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

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

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

Methotrexate (MTX)-resistance of osteosarcoma results in poor prognosis. Further understanding of the basis and ramifications of the MTX-resistance is therefore needed. The present study aimed to determine, in a super MTX-resistant osteosarcoma cell line, its degree of malignancy and the expression level of malignancy-related genes, PI3K/AKT/mTOR and c-MYC.

Methods

Super MTX-resistant 143B osteosarcoma cells (143B-MTX^SR) were selected from 143B parental osteosarcoma cells (143B-P) by culturing the cells with stepwise increasing concentrations of MTX (0.04 μM to 100 μM) for 12 months. Colony formation capacity on plastic and in soft agar was examined to compare the malignancy of 143B-P and 143B-MTX^SR in vitro. Orthotopic xenograft mouse models of 143B-P and 143B-MTX^SR, in which 2.5 × 10⁵ cells were implanted in the tibia of nude mice, were established to compare malignancy in vivo. Expression of dihydrofolate reductase (DHFR), PI3K/AKT/mTOR, and c-MYC was determined by Western immunoblotting. The mouse studies were approved by Institutional Animal Care and Use Committee of AntiCancer Inc.

Results

143B-MTX^SR gained 5500-fold resistance to MTX (IC₅₀: 147.5 μM), compared to 143B-P (0.027 μM), due to a 9.8-fold increase in DHFR. 143B-MTX^SR had reduced colony formation capacity on plastic (P = 0.032) and in soft agar (P < 0.01), indicating the reduction of malignancy. 143B-MTX^SR formed significantly smaller tumors than 143B-P (P < 0.001), further indicating that 143B-MTX^SR lost malignancy. 143B-MTX^SR showed an increased expression of PI3K (P < 0.01), phosphorylated AKT (activated AKT) (p-AKT) (P = 0.031), phosphorylated mTOR (activated mTOR) (p-mTOR) (P = 0.043), and c-MYC (P = 0.024), compared to 143B-P, along with their decreased malignancy.

Conclusions

The present study demonstrated that 143B-MTX^SR results in loss of malignancy, and for the first time, indicates that the increased expression of PI3K/AKT/mTOR and c-MYC are linked to MTX-resistance and malignancy. This new insight into MTX resistance of osteosarcoma should lead to more effective strategies to treat this recalcitrant 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

The AXINET trial demonstrated in 256 patients with extrapancreatic neuroendocrine tumors (EP-NETs) that axitinib + SSA (Somatostatin analogue) significantly improves ORR and PFS compared to placebo and SSA per central blinded assessment (Garcia-Carbonero et al, ESMO 2021). However, the benefit was limited and predictive biomarkers are necessary. Table: 28MO

The aim is to identify predictive signatures and underlying response mechanisms to axitinib in EP-NETs.

Methods

A predictive signature was developed using gene expression profiles of 126 FFPE tumours of 126 patients enrolled in the AXINET trial and the R package singscore. Genes most associated with clinical benefit in axitinib-treated patients based on PFS Cox regression and tumour shrinkage were selected. Gene set and cell type enrichment analysis was performed to unveil molecular mechanisms involved in axitinib response.

Results

A 9 gene transcriptomic signature (RPS10-NUDT3, MX2, C18orf25, SPP1, CLDN14, REXO1L2P, KLHDC3, ATXN7, CUBN) was developed based on their association with PFS (p <0.01) and its importance (VIP score) in tumour shrinkage. The signature score was significantly associated with tumour shrinkage (High vs Low, FC: 2.95; p< 0.0109) and PFS exclusively in axitinib-treated patients (H vs L, HR: 0.32, p< 0.001) but had no predictive value in the placebo arm (H vs L, HR: 0.84, ns). Pathways involved in the differential response to axitinib were EMT (H vs L, NES: -2.33; FDR =4.96∙10^-7) and Myc targets (H vs L, NES: -1.71; FDR =0.007). Finally, M1 macrophages were enriched in Low score patients (FDR =0.08) and neuron signature in High score patients (p =0.01).

Conclusions

We developed a 9-gene signature associated with axitinib benefit in EP-NETs which may be useful to select patients most likely to benefit from this therapy. Moreover, EMT, Myc targets and macrophages have been identified as potentially involved in the underlying mechanisms of response to this drug.

Legal entity responsible for the study

Rocío García-Carbonero.

Funding

Pfizer.

Disclosure

B. Antón Pascual: Financial Interests, Personal, Advisory Role: AAA, Advanz, Merck, Servier, Novartis. J. Capdevila Castillon: Financial Interests, Personal, Invited Speaker: Novartis, Novartis, Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono; Financial Interests, Personal, Advisory Board: Pfizer, Ipsen, Exelixis, Bayer, Eisai, Advanced Accelerator Applications, Amgen, Sanofi, Lilly, Merck Serono; Financial Interests, Personal, Research Grant: Novartis, Pfizer, AstraZeneca, Advanced Accelerator Applications, Eisai, Bayer. E. Grande Pulido: Financial Interests, Personal, Invited Speaker: Adacap, AstraZeneca, Bristol Myers Squibb, Eisai, Eusa Pharma, Ipsen, Janssen, Lilly, Merck KGaA, Pfizer, Roche; Financial Interests, Personal, Advisory Board: Astellas, Bayer, MSD, Novartis, Sanofi Genzyme; Financial Interests, Institutional, Advisory Board: Caris Life Sciences, OncoDNA (Biosequence); Financial Interests, Institutional, Research Grant, Independent research grant: Astellas, AstraZeneca, Lexicon, MTEM/Threshold, NanoString Technologies, Pfizer, Roche, Merck; Financial Interests, Institutional, Invited Speaker, Independent research grant: Ipsen; Non-Financial Interests, Personal, Other, Ad Board Member: ENETS. 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.