Background

Sensitive biomarkers for early cancer detection remain largely lacking. Circulating telomere DNA may help.

Methods

A case-control study with hospital hepatocellular carcinoma (HCC) cases was conducted to identify potential biomarkers for HCC detection (Discovery). We used next generation sequencing method for circulating cell-free DNA (ccfDNA) analysis. We modeled telomere and end sequence in circulation (Telecon) to detect HCC in Discovery. We validated Telecon in a prospective cohort among hepatitis B virus (HBV)-seropositive participants with biannual blood collections from 2012 till 2019, using nested case-control design (Validation).

Results

In Discovery, among short ccfDNA (25-60 nucleotides), telomere was more abundant in HCC patients than in controls (18.87-fold, P=6.4×10^-18). Telomere contributed 91% of the variation of the Telecon model, which distinguished HCC cases from controls completely (AUC=1.0). In Validation, among 18,185 participants, 2,893 were HBV-seropositive and developed 81 incident HCC cases (incidence rate 382 per 100,000 person-years). Telecon showed increasing detection performance using pre-diagnosis samples collected ≥4 years (AUC=0.538), 3-4 years (0.741), 2-3 years (0.742), 1-2 years (0.786), and 0-1 year (0.930) before diagnosis. Within one year before diagnosis and at a specificity of 98%, Telecon had a sensitivity of 68.2% (95% CI=52.4-81.4%) in detecting early HCC, yielding an estimated positive predict value of 15.2% among HBV-seropositive population. High Telecon was also associated with a higher risk of death among hospital HCC patients (hazard ratio 3.22, 95% CI=1.49-7.0), independent of tumor stage.

Conclusions

Circulating short telomere may effectively detect early and aggressive hepatocellular carcinoma in high-risk populations.

Legal entity responsible for the study

The authors.

Funding

China Scholarship Council (201808440263); Lau Grant (LC230003); Swedish Research Council (202001418).

Disclosure

Z. Zheng: Financial Interests, Personal, Royalties: ArcherDX; Financial Interests, Personal, Advisory Role: Helitec, GenEditBio. All other authors have declared no conflicts of interest.

Background

FusionPlex Dx (FP Dx) is a 2-part multimodal next-generation sequencing (NGS)-based in vitro diagnostic kitted device that detects structural alterations and oncogenic isoforms in RNA derived from formalin-fixed, paraffin-embedded (FFPE) samples from solid tumors using proprietary Anchored Multiplex PCR (AMP™) chemistry. FP Dx is approved as a companion diagnostic for five indications: METex14 skipping events, ALK, RET, ROS1 gene fusions to guide therapy in non-small cell lung cancer and NTRK1/2/3 gene fusions for all solid tumors. The assay also provides comprehensive genomic profiling for patients with solid tumors. This study summarizes the analytical performance of FP Dx.

Methods

FP Dx instructions for use were followed for all studies. Total nucleic acid was extracted from 1132 unique clinical FFPE specimens with positive or negative RNA alterations derived from ≥40 unique tumor types and 4 commercial reference FFPE samples generating a total of 3279 libraries. Libraries were sequenced on Illumina MiSeqDx and NextSeq 550Dx platforms. Pre-defined in-process control metrics were used for monitoring library preparation and sequencing, and only libraries meeting these metrics were included in the analysis (97.65%). Data were processed via Illumina sequencing software, R Analysis Suite Statistical Software, and Invitae Solid Tumor IVD Analysis.

Results

The limit of detection of FP Dx was measured to be 22 reads for structural alteration (ALK, RET, and ROS1 gene fusions), 26 – 35 reads for METex14 skipping events, and 31 reads for NTRK gene fusions. The accuracy of FP Dx was evaluated by comparison to Illumina TST-170 NGS, Oncomine Focus NGS, and Illumina TSO Comp assays. Concordance agreement results were >95%, demonstrating the accuracy of FP Dx. Overall agreement reproducibility results for NTRK, METex14, ALK, RET, and ROS1 alterations were ≥99.15%, and repeatability results were ≥92.50%, demonstrating consistent precision of FP Dx.

Conclusions

Collectively, these data support FP Dx’s ability to detect RNA structural alterations. The unique capabilities of the Assay chemistry and software allow for exhaustive characterization of Assay sensitivity for all targeted alterations, even without prior knowledge of gene fusion partners or breakpoints.

Legal entity responsible for the study

Invitae Corporation.

Funding

Invitae Corporation.

Disclosure

V. Haddad, N. Hohos, M. Stueve, A. Timm, A. Rao, H. Slocum, J. Lee: Other, Institutional, Full or part-time Employment: Invitae.

Background

The approach of targeted therapies has also evolved with a better understanding of cancer to achieve treatment outcomes accordingly. Cytochrome P450 (CYP) is one of these enzyme superfamilies that are of great pharmacogenomic interest due to its role in the biotransformation of several drugs, including anticancer drugs. These enzymes have the ability to metabolize procarcinogens and anticancer drugs, making them crucial in cancer etiology and treatment. Accordingly, the present study investigated the pharmacogenomics of Cytochrome P450 1A1, 3A4 & 3A5 genotypes in relation to treatment response (personalized medicine approach) in breast cancer cases receiving adjuvant tamoxifen.

Methods

Study participants included 300 women with breast cancer and a similar number of age-matched controls. CYP1A1, CYP3A4 & CYP3A5 genotypes were determined in genomic DNA by PCR-based RFLP. Follow-up was carried out to determine whether there was any correlation between the variants and treatment outcome. A Chi-square test and logistic regression models were used to investigate the association between genotype, use of concomitant CYP1A1, CYP3A4 & CYP3A5 inhibitors, and disease relapse rate.

Results

CYP1A1, CYP3A4 & CYP3A5 variant alleles were significantly more frequent in the cases than in the controls. Moreover, this study showed that the presence of inactive CYP1A1, CYP3A4 & CYP3A5 resulted in a decrease in the metabolic activation of anticancer agents, lowering the risk of toxicity but worsening the therapeutic response. A deeper understanding of CYP1A1, CYP3A4 & CYP3A5 could lead to more effective targeted therapies for breast cancer.

Conclusions

In spite of advances in treatment for breast cancer, an effective treatment outcome with no side effects remains a challenge in Asian countries. The study of pharmacogenomics is expected to help in the standardization of chemotherapy drugs and improve treatment outcomes in cancer patients carrying CYP1A1, CYP3A4 & CYP3A5 variant genotypes (precision medicine/targeted therapies).

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Previous studies have documented that both vitamin D deficiency and single nucleotide polymorphism (SNPs) of genes responsible for mediating downstream effects of melatonin with development of breast cancer. In India 70 percent of the population suffers from Vitamin D deficiency. There are no available reports on association of vitamin D and SNPs in Melatonin genes towards development of breast cancer in Indian population.

Methods

To this end, we evaluated 50 vitamin D-deficient breast cancer subjects and studied the gene expression patterns and SNPs of melatonin receptor genes (MTNR1a, MTNR1b) and Arylalkylamine N-acetyltransferase (AANAT). Age matched breast cancer patients without Vitamin D deficiency and age matched normal subjects (i.e without breast cancer served as control).

Results

Vitamin D-deficient studies demonstrated decreased expression MTNR1a, MTNR1b, and AANAT genes in vitamin D deficient breast cancer group as compared to subjects with normal vitamin D level (68% Vs 41%, p<0.001). Two two-staged analysis of genome-wide association (GWAS) showed association of MTNR1a, MTNR1b SNPs with cancer progression and metastasis in vitamin D deficient group. Interestingly the incidence of SNPs was 32% more in vitamin D-deficient breast cancer group when compared with the other groups.

Conclusions

Our pilot studies highlight the fact that both Vitamin D and products of melatonin have strong correlation with development of breast cancer and its invasiveness. Significant increase in SNPs of melatonin related genes under conditions of vitamin D insufficiency leads us to the contention that vitamin D and melatonin have additive effect in development of breast cancer. These experiments when repeated using large sample size coupled with animal studies in melatonin receptor knockout mice with breast cancer against vitamin D background can shed more light on the exact mechanism.

Legal entity responsible for the study

Raktim Mukherjee, Megha Dave, Vishnu Priya Veeraraghavan, Selvaraj Jayaraman.

Funding

Has not received any funding.

Disclosure

The author has declared no conflicts of interest.

Background

The advent of immune checkpoint inhibitors (ICIs) is underway to change the landscape of triple- negative breast cancer (TNBC) treatment. In this meta-analysis and position paper, we assess the role of atezolizumab and pembrolizumab in TNBC with the lens of precision medicine.

Methods

A systematic search of PubMed, Scopus, Web of Science and Google Scholar was conducted until July 15, 2022. Keywords were used as follows: triple-negative breast cancer, atezolizumab, pembrolizumab, biomarker, precision, chemotherapy.

Results

A total of 3 clinical trials (i. IMpassion 130, ii. IMpassion 131 and iii. KN355) were included. The objective response rate (ORR) was higher in the treatment arm (atezolizumab/pembrolizumab) (ORR=1.35) as compared to placebo. Moreover, the progression free survival (PFS) in the treatment arm had a positive effect size (Cohen’s d=1.5). TNBC is a known aggressive and heterogenous subtype of breast cancer that is largely associated with high recurrence rate and metastasis. While the clinical outcomes of treatment are discussed, the use of precision medicine to target TNBC patients is a work in progress. TNBC developmental therapy depends on biomarker-based and precise clinical trials. IMpassion 130 could not ascertain that these findings would extend to other chemoimmunotherapy combinations, but supported the addition of checkpoint inhibitors to standard chemotherapy in first line care of TNBC. IMpassion 131 enrolled patients through immune cell expression ≥1%, VENTANA PD-L1 (SP142) assay. KN355 classified participants based on prior treatments and chemotherapy status.

Conclusions

In the era of precision medicine, ICIs are largely being used in novel clinical trials for TNBC. Only one of the three trials tested patients with the immunohistochemical assay and reported immune expression. Prospective studies are required to further optimize care for TNBC and find the best available treatment response biomarkers and modalities in guiding breast cancer decision-making. It is also imperative to identify the subgroup of patients who would derive the greatest benefit with ICI and precision-medicine guided therapy.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Ovarian cancer (OC) is an aggressive tumour that is usually diagnosed in an advanced stage. The presence of somatic and/or germinal mutations in the genes BRCA1 and BRCA2 is known to be predictive of response to platinum agents and inhibitors of PARP (iPARP). Nevertheless, in recent years it has been shown that the efficacy can vary according to the specific mutation. In our community there is a high prevalence of patients (pts) carrying the BRCA1 c.211 A>G germline pathogenic variant, which is a founder mutation originated in the northwest of Spain. The aim of our study was to evaluate if these pts presented different outcomes when treated with first line platinum agents.

Methods

We performed a single-centre retrospective analysis of pts carrying somatic and/or germline pathogenic variants of BRCA1 and BRCA2 treated with platinum agents and iPARP between January 2014 and December 2021. Variants were detected with validated methods in tissue and/or blood samples. Data was extracted from electronic health records and analysed with SPSS software.

Results

We found 38 pts with the aforementioned characteristics. Median age upon diagnosis was 56.4 (range 40 – 82) years. The initial FIGO stage was IIIC in 57.9% and IV in 34.2% of the cases. The majority of pts had an ECOG PS of 1 (57.9%) or 0 (34.2%). 25 pts (65.8%) had a BRCA1 variant, and of those 12 pts carried the BRCA1 c.211 A>G variant. These pts presented a worse objective response rate (ORR) to first line platinum-based chemotherapy when compared to all the pts (58.3% vs 88.5%, p = 0.03) and to BRCA1 mutated pts (58.3% vs 84.6%, p = 0.14). Median progression free survival (PFS) to first line treatment was not significantly different among BRCA1 c.211 A>G variant carriers and the rest of the pts (27 vs 21 months, p = 0.44), and neither was overall survival (OS) (72 vs 91 m, p = 0.27).

Conclusions

We found that pts with BRCA1 c.211 A>G germline pathogenic variant treated in our centre had a worse response rate to platinum-based chemotherapy even thought PFS and OS were not significantly different. Further research should be carried out to test if this mutation conveys less sensitivity to DNA damaging agents.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Ovarian cancer (OC) is one of the most lethal malignancies in females. A biomarker with high sensitivity and specificity has yet not been discovered which can aid in early diagnosis. Mucin proteins (MUC) proteins have been considered promising diagnostic biomarkers in cancer. We analyzed MUC1 and MUC4 for their diagnostic role in OC.

Methods

We analyzed 31 cases of OC and 8 benign ovarian cysts. A pre-therapy whole blood sample was taken and serum levels of MUC1, MUC4 & MUC 16 (CA 125) were evaluated. Cut-off for MUC1 and MUC4 was set using ROC curve analysis at the highest sensitivity and specificity, 141.3ng/mL and 1.206ng/mL respectively. The values were compared with CA125 (established cutoff of 35 U/ml).

Results

Serum level of MUC1 was higher in 33/39 (84.6%) cases (28/31 in malignant cases, 3/8 in benign cases). However, the serum level of MUC4 was lower in 33/39 cases (26/31 in malignant cases, 5/8 in benign cases). CA125 was higher in 33/39 cases (28/31 in malignant cases, 4/8 in benign cases; table). When compared with histological variants of epithelial ovarian cancer, high levels of MUC1 were seen in HGSC, mucinous, endometrioid, and clear cell 16, 4, 3 & 2 respectively (p-value 0.567). For MUC4, a lower value serum level of MUC4 was associated with a diagnostic indicator of ovarian cancer (p= 0.9709). Higher serum level of CA125 was associated with OC (p=0.0025), Type 2 tumor (p= 0.0013), advanced stage (p= 0.0087) and presence of omental metastasis (p= 0.0311). The sensitivity and specificity of CA125 in our study were 90.32% and 62.5% respectively. The sensitivity and specificity of MUC1 in our study were 90.32% and 50% respectively. The sensitivity and specificity of MUC4 in our study were 83.87% and 37.5% respectively.

Table: 26P

Serum values in all cases including borderline and benign

Conclusions

The serum level of Mucin 1 was increased in ovarian cancer, while that of MUC4 was decreased in OC. A combined panel of mucin 1, MUC4, and ca125 can aid in a better diagnosis of OC.

Legal entity responsible for the study

AIIMS, New Delhi.

Funding

AIIMS, New Delhi.

Disclosure

All authors have declared no conflicts of interest.

Background

After the introduction of the molecular classification in EC guidelines, Next Generation Sequencing (NGS) analysis has become an essential tool for EC management. Molecular-driven therapies have also been recently tested, and some have obtained FDA approval. This retrospective cohort study aims to determine the clinical benefit rate (CBR) with the use of targeted therapies based on NGS in ECs patients.

Methods

After approval of the local Ethics Committee, a retrospective study was conducted on EC patients undergoing Foundation Medicine® testing at Fondazione Policlinico Universitario Agostino Gemelli IRCCS. All patients provided written informed consent. Formalin-fixed, paraffin-embedded (FFPE) tumor tissue specimens were analyzed by Foundation One® CDx, which detects 324 genes known to be drivers of solid tumors based on NGS assay. Efficacy outcomes were estimated by the Kaplan-Meier method and expressed as median with its 95% confidence interval. IBM-SPSS v.27.0 software was used for statistical analyses.

Results

Out of 35 tests performed, 11 patients received a targeted therapy based on actionable mutations detected with the NGS assays. All the 11 patients had been heavily pretreated (≥3 prior lines). One patient died because of COVID-19 and thus was excluded from the analysis. Out of the 10 patients included, targeted therapies showed an overall CBR of 80% in 8 patients (10% CR, 33.3% PR, 40% SD, and 20% PD). 7 patients were treated with a targeted agent belonging to the PI3K pathway, with 3 PR (42.9%), 3 SD (42.9%), and 1 PD (14.2%). 3 patients received PARP inhibitor treatment according to their HRD status, with 1 CR (33.3%), 1 SD (33.3%), and 1 PD (33.3%).

Conclusions

In our series, an outstanding CBR of 80% was achieved with the use of targeted therapy according to NGS assays in heavily pretreated patients (≥3 prior lines). Our finding underlines the importance of molecular-driven treatments and requires further investigation to confirm these results in terms of clinical benefit in a broader population. Besides, the use of molecular-driven treatments may avoid unnecessary exposure to potentially more toxic therapies and reduce the costs associated with inappropriate treatments.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

V. Salutari: Financial Interests, Personal and Institutional, Advisory Board: AstraZeneca, Clovis, GSK, Tesaro, MSD, Roche, PharmaMar, Eisai. G. Scambia: Financial Interests, Personal, Invited Speaker, Speaker: Johnson & Johnson, AstraZeneca & MSD, Olympus Europa, Baxter Healthcare, Intuitive Surgical Inc., GlaxoSmithKline; Financial Interests, Personal, Expert Testimony, Trainer: Covidien AG (Medtronic company); Financial Interests, Institutional, Invited Speaker, ‘IsoMSLN’ in Ovarian Cancer and Malignant Pleural Mesothelioma: Kiromic; Financial Interests, Institutional, Invited Speaker, Roll-over study for patients who have completed a previous cancer study with olaparib and who the investigator believes can benefit from continued treatment - ROSY-O: AstraZeneca; Financial Interests, Institutional, Invited Speaker, CATCH-R: Roll-over study to provide continuous access to clinical therapy with rucaparib: Clovis Oncology; Financial Interests, Institutional, Invited Speaker, Phase III, multicenter, placebo-controlled clinical study comparing chemo-immunotherapy (paclitaxel-carboplatin-oregovomab) versus chemotherapy (paclitaxel-carboplatin-placebo) in patients with advanced epithelial ovarian, tubal cancer of fallopian or peritoneal (FLORA-5): Oncoquest Pharmaceuticals Inc.; Financial Interests, Institutional, Invited Speaker, Phase IIb randomized, open-label, active comparator, parallel-group, multicenter study designed to evaluate the efficacy and safety of three different doses of the P2X3 receptor antagonist (BAY 1817080) versus placebo and Elagolix 150 mg in women with symptomatic endometriosis: Bayer AG; Financial Interests, Institutional, Invited Speaker, Usability of ITE transducers for sending electric fields for tumor treatment (TTFields): Novocure Ltd.; Financial Interests, Institutional, Invited Speaker, Phase III, multicentre, open-label extension trial to evaluate long-term safety and efficacy in patients with advanced cancers currently undergoing treatment or in follow-up in a pembrolizumab trial: Merck. D. Lorusso: Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speaker: GSK, Clovis Oncology, PharmaMar; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards and Invited Speakers: AstraZeneca, MSD; Financial Interests, Personal, Other, Consultancy: PharmaMar, Amgen, AstraZeneca, Clovis Oncology, GSK, MSD, Immunogen, Genmab, Seagen; Financial Interests, Personal, Advisory Board, Participation in Advisory Boards: Merck Serono; Financial Interests, Personal, Advisory Board, Invited member of advisory board: Seagen, Immunogen, Genmab, Oncoinvest, Corcept, Sutro; Financial Interests, Institutional, Funding, Grant for founding academic trial: MSD, Clovis Oncology, PharmaMar; Financial Interests, Institutional, Funding, Grant for founding academic trial: GSK; Financial Interests, Institutional, Invited Speaker, ENGOT trial with institutional support for coordination: Clovis Oncology; Financial Interests, Institutional, Invited Speaker, ENGOT trial with institutional support for coordination: Genmab, MSD; Financial Interests, Institutional, Funding, Clinical trial/contracted research: AstraZeneca, Clovis Oncology, GSK, MSD, Seagen; Financial Interests, Institutional, Funding, Clinical trials/contracted research: Genmab, Immunogen, Incyte, Novartis, Roche; Non-Financial Interests, Personal, Principal Investigator, PI of several trials, no compensation received: GSK; Non-Financial Interests, Personal, Principal Investigator, PI of several trials. No personal compensation received: AstraZeneca, Genmab; Non-Financial Interests, Personal, Principal Investigator, PI in several trials. No personal compensation received: MSD; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trial. No personal compensation received: Immunogen, Clovis, Incyte; Non-Financial Interests, Personal, Principal Investigator, PI of clinical trial. No personal compensation receive: Roche; Non-Financial Interests, Personal, Member, Board of Directors: GCIG. All other authors have declared no conflicts of interest.

Background

Recurrent medulloblastoma is a deleterious disease with a 5-year survival of less than 5% and no recognized standard treatment. In recent years, we have learned about the molecular characterization of the different types of medulloblastoma with four subgroups also appearing different subgroups, each with its oncogenic pathway activation. SHH activation is the hallmark of medulloblastoma group 2 and several molecules have been developed to block this signaling mechanism, including SMO inhibitors, that are approved for the treatment of basal cell carcinoma. The information that is known about SMO inhibitors in medulloblastoma comes from relapsed medulloblastoma trials without prior molecular selection of patients, so their actual efficacy might still be unknown.

Methods

We present a 19-year-old patient with a leptomeningeal relapse of group 2 delta medulloblastoma. Based in some sporadic response of selected patients in phase II trials, sonidegib 800 mg daily was initiated as compassionate use in a third line of treatment.

Results

After 2 months of treatment, MRI evaluation shows an almost complete response in intracranial disease and stabilization of spinal disease. In addition, the treatment was well tolerated.

Conclusions

Further molecular characterization of medulloblastoma could lead to better results in recurrent medulloblastoma, a disease for which there is currently no proven effective treatment.

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 of molecular tumor board (MTB) is to identify potential therapeutic strategies, based on genetic analysis, for patients (pts) not responding to standard therapies. All tumor types are eligible for MTB discussion and sarcomas are one of common target due to low number of standard and innovative treatments. Here we analyze the role of MTB in a sarcoma referral center.

Methods

We presented data from MTB including pts affected by soft tissue (STS) and bone sarcoma (BS) followed at Regina Elena National Cancer Institute in Rome and discussed from Dec 2019 to May 2022.

Results

We discussed 19 pts affected by STS (14 pts) and BS (5 pts). FoundationOne was performed in 74%, Archer FusionPlex Sarcoma Panel in 37%, DNA Focus Assay in 26%, Whole exome sequencing in 26%, Oncomine Comprehensive Assay Plus in 16%, Promega MSI PCR Testing Kit in 16% and immunohistochemistry for PD-L1 in 16% of pts. Techniques were chosen depending on the type of kit available, the cost, the alterations searched and the time to obtain results. Druggable targets were found in 11 pts: mTOR mutation (m), HGF amplification (amp), ATM splice site m, MET amp, KRAS m, CDK4 amp, MYC amp, PTCH1 m, PIK3CA m, MDM4 amp and PD-L1 overexpression. Three patients (16%) received precision therapy: Imatinib and everolimus for mTOR m in cordoma, Cabozantinib for HGF amp in osteosarcoma and Pembrolizumab in angiosarcoma with PD-L 1 >10%. Eight pts continued standard therapy due to maintenance of response (5 pts) or to absence of literature supporting target treatment (3 pts). Molecular analysis allowed reformulation of diagnosis for one patient due to the presence of EWSR1-CREB3L2 fusion, typical of low-grade fibromyxoid sarcoma, that led to a histology-based treatment choice. Four patients were addressed to best supportive care (21%) while 2 pts (10,5 %) died.

Conclusions

MTB could be an effective tool for decision-making in sarcoma, but the lack of literature data and drug access hinder treatment choice. Enrollment in clinical trials could lead to overcome the problem. Moreover, the timing for requesting molecular analyses, at diagnosis or at the end of standard therapies, needs to be defined, considering both the tumor heterogeneity and the delay in obtaining results and starting treatment.

Legal entity responsible for the study

Regina Elena National Cancer Institute.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Generally tissue samples from histopathology or open biopsy are used for cytogenetic analysis and only few studies have used tissue samples from Fine Needle aspiration for chromosomal analysis. To start neoadjuvant chemotherapy in bone sarcoma patients, we need final diagnosis. Open biopsy has its own disadvantages. FNAC and cytological examination can give valuable information about the tumor. Apart from immunocytochemistry and electron microscopic examination of aspirated tissue, chromosomal analysis has also become a tool in diagnosing bone sarcoma.

Methods

During the period of six years in our hospital from 2016 to 2022, we cytogenetically analyzed FNACs from 11 primary bone sarcomas (4 osteosarcomas and 7 Ewing sarcomas). Out of them one of the osteosarcomas showed abnormal, complex karyotypes seen in most highly-malignant osteosarcomas and Four Ewing's sarcoma aspirates displayed abnormal karyotypes; two of these had the characteristic 11;22 translocation, and in one of these cases molecular genetic analysis revealed the hybrid EWS/FLI1 transcript.

Results

Chromosomal analysis of FNACs from suspected osteosarcoma didn’t provide much information, few cases showed high-grade malignancy. But in Ewing's sarcomas, these were of great value in making the diagnosis. 11;22 translocation finding on chromosomal analysis was diagnostic and strongly supported the cytologic diagnosis in six cases of Ewing's sarcoma. Tissues obtained by FNAC was sufficient for cytologic, cytogenetic, and molecular genetic analysis in two tumors. Molecular genetic analysis in one tumor showed the classical EWS/FLI1 transcript in Ewing's sarcoma.

Conclusions

FNAC and cytological examination is of limited value in patients with osteosarcoma and cannot make precise diagnosis but they can give reliable information and support the diagnosis in cases of Ewing's Sarcomas and help in starting multimodality treatment for bone sarcoma patients at the earliest.

Clinical trial identification

CMCH1622.

Legal entity responsible for the study

CMCH.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Whilst liquid biopsies have emerged as a non-invasive and cost-effective alternative to tissue biopsies and are increasingly used in clinical practice, there is still uncertainty on how findings should be interpreted by treating oncologists. Here, we used liquid biopsies to characterise patients with advanced cancer and provide clinical interpretation and recommendations via the Genomic Tumour Advisory Board (GTAB) of the NHS South East Genomic Laboratory Hub.

Methods

Twenty seven patients with metastatic or unresectable disease were offered circulating tumour DNA (ctDNA) assay testing between November 2021 to January 2022 at St George’s University Hospital in London, UK. Written consent was obtained for all patients. ctDNA was isolated from peripheral blood using the FoundationOne® Liquid CDx assay that reports genomic alterations in 324 genes, microsatellite instability and blood tumour mutational burden. Assays were provided by Roche through a Familiarisation Programme. Results were reviewed by the GTAB to identify patients potentially eligible for NHS-approved clinical trials based on a genomic biomarker as well as those requiring referral to Cancer Genetics.

Results

Median age of patients was 54 years (29-85) and 63% were males. Tumour type varied and included cancers of the colorectum (40%), lung (15%), breast (15%), kidney (15%), penis (7%) and ovary (4%). Approximately 85% of the patients were previously treated with 33% having received more than two lines of treatment. ctDNA was not isolated in two patients (7%) likely due to low tumour burden. There was 100% concordance between standard molecular tissue testing and ctDNA results. Thirteen patients (48%) were eligible for at least one clinical trial based on a genomic biomarker. Three patients (11%) were referred to Cancer Genetics due to a potential germline mutation or young age and family history.

Conclusions

We found that 48% of heavily pre-treated cancer patients were eligible for a clinical trial based on a genomic biomarker. Our results support the benefits of molecular profiling for allocating patients to clinical trials, and importantly, highlight the need to support oncologists with clinical interpretation and recommendations of findings through a GTAB for subsequent patient management.

Legal entity responsible for the study

The authors.

Funding

Roche.

Disclosure

All authors have declared no conflicts of interest.