronic databases using combinations of the terms “central nervous system tumors”, “CNS tumors” “ventriculoperitoneal shunt”, “VP shunt”, “medulloblastomas”, “adults”, “extracranial metastasis”. We included patients older than 18 years of age. Quantitative analysis was conducted.

Results

Our research revealed 11 published cases of extracranial metastasis due to a VPS in adults with CNS tumors (Table) and 3 published articles regarding 5 patients in total, in those with medulloblastoma. Table: 7P

Conclusions

In adult patients, extracranial metastasis due to a VPS are rare in CNS tumors and even more rare in cases of medulloblastoma compared to the paediatric population group. It is important due to the rarity of these cases that each one is documented. There needs to be a high level of clinical suspicion that metastasis due to a VPS might take place.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare subtype of liver cancer that primarily affects young adults and is characterized by a distinct histological appearance. Despite its rarity, FL-HCC has a worse prognosis compared to more common forms of liver cancer, and there is a significant lack of understanding of the epidemiology and risk factors associated with this disease. This study aims to investigate the epidemiology and risk factors of FL-HCC using the Surveillance, Epidemiology, and End Results (SEER) database.

Methods

The study used SEER database (2000-2019) to extract cases of FL-HCC and data on demographics, tumours and treatment. Demographic, tumour and treatment information was collected for each case. Data on age, sex, race, and other demographic factors for the general population was also extracted. Survival analysis using Kaplan-Meier and Cox proportional hazards was conducted to investigate the associations between demographic factors and FL-HCC survival rate. Analysis was done using Statistical Package for the Social Sciences (SPSS) 27.

Results

Three hundred thirty-eight patients were included, with Males 210 (62.1%) and white race 266 (78.7%) as the majority. Surgery was performed in 173 (51.2%) patients. At the end of the study period, 220 (65.1%) had died, and the median (IQR) survival rate of all study populations was 24 (7 - 59.3) months. Participants who underwent surgery had a median survival of 50 (24 - 88.5) months compared to those without surgery, with a median survival of 10 (2 - 22.5). The survival distributions for surgery were statistically significantly different, χ2(2) = 118.228, p < 0.001. Only younger age and performance of surgery had a significant effect on survival per Cox proportional hazard model, while sex and race had no significant effect on survival.

Conclusions

The results of this study provide a comprehensive overview of the epidemiology and survival factors of FL-HCC. However, additional studies would be required to identify risk factors for patients with this type of cancer, which would aid in developing new prevention and treatment strategies.

Legal entity responsible for the study

The author.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

Background

Appendix cancers (AC) are rare, with frequent peritoneal metastasis (PM). Limited chemotherapy options are extrapolated from colorectal cancer. The aim was to evaluate outcomes of AC by molecular subgroup to understand chemotherapy outcome and new opportunities for treatment.

Methods

We collected clinically indicated next generation sequencing (NGS) data from PM or primary tumour specimens from a prospective database of patients with AC. Testing was done on FFPE tissue (<=37 genes) or on fresh blood (>300 genes). Primary outcome was overall survival (OS).

Results

There were 55 AC patients with molecular data between 2005-2022: Adenocarcinoma types: 21 mucinous (MAC), 8 not otherwise specified (ANOS), 25 goblet cell (GCA) and 1 signet ring cell (SRC). Median age was 55 (31-75) and 51% were male. There were 47 (85%) with PM. Median peritoneal cancer index (PCI) was 11 (0-39). There were 42 (76%) who had cytoreductive surgery; 26/42 (62%) had no or <0.25cm residual disease. There were 48 (87%) who had chemotherapy; 10 (9 GCA) received anti-EGFR antibody (antiEGFR). Neoplastic cell content was reported in 18 samples; 8 were <20% (included) and 2 were insufficient (excluded). Of 53 remaining, 27 (55%) had a KRAS mutation (KRASm) of which 12 (24%) were G12D. Median mutant allele frequency was 10% (2-33%). NGS >300 gene panel was done on 6 (12%) patients. Other mutations included 3 TP53, 2 NRAS, 2 GNAS, 1 PI3KCA and 1 BRCA2. After median follow-up 51 months (m), KRASm patients had similar survival to those irrespective of histology or chemotherapy receipt (Table). Patients without KRASm who had chemotherapy and antiEGFR had shorter OS compared to chemotherapy alone (median NR vs 20m, 95% CI 7-34, p=0.015; Table). Table: 10P

Conclusions

KRASm are common in AC, the most frequent in our series being G12D at 24%, with implications for access to trials of pan and KRAS^G12C inhibitors. AntiEGFR was associated with a worse prognosis in our series of mostly GCA. A challenge for molecular testing includes lower neoplastic cell content due to diffuse PM.

Legal entity responsible for the study

The Christie NHS Foundation Trust.

Funding

Has not received any funding.

Disclosure

M.C. Strach: Financial Interests, Personal, Advisory Board: Specialised Therapeutics; Financial Interests, Personal, Other, Fellowship: ESMO; Financial Interests, Institutional, Research Grant: Royal Prince Alfred Hospital; Financial Interests, Personal, Funding, Travel Fellowship: Royal Australasian College of Physicians; Financial Interests, Personal, Funding, PhD Scholarship: Australian Government Research Training Scholarship; Financial Interests, Institutional, Funding: Christie Charitable Funds. S. O'Dwyer, O. Aziz: Financial Interests, Institutional, Research Grant: Cancer Research UK; Financial Interests, Personal, Member, Academy: R&D. J. Barriuso: Financial Interests, Personal, Invited Speaker: Pfizer, Ipsen, NanoString, Servier; Financial Interests, Personal, Advisory Board: Nutricia; Financial Interests, Personal, Expert Testimony: AAA; Non-Financial Interests, Personal, Project Lead: EORTC; Non-Financial Interests, Personal, Invited Speaker: GETNE; Non-Financial Interests, Personal, Principal Investigator: ENETS. All other authors have declared no conflicts of interest.

Background

Renal cell carcinoma represents 2% of all adult tumors. Histologically, the most common subtype is Clear cell while papillary and chromophobe subtypes are very rare. Metastasis is a poor prognostic factor for renal cell carcinoma and racial disparities betweens African-Americans (AA) and Caucasians (C) in metastasis patterns require further investigation. So this study aims to compare the patterns of metastasis between African-Americans and Caucasians among different histological subtypes of renal cell carcinoma.

Methods

Data were extracted from Surveillance, Epidemiology, and End Results Program (SEER) database from 2010-2019. We extracted data of patients with clear cell, papillary, and chromophobe renal cell carcinoma who presented with metastasis to bone, brain, liver, or lung at the time of diagnosis. We calculated the relative risk (RR) and confidence interval (CI) using SPSS software, version 25.0 (IBM).

Results

Clear cell carcinoma was the most prevalent subtype of renal cell carcinoma. Compared to African-Americans, Caucasians had lower risk of liver metastasis in clear cell subtype (RR=0.76, 95% CI: 0.61-0.94, P=0.11) while Caucasians who had clear cell subtype showed higher risk of lung metastasis (RR=1.22, 95% CI: 1.08-1.39, P>0.001). Papillary subtype tend to metastasize more to the lungs with no statistical significance between Caucasians and African-Americans (1.8% and 2.1% respectively, RR 1.13, CI: 0.87-1.45, P=0.34). Table: 12P

Conclusions

Across multiple subtypes of renal cancer, clear cell carcinoma showed significant differences regarding liver and lung metastasis between Caucasians and African-Americans regarding the risk of metastasis. Further studies of genetic and biological factors are warranted.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Non-epithelial ovarian tumours encompass a heterogeneous group of neoplasms comprising germ cell tumours (GCT) and sex-cord stromal tumours (SCST). These tumours are characterized by an extensive inter- and intratumoral heterogeneity. To better understand the landscape of immune cells in non-epithelial ovarian cancer, we construct a blueprint of stromal heterogeneity using single-cell RNA sequencing (scRNA-seq).

Methods

We performed scRNA-seq of 66 919 cells from fresh tissue collected from 12 patients, both in primary and recurrent setting. Most tissue samples were derived from SCST (n=9), including 7 adult granulosa cell tumours, 1 primary juvenile granulosa cell tumour and 1 primary Sertoli-Leydig cell (SL) tumour. Three samples were obtained from treatment-naïve GCT (2 immature teratomas (IT) and one dysgerminoma (DG)). We characterise immune cell subtypes phenotypically by highlighting its specific marker genes.

Results

Based on differential expression analysis and expression of transcriptomic markers, we identified 27 clusters consisting of 9 tumour cell and 18 stromal cell clusters. By clustering the transcriptome of 5961 T-cells and natural killer (NK) cells, T and NK cells deriving from DG (58%) and Sertoli-Leydig cell (20%) were found to be predominantly expressed. Remarkably, the DG tumour sample exhibited a pronounced cytotoxic environment, dominated by CD8+ exhausted T-cells whereas in the SL tumour a more naïve condition was observed. Half of the B-cells, mainly in differentiated cell states, derived from the DG sample. A nearly absence of B cells in all granulosa cell tumors. Regarding the myeloid lineage, the granulosa cell samples were dominated by LYVE1 and CX3CR1 macrophages. The latter are known to be inversely correlated with T cell expansion and thus predictors of low response to anti-PD-1 treatment.

Conclusions

With this analysis, we generate a comprehensive blueprint of the tumour micro-environment in non-epithelial ovarian cancer. Despite a limited sample size, we obtain high-resolution insights. The cytotoxic environment of dysgerminoma and immune desert profile of granulosa cell tumours are novel findings, which, however, need to be validated in larger datasets.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

L. Loverix: Financial Interests, Institutional, Invited Speaker, 2021 and 2022: AstraZeneca; Financial Interests, Institutional, Invited Speaker - institutional fee: GSK; Financial Interests, Personal, Invited Speaker, Reimbursement of travel/conference fee: Twist Biosciences; Financial Interests, Personal, Other, Non-profit Organisation FWO - Research Foundation Flanders - PhD Scholarship Strategic Based Research since November 2020: FWO Research Foundation Flanders. T. Van Gorp: Financial Interests, Institutional, Advisory Board, Apr-2021 until present: MSD; Financial Interests, Institutional, Advisory Board, May-2021 until present: GSK; Financial Interests, Institutional, Advisory Board, Feb-2021: OncXerna Therapeutics; Financial Interests, Institutional, Advisory Board, Jan-2021: Eisai; Financial Interests, Institutional, Advisory Board, Jan-2021 until present: AstraZeneca; Financial Interests, Institutional, Invited Speaker, Apr 2022: GSK; Financial Interests, Institutional, Research Grant, Oct-2020 until Oct-2021: Amgen; Financial Interests, Institutional, Research Grant, Oct-2020 onwards: Roche. I.B. Vergote: Financial Interests, Personal, Advisory Board, Consulting: Agenus (2021), Aksebio China (2021), AstraZeneca (2021-2022), Bristol Myers Squibb (2021), Deciphera Pharmaceuticals (2021), Eisai (2021), F. Hoffmann-La Roche Ltd. (2021), Genmab (2021), GSK (2021), Immunogen Inc. (2021-2022), Jazzpharma (2021-2022), Karyopharm (2021), MSD (2021-2022), Novocure (2020-2022), Novartis (2021), Oncoinvent AS (2021-2022), Seagen (2021), Sotio a.s. (2021-2022); Financial Interests, Institutional, Advisory Board, Consulting: AstraZeneca (2019-2020), Deciphera Pharmaceuticals (2020), Elevar Therapeutics (2020), F. Hoffmann-La Roche Ltd. (2019-2020), Genmab (2019-2020), GSK (2019-2020), Mersana (2020), MSD (2019-2020), Oncoinvent AS (2019-2020), Sotio a.s. (2019-2020), Verastem Oncology (2020), Zentalis (2020), Amgen (Europe) 2019, Clovis Oncology Inc. (2019), Carrick Therapeutics (2019), Millennium Pharmaceuticals (2019); Financial Interests, Institutional, Research Grant, Contracted Research (via KU Leuven): Oncoinvent AS (2019-2020); Financial Interests, Institutional, Research Grant, Contracted Research (via KU Leuven): Genmab (2019); Financial Interests, Institutional, Research Grant, Corporate sponsored research: Amgen (2019-2020), Roche (2019-2020). All other authors have declared no conflicts of interest.

Background

Due to the scarcity of cases of Placental site trophoblastic tumor (PSTT) and Epithelioid trophoblastic tumor (ETT), their clinicopathological characteristics and prognosis have not been well summarized. Consequently, we conducted the largest to date series sample of both types to investigate the outcomes and prognostic factors in patients with PSTT and ETT. We set gestational choriocarcinoma (GCC) as a control group to show the clinical features of PTSS and ETT.

Methods

Female patients with a confirmed diagnosis of PTSS, ETT and GCC as their only primary tumor were extracted from the Surveillance, Epidemiology, and End Result (SEER) database (2000-2019). Patients were analyzed for age, race, marital status, stage, tumor size, treatment, and long-term survival. Dichotomous variables were analyzed using chi-square tests. The Kaplan–Meier method and the Cox proportional hazards regression model were used to evaluate overall survival (OS) and cancer-specific survival (CSS).

Results

We included 728 patients; 142(19.5%) had ETT, 107(14.7%) had PSTT and 479(65.8%) had GCC. Most patients were 30 years old or above with the predominant race being White (n=462). Primary surgical resection was performed on 58.2% of patients (n=424), while 75.5% had undergone chemotherapy and 4.3% were administered radiotherapy. There is no significant difference in OS and CSS between the different tumor groups and the median OS and CSS were not reached in any of the gestational trophoblastic neoplasms (GTN)groups. After multivariate adjusting, older age, not undergoing primary surgical resection, radiotherapy and/or chemotherapy, and metastasis of the primary tumor were all significant prognostic factors for adverse OS and CSS. Being unmarried was only a significant prognostic factor for worse CSS.On the contrary, tumor size, stage and race did not have any significant effect on OS/CSS. Between the GTN groups, there was no significant difference in the effects of chemotherapy and/or primary surgical resection on OS/CSS.

Conclusions

There was no discernable survival benefit difference detected in ETT and PSTT compared to GCC. But due to the scarcity of the data available on GTN, more research is needed to deepen our understanding of these rare cancers.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Low-grade serous ovarian cancer (LGSC) is a rare ovarian cancer subtype that has distinctive genomic, histopathological and clinical characteristics, compared to the more common high-grade serous ovarian cancer (HGSC). Response to platinum-based chemotherapy, the mainstay of ovarian cancer treatment, is sub-optimal and outcomes for advanced LGSC can be poor. Additional treatment options are needed for LGSC, and non-platinum chemotherapy regimens have not been fully explored. Therefore, the aims of our study were to: 1. Assess real-world treatment and response patterns in LGSC; 2. Examine response to non-platinum agents in LGSC cell lines.

Methods

A LGSC cohort (n=99) with clinical data available, was identified from >4,000 patients recruited to the Australian Ovarian Cancer Study, GynBiobank and the INOVATe study. LGSC diagnoses were verified by stringent histopathological criteria and absence of TP53 mutations. Responses to non-platinum chemotherapy agents, including docetaxel and paclitaxel were assessed in eight patient-derived LGSC cell lines: HOC7, HCC5075, MPSC1, WMOV24, AOCS2, WMINV10, WMINV13 and HO433; by a cell viability assay.

Results

More than 12 different chemotherapy drugs were used in the clinical management of LGSC patients (1992-2017), either as single agent or in combination. The most common single agent chemotherapies used were liposomal doxorubicin (n=19), carboplatin (n=11), paclitaxel (n=9) and docetaxel (n=7). In patients with an evaluable treatment response, highest response rates were seen to the taxanes docetaxel (2/3, 67%) and paclitaxel (2/7, 28.5%). Three LGSC lines (MPSC1, HCC5075 and HOC7) were relatively sensitive to docetaxel (IC₅₀ 1.8-3.8 nM), and of these two were also sensitive to paclitaxel (HCC5075, HOC7) (IC₅₀ 1.5-2 nM). There was no association between taxane sensitivity in LGSC cell lines and MAPK pathway gene alterations, which is the most prevalent molecular feature of LGSC, found in ∼50% of cases.

Conclusions

Preliminary results suggest that taxanes could be an effective chemotherapeutic option for LGSC. However, these results need to be validated in larger cohorts, and biomarkers predictive of response are needed.

Legal entity responsible for the study

The authors.

Funding

Westmead Charitable Trust ECR Medical Clinician-Researcher Grant 2021, Cancer Council NSW (RG-15-23) and Cancer Australia (APP1142697). The INOVATe study has received funding from the Cancer Institute NSW (Translational Program Grant 14/TPG/1-15), the Cancer Council NSW (Translational Program Grant TPG 20-01) and the University of Sydney.

Disclosure

All authors have declared no conflicts of interest.

Background

Uterine leiomyosarcomas (uLMS) are aggressive tumors with poor prognosis and high risk of hematologic spread. Currently, no effective therapeutic agents are available for metastatic and relapsed cases. In general, uLMS are considered ‘immune-desert' tumors with very low levels of immune infiltration and therefore not prone to respond to immune checkpoint blockade (ICB). Recent research has focused on identifying feasible approaches to inflame ‘immune-desert’ tumors and prime them for ICB. Here we show that PI3K/mTOR inhibitors (PI3K/mTORi) are able to substantially remodel the TME of uLMS with high S6 phosphorylation levels (pS6^high), and promote responses to PD-1 blockade.

Methods

hCD34+ hematopoeitic stem cell engrafted (Transcure, France) and immunocompromised uLMS patient-derived xenografts (PDXs) were treated with combinations of (i) sapanisertib (0.3 mg/kg/day) + alpelisib (25 mg/kg/day), (ii) nivolumab (10 mg/kg, 2/wk) or (iv) vehicle. Tumor biopsies were collected pre- and post-treatment and subjected to bulk and single-cell RNA/TCR sequencing and multiplex immunohistochemistry. Data analysis was performed in R.

Results

Transcriptional profiling of pre- and post-treatment biopsies revealed that PI3K/mTORi induce a pro-inflammatory expression profile in pS6^high uLMS PDXs. In humanized pS6^high uLMS PDXs treatment with PI3K/mTORi leads to tumor growth suppression vs. resistance development and regrowth in immunodeficient PDXs, suggesting PI3K/mTORi are able to promote an anti-tumor immune response in an immunocompetent background. When combining PI3K/mTORi with anti-PD-1 blockade, a synergistic response was observed leading to partial or complete responses. Tumors treated with PI3K/mTORi and anti-PD-1 blockers show high levels of clonally expanded, tumor-infiltrating T-cells with enhanced expression of activation and cytotoxicity markers.

Conclusions

Here, we show that PI3K/mTOR inhibitors are able to enhance immune infiltration in humanized pS6^high uLMS PDXs and sensitize these tumors for ICB.

Legal entity responsible for the study

The authors.

Funding

Kom op Tegen Kanker.

Disclosure

All authors have declared no conflicts of interest.

Background

Malignant Brenner tumor is a rare histological subtype of epithelial ovarian cancer representing 1% of all ovarian tumors. The standard treatment is based on surgery but there are no available studies to compare the outcome of different surgery approaches for malignant ovarian Brenner tumor. Fertility-sparing surgery became preferred in oncologic gynecologic settings to preserve the ovarian tissue and the uterus. In addition, it can improve the sexual function and psychological wellbeing after cancer diagnosis and treatment. So this study aim is to evaluate the survival of fertility-sparing surgery versus radical hysterectomy in malignant Brenner tumor to support the limited current evidence on this rare type.

Methods

We used Surveillance, Epidemiology and End Results(SEER) program software to extract the data of 100 female patients with malignant Brenner tumor of the ovary diagnosed from 2000-2019. We divided them into two subgroups according to the surgery approach; fertility-sparing surgery (salpingo-oophorectomy without hysterectomy) and radical hysterectomy. We used SPSS for data analysis. Kaplan-Meier curve, Log-rank test for survival analysis.

Results

Out of 100 case, 82 had radical hysterectomy and 18 had fertility-sparing surgery. The overall 3-year and 5-year relative survival was (84.8% and 73.7%, respectively) while the 5-year survival outcome of fertility-sparing surgery and radical hysterectomy was (74.7% and 72.9%; P=0.7).

Conclusions

This study has a large sample for this rare type and the results showed fertility-sparing surgery had quiet similar survival outcome as radical hysterectomy which support fertility-sparing surgery to substitute radical hysterectomy for malignant Brenner ovarian tumor management for better quality of life for patients.

Legal entity responsible for the study

The author.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

Background

Patients treated for non-epithelial rare germ cell tumors (GCT) and sex cord stromal tumors frequently have long survival. Treatments mainly include conservative surgery plus chemotherapy (CT) [bleomycin, etoposide and cisplatin (BEP)] that may induce late side effects with negative impact on quality-of-life (QOL), as reported in testicular cancer survivors. The French Rare Malignant Gynecological Tumors (TMRG)/GINECO case-control study assessed long term QOL among survivors as compared to age-matched healthy women (HW).

Methods

Non-epithelial ovarian cancer survivors (nEOCS), cancer-free ≥2 years after end of treatment, were identified from the INCa French Network for TMRG. HW were issued from the ‘Seintinelles’ research platform. QOL (FACT-G/FACT-O), chronic fatigue (MFI), anxiety/depression (HADS), insomnia (ISI), neurotoxicity (FACT/GOG-NTX), cognition (FACT-COG) and sexuality items (from FACT-O OCS) were compared between nEOCS and HW. A minimal 5% difference of scores between groups was considered as clinically relevant. A specific questionnaire evaluating affective relationships was used for nEOCS (non applicable for HW). This analysis focuses on sexual life of nEOCS.

Results

Among the 144 nEOCS (including 112 GCT) enrolled (mean age at inclusion: 38; 60% <40), the median delay from the end of treatments to inclusion was 6 yrs. Affective relationships were modified for 74 (61%) of patients, with 18% of patients getting a divorce. These modifications were attributed to cancer diagnosis and treatment for 69% (n=52). Deterioration of sexual life was experimented for 34% (n=47). Despite these alterations of sexual living, 59% (n= 83) weren’t proposed to discuss these difficulties with their healthcare providers. In comparison with HW, we previously demonstrated that nEOCS felt less like a woman (68% vs 81%, p<0.02), reported less interest in sex (35% vs 55%, p<0.001) and more concern of childlessness (31% vs 13%, p=0.007) than HW.

Conclusions

Most of the long-term nEOCS reported disturbance in their sexual life, even 6 years after the end of treatments that may impact their daily life. Sexual disorders are probably underestimated and need to be more precisely evaluated by healthcare providers.

Clinical trial identification

NCT03418844.

Legal entity responsible for the study

Centre François Baclesse.

Funding

Fondation ARC pour la Recherche sur le Cancer.

Disclosure

All authors have declared no conflicts of interest.

Background

Malignant ovarian germ cell tumors (MOGCT) are rare malignancies constituting 2-3% of ovarian neoplasms. They affect female patients in the second or third decades of life, hence decisions on fertility-sparing procedures and chemotherapy are vital. While improved survival outcomes have been reported over the past three decades with multidisciplinary management, Indian data remains sparse.

Methods

We performed a retrospective study at the All India Institute of Medical Sciences on patients diagnosed with MOGCTs were registered at the Department of Medical Oncology between April 2005 to July 2022. File records were reviewed for clinico-pathologic and management details along with the survival outcomes.

Results

We identified 67 patients with median age of 22 years (range 10-49), predominantly premenopausal (n=61, 91%), and most commonly nulliparous (n=51, 75.3%). 59 (88%) patients presented with abdominal pain and/or distension while others presented with primary amenorrhea (n=3, 4.4%), fever (n=4, 5.9%), backache (n=1, 1.4%). Dysgerminoma (n=25, 37.3%) and mixed GCT (n=14, 20.8%) were commonest subtypes; 1 (1.4%) patient of non-gestational ovarian choriocarcinoma was found. Patients usually presented in stage I in 36 (53.7%) and in stage III in 22 (32.8%) with most cases (n=51, 76.1%) having a tumor size of more than 10 centimeters. 56 (83.5%) patients underwent fertility-sparing surgery. 58 (86.5%) patients were operated upfront while 7 (10.45%) received neoadjuvant chemotherapy (NACT). 51 (76.1%) patients received chemotherapy in first-line while 5 (7.4%) received it at time of recurrence. Etoposide and cisplatin with/without bleomycin was the commonest regimen administered with mean intensity of 81.7% and median 3 cycles (range 0-8). 6 (75%) patients attained pathological complete response (pCR); 5-year Disease-free survival (DFS) was 78.8% and Overall survival (OS) was 100%. Menstrual function resumed in 33 patients; 6 (23%) patients have had one or more successful pregnancies on follow-up.

Conclusions

Concerted management of MOGCT produces impressive survival outcomes. NACT is an option in advanced, unresectable disease and fertility sparing surgery can be performed in most cases.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Medullary carcinoma, first described by Foote and Moore in 1949, is a rare cancer, encountered in less than 5% of cases. It is a well-defined carcinoma, made up of poorly differentiated cells without associated glandular edification in a scanty stroma with a significant lymphoplasmacytic infiltrate.

Methods

This is a retrospective study of 18 patients treated at the CHU Farhat Hached Sousse radiotherapy department over a period of twenty-five years, from 1995 to 2020 for typical medullary carcinoma of the breast, histologically confirmed according to Ridolfi's criteria.

Results

All reported cases are female. The average age of the patients was 48.27 years with predominant involvement of the right breast (61.1%) and upper quadrants (72.2%). The average tumor size was 3.27 cm. 72.2% was in stage T2 and 22.2% was N1. Two patients had a bilateral breast carcinoma and contralateral was an infiltrating ductal carcinoma. All patients received surgical treatment, conservative in 39% of cases and radical in 61%. Radiotherapy was indicated in all cases except one, chemotherapy in 77.7% of cases and hormone therapy in 22.2% of cases. The five-year relapse-free survival rate was 83%.

Conclusions

Medullary breast carcinoma is a rare form of malignant breast tumor. Therapeutic indications are identical to other breast carcinomas. Our results agree with those of the literature and confirm the favorable prognosis of this histological form.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Nasal cavity and paranasal sinus tumors are relatively rare head and neck malignancies. Surgery followed by post operative radiotherapy is a commonly used treatment approach for these tumors. The aim of this study was to evaluate recurrence patterns and treatment outcomes in patients undergoing post operative radiotherapy using volumetric modulated arc therapy (VMAT).

Methods

Patients with nasal cavity and paranasal sinus cancers were included in this retrospective analysis. All patients were planned for post operative VMAT using 6MV photons. Statistical analysis was done using SPSSv.20. Univariable cox regression analysis was done to evaluate relationship between recurrence patterns and patient, tumor and treatment variables. Kaplan-Meir analysis was used for survival analysis. A p value of <0.05 was considered significant.

Results

Fifty patients were evaluated and included malignancies of the nasal cavity (68%), maxillary sinus (26%), ethmoid (2%) & sphenoid sinus (1%). Squamous cell carcinoma was the most common histology (42%). Other variants included adenoid cystic carcinomas (22%), esthesioneuroblastoma (18%), adenocarcinoma (4%) & small cell carcinoma (2%). Stage IV, III & II disease was seen in 44%, 30% & 8 % patients. Nine patients had Kadish C esthesioneuroblastomas. Functional endoscopic sinus surgery was done in 42% patients. Other surgical procedures included maxillectomy in 28%, wide local excision in 28% & orbital exenteration in 2%. Post operative radiotherapy dose ranged from 50-60 Gy. Neoadjuvant & adjuvant chemotherapy was given in 12% & 16% patients only. At 3 year follow up recurrences were seen in 34% patients. Local, local & nodal & nodal recurrence were seen in 20%, 4% & 4%. Distant metastasis were seen in 6% cases. On univariate analysis patient with age less than 40 years had more recurrences (53.3% versus 25.7%) than those with age more than 40 years(p=0.05). Intracranial extension was another adverse prognostic factor with recurrence seen in 83.3% versus 27.3% (p=0.007). The median disease-free survival was 24± 2.71 months. The overall survival at 3 years was 72%.

Conclusions

Age less than 40 years and intracranial involvement at presentation emerged as poor prognostic factors for recurrences.

Legal entity responsible for the study

Dr Amit Bahl.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Nasopharyngeal carcinoma (NPC) has excellent local control in the IMRT era. Nevertheless, distant metastases are the leading cause of death and challenge the scientific community. We report our results of mass-spectrometry based research for biomarkers to predict metastasis.

Methods

We retrieved clinical image and outcomes of biopsy-proven untreated NPC patients between 2009 and 2013 treated with IMRT with or without concurrent chemotherapy. One slice of 10um of formalin-fixed paraffin-embedded sample from each patient was submitted to label-free quantitative proteomics analysis. Label-free quantification was carried out using MaxQuant software V1.6.0.16. Database searches were performed using the Andromeda search engine with the UniProt-SwissProt Human Uniprot Proteome database as a reference and a contaminants database of common contaminants. Clinical results of distant metastasis outcomes were compared to proteomic analysis.

Results

We retrieved 82 patients, from which 18 developed distant metastases (M1). A pool of 25 proteins significantly up-regulated and 303 proteins down-regulated in M1 patients. Among differentially expressed proteins, tumor protein D54 (TPD54) had the highest difference in M1 patients (-Log(P-value) = 6,223915243; Difference = -0,466002574; Gene TPD52L2; p<0.01). Other proteins are CALM-1, SGT1, immunoglobulin, and ribosomal proteins (p<0.01). Among signalling pathways found, Ras-related protein Rab-33A (gene RAB33A) was significantly up-regulated in M1 patients (p<0.01).

Conclusions

We report a tumour profiling of 25 proteins up-regulated in metastatic NPC from a European cohort. TPD54 was identified as a potential biomarker candidate for metastasis prediction, and Ras GTPase signaling pathway was also up-regulated in metastatic patients.

Editorial acknowledgement

Prof. J.L. Capelo-Martínez for his assistance in this study.

Legal entity responsible for the study

The authors.

Funding

IPOLFG Research Fund [grant 2015/UIC901].

Disclosure

All authors have declared no conflicts of interest.

Background

Agent targeting HER2 is promising and is the best studied therapy in patients with HER2-positive salivary duct carcinoma (SDC). RC48-ADC (Disitamab Vedotin) is a novel humanized anti-HER2 antibody-drug conjugate (ADC). But the efficacy and safety of RC48-ADC is still unknown in metastatic SDC with HER2-positive.

Methods

Eligible patients from Zhejiang Cancer Hospital were 35∼76 years old, with confirmed, histologically HER2-expression (IHC1+, 2+, 3+), metastatic SDC. Patients had at least one line of systemic chemotherapy. Patients received RC48-ADC at 1.5 or 2 mg/kg, every two weeks. Clinical efficacy and safety were assessed.

Results

This study enrolled HER2-expression metastatic SDC patients from June 2022 to Dec 2022. 10 mSDC patients (8 males, 2 females) were enrolled. 90% patients had received ≥2 lines systemic chemotherapy. 80% patients had visceral metastases. As of 05 Jan 2023 (data cutoff), 1 patient received CR, 4 patients received PR, 4 patients received SD, and only 1 patient received PD. The overall confirmed DCR was 90%. Most common treatment-related AEs were hypoaesthesia (70%), asthenia (60%), Leukopenia (30%), decreased appetite (20%), alopecia (10%). The grade≥3 TRAEs only included hypoaesthesia (30.0%) and neutropenia (10%).

Conclusions

RC48-ADC showed continuously a promising efficacy with a manageable safety profile in HER2-expression mSDC patients who had failed at least one line systemic chemotherapy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Sinonasal teratocarcinomas (SNTCS) are very rare and highly aggressive tumors. Histologically they display mixed epithelial, mesenchymal, and neuroendocrine components. Recent genetic studies indicated recurrent alterations in genes SMARCA4, SALL-4 and CTNNB1. No effective pharmacological therapy is currently available, partly due to a lack of experimental models for studying the pathobiology and drug responsiveness of this tumor. Our aim was to set up and characterize an in vitro model of this tumor type.

Methods

A cell line named TCS627 was established from a 68-year-old man with a previously untreated, primary stage T4 SNTCS originating in the ethmoid sinus with invasion into the brain. Both primary tumor and cell line were histopathologically characterized using immunohistochemical markers, and genetically by whole exome sequencing (WES).

Results

The primary tumor showed epithelial, mesenchymal, neuroendocrine and germ cell histological features and expressed diagnostic markers CK8, S-100, enolase and SALL4, respectively. TCS627 grew in various proportions of cuboid, fusiform and small round cells with scant cytoplasm, dependent on population density and culture medium conditions. TCS627 cells expressed the same histological markers as its corresponding primary tumor. Population doubling time was 48 hours. The cell line had a predominant tetraploid karyotype with copy number loss at 1p and gains at 1q and 12p. WES revealed somatic frameshift mutations in ARID2 and CDKN2A, splicing mutations in SATB2 and SMARCA4, and missense mutations in NOTCH3, STAG2 and TET2, both in the primary tumor and the cell line. SMARCA4 protein expression was lost in the cell line but not in the primary tumor. CTNNB1 mutation or nuclear β-catenin staining was not observed.

Conclusions

To our knowledge, this is the first report of an in vitro model of SNTCS. It expresses epithelial, mesenchymal, neuroendocrine and germ cell markers and harbours the previously described chromosomal gains and losses, as well as SMARCA4 mutation. Therefore, TCS627 constitutes a useful tool for testing new therapeutic approaches for SNTCS.

Legal entity responsible for the study

The author.

Funding

Instituto de Salud Carlos III grant PI19/00191.

Disclosure

The author has declared no conflicts of interest.

Background

A recent bi-centric retrospective study (Cosentini D et al JCEM 107(5):e2167-e2176), showed that the administration of mitotane, the reference drug in the management of patients with adrenocortical carcinoma (ACC), is associated with a great proportion of vertebral fractures (VFs) independently from cortisol supplementation. These data prompted us to investigate the prevalence of densitometric osteoporosis in ACC patients treated with mitotane.

Methods

Data of a consecutive series of ACC patients who performed a DEXA (Dual Energy X-ray Absorptiometry) scan has been collected. The primary aim was to evaluate the prevalence of osteoporosis in patients treated with mitotane. Secondary aims were: 1) differences in densitometric parameters on the basis of the presence of VFs or not; 2) changes in these parameters during at least 6 months of mitotane treatment.

Results

Eighty-four ACC patients were included in this study. Twenty-eight were males and 56 females. Median age was 52 years (range: 18-77), 46 had hormone secreting tumors. Osteoporosis was observed in 31 patients (37%) and osteopenia in 30 patients (36%) after a median mitotane treatment of 11 months (range: 6-1454). VFs were found in 16 patients (19%), which were moderate-severe in 8 of them. Age and the presence of previous hip or VFs were found to be associated with a higher risk of VFs during mitotane (p 0.04 and 0.01, respectively). Neither BMD nor body composition differed on the basis of VFs. FRAX score corrected for trabecular bone score (TBS) was found to be related to a higher risk of VFs (p 0.03 and 0.04 respectively). In the 26 patients in whom 2 DEXA scans were available before and after mitotane therapy, an increase in fat body mass was found (p 0.01) while there was no significant variation in the bone related DEXA parameters.

Conclusions

ACC patients receiving mitotane therapy are at high risk of osteoporosis and VFs. FRAX corrected for TBS could be a useful predictive factor for VF risk.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Berruti: Financial Interests, Personal, Advisory Board: Amgen, Astellas, Janssen, Ipsen; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker, Public speaking in international webinar: HRA; Financial Interests, Institutional, Funding: Astellas, Janssen; Non-Financial Interests, Institutional, Product Samples: Sanofi, Novartis. All other authors have declared no conflicts of interest.

Background

Pheochromocytomas and paragangliomas (PPGLs) are rare tumors that frequently metastatize to bone. Limited data are available on the frequency of adverse skeletal related events (SREs) in PPGL patients with bone metastases (BMs).

Methods

This retrospective, observational, international, multicenter study, that recruited PPGLs patients with BMs to describe the frequency of SREs, such as pathological fractures, spine compression and hypercalcemia. Secondary aims were to define predictive factors for SRE development and prognostic factors.

Results

Data of 294 patients who were recruited in 6 countries (USA, Brazil, UK, The Netherlands, Germany and Italy) were analyzed. SREs occurred in 90 (31%) of patients, including 55 (19%) bone fractures, 47 (16%) spinal cord compressions, 11 (4%) hypercalcemias. Bone pain was reported in 144 patients (49%). Sixty-four patients underwent bone surgery (22%) and 136 bone radiotherapy (46%). SRE frequencies resulted similar comparing US vs the European-Brazilian case series. Median overall survival was 5.2 years. In multivariate analysis, younger age of 48 years (hazard ratio (HR) 0.5, 95% confidence interval (CI): 0.2-0-9, P<0.005), PPGL of the head and neck (HR 0.4, CI:0.2-0.9, P< 0.005) and the absence of liver metastases (HR 0.6, CI:0.3-0.9, P< 0.005) were significantly associated with a lower mortality risk while the prognostic role of bisphosphonates and denosumab treatment just failed to attain the statistical significance (HR 0.6, CI:0.4-1, P = 0.057). Median time for development of true SRE was 4.2 months. Bisphosphonates or denosumab treatment (HR 0.5, CI:0.3-0.8, P< 0.005) and metachronous bone metastases (HR 0.3, CI:0.2-0.6, P<0.005) correlated with a longer time to development of SREs.

Conclusions

PPGL patients with bone metastases have a relatively long-life expectancy and are at high risk of SREs. Bone resorption inhibitors could decrease the SRE risk and potentially improve patients’ outcome.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Berruti: Financial Interests, Personal, Advisory Board: Amgen, Astellas, Janssen, Ipsen; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker, Public speaking in international webinar: HRA; Financial Interests, Institutional, Funding: Astellas, Janssen; Non-Financial Interests, Institutional, Product Samples: Sanofi, Novartis. All other authors have declared no conflicts of interest.

Background

Parathyroid cancer is rear tumour with usually long natural history. PC is generally consider as radioresistant and there are not widely accepted standards for radiation therapy.

Methods

Analysis of the response to radiation therapy (RT) for 28 lesions in 14 patients treated in NRIO Gliwce. Fourteen patients diagnosed with PC were treated with RT between 1995-2020. Twenty eight lesions/areas were irradiated and the response to RT was assessed. Mean age at diagnosis was 47. Three patient was irradiated in adjuvant setting (after R0 or R1 surgery) and 7 after R2 surgery. Seven patients were irradiated due to local inoperable recurrences. Eleven distant metastatic lesions were irradiated (7 in lung, 2 in bone) and 9 local metastases. Patients were irradiated according to different scheduled based on discretion of physician. Doses range from 20 – 72 Gy. Five treatment were done with palliative intend. Nineteen treatments were for lesions/areas in the neck and/or mediastinal region/, 7 for lung’s lesions, 2 for bone’s lesions. The effect of RT was evaluated based on radiological imagining.

Results

Regression or stabilisation was documented for 21 lesions (75%): stable disease or partial response in 14 (50%) and complete response (CR) in 7 (25%). Complete response were observed in metastatic lesions in neck, mediastinum and lung treated with high dose. Mean duration of response was 55 months. Lack of response to radiotherapy was seen in 3 lesions-two of them were reradiated, in one lesion after multiple surgeries. A favourable response was most often observed in case of irradiation of metastases (7 cases out of 19) comparing to local recurrence ( 7 cases with no one CR but 6 stabilization or partial response) and CR was most often documented in case of nodal recurrence in neck and mediastinum (5 cases out of 9).

Conclusions

The analysis involves heterogenic group of patients, in majority heavily pre-treated yet the results shows that radiation treatment could be effective for patients with pathyroid cancer The best effect were observed for metastatic lesions, the worst in local recurrence after multiple reoperations. Especially for disseminated disease o radiation therapy should be considered.

Legal entity responsible for the study

Marzena Gawkowska.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Pheochromocytoma (Pc) is a rare cause of hypertension during pregnancy, with increased mortality if undiagnosed. Data to guide management is limited. Whether there are any long-term effects on the child is also unknown. The aim of this study was to identify all women diagnosed with Pc during pregnancy in Sweden 1973-2015, and to compare the impact of different treatment strategies on maternal and fetal outcome, as well as long-term outcome for the child.

Methods

National Swedish registries were used and crosschecked to identify mothers with Pc diagnosis within nine months before and one year after delivery. Medical charts were reviewed to confirm the diagnosis and treatment. Registered diagnoses and treatments for each child and five age matched controls were collected, from birth to 18 years of age.

Results

A total of 21 women and 23 children were identified (incidence 4.9/million births). Nine women (43%) were hypertensive during pregnancy. Only six (29%) were diagnosed with Pc during pregnancy. One had surgery during early second trimester, four had combined caesarean section and tumor removal and one was operated post-partum. Fifteen (76%) were diagnosed post-partum. There was no maternal or fetal mortality. High maternal blood pressure and hormone levels correlated with lower APGAR scores after one minute (p 0.009) and five minutes (p<0.001) respectively, but APGAR scores were not significantly lower than in controls. Timing of tumor removal did not affect gestational weight or APGAR scores. Pc affected children were not significantly smaller for gestational age but preterm delivery was seen in 30.4% as opposed to 5.5% in controls (p <0.001). There was no difference in health care consumption between children affected by maternal Pc and controls at long term follow up.

Conclusions

Pc during pregnancy is rare and most patients were diagnosed after delivery. Preterm delivery was more common in women with Pc but there was no maternal or fetal mortality nor any long-term impact on the children. Timing of tumor removal did not affect outcome but increased detection of Pc in hypertensive pregnant women should be aspired.

Legal entity responsible for the study

Sahlgrenska University Hospital.

Funding

Lions Cancerfond Väst.

Disclosure

All authors have declared no conflicts of interest.

Background

Neuroendocrine neoplasms (NENs) comprise a broad spectrum of disease ranging from slowly progressive to aggressive carcinomas with dismal prognosis. Next-generation sequencing (NGS) has improved our knowledge on the molecular underpinnings of NENs over the last years. However, whether this genomic characterization can have an impact on treatment decision and personalized medicine in NENs is yet to be unveiled. The aim of this study is to perform a genomic characterization of NENs and its association with clinical features.

Methods

NGS was performed in blood (N=15), tumor samples (N=49) or both (n=7) from 72 patients with advanced NENs treated between 2020 and 2022. The association between relevant alterations and clinical features was assessed with χ 2 or Fisher’s tests, Kaplan-Meier and Log-Rank tests.

Results

The most frequently altered genes in NETs were MEN1 (n=11), DAXX (n=7), DNMT3A (n=4), SMAD4 (n=3) and in NECs were TP53 (n=15), RB (n=8), MYC (n=6), KRAS (n=5), APC (n=7), SMAD4 (n=4), FGFR1-4 (n=3). TMB (median (range)) was 3.46 in NETs and 4.45 in NECs (range 0-35), and 2 cases were MSI (1 PanNEC and 1 G3 PanNET). 2 NET (5%) and 4 NECs (13%) were TMB-H (>10mut/Mb). Survival analysis revealed that KRAS (p=0.002), TP53 (p=0.012) and MYC (p=0.002) alterations were significantly associated with a worse outcome. TMB-H was also associated with a worse survival (p=0.004). Table: 34P

Conclusions

We have molecularly profiled a series of NENs and identified genomic alterations of potential therapeutic relevance and/or significantly associated with patient’s prognosis. Further studies are underway to assess their association with primary tumor location and response to therapy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

R. Garcia-Carbonero: Financial Interests, Personal, Advisory Board: AAA, Advanz Pharma, Amgen, Bayer, BMS, HMP, Ipsen, Merck, Midatech, MSD, Novartis, PharmaMar, Pierre Fabre, Servier; Financial Interests, Institutional, Research Grant: BMS, MSD, Pfizer; Non-Financial Interests, Personal, Leadership Role, Global PI of investigator-initiated clinical trials (AXINET, NICENEC, PEMBROLA): BMS, MSD, Pfizer; Other, Personal, Other, Honoraria received by spouse for advisory board or invited speaker roles: Abbie, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Genomica, Lilly, MSD, Merck, Novartis, Pfizer, PharmaMar, Roche, Sanofi, Servier, Takeda. All other authors have declared no conflicts of interest.

Background

EDP-M (etoposide, doxorubicin, cisplatin + mitotane) is the standard first-line therapy for advanced adrenocortical carcinoma (ACC). Preclinical data from our lab showed that Progestins, commonly used in cancer patients to manage cachexia, exert a cytotoxic effect on ACC both in vitro and in vivo and could potentially improve EDP-M tolerability and efficacy.

Methods

We present the feasibility and tolerability of adding oral megestrol acetate (320 mg daily) to EDP-M (EDP-MM) in 24 metastatic ACC patients (pts) with low performance status (PS) consecutively followed in our center. Secondary objectives were to evaluate the objective response rate (ORR), the Clinical Benefit Rate (CBR), progression-free survival (PFS) and overall survival (OS). A control group of 48 patients treated with EDP-M alone was added, they were matched based on the propensity score according to the GRAS score.

Results

ECOG Performance Status (PS)>1 was observed in 70.8% of EDP-MM treated patients vs 14.6% of EDP-M ones. 13 EDP-MM pts (54.2%) developed progestin-related toxicities: vaginal bleeding (5 pts, 20.8%); weight gain (4 pts, 16.7%); thromboembolic events (2 pts, 4.2%), hypertension and hyperglycemia (2 pts, 4.2%). Four patients (16.7%) discontinued megestrol acetate due to toxicity. No differences in EDP-M-related toxicities were reported (95.8% for cases vs 97.4% for controls), except for nausea and asthenia, more frequent in the megestrol acetate group. 29.2% EDP-MM pts and 20.8% EDP-M ones reduced the EDP dose. ORR and CBR were 50% vs 41.6% and 75% vs 60.4% in EDPMM and EDP-M pts, respectively. PFS and OS curves were similar in both groups.

Conclusions

The combination of EDP-M + megestrol acetate is feasible and well tolerated in ACC patients. Despite being administered to patients with low PS, EDP-MM appeared not inferior to EDP-M in terms of activity and efficacy.

Clinical trial identification

The study was approved by Ethic Committee of Brescia in date 15/11/2022 (NP 5525).

Legal entity responsible for the study

Alfredo Berruti.

Funding

Has not received any funding.

Disclosure

A. Berruti: Financial Interests, Personal, Advisory Board: Amgen, Astellas, Janssen, Ipsen; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker, Public speaking in international webinar: HRA; Financial Interests, Institutional, Funding: Astellas, Janssen; Non-Financial Interests, Institutional, Product Samples: Sanofi, Novartis. All other authors have declared no conflicts of interest.

Background

Peptide receptor radionuclide therapy (PRRT) with 177Lu-DOTATATE and 90Y-DOTATOC has shown efficacy in the metastatic setting of pheocromocytomas (PCCs) and paragangliomas (PGLs) where no standard therapies have been established. A search in peer-reviewed and English articles reporting on 177Lu-DOTATATE and 90Y-DOTATOC efficacy was performed through Medline and Scopus.

Methods

A subsequent meta-analysis was performed to evaluate the pooled effect size on response to PRRT. Secondary end-points were description of patients’ genetic characteristics, hematologic toxicity, time-to-outcome. The pooled effect was estimated with both a mixed effects model and a random effects model.

Results

Twelve studies met the criteria for this meta-analysis: 10 with 177Lu-, 2 90Y-PRRTs (213 patients). The largest one included 46 patients. Median ages ranged from 32.5 to 60.4 years. When reported, mutations of SDHB were the most frequent genetic alterations. The pooled DCRs were 0.83 (95% CI: 0.75-0.88) and 0.76 (95% CI: 0.56-0.89) for 177Lu- and 90Y-PRRT, respectively. The pooled DCR for PRRT was 0.81 (95% CI: 0.74-0.87).

Conclusions

We report and updated and solid estimate of DCR achieved with 177Lu- and 90Y-PRRT in PCCs and PGLs showing that these therapies can be considered in the multidisciplinary treatment of PCCs and PGLs alternatively to I-131 MIBG and chemotherapy.

Legal entity responsible for the study

The author.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

Background

Appendiceal goblet cell carcinomas (aGCC) are rare tumours and present with overlapping features of both neuroendocrine neoplasms and adenocarcinomas. Formerly, aGCC were named goblet cell carcinoids and therefore often grouped together with appendiceal neuro-endocrine tumours (ANET). A previous study found ANET with peritoneal metastases to have a poor 5-year survival rate of 7%. However, recent studies show that ANET rarely metastasizes, contrary to aGCC behaving more aggressively. Recent World Health Organization (WHO) classifications excluded aGCC from the group of NET and classified it as adenocarcinomas of the appendix. The aim of this study is identifying the different disease courses between ANET and aGCC. Furthermore, prognostic factors for recurrence free survival (RFS) and disease specific survival (DSS) were identified.

Methods

In this single center retrospective cohort study patients with histopathological proven ANET or aGCC with surgical therapy at baseline, referred to the Netherlands Cancer Institute between 2000 and 2019 were included. Primary endpoints were RFS and DSS. Kaplan-Meier curves and cox regression were used for survival and identification of prognostic factors.

Results

In total 95 patients with ANET and 31 patients with aGCC were included. None of the patients with ANET died of disease and 1 (3%) patient with ANET presented with local recurrence and peritoneal disease. In the group with aGCC, 11 (36%) patients died of disease and 9 (29%) patients presented with metastasis after curative intent of which 2 patients also showed local recurrence. All of these patients with aGCC had peritoneal metastasis either at diagnosis or at recurrence. Lymph node involvement at diagnosis was found to be a predictor for worse RFS (p=.014), whereas increased WHO grade was associated with poorer DSS (p=.018) in aGCC.

Conclusions

Patients with ANET have a much better prognosis as compared to aGCC, indeed indicating a difference in disease course. Lymph node involvement at diagnosis and WHO grade were shown to be independent predictors for RFS and DSS in aGCC, respectively. The extremely good prognosis of patients with ANET raises the question whether more restrictive surgery should be the standard in all patients with ANET.

Legal entity responsible for the study

The author.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

Background

Neuroendocrine Neoplasms are rare and very heterogeneous group of tumours. Their incidence has continued to rise. They appear most frequently in the gastrointestinal tract. While some features of NENs are unique to the site of origin, other characteristics are shared, regardless of the site. The aim of this analysis is to evaluate clinical and histopathological characteristics, treatments and outcomes of patients, in our single institute experience during the last 10 years.

Methods

All grades and sites of neuroendocrine neoplasms diagnosed from January 2011 to December 2020 were included. Small cell lung cancers were excluded.

Results

183 patients were diagnosed with neuroendocrine neoplasms, 94 females and 89 males. Median age was 55,56 years (19-85). Primary tumors sites were small intestine 40%, pancreatic 20%, gastric 11%, lung 6%, appendix 3%, colorectal 4 %, biliary tract 5.2% and primary unknown 8% with one case of prostatic, bladder, thymus, laryngeal and breast NEN. 64% was metastatic disease (80% to the liver), 8% a locally advanced disease and 28% a localized disease. Clinically 25% of patients presented a carcinoid syndrome. 75% of patients had well differentiated morphology with 24% of grade 1, 42.75% of grade 2 and 8.25% of grade 3. 24.5% had neuroendocrine carcinoma and 0.5% had a MINENs. NENs treatment is very varied and depends on several factors such as type, primary site, pathological classification and the stage of disease. The therapeutic decision is always collegial within multidisciplinary team. Surgery was used in 41% patients and 16% didn’t receive medical treatment. The remaining patients received combination medical treatment. First-line somatostatin was administrated in 33% of patients, targeted therapy in 16% and chemotherapy in 35% of patients.

Conclusions

Neuroendocrine neoplasms are heterogeneous diseases, with different behaviours. Their treatment is changing rapidly, and takes effort from different specialties to deliver a personalized, integrative treatment plan for each patient.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Standard chemotherapy for advanced AdrenoCortical Carcinoma (ACC), an extremely rare and aggressive neoplasm, is etoposide, doxorubicin, cisplatin in association with oral mitotane (EDP-M). The efficacy of this regimen, however, is limited. Progesterone has demonstrated to exert a cytotoxic effect on ACC cell viability, due to the interaction with its intracellular receptors (PgRs), which are involved in the regulation of ACC cell growth, proliferation, and invasiveness. Wnt/β catenin pathway is a target of progesterone activity. This study will address the hypothesis that megestrol acetate has a potentiating effect to EDP-M in inducing tumor shrinkage in locally advanced/metastatic ACC patients.

Trial Design

Prospective randomized, double blind, placebo-controlled phase II study in which ACC patients with locally advanced or metastatic disease not amenable to radical surgery will be randomized 1:1 to receive EDP-M or EDP-M plus megestrol acetate (320 mg daily). Primary objective is to assess the activity in terms of disease response according to RECIST criteria in patients of both treatment arms. Secondary objectives are: 1) treatment toxicity, 2) impact on hormone response in patients with secreting ACC, 3) disease response assessed by the CHOI criteria, 4) changes of Standardized Uptake Value (SUV) at FDG Positron Emission Tomography (PET) scan, 5) progression free survival (PFS), 6) overall survival (OS), 7) evaluation of the quality of life according to validated questionnaires. The total required sample size is 80 patients (40 per arm), to test the hypothesis that addition of progesterone will improve the response rate of EDP from 25% to 55% considering an alpha error of 5% and a potency of 80%. Patients’ enrollment began on 9^th August 2022 and is ongoing.

Legal entity responsible for the study

The authors.

Funding

AIRC.

Disclosure

A. Berruti: Financial Interests, Personal, Advisory Board: Amgen, Astellas, Janssen, Ipsen; Financial Interests, Personal, Invited Speaker: Amgen; Financial Interests, Personal, Invited Speaker, Public speaking in international webinar: HRA; Financial Interests, Institutional, Funding: Astellas, Janssen; Non-Financial Interests, Institutional, Product Samples: Sanofi, Novartis. All other authors have declared no conflicts of interest.

Background

Salivary Gland Cancers (SGC) are rare. Over 23 distinct types account for only c.0.3% of cancer cases globally each year. They represent less than 5% of all head and neck cancers and encompass ‘salivary type’ histologies presenting in other areas of the body in the secretory glands, including the lacrimal gland, trachea and the vulva. There is an unmet need for a salivary cancer specific advocacy group to support patients and provide support for the development of new treatment options to improve outcomes for patients.

Methods

We established Salivary Gland Cancer UK (SGC-UK) which is a unique charity world-wide focused specifically on these cancers. A collaboration between a patient advocate and a salivary cancer medical oncologist it was launched in April 2019 to address the unmet need for patients, carers and those treating and researching these cancers. Using co-production to build an active patient and research community, SGC UK is working to advance understanding of SGC biology, advance research, develop new treatments, and support patients and carers.

Results

Patients with all SGC types are supported. Patients from across the UK can have clinical input through a specialist hub at The Christie NHS Foundation Trust, Manchester, UK A biobank of tumour and blood samples has been established supporting national and international research Regular national/international meetings build and support the community, provide networking opportunities and research updates Focus over the last 24 months was SGC pathology/genomics, lab studies, carbon ion treatment, and real-world outcomes Researcher – Patient co-production via discussion days informing organisational priorities and aims ensuring relevance and impact within the patient population Reliable patient information was co-produced including ‘Could gene profiling help you' information sheets and return to work guides including real-life stories and videos from our network empowering patients/advocates.

Conclusions

SGC-UK is a unique collaboration addressing a significant unmet need. A biobank/database is being established to drive forward national and international research. Reliable information and support is being provided to patients, carers and clinicians. Collaboration and co-production to benefit all.

Legal entity responsible for the study

Salivary Gland Cancer UK.

Funding

Has not received any funding.

Disclosure

E. Kinloch: Non-Financial Interests, Institutional, Member of the Board of Directors: Salivary Gland Cancer UK. All other authors have declared no conflicts of interest.

Background

Cancer immunotherapy represents currently the leading treatment option for metastatic diseases, however, the response to immunotherapy varies among cancer types and also, among individuals. As opposed to melanomas, soft tissue sarcomas (STSs) do not seem to respond very well to immune checkpoint inhibitors (ICIs). This may be given the fact that the STS tumor microenvironment (TME) is not sufficiently understood and the factors that modulate the infiltration of the TME with immune cells are unknown. Because ICIs were shown to be more effective in combinatorial settings, novel treatment options must be investigated also in STSs.

Methods

We have enrolled over 60 patients that were surgically treated for the STS diagnosis. Each resected tissue sample was immunohistochemically scored by an experienced pathologist to decipher the histological subtypes of STS that are most likely to benefit from immunotherapy. In the next step, we isolated the tumor-infiltrating immune cells (TIICs) from the resected tissues and cultured these cells in vitro with therapeutic antibodies, such as anti-PD-1, anti-CD47 and with therapeutic cytokines, such as Oncostatin M. With the use of flow cytometry and multiplex bead-based immunoassays, we have analyzed the effects of these therapies on the immune phenotypes, proportions and activation statuses in the STS TME.

Results

In most cases, CD47 was highly expressed in the total tumour area. The most profound response to anti-CD47 therapy was observed in undifferentiated pleiomorphic sarcoma and the most profound response to anti-PD-1 therapy was in a high-grade leiomyosarcoma. All samples cultured with both anti-PD1 and anti-CD47 showed a dramatic reduction in cytokine secretion. The addition of Oncostatin M to anti-PD-1 did not seem to elicit enrichment of the T cell proportions in the peripheral blood but was shown to increase the susceptibility to apoptosis in tumor cells. Apoptotic receptors Fas-R and TRAIL-R in STS patients were significantly affected by Oncostatin M.

Conclusions

Our data suggest that only a close evaluation of the TME, together with well-designed histotype-tailored pre-clinical studies may allow better understanding of the potential effects of combinatorial treatment approaches in STS.

Legal entity responsible for the study

The authors.

Funding

Ministry of Health, Czech Republic–Conceptual Development of Research Organization, Motol University Hospital, Prague, Czech Republic (No. 6028); L’Oreal-UNESCO For Women in Science, and Cooperatio Program, Research Area SURG.

Disclosure

All authors have declared no conflicts of interest.

Background

Trabectedin induces long-lasting objective remissions in about 20% of patients with pretreated/resistant soft-tissue sarcoma (STS). Thus, the identification of novel therapeutic strategies to increase trabectedin efficacy is an unmet clinical need. We performed an in silico analysis using two public datasets to identify genes that were modulated by trabectedin exposure in several STS cell lines and, simultaneously, associated with prognosis in STS patients. Among the potential targets, glyoxalase-1 (Glo1) was the only druggable by the already available compound S-p-bromobenzylglutathione cyclopentyl diester (BBGC) also suitable for in vivo use.

Methods

The effect of trabectedin, doxorubicin and gemcitabine, alone or in combination with BBGC, was evaluated on STS cell lines by MTT assay. Synergy analysis was calculated using SynergyFinder web application. HT-1080 fibrosarcoma orthotopic murine model was obtained injecting 1x107 HT-1080 cells into gastroecnemius muscle of athymic nude-foxn1 nu/nu.

Results

Data showed a strong synergistic effect between trabectedin and BBGC in HT1080, SW872 and SK-LMS-1 cell lines (Synergy score HT1080: 30.395; Synergy score SW872: 57.318; Synergy score SK-LMS-1: 38.058). Intriguingly, in 402-91 trabectedin resistent cells characterized by higher Glo-1 protein levels compared to sensitive cells, we found an increased synergist effect (Synergy score 402-91 ET: 37.218; Synergy score 402-91 WT: 13.662) in terms of cell viability. This strong synergistic effect was not observed using BBGC in combination with doxorubicin or gemcitabine across the STS cell lines tested suggesting a potential direct involvement of Glo1 in trabectedin acquired resistance mechanisms. Confirmatory results were obtained in in vivo murine models where the combination BBGC with trabectedin significantly increased the antitumor effect as compared with tractedin as single agent.

Conclusions

Our results identify a new potential target to potentiate the efficacy of trabectedin and potentially overcome resistance mechanism. The availability of the specific Glo-1 inhibitor, BBGC, could accelerate its potential translational in clinical practice.

Legal entity responsible for the study

The authors.

Funding

PharmaMar S.A.

Disclosure

All authors have declared no conflicts of interest.

Background

Angiosarcomas are a group of aggressive rare tumors of endothelial origin. The genomic landscape of the disease was recently characterized, identifying distinct subtypes defined by ultraviolet (UV) mutational signatures and human herpesvirus-7 (HHV-7) as possible aetiologies.

Methods

To further characterize the molecular events regulating angiosarcoma development, we investigated the epigenomic enhancer landscape using H3K27ac chromatin immunoprecipitation with sequencing (ChIP-seq) of tumor samples (n=14) and their matched normal tissue where available (n=9). RNA-seq was also performed for tumor (n=16) and normal tissue (n=7) samples. Tumor (MO-LAS, ISO-HAS, ASM) and normal HDMEC cell-lines were similarly profiled.

Results

Unsupervised hierarchical clustering of H3K27ac signals at enhancers revealed global similarity between tumor samples, regardless of UV or HHV-7 status. Among the top ranking tumor-specific differentially-bound enhancers and expressed genes include PREX1, CCR1, LYN, PIK3R6, CSF2RB, CKAP2L, BCL2A1, HCK, RHOH and CXCL6. We focused on LYN, a potentially-druggable Src-family kinase. In keeping with initial observations, LYN was expressed higher in the tumor cell-lines by quantitative PCR and further validated on Western blot. Bafetinib, a known inhibitor of LYN kinase, was able to inhibit the viability of all tumor cell-lines in a dose-dependent manner at 72 hours (IC50 all between 5-10 μM), while decreasing protein expression of LYN and phospho-LYN. However, HDMEC cells were relatively resistant (IC50 > 10 μM). Finally, to investigate transcription factor-binding site enrichment, we analysed frequencies of cognate consensus DNA-binding motifs at super-enhancer regions using HOMER motif analysis and identified bZIP-domain and EST-domain transcription factors as candidate angiosarcoma regulators, including that of LYN expression.

Conclusions

We described the enhancer landscape of human angiosarcomas, highlighting LYN as a potential therapeutic target. Our preliminary analysis of potential transcription factor binding identified candidate transcription factors responsible for regulating LYN expression.

Legal entity responsible for the study

The authors.

Funding

This work was supported by the Singapore Ministry of Health’s National Medical Research Council under its Transition Award (TA21jun-0005) and RTF Seed Fund (SEEDFD21jun-0002); SingHealth Duke-NUS Academic Medical Centre and Oncology ACP Sarcoma Research Fund (08-FY2020/EX/25-A96 and 08-FY2020/EX/75-A151).

Disclosure

J.Y. Chan: Financial Interests, Personal, Invited Speaker: Takeda Pharmaceuticals, AstraZeneca, Novartis, Roche, MSD, Specialised Therapeutics; Financial Interests, Personal, Advisory Board: Antengene; Financial Interests, Personal, Research Grant: SymBio Pharmaceuticals, Scinnohub Pharmaceuticals, Invitae, Miltenyi Biotec; Financial Interests, Personal, Product Samples: Stemcell Technologies, MGI Tech, Twist Biosciences; Financial Interests, Personal, Other, Travel support: Janssen, Amgen. All other authors have declared no conflicts of interest.

Background

Single agent anti-PD1 therapy has shown limited clinical benefit in liposarcoma (LS). The MDACC-led study (NCT02815995), which combined anti-CTLA4 and anti-PDL1 across multiple soft-tissue sarcomas, showed increased expression of CD73 in T cells on treatment. CD73 is related to immunosuppression, reduced antitumoral responses, immune therapy resistance and metastasis. However, on T cells, CD73 induces long-lived memory properties, higher proliferation and survival or the reduction of effector capacity and survival depending on the activation state. Understanding the biology of this receptor will support the rational use of CD73 blockade therapy in LS.

Methods

Resected LS samples (well-differentiated (WDLS) and de-differentiated (DDLS)) were divided for phenotyping by flow cytometry, TIL expansion, adenosine quantification and cytokines. Phenotypic analysis included: CD73, A2aR, PD-1, Tim3, CTLA-4, LAG3, OX40, ICOS and 41BB. Expanded TIL were assessed for cytotoxicity by IFNg production and metabolic state (ROS, mitochondrial activity) by flow cytometry.

Results

The frequency of CD45+ cells (n=47, 0-89.60%) varied. T cell subsets from WDLS express higher CD73 compared to DDLS (p=0.0017 for CD4+ TIL and 0.0049 for CD8+ TIL). CD73 expression was observed in CD4 and CD8 TIL, irrespective of PD-1 co-expression. Adenosine levels were highly variable (0-84.05 nmol/g tissue) and did not correlate with TIL phenotype or tissue cytokines. Tumors were rich in growth and survival factors and chemokines but lacked a correlation with LS subtypes or TIL phenotypes. TIL expansion success was 48% (n=25 cases). The frequency of CD8+CD73+ TIL were significantly higher in cases with successful TIL expansion (p=0.049) and was highest in those expanded from WDLS cases. IFN-g production from expanded TIL was related to intrinsic metabolic profiles associated with mitochondrial mass and ROS production.

Conclusions

LS exhibited an immunosuppressive environment linked to high PD-1 expression and a diverse cytokine landscape. CD73 expression and co-expression with PD-1 differed between WDLS and DDLS, suggesting a differential impact of anti-CD73 on TIL. We hypothesize that CD73 expression on CD8⁺ T cells may identify more functional, less exhausted TIL.

Legal entity responsible for the study

The authors.

Funding

Generous donation by the William Oates family.

Disclosure

N. Somaiah: Financial Interests, Institutional, Research Grant: AstraZeneca; Financial Interests, Personal, Advisory Board: Boehringer Ingelheim, Epizyme, Aadi Biosciences. C. Haymaker: Financial Interests, Personal, Other, Participation in an advisory working group: Nanobiotix; Financial Interests, Personal, Other, Session Chair: Society for Immunotherapy of Cancer; Financial Interests, Personal, Other, Stock options as a member of the Scientific Advisory Board: Briacell; Financial Interests, Institutional, Research Grant, Research funding provided to institution: Iovance; Financial Interests, Institutional, Research Grant: Dragonfly, BTG, Sanofi; Non-Financial Interests, Personal, Advisory Role, Member of the SAB: Mesothelioma Applied Research Foundation. All other authors have declared no conflicts of interest.

Background

Dermatofibrosarcoma protuberans (DFSP) is a rare and indolent cutaneous sarcoma, with the risk of aggressive fibrosarcomatous transformation. Limited effective options are available for unresectable or metastatic DFSP beyond targeting the oncogenic PDGF pathway with imatinib therapy.

Methods

We established a patient-derived xenograft (PDX) and cell-line model (designated MDFSP-S1) of imatinib-resistant DFSP with fibrosarcomatous transformation.

Results

Whole genome sequencing identified high level amplification at chromosomes 17 and 22, while homozygous deep deletion was demonstrated at chromosome 9 (CDKN2A, CDKN2B, MTAP). RNA sequencing followed by Sanger sequencing confirmed the pathognomonic COL1A1-PDGFB t(17;22) rearrangement in the original tumor, PDX and cell-line model. Immunohistochemistry profile of the PDX model was consistent with the patient’s tumor sample (CD34+/MIB1+/SOX10-). Gene set enrichment analysis highlighted top-scoring Hallmark gene sets in several oncogenic signaling pathways, including potentially targetable MTORC1 signaling and angiogenesis pathways. Antiangiogenic agents (sunitinib, regorafenib, pazopanib, axitinib) and the third-generation irreversible epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor osimertinib exhibited modest anti-proliferative activity in the cell-line, with IC50 values between 1 μM and 10 μM at 72 hours. No significant activity was observed with imatinib, palbociclib, everolimus, olaparib, gefitinib and erlotinib (IC50 all > 10 μM).

Conclusions

In conclusion, we established MDFSP-S1, a new PDX and cell line model of imatinib-resistant DFSP with fibrosarcomatous transformation.

Legal entity responsible for the study

The authors.

Funding

Singapore Ministry of Health’s National Medical Research Council under its Transition Award (TA21jun-0005) and RTF Seed Fund (SEEDFD21jun-0002); SingHealth Duke-NUS Academic Medical Centre and Oncology ACP Sarcoma Research Fund (08-FY2020/EX/25-A96 and 08-FY2020/EX/75-A151).

Disclosure

J.Y. Chan: Financial Interests, Personal, Invited Speaker: Takeda Pharmaceuticals, AstraZeneca, Novartis, MSD, Specialised Therapeutics; Financial Interests, Personal, Advisory Board: Antengene, Roche; Non-Financial Interests, Personal, Research Grant: SymBio Pharmaceuticals; Financial Interests, Personal, Research Grant: Scinnohub Pharmaceuticals, Invitae, Miltenyi Biotec; Financial Interests, Personal, Product Samples: Stemcell Technologies, MGI Tech, Twist Biosciences; Financial Interests, Personal, Other, Travel support: Janssen, Amgen. All other authors have declared no conflicts of interest.

Background

Rhabdomyosarcoma (RMS) is the most frequent soft tissue sarcoma in childhood. This study evaluated the efficacy of SFX-01(Evgen Pharma plc, UK), a complex of synthetic d,l-sulforaphane stabilized in alpha-cyclodextrin, in two RMS in vitro models, alveolar (ARMS) and embryonal (ERMS), as single agent and in combination with ionizing radiation (IR).

Methods

Cell cycle and apoptosis were analysed by flow cytometry, whilst the modulation of specific genes was measured by real-time PCR and Western blotting assays. Irradiation was carried out exposing RMS cells to a single dose of 4 Gy and the radiosensitivity was assessed by clonogenic and modified high density survival assays. DNA damage repair (DDR)-related markers were studied by Western blotting and Protein Simple WES technology. The effects of SFX-01 on cancer stem cells were assessed by evaluating rhabdosphere formation in ultra-low attachment plates.

Results

SFX-01 (10 μM) treatment reduced the growth of RH30 (ARMS) and RD (ERMS) cells by inducing G2 cell cycle arrest with the concomitant Cyclin B1 up-regulation and triggering early-apoptosis. Interestingly, the specific knocking down of Cyclin D1 expression by RNA interference seems to enhance the cytostatic/cytotoxic effects induced by SFX-01 on RMS cells. We also found both p62 and LC3 II over-expression after SFX-01 exposure, this suggesting a block of late-stage autophagy. SFX-01 drug synergized with IR by strongly enhancing the effects of both single-agent treatments by showing a drastic reduction of clonogenic ability, block of DDR (persistent activation of γ-H2AX) and increased G2/M cell cycle arrest. Finally, pre-treatment with SFX-01, alone and in combination with IR, significantly affected the ability to form rabdospheres in both the parental and the clinically relevant radioresistant RMS cells.

Conclusions

For the first time, we described the antitumor activity of SFX-01 in preclinical models of RMS tumours. SFX-01 and IR have strong cytotoxic effects and drastically inhibit the formation of cancer stem cell-derived tumorspheres, this indicating that the combined treatment might have therapeutic benefits, mainly in the clinical managements of patients with aggressive RMS disease.

Legal entity responsible for the study

The authors.

Funding

Sapienza University of Rome and The Italian Foundation for Cancer Research (AIRC).

Disclosure

All authors have declared no conflicts of interest.

Background

Phase II clinical trial evaluating the activity of cyclin-dependent kinase 4/6 (CDK4)/6 inhibitor palbociclib in soft tissue sarcoma (STS) including liposarcoma (LPS) has achieved disappointing results when used as monotherapy. In this regard, the observations warranted additional studies to elucidate the role of these cyclin-dependent kinases as promising biomarkers for prognostic and therapeutic approaches in (CDK4)/6 amplified and non-amplified STS.

Methods

This prospective study enrolled 21 adult patients affected by LPS (ALT/WDLPS=5 and DDLPS=16). CDK4 and MDM2 expression were investigated in surgically resected FFPE specimens. Furthermore, taking advantage of our integrated approach combining 3D culture systems with collagen-based scaffold and patient-derived primary cultures, chemobiogram analyses were carried out. First- and second-line treatments for STS management were assessed in combination and sequential schedules. Finally, public datasets including 260 sarcoma patients were interrogated to perform in silico analyses.

Results

DDLPS showed higher expression of CDK4 and MDM2 compared to ALT/WDLSP. However, despite being both coded by 12q13-15 amplicon, we observed a lack of correlation between their expression (e.g. 100% of CDK4 and 2% of MDM2 in the same patient). This finding prompted us to hypothesize that a patient could benefit from anti-CDK4 therapy even in absence of MDM2 overexpression. In addition, pharmacological profiling showed a synergistic effect exerted by sequential treatment with palbociclib and chemotherapeutics (CT) including trabectedin, dacarbazine, eribulin and lenvatinib, with a 10% increase in cell proliferation inhibition compared to standard treatment. Moreover, in silico analyses highlighted a correlation between CDK4 expression and prognostic outcome in STS.

Conclusions

This study highlighted the promising role of CDK4 in the management of LPS patients. In detail, we report encouraging results with sequential treatment combining CDK4 inhibitor palbociclib and standard CT. Furthermore, preliminary analyses pointed out the involvement of this biomarker as a potential prognostic tool for STS.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Controlling metastasis is the key to improve outcomes for osteosarcoma (OS) patients. Our knowledge of metastasizing mechanisms in OS is still not sufficient. Neurofibromatosis gene 2 (NF2) is a known tumor suppressor in various solid tumors in which we found gene mutations in 15% of OS patient samples in our clinic (Molecular Tumor Board, TUM, 2019-2022) while downregulation of NF2 has been reported to correlate with a declined long-term survival.

Methods

Since NF2 remodels the cytoskeleton through small GTPases and metastasis is a complex process involving cancer cell adhesion, migration and invasion, we examined actin-dependent cell functions. First, we studied alterations in molecular mechanisms of NF2 signaling between non-metastatic human OS cell lines (HOS, HOS-MNNG, U2OS) and the metastatic OS cell line (HOS-143B).

Results

Immunofluorescence revealed a downregulation of NF2 and reduced stress fiber formation in metastatic compared to non-metastatic HOS cell lines. Furthermore, in HOS-143B cells, the activity of a small GTPase was enhanced, accompanied by decreased PAK4. Moreover, HOS-143B cells show dysfunctional autophagy, measured by Cyto-ID and Lamp1/LC3 co-localization. In line with our previous work (Landspersky et al., Blood, 2022), dysfunctional autophagy in HOS-143B cells correlated with a disoriented actin cytoskeleton. To rescue the damaged cytoskeletal changes, we treated HOS-143B with an inhibitor of the small GTPase activity. This treatment revealed not only a restored actin stress fiber formation, but also a significantly reduced growth rate of the metastatic cell line. Cell adhesion, migration as well as cellular invasiveness into Matrigel was additionally reduced upon small GTPase inhibition within the HOS-143B cell line.

Conclusions

Our results show that metastatic processes are in part dependent on F-actin fiber organization and small GTPase activation. Most importantly, our results suggest that treatment of metastatic OS cells with a GTPase inhibitor specifically reduces the growth rate of metastatic cells. Our findings help to dissect and understand mechanisms of actin-dependent metastatic processes and suggest new strategies to reduce the growth rate and possibly also the spread of OS cells to metastatic sites.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Liposarcomas (LPS) are rare soft tissue tumors of mesenchymal origin. The two main histological subtypes are well-differentiated (WD) and dedifferentiated (DD) LPS. Aggressive surgery is the only curative treatment to date and local recurrences remain frequent. Surgeons need new tools to maximize benefit from surgery. The aim of this project was the development and validation of antibodies (Ab) for fluorescence guided surgery.

Methods

The systematic amplification of MDM2 in this subgroup of tumors results in a metabolic signature related to serine metabolism. We showed that MDM2 is recruited to chromatin to regulate a transcriptional program involving amino acid metabolism and particularly to the 3 enzymes of the serine synthesis pathway and its transmembrane transporter (SLC)-1A4.

Results

We confirmed that the serine carrier SLC1A4 is overexpressed in LPS cell lines and on fresh patient’s tumors in LPS-WD and LPS-DD. Using Phage display technology, we developed six antibodies against the extra membrane loop domain of the SLC. We validated four Antibodies in western blot, QPCR, FACS and immunofluorescence microscopy using cell lines with or without expression of SLC1A4 and LPS cell lines with Sh-SLC1A4. We confirmed the same tropism in immunohistochemistry on human kidney, testicular and skin samples as the commercial antibody targeting the intracellular part of the transporter. We started testing them for diagnosis on several LPS and other sarcomas with promising results. We also confirmed their specificity on mice tissue samples, that allow us to test human form of the antibodies in PDX LPS models. In a collaborative study with the expert company SurgiMab, we managed to show intense fluorescent signal in the tumor since 12 hours after peritoneal injection until more than five days with no secondary effect on mice.

Conclusions

In conclusion, the use of these new biomarkers for histopathological diagnosis in LPS-WD and LPS-DD appears feasible with further development. In vitro and in vivo experiments are very encouraging for “fluorescence guided surgery” and have to be tested on human in a clinical trial after conducting a study on the pharmacodynamics, pharmacokinetics and toxicity.

Legal entity responsible for the study

Inserm.

Funding

Institut National du Cancer.

Disclosure

All authors have declared no conflicts of interest.

Background

Defects in homologous recombination repair (HRR) in tumours correlate with poor prognosis and metastases development. Determining HRR deficiency (HRDness) is of major clinical relevance as it is associated with therapeutic vulnerabilities and remains poorly investigated in sarcoma. Sarcomas are rare mesenchymal cancers, accounting for approximately 1% of all malignancies. Standard of care mostly relies on chemotherapy but sarcoma often show chemoresistance and metastatic disease is associated with a poor prognosis. There is an increasing emphasis on understanding the cancer biology of individual sarcoma subtypes to inform the development of personalized targeted treatment approaches.

Methods

We investigated genomic and transcriptomic features of HRDness in sarcoma and cross-validated our findings among several datasets. We established and molecularly profiled eight patient-derived ex vivo sarcoma cell models. We functionally tested the sensitivity of our models to several targeted therapies including PARPi as gold standard treatment for HRDness and chemotherapies in six-point dose response curves either in monotherapy or in combination.

Results

We show that specific sarcoma entities exhibit high levels of genomic instability signatures and molecular alterations in HRR genes, while harbouring a complex pattern of chromosomal instability. Furthermore, sarcomas carrying HRDness traits exhibit a distinct SARC-HRD transcriptional signature that predicts PARPi sensitivity in patient-derived sarcoma cells. Concomitantly, HRDhigh sarcoma cells lack RAD51 nuclear foci formation upon DNA damage, further evidencing defects in HRR. We further identify the WEE1 kinase as a therapeutic vulnerability for sarcomas with HRDness and demonstrate the clinical benefit of combining DNA damaging agents and inhibitors of DNA repair pathways ex vivo and in the clinic.

Conclusions

We show that a subset of sarcoma entities exhibit features of HRDness at the genomic and transcriptomic level and highlight the need to characterize sarcoma patients with multiple parameters to better identify those with HRDness. In summary, we provide a personalized oncological approach to treat sarcoma patients successfully.

Legal entity responsible for the study

The authors.

Funding

Swiss Cancer Research Foundation [KFS-5270-02-2021] and the Olga Mayenfisch Foundation.

Disclosure

All authors have declared no conflicts of interest.

Background

Soft tissue sarcomas (STS) are a heterogeneous and complex group of tumors with significant metastatic potential. We focused our analysis on miRNA-mRNA networks, in order to identify potential biomarkers and therapeutic targets for these malignancies.

Methods

We performed miRNA profiling on tissue and plasma samples obtained from 12 patients enrolled at the Careggi University Hospital, Florence (RESEARCH study) using the nCounter Human v3 miRNA Expression Assays Panel on the NanoString nCounter platform. In order to identify differentially expressed miRNAs in relapsed vs non-relapsed patients, miRNA counts were normalized and compared with a reduced model likelihood test. Prognostic value of miRNAs was evaluated by ROC analysis.

Results

Differential expression analysis revealed that 4 miRNAs involved in FOXO pathway (miR-21-5p, miR-15a-5p, miR-221-5p and miR-205-5p) showed higher expression in relapsing patients (adjusted p-value <0.05, Fold Change >2). ROC analysis on this panel revealed that the combination of hsa-miR-21-5p, hsa-miR-15a-5p and hsa-miR-221-3p displayed good predictors of relapse (AU-ROC = 0.933) in STS. Validated targets of these miRNAs (FOXO, PTEN and PI3KR1) also showed high prognostic values of relapse (AU-ROC = 0.72 – 0.81).

Conclusions

Our data indicate that a network of mRNA-miRNAs is differentially regulated in tissue samples of who will experience relapse vs not relapsing STS patients. The combination of 4 miRNAs and 3 target genes could potentially serve as biomarker for predicting tumor relapse of STS patients.

Legal entity responsible for the study

AOUC.

Funding

Tuscany Region.

Disclosure

All authors have declared no conflicts of interest.

Background

Relation between immune status within pleomorphic sarcomas (PS) microenvironment and clinical outcome has been recently addressed, but still needs further investigation. Patients with PS have different immune microenvironment characteristics and, therefore, have different responses to immunotherapy; hence, studying the immunological characteristics of PS tissues may contribute to improving immunotherapy efficiency. Dendritic cells (DC), being the most potent antigen presenting cells (APCs), are of great interest in the study of potential prognostic or immunotherapeutic factors.

Methods

PS tissue samples were obtained from 12 patients enrolled at the Careggi University Hospital, Florence (RESEARCH study). We performed an immunologic profiling analysis using the Human Immunology V2 Panel on the nano String nCounter platform. The prognostic value of immune-cell signatures on Disease Free Survival (DFS) was assessed through a log-rank test.

Results

Differential expression analysis of immune-related genes revealed heterogeneity of genes representative of certain immune populations (B-cells, CD8 T cells, Cytotoxic cells, Exhausted CD8, Macrophages, Neutrophils, NK cells, T-cells, Th1 cells and Treg) between samples. DC related genes also shown heterogeneity between samples, however patients characterized by an increased DC phenotype showed a significant higher median DFS compared with patients with a low DC phenotype.

Conclusions

In the present study, we explored genes associated with immune cell infiltration and we found that PS patients with an increased DC phenotype showed a better prognosis.

Legal entity responsible for the study

AOUC.

Funding

Tuscany Region.

Disclosure

All authors have declared no conflicts of interest.

Background

In primary retroperitoneal sarcoma (RPS), loco-regional and distant relapse occur frequently despite optimal surgical management. The role of chemotherapy in improving outcomes is unclear. The Australia and New Zealand Sarcoma Association (ANZSA) sought to develop clinical practice guidelines based on systematic review of the literature using the PICO model.

Methods

A systematic review of ‘Does chemotherapy improve outcomes in adults with primary RPS?’ was conducted. Three databases were searched (Medline, Embase and Cochrane Central) for publications from 1946 to June 2022. Two independent reviewers screened studies by title and abstract, reviewed full texts for eligibility, and extracted qualitative and quantitative data from eligible studies. Quality assessments were performed using the NHMRC evidence hierarchy and the Newcastle-Ottawa quality assessment scale.

Results

23 studies were identified (one meta-analysis of retrospective studies, 22 retrospective studies). The majority of studies had level III-2 NHMRC evidence. The quality of retrospective cohort studies was good for 12 studies and poor for 10 studies. Most studies did not analyse the outcomes by histology. The evidence summaries for this topic include: the addition of chemotherapy to surgery was not associated with improvement in local recurrence rates, metastases-free or disease-free survival and overall survival in primary RPS. There is some evidence of an association of chemotherapy with worse overall survival. One single-centre study showed that neoadjuvant chemotherapy was not associated with increased post-operative morbidity compared to surgery alone in primary RPS. The evidence-based recommendation of the guidelines working group is that there is no evidence to recommend chemotherapy in addition to surgery for patients with resectable RPS. Patients with RPS should be managed by a specialised sarcoma centre. Patients may be considered for chemotherapy in a clinical trial setting.

Conclusions

There is currently no evidence to recommend the addition of chemotherapy to surgery for patients with primary resectable RPS. Prospective randomised high-quality data is required to conclusively determine the role of chemotherapy in RPS.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Kaposi sarcoma (KS) is a mesenchymal malignancy induced by human herpes virus-8 (HHV-8) in immune compromised subjects. Despite the drastic reduction in its incidence after the introduction of cART to treat HIV, it remains the most common neoplasia in people living with HIV (PLHIV), and up to 15% of HIV-associated KS develop or progress even in the background of well controlled infection (cART refractory KS). In these cases, HIV-mediated immune exhaustion is meant to play a central role. Previous research from our group demonstrated overactivation of the PD-1/PDL-1 pathway in cART refractory KS. Therefore, the rationale for using immune-checkpoint inhibitors (ICI) in this setting. No study to date has comprehensively evaluated safety, efficacy and molecular correlates of response to ICI in cART refractory KS. We have designed a phase Ib study to assess the safety and tolerability of the anti PD-1 antibody dostarlimab in patients affected by cART refractory KS.

Trial Design

The StarKap trial is a single-centre study enrolling up to 20 patients aged 16 or above, affected by histology proven cART refractory KS to receive dostarlimab for up to 49 weeks. Patients must be fully adherent to cART for at least 3 months, with well controlled HIV, defined as HIV RNA < 200 cp/ml and CD4+ T-cell count >100/ml at screening. Safety is the primary objective, and it will be evaluated as the incidence of adverse events by NCI CTC criteria v.5.0 up to 90 days from last dose of treatment. The first 6 patients are enrolled in the safety lead-in-phase and, in the absence of dose limiting toxicities in the first 21 days safety window period, recruitment will continue. The efficacy of dostarlimab, its impact on HIV specific outcomes and quality of life are secondary objectives. Pre-treatment and on-treatment tissue samples, peripheral blood mononucleate cells and stool samples are collected to preliminarily identify correlates of response to dostarlimab, by performing immune-histochemistry, single cell RNA sequencing (tissue), mass cytometry (bloods) and sequencing of the hypervariable V1-V2 region of 16S rRNA gene from stool DNA. The study is sponsored by Imperial College London and is funded by GSK.

Clinical trial identification

NCT05646082.

Legal entity responsible for the study

Imperial College London.

Funding

GSK.

Disclosure

All authors have declared no conflicts of interest.

Background

Osteosarcoma treatment can entail up to 44 nights in hospital and may result in significant social isolation and restriction of normal activities for young patients. In Australia, high dose methotrexate (HDM) is currently delivered under inpatient settings as it requires intensive fluid hydration and supportive care measures. We hypothesised that: 1. HDM could be delivered safely through an ambulatory care program (ACP) with patient satisfaction and health economic benefits; 2. outpatient care would be preferable to inpatient admission and could improve health related quality of life, and 3. demonstration of 1 and 2 would support national implementation of ACPs for delivery of HDM and other complex regimens.

Trial Design

A prospective multi-centre single arm intervention study of an ACP for delivery of HDM in Adolescent and Young Adult (AYA) osteosarcoma patients. We aim to recruit 10-15 patients over 24 months. The primary objectives are to evaluate the safety and feasibility of an ACP. Secondary objectives are to evaluate the acceptability and impact to patients and carers of an ACP and to undertake a health economic assessment of an ACP compared with inpatient delivery. Selection criteria include a diagnosis of osteosarcoma, age 15-39, successful completion of two inpatient cycles of HDM without complication, the ability to attend hospital for review daily while receiving HDM and willingness to comply with study requirements. The ACP will entail daily bloods and clinician reviews until the methotrexate level is <0.1μmol/L. AYAs will receive 3L of intravenous fluids daily provided in a backpack. Patients/carers will be required to complete urine pH monitoring, record fluid balance, and use oral leucovorin and other medications as required. To measure safety and feasibility, we will record the number of admissions, medication errors, adverse events (compliance and CTCAE toxicity), pump failures, and percentage achieving HDM clearance in 72 and 96 hours. Qualitative interviews and cost consequence analysis will be used for acceptability and economic assessment. Recruitment commenced in August 2022 in an adult sarcoma centre and a paediatric hospital.

Legal entity responsible for the study

The authors.

Funding

This trial is supported by the Australia New Zealand Sarcoma Association (ANZSA), and Kicking goals for Xav, Sarcoma Research Grant (2022).

Disclosure

M.C. Strach: Non-Financial Interests, Personal, Advisory Board, received personal fees: Specialised Therapeutics; Non-Financial Interests, Personal, Funding, fellowship funding from ESMO for unrelated research: ESMO; Non-Financial Interests, Personal, Funding, for unrelated work: RPAH Cancer Services, The Royal Australasian College of Physicians, The Christie Charitable Funds; Non-Financial Interests, Personal, Funding, ANZSA Clinical Research Fellowship and acknowledges funding of this award by Rainbows for Kate Foundation and The Kids Cancer Project: ANZSA. All other authors have declared no conflicts of interest.

Background

Mecbotamab vedotin (BA3011) is a conditionally active biologic (CAB) anti-AXL antibody-drug conjugate being developed as an anticancer therapy for patients with advanced solid tumors. Conditional and reversible binding by CABs is designed to reduce off-tumor toxicity and immunogenicity, avoid tissue-mediated drug deposition, and improve pharmacokinetics. AXL is a cell-surface transmembrane receptor protein tyrosine kinase highly expressed in several tumor types including sarcoma subtypes such as undifferentiated pleomorphic sarcoma (UPS). Increased AXL expression has been associated with tumor resistance to chemotherapy, programmed death-1 (PD-1) inhibitors, molecular targeted therapy, and radiation therapy.

Trial Design

Study BA3011-001 is an ongoing multi-center, open-label phase I/II first-in-human trial designed to evaluate the safety, tolerability, PK, immunogenicity, and antitumor activity of BA3011 alone and in combination with the PD-1 inhibitor nivolumab in adult and adolescent patients 12 years and older with advanced solid tumors. Phase I comprises Dose Escalation and Dose Expansion and is designed to evaluate the safety and tolerability of BA3011 in adult patients with advanced solid tumors and to identify the BA3011 maximum tolerated dose and/or RP2D. Enrollment in phase I is completed. Phase II consists of 2 parts. Phase II part 1 is an open label study of BA3011 alone and in combination with nivolumab in adult and adolescent patients with high AXL-expressing tumor membrane percent score (TmPS) ≥ 50 with advanced refractory sarcoma. Enrollment is expected to be completed in 1H 2023. Phase II part 2 will enroll patients with locally advanced unresectable or metastatic UPS and high AXL expression (TmPS ≥ 50 ), randomized to receive open label BA3011 at two different dosing regimens. UPS patients may have received no more than 3 prior systemic regimens including investigational treatments but excluding treatment with PD-1/L1 inhibitor. Enrollment in phase II part 2 is expected to commence in January 2023.

Clinical trial identification

NCT03425279; EudraCT 2022-001111-10.

Legal entity responsible for the study

BioAtla, Inc.

Funding

BioAtla, Inc.

Disclosure

B. Wilky: Financial Interests, Personal, Other, Consulting and Educational Program Development: Springworks; Financial Interests, Personal, Advisory Board: Deciphera, Adaptimmune, Daiichi Sankyo, Epizyme, Adcendo, Polaris; Financial Interests, Institutional, Research Grant: Exelixis; Financial Interests, Institutional, Invited Speaker: Agenus Bio. J. Rodon: Financial Interests, Personal, Advisory Board: Peptomyc, Kelun Pharmaceuticals/Klus Pharma, Ellipses Pharma, Molecular Partners, iOnctura SA; Financial Interests, Institutional, Other, Clinical Research: Bayer, Novartis, Spectrum Pharmaceuticals, Symphogen, BioAlta, Pfizer, GenMab, CytomX, Kelun-Biotech, Takeda-Millenium, GlaxoSmithKline; Financial Interests, Institutional, Other, Research Funding: Blueprint Medicines, Black Diamond, Merck Sharp & Dohme; Financial Interests, Institutional, Research Grant, Research Funding/Clinical Research: Hummingbird, Yingli; Financial Interests, Institutional, Research Grant, Research Funding: Vall d'Hebron Institute of Oncology/Cancer Core Europe; Financial Interests, Institutional, Research Grant, Clinical Research: Bicycle Therapeutics, Taiho, Roche Pharmaceuticals, Merus, Curis, AadiBioscience, Nuvation, ForeBio, BioMed Valley Discoveries, Loxo Oncology, Hutchinson MediPharma, Cellestia, Deciphera, Ideaya, Amgen, Tango Therapeutics, Mirati, Linnaeus Therapeutics; Other, Personal, Other, Other: VHIO/Ministero De Empleo Y Seguridad Social, Chinese University of Hong Kong, Boxer Capital, Llc, Tang Advisors, Llc; Other, Personal, Other, Travel Reimbursement: European Society for Medical Oncology. M. Ingham: Financial Interests, Personal, Advisory Role: Apexigen, Caris Life Sciences, Daiichi Sankyo, Epizyme, Xencor; Financial Interests, Personal, Research Grant: Apexigen, APICES, Mirati Therapeutics, PTC Therapeutics; Financial Interests, Personal, Other, Travel expenses: Genentech. S. Pollack: Financial Interests, Personal, Advisory Role: T-Knife, Epizyme, Aadi Bioscience, Obsidian, Bayer Corporation, Sensei, Springworks; Financial Interests, Personal, Advisory Board: Deciphera; Financial Interests, Personal, Other, Contractor: GlaxoSmithKline, SynOx, Springworks; Financial Interests, Personal, Research Grant: Obsidian; Financial Interests, Personal, Speaker’s Bureau: Deciphera. A.P. Conley: Financial Interests, Personal, Advisory Role: Bayer, Deciphera, Genentech, Guidepoint Global, InhibRx, Medscape, Nektar, Novartis, OncLive, Schlesinger Associates; Financial Interests, Personal, Research Grant: Bavarian Nordic, Ignyta, Iovance Biotherapeutics, Medimmune, NantHealth; Financial Interests, Personal, Other, Travel expenses: Genentech.

Background

Extrapleural pneumonectomy (EPP) is a procedure for salvage treatment of thoracic sarcoma with pleural involvement. It entails en-bloc resection of parietal and visceral pleura, lung, pericardium and homolateral diaphragm. Promising outcomes have been reported for selected patients in high-volume centres. We aimed to determine the characteristics and outcomes of adults who underwent EPP at a specialised centre.

Methods

We collected clinicopathologic variables, surgical and outcome details on eight patients who underwent EPP between 2010-2020. Primary outcomes were event-free survival (EFS) and overall survival (OS). Secondary outcomes were early and late postoperative complications.

Results

The clinicopathological variables and outcomes are shown in the table. At median follow-up of 22.5 months, six patients had disease recurrence: five died of disease (DoD) and one is alive with disease (AwD). Two patients had not recurred: one died of a radiation-related complication (esophageal rupture) and one is well with no evidence of disease (NED) at 37 months. Two patients received preoperative chemotherapy; both achieved partial metabolic response to doxorubicin/ifosfamide. Two patients received postoperative radiation. Characteristics of patients with the longest EFS included low-grade histology (patient 7, 37.0 m) and partial metabolic response to preoperative chemotherapy (patients 4 and 8, 42.3 m and 20.7 m). Early postoperative complications included: one ventilator-associated pneumonia with new-onset atrial fibrillation and two with hydropneumothorax. One late surgical complication involved infective endocarditis and septic shock. Table: 51P

Baseline characteristics and survival outcomes of EPP patients

Conclusions

In adult sarcoma patients, EPP is rarely curative but appears to be a feasible salvage procedure when performed at specialised centres. Patient selection is critical with a strong consideration for neoadjuvant systemic therapy to optimise oncological outcomes.

Legal entity responsible for the study

Chris O'Brien Lifehouse.

Funding

Has not received any funding.

Disclosure

A. Wilson-Smith: Financial Interests, Personal, Sponsor/Funding: Australian Government Research Training Program. M.C. Strach: Financial Interests, Personal, Funding: Specialised Therapeutics, European Society of Medical Oncology, Royal Prince Alfred Hospital Cancer services, The Royal Australasian College of Physicians, The Christie Charitable Funds; Financial Interests, Personal, Research Grant: ANZSA Clinical Research Fellowship. All other authors have declared no conflicts of interest.

Background

To improve outcomes for patients with Ewing sarcoma, the Ewing Family of Tumors (EFT) regimen was developed as a further dose intensification of the Memorial Sloan Kettering Cancer Center (MSKCC) P6 regimen, increasing the cumulative dose of ifosfamide from 27 g/m2 to 42 g/m2. We assessed the long-term outcomes of patients treated with both regimens to determine both the long-term safety and efficacy of ifosfamide dose intensification.

Methods

The regimens are described in the table. A retrospective chart review of newly diagnosed patients with localized Ewing sarcoma treated with the EFT regimen at MSKCC from 2003 – 2011 was conducted and compared to long term outcomes of patients treated on a prospective trial utilizing the P6 regimen enrolled from 1991 to 2001.

Results

A total of 44 patients (median age=17, range 3-33 years) were treated with P6 and 52 patients treated with EFT (median age=19, range <1-40 years). The median follow up duration for P6 was 23.5 years (range 1-32 years) and 12.3 years for EFT (range <1-19 years). There was no difference in overall survival (OS) between EFT and P6 (p=0.697), with a 10-year OS of 81.6% (95% CI: 66.5-90.3) for P6 and 78.1% (95% CI: 63.9-87.2) for EFT. The combined 10-year OS for patients on both regimens was 79.7% (95% CI: 70.0-86.5). There was no difference in time to recurrence, with median time to recurrence of 3.7 and 1.5 years for P6 and EFT respectively (p=0.097). There was no difference in the cumulative incidence (CI) of secondary neoplasms between the two regimens (p=-0.68), with a 10-year CI of 7.2% (95% CI: 63.9-87.2) for P6 and 2.3% (95% CI: 0.1-15.1) for EFT. Table: 52P

P6/EFT regimen chemotherapy

Conclusions

Ifosfamide dose intensification failed to improve outcomes for patients with localized Ewing sarcoma. Outcomes reported for either regimen are comparable in efficacy to interval dose compressed chemotherapy and 7 weeks shorter, making P6/EFT an attractive backbone for future trials looking to incorporate maintenance therapies.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

W.D. Tap: Financial Interests, Personal, Advisory Board: Eli Lilly, EMD Serono, Mundipharma, C4 Therapeutics, Daiichi Sankyo, Deciphera; Financial Interests, Personal, Advisory Role: Adcendo, Amgen. All other authors have declared no conflicts of interest.

Background

STS are a heterogeneous group, with increase in incidence over 70 years of age and unfavorable outcome beyond second-third-line chemotherapy. In elderly and unfit patients (with comorbidities, polypharmacy, low PS) the treatment decision is more difficult, although treatments with a good toxicity profile and efficacy in different tumors included STS, as Cy, have been shown in small studies (Mir et al., Comandone A et al.) to be an option. We analyzed this population in our center.

Methods

18 patients (10 F; 8 M) were analyzed in a retrospective study, who received treatment with MCy (given daily at total dose of 50 mg/day, without interruption excepted for toxicity or progressive disease), between 2016-2021 in our center. We used SPSS 23.0.

Results

The mean age was 70 years (60-87), considered “unfit” for aggressive chemotherapy due to PS>2 (n=6), comorbidities: Charlson Score>1(n=14), cardiovascular disease (n=9), respiratory (n=1) or renal clearance <60ml/min (n=3). Histological subtypes were: angiosarcoma 1, chondrosarcoma 3, fibrosarcoma 2, leiomyosarcoma 6, undifferentiated sarcoma 6. Treatment toxicity was acceptable, only 2 patients had anemia G3/4 (n=2). Response rate was: 61.1% (n=11) presented stable disease, 5.6% partial response (n=1) and 33.3% (n=6) disease progression. The median PFS was 4.45 months (2.30-21.80), 27.8% (n=5) were treated in the first-line with PFS 4’33 month (2’30-5’29), 13 patients were pretreated: 4 patients in the second-line, 7 in the third-line and 2 in the fourth-line. (53.8% with higher PFS than in previous lines).

Conclusions

In this study, MCy is shown as a safe option for elderly/unfit patients with an acceptable toxicity profile and efficacy. These data and from previous studies referred, should be evaluated in a larger prospective study.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Gastrointestinal stromal tumour, GIST, is the most common intra-abdominal sarcoma and can occur throughout the gastrointestinal tract but most often in the stomach or small intestine. The treatment is surgical resection, sometimes combined with an adjuvant tyrosine kinase inhibitor. Neoadjuvant treatment with imatinib is indicated for large tumours and to minimize postoperative morbidity. The effect of the neoadjuvant treatment depends on the sensitivity of the tumour-driving mutation to imatinib. It is evaluated structurally with a computed tomography scan or metabolically with FDG-PET. We have investigated the clinical utility of FDG-PET in the neoadjuvant treatment setting of GIST at Sahlgrenska University Hospital in Gothenburg, Sweden.

Methods

We identified patients diagnosed with GIST between 2002 and 2020 who received pretreatment with imatinib at Sahlgrenska University Hospital. The response was assessed based on the FDG-PET examinations and compared with the mutational analysis.

Results

Of 125 patients who received neoadjuvant imatinib, 69 had at least one PET scan. Mutation analysis was missing in 19 patients, so the patient cohort consisted of 51 patients. Tumours with mutations sensitive to imatinib showed a response to PET in 87% (n=34) of patients with an odds ratio of 4.86 (p=0.037). In cases where the sensitivity of the tumour mutation to imatinib was uncertain, reduced FDG uptake at PET occurred in 58% (n=7) of the patients.

Conclusions

The PET examination was often challenging to interpret. It contributed to managing patients without FDG-PET response and with an uncertain imatinib-sensitive tumour mutation. Evaluation of neoadjuvant treatment with FDG-PET was unnecessary in patients with imatinib-sensitive tumour mutation.

Legal entity responsible for the study

Stefan Lindskog.

Funding

Gothenburg University.

Disclosure

All authors have declared no conflicts of interest.

Background

Uterine sarcoma make up about 1–2% of all malignant gynecological tumors and have an aggressive clinical course with a high relapse-rate. Because of it, patients contribute maximal comprehensive treatment. The rationale of hormonal therapy is generally extrapolated from data of hormone-sensitive breast cancer.

Methods

Among 129 uterine sarcoma patients, stages IB – IIA (T1b-2aNxM0), in 70 (54,3 %) of them there were detected expression of hormone receptors. All the patients underwent surgery, radiation therapy and chemotherapy. Hormone therapy was administered in 42 patients (1 st group) with expression of ERPR-receptors in tumor tissue, and was not prescribed for 28 patients of the (2nd group) without it. The expression of hormone receptors was conducted by immune-hystochemical analyze. The follow-up of these patients was 6–36 months, its median — 22 months, the average duration — 22.0 ± 2.8 months.

Results

Expression of PR was detected in 88,6% (62 of 70 patients), among them: in 88,5% of LMS patients, in 100,0% of ESS patients and in 50% of NDS patients. The co-expression of ER/PR was determined in 81,0% of cases. The relapse was detected in 16,7% patients, among them were in 20,0% of LMS patients and 0% of ESS patients, in comparison to 42,9% of those patients, who haven’t obtained adjuvant hormonetherapy.

Conclusions

It was confirmed that the hormone receptors are important targets of therapy in uterine sarcoma patients, and was found that the adjuvant hormone therapy in hormone-positive patients with leiomyosarcoma contributes to 90% two-year recurrence-free survival.

Editorial acknowledgement

This academic study was approved by National academy of medical sciences in Ukraine, with support of UkrGOG (Ukrainian Group of Oncologists and Gynecological oncologist).

Legal entity responsible for the study

National Academy of Medical Sciences in Ukraine, with support of UkrGOG (Ukrainian Group of Oncologists and Gynecological oncologist).

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Between August 2021 and October 2022 7 patients were enrolled. Median age at diagnosis was 45 years (range 29 – 77). All patients enrolled had received at least 2 previous lines of systemic therapy. At a median follow-up of 66 months (range 45 – 256) median Pembro-PFS was 2.5 months (range 2 – 7). Median OS for metastatic disease was 46 months (15 – 125). Best treatment response was PD for 71% (5 pts) of patients enrolled; SD was achieved as the best treatment response only in 2 patients.

Methods

In this prospective non-randomized monocentric study, we enrolled 7 patients with metastatic sarcoma or GIST who failed standard therapies had at least one measurable lesion by RECIST 1.1. The primary endpoint of the study was Pembro-PFS. Secondary endpoints included OS and clinical benefit. Among 7 patients enrolled, 4 had a diagnosis of soft tissue sarcoma (1 pleomorphic rhabdomyosarcoma, 1 leiomyosarcoma, 1 extraskeletal mesenchymal chondrosarcoma, 1 epithelioid sarcoma) 1 bone sarcoma (chordoma) and 2 cKIT exon 11 GISTs. All patients were treated with pembrolizumab at 200 mg intravenously every 3 weeks until disease progression or inacceptable toxicity. For patients with GISTs, Pembrolizumab was associated with Imatinib 400mg orally per day. Imaging was performed at week 8 and every 12 weeks thereafter.

Results

Between August 2021 and October 2022 7 patients were enrolled. Median age at diagnosis was 45 years (range 29 – 77). All patients enrolled had received at least 2 previous lines of systemic therapy. At a median follow-up of 66 months (range 45 – 256) median Pembro-PFS was 2.5 months (range 2 – 7). Median OS for metastatic disease was 46 months (15 – 125). Best treatment response was PD for 71% (5 pts) of patients enrolled; SD was achieved as the best treatment response only in 2 patients.

Conclusions

Sarcomas are rare and aggressive neoplasms. The use of immunotherapy for all-comers did not show any benefit. Further studies on predictive biomarkes are needed to identify patients with a higher chance of response to immunotherapy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma tumor in children, but its occurrence in adults is rare. Pazopanib (Pazo) is a multiple kinase inhibitor that limits tumor growth by targeting angiogenesis via inhibition of enzymes including vascular endothelial growth factor receptor (VEGFR), platelet-derived growth factor receptor (PDGFR), c-KIT and FGFR. Pazo has been shown to have antitumor efficacy against soft-tissue sarcomas in the Palette trial and is currently in clinical use. However, few reports mention the antitumor effect of Pazopanib on RMS.

Methods

We report our clinical experience with two cases treated with Pazo in adults with relapsed or curatively untreatable RMS at our institution.

Results

A 37-year-old Japanese woman was diagnosed with embryonal type/spindle cell rhabdomyosarcoma of the right pterygopalatine fossa in other institution (IRS-IV: Stage III, T2N0M0). Radical surgery was not selected due to cosmetic reasons, and chemoradiotherapy with VC (vincristine plus cyclophosphamide) was selected. However, the patient did not achieved a complete response. Pazo administration started in our institution in April 2015. Post-treatment imaging evaluation showed a qualitative changes. Treatment was continued, however, the patient had a cerebral hemorrhage and died in December 2015. A 25-year-old Japanese man was diagnosed with rhabdomyosarcoma, not otherwise specified of the right sub-temporal fossa in our institution (IRS-IV: Stage I, T2aN0M0). Radical surgery was not selected due to cosmetic reasons, and chemoradiotherapy combined with VAC (vincristine plus cyclophosphamide plus dactinomycin) therapy was performed. However, the patient did not achieved a complete response. Pazo was started in October 2017 due to tumor remnant. Initial imaging findings showed no increase in tumor size and qualitative changes, indicating a response to treatment. However, imaging evaluation in March 2018 showed an increase in tumor size, and treatment was terminated. Eribulin was administered as a subsequent therapy, but tumor growth was observed. The patient died in January 2019.

Conclusions

Pazo treatment should be considered as a viable treatment option in adult patients with RMS.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

A. Tsuji: Financial Interests, Personal, Invited Speaker: Eli Lilly Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Merck BioPharma, Bayer, Ono Pharmaceutical, Daiichi Sankyo. All other authors have declared no conflicts of interest.

Background

Classification of bone and soft tissue tumors can be challenging and requires evaluation of clinical presentation, imaging, molecular findings and histopathology. In clinical pathology, direct or indirect evidence of specific molecular alteration is required for certain tumor classes, but the role of whole genome and transcriptome sequencing (WGTS) in the routine diagnostic workup has yet to be established.

Methods

In this prospective single-center study, we offered WGTS as part of the diagnostic workup to patients with a bone or soft tissue tumor suspicious of sarcoma. DNA (tumor and normal) and RNA (tumor only) were isolated from fresh frozen tissue or peripheral blood (normal DNA only) and sequenced on an Illumina NovaSeq platform once per week. For bioinformatics we used BALSAMIC and MIP, and an in-house developed AutoSeq Informatics framework, including assessment of single nucleotide variants, structural rearrangements and copy number alterations. Germline variants were assessed by ACMG criteria and pathogenic variants were acted upon according to local clinical guidelines. Somatic variants and germline variants were evaluated by clinical pathologists and geneticists, respectively.

Results

A total of 210 patients have been included in the study so far. Genomic data was frequently used for the histopathological classification. However, in >10% of the cases the genomic sequencing (completed after the pathology report) challenged the first diagnosis and resulted in a revised histopathological diagnosis. For these patients the individual impact varied but was frequently significant with an altered treatment plan. In our germline analysis, we identified pathogenic variants associated with an inherited cancer syndrome in >10% of the cases analyzed so far, including RB1, BRCA1, MLH1, FH, or CHEK2. Each participant had in average 15 variants classified as of an unknown significance or a heterozygous pathogenic variant for a recessive syndrome.

Conclusions

Used correctly, WGTS has potential of becoming an important complementary tool for sarcoma diagnostics, and germline analysis can be added in parallel to screen for hereditary cancer syndromes.

Legal entity responsible for the study

Karolinska Institutet.

Funding

Illumina.

Disclosure

F. Haglund de Flon: Financial Interests, Institutional, Funding: Illumina. All other authors have declared no conflicts of interest.

Background

Recent technological advances now allow the detection of minute amounts of cell-free tumor-derived DNA (ctDNA) in blood plasma. Therefore, ctDNA analyses can facilitate the diagnosis, monitoring, and tracking of minimal residual disease (MRD) of cancer patients. Given the clinical need of a sensitive and specific biomarker for monitoring of paediatric and adolescent sarcoma patients, we implemented a longitudinal ctDNA monitoring workflow for paediatric sarcoma patients into clinical routine.The aim of the observational study was to analyze if changing levels of ctDNA are associated with treatment response and long-term outcome.

Methods

Since the detection of fusion breakpoints is one of the most sensitive detection method for ctDNA, we designed patient-specific ddPCR assays to track ctDNA in blood plasma collected before, during, and after therapy. To this end, fusion breakpoints were established from whole genome sequencing data of tissue samples. Overall, 19 children and young adults (10 female, 9 males) with a mean of 12 years (range 2-19) were analyzed. Of those, 15 had Ewing sarcomas (ES) and 4 other fusion-related sarcomas.

Results

ctDNA levels assessed as copies of fusion breakpoints were clearly associated with treatment response. In patients with durable response ctDNA declined and remained low or undetectable. In contrast, in patients with unfavorable clinical courses, ctDNA dynamics were more volatile and rising ctDNA level indicated recurrence and progression. Although changing ctDNA levels correlated well with clinical outcome within individual patients, a high variability was observed between patients. Moreover, ctDNA levels did not correlate with tumor burden or other risk factors.

Conclusions

Our data prove practical feasibility for real-time ctDNA monitoring in sarcoma patients. Once the breakpoint and the respective assays are established, ddPCR can be performed within one day and provide useful data of molecular responses. The evidence of increasing amounts of ctDNA or its absence clearly helps in the treatment decision making process (e.g. as indicator of suspected recurrence or treatment response, respectively).

Legal entity responsible for the study

Medical University of Graz.

Funding

Has not received any funding.

Disclosure

A. Leithner: Financial Interests, Institutional, Other, Institutional educational grant: Johnson & Johnson, Alphamed, Medacta, Implantec; Non-Financial Interests, Personal, Other, Board Member: European Musculoskeletal Society (EMSOS); Non-Financial Interests, Personal, Other, Board member: International Society of Limb Salvage (ISOLS); Non-Financial Interests, Personal, Leadership Role: Austrian Society of Orthopaedic Surgeons (ÖGO); Non-Financial Interests, Personal, Member: Connective Tissue Oncology Society (CTOS). All other authors have declared no conflicts of interest.

Background

The rarity and diversity of sarcomas, coupled with a lack of public awareness and limited expertise in primary and secondary care, presents challenges in achieving timely and accurate diagnosis of sarcoma. The consolidation of sarcoma treatment in specialized centers results in improved therapeutic options, making it essential that patients are promptly and efficiently referred. The aim of this study was to quantify the various diagnostic intervals (patient-, primary-, secondary- and tertiary interval) involved in the route to sarcoma diagnosis in the Netherlands (NL) and the United Kingdom (UK).

Methods

Adult sarcoma patients from NL and UK were retrieved from the QUEST study. For this study, only diagnostic interval data were included. Descriptive statistics were calculated for the following intervals: time between start of symptoms and first time the patient talked to a doctor about the symptoms (patient interval), time between first appointment with the GP about the symptoms and the moment of hospital referral (primary care interval), time between first visit medical specialist and moment of referral to a sarcoma center (secondary care interval), time between first appointment in the sarcoma center and sarcoma diagnosis (tertiary care interval). Differences between NL and UK characteristics and intervals were examined with t-tests or chi-square tests.

Results

In total, 319 NL patients (mean age 57.9 years, 59.2% males) and 240 UK patients (mean age 61.8 years, 52.5% males) were included. The majority of patients in both countries had a patient interval of 2-4 weeks (19.4% and 20.8%). In the NL, 18.2% of patients had a primary care interval of less than one week, while in the UK, 18.8% of patients had a primary care interval of 2-4 weeks. The primary care interval was shorter in the NL compared to the UK (p=0.004). In both countries, the majority of patients had a secondary care interval of 1-3 months (21.3% in the NL, 16.7% in the UK) and a tertiary care interval of less than one week (37.6% in the NL, 40% in the UK).

Conclusions

The primary care interval was significantly shorter in the NL compared to in the UK. Increased awareness among healthcare providers and patients may contribute to a shorter sarcoma diagnostic trajectory.

Legal entity responsible for the study

The authors.

Funding

Institute of Cancer Research.

Disclosure

All authors have declared no conflicts of interest.

Background

Pazopanib is an oral, multitarget, tyrosine kinase inhibitor (TKI) approved for the treatment of patients with advanced non adipocytic soft-tissue sarcomas (STS) who have received prior chemotherapy. In Italy, the use of Pazopanib for STS patients has been monitored from 2013 to 2019 through a registry run by the national drug regulator (the Italian Medicines Agency AIFA).

Methods

Data on STS patients treated with Pazopanib in Italy were prospectively collected from July 2013 to December 2019 by AIFA. The primary objectives were to describe clinical characteristics, histological subtypes captured at the time of Pazopanib treatment start and clinical outcomes, assessed by measuring Time to Treatment Discontinuation (TTD), defined as the time between the initial prescription of Pazopanib and the date of treatment discontinuation for any cause, real-world Progression Free survival (rw-PFS).

Results

In total, we analyzed data from 1,965 sarcoma patients. The most represented histological subtypes were tumors with leiomyosarcoma (45%), undifferentiated pleomorphic sarcoma (13%) and synovial sarcoma (8%). 515 patients (26.3%) required at least a dose reduction during treatment, with a median time to dose reduction of 56 days. Overall, the median TTD was 109 days while median PFS was 142 days. In the final AFT model, the variables significantly associated to longer TTD were ECOG PS0 and histological diagnosis of alveolar soft part sarcoma, malignant solitary fibrous tumor and synovial sarcoma. Therefore, covariates significantly associated to longer PFS were ECOG PS0, treatment in high volume centers, treatment offered as first or second-line and histological diagnosis of alveolar soft part sarcoma and pecoma.

Conclusions

In this real-world survey, pazopanib seemed to have variable effectiveness across STS histologies, highlighting the impact of treatment in high volume centers. These real-world data can complement data from randomized controlled trials and may help understand the actual potential of one of the few approved agents in advanced soft tissue sarcomas.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

B. Vincenzi: Financial Interests, Personal, Funding: PharmaMar. A. Comandone: Financial Interests, Personal, Advisory Board, Advisory board on PEG GCSF: Sandoz; Financial Interests, Personal, Invited Speaker, Focus on Trabectedin: PharmaMar. P.G. Casali: Financial Interests, Institutional, Funding: Amgen Dompé, Advenchen, Bayer, Blueprint, Deciphera, Eli Lilly, Epizyme, Daiichi Sankyo, GlaxoSmithKline, Karyopharm, Novartis, Pfizer, PharmaMar, AROG Pharmaceuticals, Eisai; Non-Financial Interests, Personal, Leadership Role, Coordinator of the Steering Committee: Rare Cancers Europe. All other authors have declared no conflicts of interest.

Background

Soft (STS) and bone tissue sarcomas (BS) account for approximately 1%. Patients (P) management is often complicated by young age, histological heterogeneity and rarity of the disease. Although guidelines for the application of narrative medicine into clinical practice exist, a standard approach is still lacking. The objective of the study is to assess the feasibility (F) and utility (U) of a model integrating a theme-oriented digital narrative diary in the management of STS and BS P, according to both P and healthcare professionals (HCP) evaluation.

Methods

From January 2021 to June 2022 a prospective descriptive study was conducted at the IRCCS "Regina Elena" National Cancer Institute in Rome enrolling adult Italian-speaking P affected by STS or BS during treatment or follow-up. P were invited by HCP to access the platform (DNMLAB) for the application of narration in clinical practice in accordance with health data confidentiality criteria. P told about him/herself in a digital diary using a guided narrative path. HCP (3 oncologists, 1 psychologist, 1 case manager) read, shared and used the stories to personalize the cure. A semi-structured questionnaire (5-point Likert scale and open-ended questions) investigating F and U items was administered to HCP (twice) and to P (study end). Ethics Committee approved the study. A written informed consent was required.

Results

17 out of 30 invited P (56.7%) participated: 9/8 with STS/BS, M/F: 6/11, mean age 41 years (SD 8.2). 16 P assessed F and U items (easiness of use, opportunity to provide personal information, improvement of care relationship, awareness and coping capacity): medium scores ranged from 4.4 to 4.8. HCP F and U items assessment increased from T1 to T2 (mean score range: 3.2 – 4.8 vs 3.6 - 4.8). The main advantages were the improvement in: communication, therapeutic alliance and time management during the visits (mean score: 4.8). P and HCP recommended diary use in clinical practice. Lack in participation (13 P) was due to: technical problems (39%), preferring to talk orally (39%).

Conclusions

Theme-oriented narration is a useful tool in daily P care. Both P and HCP agreed on the F and U of the digital diary and strongly encouraged its introduction in clinical practice.

Legal entity responsible for the study

Istituto Regina Elena.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Gastrointestinal stromal tumours (GIST) represent the most common intra-abdominal sarcoma and have variable malignant potential. Risk classification systems have been proposed to identify tumour properties that correlate to patient outcomes. However, determining treatment strategies as well as the need for, and length of, routine follow-up has been debated.

Methods

We conducted a retrospective observational study of all patients diagnosed with GIST at Sahlgrenska University Hospital between January 2004 and December 2020. Medical records were reviewed for clinical details regarding diagnosis, treatment and follow-up, and correlated to recurrence-free survival (RFS), disease-specific survival (DSS) and overall survival (OS).

Results

Some 468 patients, whereof 223 females, with a mean age of 67 (24-93) years were included; 200 high-, 73 intermediate-, 144 low- and 51 very low-risk tumours according to the revised NIH criteria. The most frequent tumour site was the stomach (66 %) followed by the small intestine (29 %). Without pretreatment, non-radical resections occurred in 17% and in 9% after pretreatment with imatinib (p<0.05). Among the 388 patients who had surgery with a curative intent, the overall five-year RFS was 82%, and 68%, 100%, 93% and 100% for high, intermediate low and very low-risk groups, respectively (p<0.001). The 5-year overall DSS was 87.5% in the whole group, 78% in the high-risk group and 98.6-100% in the other risk groups (p<0.001). The difference remained statistically significant after adjusting for age and comorbidities. The overall survival was 76% without significant difference between the risk groups in the initial analysis but after adjusting for age and comorbidities, the low-risk group had significantly better OS compared to the high risk-group (HR: 0.6, 95% CI: 0.39−0.94) (p<0.01).

Conclusions

We show that in our cohort, the significant difference in RFS, DSS and OS between risk groups questions the value of current follow-up recommendations for risk groups other than the high-risk group.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Single agent anthracycline chemotherapy remains the standard first-line systemic treatment of advanced/metastatic soft tissue sarcomas (STS), with limited efficacy (4-6 months median progression free survival (PFS)). This emphasizes the need to focus on the predictive factors of doxorubicin (dox) efficacy. A subgroup of STS are characterized by the presence of tertiary lymphoid structures (TLS) that might represent both a good prognostic factor with improved survival and a predictive factor for response to PD1 blockade. The primary aim of this retrospective study was to compare dox efficacy in STS patients (pts) with or without TLS.

Methods

All pts from the Centre Léon Bérard (CLB) with a diagnosis of advanced STS from October 2008 to March 2021 and screened for TLS were registered. Histological diagnosis and TLS expression were done with a central review by expert pathologists. Two groups of pts were studied: TLS positive (TLS+ cohort) and TLS negative (TLS- cohort). Overall Survival (OS), Relapse Free Survival (RFS) and PFS were calculated using the Kaplan-Meier method and the log-rank test.

Results

Among the 42 pts, sex ratio was 2 (28M/14F), the median age at diagnosis was 55 [18-84] and 38 pts had an ECOG PS ≤ 1 (90%). Comparing pts characteristics from cohorts TLS + (N=14) and TLS- (N=28), there were no statistically significant differences for age at diagnosis, tumor size and tumor grade (P=0.1, P=0.08 and P=0.34). Interestingly, angiosarcomas (100%) were all in the TLS+ cohort (P=0,03). With a mFUP of 27 mo, 32 pts (76%) died of the disease. Median OS after the diagnosis of metastasis was 17.5 months, with no significant difference between both cohorts (mOS 13 vs 28 mo for TLS + and – respectively HR=1.35; 95% CI 0,6 to 2,9; P=0.4). In the subgroup of pts with localized disease, median RFS was 16 mo (TLS+) vs 6.5 mo (TLS-) (P=0.08). Focusing on doxorubicin as 1^st M+ therapy, median PFS was 4 mo in TLS+ versus 7 mo for TLS- (P=0.5).

Conclusions

This retrospective series from CLB confirms the aggressive clinical course of STS patients regardless of the TLS expression. While TLS might represent a predictive factor to response to PD1 blockade, it does not seem to impact on doxorubicin efficacy and can be a good argument to explore combination.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Soft tissue sarcomas consist of a group of mesenchymal malignancies and commonly arise in the extremities. Several factors impact the survival of those diagnosed with extremity soft tissue sarcoma (ESTS). Most of the existing population-based studies about ESTS are limited by sample size or data from single institutions. This study is an update to a previous study that evaluated the 5-year year survival rate of ESTS from 1991–2010, which showed an increase from 28% in the earliest time period to 62% in the latest. We will evaluate the incidence and survival rate of ESTS from 1992–2019.

Methods

This was a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database. The patients selected for this study were aged 15 years and older and diagnosed with ESTS from 1992 to 2019. Patients with unknown tumor size, grade, metastasis, or surgery record were excluded. Patients were divided by year of diagnosis into four subgroups for comparison: 1992–1998, 1999–2005, 2006–2012, and 2013–2019. The demographic characteristics, tumor characteristics, and survival information were analyzed. Kaplan-Meier curves were computed for the time periods, and the log-rank test was performed. The Cox proportional hazards multivariate regression model included the statistically significant survival-associated variables in the univariate analysis.

Results

There is progressive improvement in the 5-year overall survival of ESTS during the study period, from 37% in 1992–1998 to 48% in 1999–2005, to 61% in 2006–2012, and to 79% in 2013–2019 (P<.001). The mortality rate progressively declined from the 1992–1998 group (HR: 4.303, CI:3.754 – 4.932, P<0.001) to the 1999–2005 group (HR: 3.316, CI:2.938 – 3.743, P<0.001), to the 2006–2012 group (HR: 2.043, CI:1.821 – 2.292, P<0.001), to the 2013–2019 group which have the best overall survival.

Conclusions

Overall survival of ESTS continued to improve over time along the 28-years of analysis. This improvement in overall survival occurred despite the increase in the proportion of older patients and in the proportion of those with large tumors. Furthermore, there was a decrease in the proportion of patients with metastatic disease.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Antibody-drug conjugates (ADCs) combining targeted antibody and cytotoxic agents recently reached approval in hematologic malignancies and carcinomas. As gene expression is a positively correlated to protein expression, RNA-seq data analyses can be used to screen possible ADC targets of interest in rare tumors including sarcomas.

Methods

An analysis of gene expression of selected target genes was analyzed in pan-cancer public databases (TCGA RNA-seq) and an institutional in-house database enriched in rare tumors including FFPE-based whole-exome RNA sequencing (n= 6530 samples including 2140 sarcomas, 684 carcinomas, 982 melanocytic tumors, 636 mesotheliomas and other rare tumors as of January 2023. To identify potent high expressers as candidates to ADC development the expression level of target genes was analyzed to compare expression (i) between sarcomas and different carcinomas (ii) among sarcomas and rare tumors to identify the top-expressing subtypes and level of heterogeneity of gene expression.

Results

First analyses focused on the gene expression of the top seven protein targeted with ADC in solid tumors: ERBB2, TACSTD2 (encoding TROP-2), Nectin-4and F3 (encoding tissue factor), ERBB3, FOLR1 (encoding alpha receptor) SLC34A2 (encoding NaPi-2). In the TCGA database, the level of expression of each of the targets was significantly lower in the sarcoma cohort (n=259) as compared to cohorts of carcinomas (p<10-3 for each target). In our in-house database the 2140 sarcomas, sarcomas were not collectively high expressers compared to carcinomas but some specific rare subtypes had a significant median expression of ERBB2 (e.g. rhabdomyosarcoma, dermatofibrosarcoma, smarca-4deficient or epithelioid sarcomas), F3 (e.g. mesenchymal chondrosarcoma) or NECTIN4. Most of sarcoma subtypes poorly expressed TACSTD2, ERBB3, FOLR1, SLC34A2 in median, although some individual sarcomas could be in the top expressing tumors.

Conclusions

On the whole, gene expression of the current carcinoma's ADC target gene are highly expressed in only a minority of rare sarcomas subtypes. Further trials may select these subtypes and confirm through immunohistochemical staining. Other surface markers may be more specific of mesenchymal tumors and may be targeted by novel ADC constructs.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M. Brahmi: Financial Interests, Institutional, Research Grant: Bayer, GSK. P. Cassier: Financial Interests, Personal, Expert Testimony: Iteos, Amgen, Jansen; Financial Interests, Personal, Advisory Board: Ose Immunotherapeutics; Financial Interests, Institutional, Research Grant: Bayer, GSK, Janssen, Lilly, AstraZeneca, Roche, Merck, Toray, Novartis, Innate, Loxo, Blueprint, Celgene, AbbVie. J-Y. Blay: Financial Interests, Personal and Institutional, Expert Testimony: GSK, AstraZeneca, Bayer, Novartis. A. Dufresne: Financial Interests, Institutional, Research Grant: Bayer, GSK. All other authors have declared no conflicts of interest.

Background

The COVID-19 pandemic had a significant impact on the healthcare system globally, including oncology. Which, in turn, led to significant delays in diagnostic and therapeutic procedures. This work aims to evaluate COVID-19 impact on the treatment of bone sarcoma in adult patients based on experience in a single, high-volume institution.

Methods

We have analyzed the early local outcomes (i.e., the possibility of limb-sparing surgery) in all patients with primary bone tumours treated between 2016-01-28 and 2022-11-07 in Polish main sarcoma reference center. Patients treated in the 2016-2019 period were labelled as a “pre-pandemic” group, and patients treated in the 2020-2022 - “pandemic”. Mann–Whitney U and Chi-square tests were used in the statistical analysis.

Results

There were 302 eligible patients identified. The group characteristics are presented in the table. There were no differences in patient-related variables and histological subtypes of tumours between the two groups. The tumour size did not differ (p = 0.053), when all tumour grades were considered, but high-grade tumours were larger in the “pandemic” group (p = 0.034). This was reflected in the percentage of limb-sparing surgeries which dropped from 83.3% to 68.2% (“pre-pandemic” vs “pandemic”, p = 0.004). This difference was even more evident in the case of high-grade tumors - 78% vs. 54%, respectively (p = 0.001). Table: 67P

Conclusions

To our knowledge, this is the first report of the long-lasting detrimental impact of the COVID-19 pandemic on oncologic treatment outcomes in adult patients with primary malignant bone tumors.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

The aim if the study is to analyze the effectiveness of the surgery with and without denosumab, as well as long-term denosumab for metastatic or unresectable GCT.

Methods

We observed 295 GCT cases from 2005 till 2020. The median follow-up was 56±52.2 months. There were 3 groups: only surgery; neoadjuvant denosumab and surgery; long-term and maintenance denosumab for unresectable or metastatic GCT. The primary malignant GCT was 1.4%. GCT metastases at presentation were 3.1%.

Results

Neoadjuvant denosumab and radical surgery significant decrease the recurrence rate compared with only radical surgery, from 12.5% to 0% (p < 0.05). Neoadjuvant denosumab and curettage showed almost the same recurrence rate compared with curettage alone, 57.6% and 53.6% respectively (p > 0.05). However, long-term neoadjuvant denosumab significantly reduces the risk of recurrence for curettage, considering the stabilization and additional injections (correctly predicted values - 82.14%, p < 0.05). Compound localization and curettage were significant for recurrence risk (p < 0.05). Radical surgery and neoadjuvant denosumab significantly reduced the incidence of complications from 36.9% to 12.5% compared with radical surgery alone (p < 0.05). Compound localization in the upper and lower extremities and the radical surgery were significant for complications risk (p < 0.05). For unresectable or metastatic GCT continuous denosumab therapy achieved long-term disease control (100%), including switching to maintenance therapy once every three months. The 3-year PFS for denosumab withdrawal was 10% (95% CI: 15.5–64.1). The development of metastasis is significantly affected by the curettage and the compound localization in the upper and lower extremities and the axial skeleton (p < 0.05).

Conclusions

Neoadjuvant denosumab and surgery for resectable GCT reduces the risk of recurrence, time of surgery and blood loss. Localization of the disease and the type of surgery may affect the results of treatment. Long-term neoadjuvant denosumab reduces the recurrence risk in a case of compound localizations and high risks of complications. Continuous and maintenance denosumab therapy for unresectable or metastatic GCT can achieve long-term disease control.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Trabectedin is an anticancer marine-derived drug approved for the treatment of adults with advanced soft tissue sarcoma (STS) after anthracycline and ifosfamide failure, or for those patients who are unsuited to receive these agents. Trabectedin has efficacy mainly on liposarcoma and leiomyosarcoma patients (L-sarcomas).

Methods

This is a pilot study to evaluate the efficacy and toxicity of trabectedin, administered as “rechallenge” in advanced sarcoma patients after progression to previous treatment with trabectedin. From January 2022 to January 2023, metastatic STS patients without any other standard treatment available were treated with trabectedin 1.3 mg/m² body surface area, administered as an intravenous infusion over 24 hours with cycles repeated every 21 days.

Results

Six (6) patients were included in the analysis. The median age was 43 years (range, 23-60); 4 patients were men (66.7%) and 2 were women (33.3%). The histology subtypes were: n.2 leiomyosarcoma, n.2 liposarcomas, n.1 myoepithelioma, and 1 epithelioid sarcoma. Six (6) patients were treated with trabectedin re-challenge in different line of treatment. The overall response rate was 33.3 %. Two (2) patients (33.3%) had a partial response (RP), 1 patient (16.7%) had a stable disease (SD) and 3 patients (50.0%) had a progression disease (PD) as best response. Notably, the 2 responder patients were the myoepithelioma, and epithelioid sarcoma patients. The median duration of response was not reached and the median progression-free survival (PFS) was 6.5 months. The trabectedin at rechallenge was well-tolerated. No grade 3 and/or 4 toxicities were recorded.

Conclusions

Disease control rate and toxicity profile of drugs are major objectives in the treatment of advanced STS. To the best of our knowledges, this is the first pilot study on trabectedin rechallenge in advanced sarcoma patients, after progression to previous treatment with trabectedin. In our experience, trabectedin rechallenge is active with a 50% disease control rate, without dose-limiting toxicity.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Despite the improvement in the survival of patients with high-grade osteosarcoma after the implementation of perioperative chemotherapy, this malignancy has been among the most lethal cancers yet. Prescription of all chemotherapy courses before the surgery may provide this opportunity to eliminate micrometastases more efficiently and increase the chance of pathologic complete response and organ preserving surgery. This study aimed to compare the outcomes of total neoadjuvant chemotherapy (TNT) vs. standard perioperative chemotherapy with cisplatin/doxorubicin regimen in patients with extremities osteosarcoma.

Methods

In this retrospective cohort, all patients with high-grade osteosarcoma referred to Firoozgar hospital, Tehran, Iran during 2015 to 2021 were enrolled. Organ preserving rates, pathologic responses, and survival of patients who received all six courses of cisplatin/doxorubicin regimen preoperatively were compared to those who received the regimen perioperatively.

Results

63 patients were enrolled (TNT: 32 patients and perioperative chemotherapy: 31 patients) (Table). In TNT and perioperative chemotherapy groups, favorable pathology responses (necrosis>90%) were reported in 80.6% and 15.6% of patients, respectively. With a median follow-up of 24 months, median overall survival of TNT and perioperative chemotherapy groups were 21.2 months (95%CI 21.3-23.2) and 23.4 months (95%CI 22.7-24.1), respectively (p=0.2). The median disease-free survival of patients in TNT and perioperative chemotherapy groups were 19.5 months (95%CI 17.0-22.0) and 21.3 months (95%CI 19.4-23.2), respectively (p=0.2). Table: 70P

The baseline characteristics

Conclusions

Our results showed that prescription of all courses of the doxorubicin/cisplatin chemotherapy prior to surgery can improve the pathologic response, although this improvement is not translated into overall and disease-free survival.

Legal entity responsible for the study

Iran University of Medical Sciences.

Funding

Iran University of Medical Sciences.

Disclosure

All authors have declared no conflicts of interest.

Background

Outcomes and toxicity data of Osteosarcoma (OGS) in adults over 40 years are sparse and merit exploration.

Methods

This was a retrospective analysis of prospectively collected data of histopathologically confirmed OGS patients over the age of 40 years, who were registered at our institute between 2013 and 2020. They were analyzed for overall survival (OS), event-free survival (EFS), and treatment-related toxicities.

Results

The median age of 91 patients included in the study was 48 years, including 58 (63.7%) males. Twenty-seven (29.7%) patients had distant metastasis at the time of diagnosis and 82 (90.1%) had primary in the appendicular skeleton. Sixty-two out of the 64 patients with no metastasis at presentation undertook treatment. Fifty-four (87.1%) patients could undergo surgical resection of the primary tumor, while 53 (85.5%) patients were offered systemic therapy with 9 (27.3%) patients achieving tumor necrosis of more than equal to 90% after neoadjuvant chemotherapy. Thirty-seven (69.8%) patients had grade 3/4 toxicity, mostly hematological including febrile neutropenia in 25 (47.2%) patients. Thirty-one (58.5%) of patients completed planned perioperative chemotherapy, however, dose reduction in subsequent cycles was required in 19 (45%) of the patients. After a median follow-up of 61 months and 29 events among 62 patients who started treatment, the median event-free survival (EFS) was 36 (95% CI, 23 - 49) months, while the median overall survival (OS) was 44 (95% CI, 23.8 – 64.2) months. Among the 27 patients with metastasis, progression-free survival (PFS) was 5 (95% CI, 0.0 – 12.7) months for 7 patients treated with palliative intent.

Conclusions

Older patients benefit from aggressive multimodality treatment. However, carefully selected patients with adequate dose modifications are required as they seem to develop higher toxicity. Further collaborative studies are needed to improve survival in this fragile cohort.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

P.G. Bhargava: Financial Interests, Institutional, Invited Speaker: Novartis, Intas, Roche, Pfizer; Financial Interests, Institutional, Advisory Board: Mankind, Zydus. J. Bajpai: Financial Interests, Institutional, Invited Speaker, Institutional financial interests for conducted research: Eli Lilly; Financial Interests, Institutional, Invited Speaker, Institutional financial interests for conducted research: Novartis, Roche, Paxman Coolers Ltd.; Financial Interests, Institutional, Invited Speaker, Institutional financial interests for conducted research (completed study): Samsung Bioepis Co. Ltd.; Financial Interests, Institutional, Invited Speaker, Institutional financial interests for conducted research (completed study): Sun Pharma; Non-Financial Interests, Personal, Advisory Role: Novartis; Non-Financial Interests, Personal, Leadership Role, Founder General Secretary: Immuno-Oncology Society of India (IOSI); Non-Financial Interests, Personal, Leadership Role, Executive Committee Member: Indian Society of Medical and Paediatric Oncology (ISMPO); Non-Financial Interests, Personal, Leadership Role, Founder Member and Joint Secretory: Teenage and Young Adult Cancer Foundation (TYAcan); Non-Financial Interests, Personal, Leadership Role, Managing Committee Member: Indian cooperative Oncology network (ICON); Non-Financial Interests, Personal, Leadership Role, Women for Oncology - Core Committee Member: ESMO; Non-Financial Interests, Personal, Leadership Role, Faculty-investigational immunotherapy: ESMO. All other authors have declared no conflicts of interest.