Background

While the primary genetic alteration of Ewing Sarcoma (ES) is fusion of EWSR1 and ETS family transcription factors, genomic profiling studies have uncovered recurrent secondary alterations in STAG2, TP53, and ERF, usually associated with a more aggressive phenotype. Mutations in EZH2, have also been sporadically reported in ES. Here, we systematically evaluated the frequency of EZH2 mutations, their relationship to other secondary alterations, and examined their role in ES biology.

Methods

Patients with ES harboring activating EZH2 mutations were identified from a cohort of MSKCC patients prospectively tested with the MSK-IMPACT large panel NGS assay and a cohort of ES patients from MSCNRIO in Warsaw tested with the Oncomine Comprehensive assay. The functional effects of EZH2 mutations were assessed in engineered isogenic ES cell lines (TC71, CHP100) expressing EZH2^wt, EZH2^Y646F or EZH2^A692V. We assessed proliferation, migration/invasion, and histone methylation, and performed transcriptome and epigenetic profiling.

Results

Among 222 cases, we identified 8 patients (3.6%) with 9 EZH2 mutations, of which 8 were located in the enzymatic SET domain (Y646F/H/N, A692G, A692V) and one in the CXC domain (K515R). Over a median follow-up of 55 months, 5 patients developed distant metastases, four of whom died of disease. EZH2 mutant samples showed strong and diffuse H3K27me3 nuclear expression. TC71 and CHP100 cells with EZH2^Y646F or EZH2^A692V had enhanced H3K27 trimethylation by Western blot and epigenetic profiling. No difference in growth were observed between EZH2 mutant and wild-type cells in vitro. RNA sequencing of cell lines with EZH2^Y646F revealed a highly repressive transcriptional landscape with significant downregulation of 623 genes and increased expression of 257 genes compared to EZH2^wt cells. Cancer testis antigens (CTAs) MAGE-C1, MAGE-C2, MAGE-C3 and TEX-19 were among the most upregulated genes.

Conclusions

Recurrent activating EZH2 mutations lead to broad transcriptional changes that may define a distinct clinical and biological subset of ES. While this aggressive subset is small, it is of particular therapeutic interest given the availability of EZH2 inhibitors and because overexpressed CTAs may also make it a candidate for immunotherapy.

Legal entity responsible for the study

The authors.

Funding

Pawel Sobczuk has received funding from the Polish National Agency for Academic Exchange and the Kosciuszko Foundation.

Disclosure

P. Sobczuk: Financial Interests, Personal, Other, Travel grant: Novartis; Financial Interests, Personal, Other, Travel Grant: MSD, Pierre Fabre, BMS; Financial Interests, Personal, Invited Speaker: Swixx BioPharma, BMS, Gilead; Financial Interests, Personal, Stocks/Shares: CelonPharma; Non-Financial Interests, Personal, Leadership Role, Board Member, Chair of Young Oncologists Section: Polish Society of Clinical Oncology. P. Rutkowski: Financial Interests, Personal, Invited Speaker, honoraria for lectures: MSD, BMS, Pierre Fabre; Financial Interests, Personal, Advisory Board: MSD, BMS, Pierre Fabre, Merck, Sanofi, Blueprint Medicines, Philogen; Financial Interests, Personal, Invited Speaker: Merck, Sanofi, Novartis; Financial Interests, Institutional, Research Grant, research grant for ISS: Pfizer; Financial Interests, Institutional, Funding, research grant for institution: BMS; Non-Financial Interests, Personal, Invited Speaker: Polish Society of Surgical Oncology; Non-Financial Interests, Personal, Officer: ASCO; Non-Financial Interests, Personal, Invited Speaker, President Elect: Polish Oncological Society. All other authors have declared no conflicts of interest.

Background

Pleomorphic liposarcoma (P-LPS), a rare high-grade subtype of sarcomas, is the less common among liposarcomas. Management of P-LPS is based on guidelines for other types of sarcomas. There is an unmet need for specific data on P-LPS from experienced centers due to their unique features. This paper aims to evaluate the clinical characteristics and treatment outcomes of P-LPS patients with emphasis on survival data and response to systemic therapy.

Methods

This is a retrospective analysis of all P-LPS pts at Gustave Roussy from March 1988 to July 2022. Clinical and demographic data, as well as survival outcomes, were retrieved from electronic records. Additional data on response to systemic therapy were also gathered.

Results

76 P-LPS patients (pts) were included. There were 41 women (53.9%) and the mean age was 57 years (16-85). 59 pts had localized disease (77.6%) at diagnosis and the majority (97.2%) had grade 2 or 3 tumors. The most common primary site was in the lower limbs (41.5%) followed by the upper limbs and the trunk (20.8% and 19.5%, respectively). The median local-RFS (relapse-free survival) at 1 and 5 years were 81.1% and 50.1% while the metastatic RFS was 85.4% and 64.8%, respectively. On multivariate analysis (MA), age and gender were found to be prognostic factors for local recurrence while only tumor grade was for distant relapse. Overall survival in the whole population at 1 and 5 years was 95.6% and 74.9%, respectively. Adjuvant chemotherapy (21 out of 71 pts) was a negative prognostic biomarker for OS on MA. Among 25 pts with advanced disease, response rates were higher with eribulin (in 4 pts, ORR=25% and DCR=75%) and trabectedin (in 7 pts; ORR=57% and DCR=86%) in the first or later lines of therapy, in comparison to conventional chemotherapy (doxorubicin-based; in 17 pts, ORR=5.9% and DCR=47%). In the first-line setting, the ORR reached 13.6% versus 8.3% in the second-line setting.

Conclusions

P-LPS is a rare and aggressive entity with a high risk of local and distant recurrence. In the advanced setting, Eribulin and trabectedin showed significant activity in comparison to conventional therapy. Larger multicentric data collection with better identification of molecular characteristics is needed to optimize the management of this entity.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

All authors have declared no conflicts of interest.

Background

Alveolar soft part sarcoma (ASPS) is a rare disease that occurs most frequently in young adult patients (pts). In December 2022, the FDA approved atezolizumab (Atezo) for pediatric and adult patients with metastatic ASPS based on the results of this phase II trial of single-agent Atezo. For study patients who progressed on single-agent Atezo, an anti-VEGF agent, bevacizumab (Bev) was added to potentiate checkpoint inhibitor activity. We are reporting the activity of the combination of Atezo and Bev (Genentech), in pts with advanced ASPS after progression on Atezo.

Methods

Open label, phase II crossover trial; Atezo is administered intravenously at a fixed dose of 1200 mg and Bev at 15mg/kg once every 21 days in adults only. Pts with recent history of hemoptysis are not eligible. The primary objective for this portion of the study is to determine the objective response rate of Atezo plus Bev upon progression with Atezo using RECIST v 1.1. Secondary objectives include duration of response (DOR) and comparison of RECIST v 1.1 vs iRECIST. Biopsies for pharmacodynamic assessment are performed at baseline, prior to cycle 3 day 1, or at any point where there is evidence of clinical response.

Results

Eight pts have crossed over from single agent Atezo as of 1/3/2023. The average age in this group is 24.5 years (17–29). There are 4 female, 2 white, 3 black, 1 Asian, 2 unknown and 1 Hispanic/Latino pts. All 8 pts have the best response of stable disease. Median time on Atezo and Bev is 10.9 months (range, 4.3–19.1) compared to 9.7 months (range, 3.4–40.2) on single-agent Atezo. Six pts are still on treatment; 2 others had progressed post Cycles 5 and 8. Median PFS has not been reached. Grade 3 drug-related adverse events included hypertension (n=1), and lipase increase (n=1). Grade 1/2 seen > 1 pt include hypothyroidism, proteinuria, anemia, nausea, amylase increase, hyponatremia, hypokalemia and headache. No grade 4 or 5 events have been reported.

Conclusions

The combination of Atezo and Bev is well tolerated with no unexpected toxicities. These results are encouraging, and trial is ongoing.

Clinical trial identification

NCT03141684.

Legal entity responsible for the study

Alice Chen, M.D., Experimental Therapeutics Clinical Trials Network, Cancer Therapy Evaluation Program, Division of Cancer Treatment and Diagnosis, National Cancer Institute.

Funding

NIH Contract # 75N91019D00024; Genentech, member of the Roche group, supplied drug and funding.

Disclosure

B.A. Van Tine: Financial Interests, Personal, Invited Speaker, Educational Speaker: Targeted Oncology; Financial Interests, Personal, Advisory Board, Also, Travel paid to conference to present abstract: Adaptimmune Limited; Financial Interests, Personal, Other, Consulting. Also attended and Ad Board meeting. Travel was paid to attend an Ad board meeting: Epizyme; Financial Interests, Personal, Other, Consulting- ADRx working on a cancer project and they are requesting my expertise: ADRx; Financial Interests, Personal, Advisory Board, Tenosynovial Giant Cell Tumors (TGCT): Ayala Pharmaceuticals; Financial Interests, Personal, Other, Consulting and Ad Board: Bayer; Financial Interests, Personal, Other, OncLive Virtual Workshop: Intellisphere Llc; Financial Interests, Personal, Advisory Board, Attended Advisory Board Meeting: Apexigen Inc.; Financial Interests, Personal, Advisory Board, Attended an Advisory Board Meeting: Daiichi Sankyo; Financial Interests, Personal, Advisory Board: PTC Therapeutics, Boehringer Ingelheim, Agenus, Regeneron Pharmaceuticals; Financial Interests, Personal, Other, Consulting: Advenchen; Financial Interests, Personal, Invited Speaker, Sigma-2 Receptor Ligands and Therapeutic uses therefor (006766), Modular Platform for Targeted Therapeutic Delivery (006755), Sigma-2 Receptor Ligand Drug Conjugates as Antitumor Compounds, Methods of synthesis and Uses Thereof (014229): Accuronix Therapeutics; Financial Interests, Institutional, Research Grant: Pfizer, Merck, Tracon Pharm, GSK; Non-Financial Interests, Personal, Invited Speaker, Non-paid: Polaris. All other authors have declared no conflicts of interest.

Background

Cancers affecting <6/100,000/year are classified as rare, but they account for almost 25% of all cancers. They have worse 5-year survival than more common cancers and limited treatment options. Early-phase clinical trials (EPCT) have evolved with novel designs and the increasing use of precision medicine and molecular profiling. Therefore, EPCTs may represent a potential treatment option for patients with rare cancers.

Methods

We conducted a retrospective study of patients with a rare cancer referred to a large EPCT team at a UK specialist centre over a 5-year period (2016-2020). Data collection included patient demographics, medical and oncological history, genomic variants, EPCT participation and associated response and survival outcomes.

Results

We included 240 patients with a rare cancer. The mean age at diagnosis was 51.7 years (range 16-84), 54.2% of the patients were female. The most frequent rare cancer originated from the digestive system (27.1%), female genital tract (20%) and head and neck (H+N) (18.3%). At the time of referral, 86.2% of the patients had at least one site of distant metastasis while 190 patients (79.2%) had received at least one line of systemic anticancer treatment. Molecular profiling was offered to 45.5% of the population, median number of gene alterations was 3 per patient (range 1-20) and genes most commonly mutated were TP53 (43.4%), PIK3CA (24.1%), and KRAS (15.7%). 51 patients participated in EPCTs, with 39.2% achieving SD and 11.8% PR. Median OS in the trial patients was 44 months (95% CI 30.1 – 57.90) and 32 months (95% CI 27.63 – 36.37) for patients whom did not participate in an EPCT (p = 0.009, HR 0.62). Patients with sarcomas had the longest median OS (46 months), followed by patients with H+N cancers (39 months) and NETs (35 months). Good Royal Marsden Hospital (RMH) prognostic score (0-1) was correlated with favourable survival when controlling for age and gender (HR 0.67, 95% CI 0.46 – 0.96, p = 0.03).

Conclusions

Participation of rare cancer patients in EPCTs may be associated with a survival benefit and potentially lead to the development of new treatments for these patients. Moreover, expanded use of precision medicine is paramount as it can offer crucial information for treatment selection in this heterogenous group.

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

N. Cook: Financial Interests, Institutional, Invited Speaker: Roche, Taiho, AstraZeneca, RedX, Orion, Avacta, Bayer, Eisai, UCB, Starpharma, Boehringer Ingelheim, Stemline, Ergomed; Non-Financial Interests, Personal, Advisory Role: Roche. D.M. Graham: Financial Interests, Personal, Advisory Board, Consulting role on advisory board: Clinigen; Financial Interests, Personal, Invited Speaker: Cancer Drug Development Fund; Financial Interests, Personal, Advisory Board: McCann Health; Financial Interests, Institutional, Invited Speaker, Institutional funding from study: MSD, Codiak Biosciences, Starpharma, Faron Pharmaceuticals, Synthon, Janssen; Financial Interests, Institutional, Other, Sub-I: Institutional funding from study: AstraZeneca, Roche, BerGenBio, GlaxoSmithKline, Bayer, Bicycle Pharmaceuticals, Carrick, Taiho Pharmaceuticals, CytomX Therapeutics, RedX Pharma PLC, Eisai Inc., Octimet, Orion Pharma, Kinex Pharmaceuticals, Boehringer Ingelheim, BMS, Turning Point Therapeutics, Immutep, Agalimmune, Kymab, Blueprint, Astellas, Cellcentric, UCB Biopharma USL, Eli Lilly, Seagen, Repare Therapeutics, Timepoint Therapeutics, Astex, Stemline, Crescendo Biologics Ltd., ADC Therapeutics, Genentech, Avacta Life Sciences Ltd., Nurix Therapeutics Inc.; Financial Interests, Institutional, Other, Sub-I: Institutional finding from study: Chugai Pharmaceuticals; Financial Interests, Institutional, Invited Speaker: Incyte. M.G. Krebs: Financial Interests, Personal, Advisory Board: Bayer, Roche, Janssen, Guardant Health; Financial Interests, Personal, Invited Speaker: Roche, Janssen; Financial Interests, Institutional, Expert Testimony: AstraZeneca; Financial Interests, Institutional, Advisory Board: Seattle Genetics; Financial Interests, Institutional, Invited Speaker: AstraZeneca, Blueprint, Astex, Bayer, BerGenBio, Carrick, Immutep, Janssen, Novartis, Nurix, Nuvalent, Pyramid Biosciences, Roche, Seattle Genetics, Turning Point Therapeutics; Financial Interests, Institutional, Research Grant: Roche, Novartis; Other, Personal, Other, Travel expenses for congress: Immutep, Janssen. F. Thistlethwaite: Financial Interests, Personal, Advisory Board: BMS; Financial Interests, Personal, Advisory Board: GSK; Financial Interests, Personal, Advisory Board, Adboard/consultancy: T-Knife Therapeutics; Financial Interests, Personal, Advisory Board: Adicet, Janssen, EnaraBio, Immatics, Ixaka, Scenic Biotech, F-Star, Leucid; Financial Interests, Institutional, Advisory Board: Pfizer; Financial Interests, Personal, Invited Speaker: Kite Gilead; Financial Interests, Personal, Other, Occasional individual consulting: Guidepoint; Financial Interests, Institutional, Other, iMATCH is a 12 partner consortium funded by not for profit Innovate UK (UK government body) partners include commercial, clinical and academic institutes. I am director and my salary (0.1WTE) is supported through this work as a grant to my institution (The Christie NHS foundation trust - not for profit NHS hospital) from IUK: iMATCH director; Financial Interests, Institutional, Officer, Clinical lead for this 10 partner consortium of clinical academic and commercial partners. My salary is partly supported (approx. 0.05WTE) through this by a grant paid by Innovate UK (a NFP government body) to my institution (The Christie NHS foundation trust a NFP UK hospital): SAMPLE; Financial Interests, Institutional, Invited Speaker, NCT02890069: Novartis; Financial Interests, Institutional, Research Grant, Sarcoma pathways project: GSK; Financial Interests, Institutional, Invited Speaker, NCT02493751: Pfizer; Financial Interests, Institutional, Invited Speaker, NCT03245736, NCT02988817, NCT02552121, NCT02001623: GenMab; Financial Interests, Institutional, Invited Speaker, NCT02277717: Synthon; Financial Interests, Institutional, Invited Speaker, NCT03013491: CytomX; Financial Interests, Institutional, Invited Speaker, NCT03314935: Incyte; Financial Interests, Institutional, Invited Speaker, NCT02908906: Janssen; Financial Interests, Institutional, Invited Speaker, NCT03132792, NCT04044768: Adaptimmune; Financial Interests, Institutional, Invited Speaker, NCT03400332: BMS; Financial Interests, Institutional, Invited Speaker, NCT04262466, NCT03973333, NCT03515551: Immunocore; Financial Interests, Institutional, Invited Speaker, EudraCT Number: 2018-001005-85, 2018-003446-16: Achilles Ltd.; Financial Interests, Institutional, Invited Speaker: Agalimmune Ltd.; Financial Interests, Institutional, Invited Speaker, NCT02834247: Millenium Pharmaceuticals/Takeda; Financial Interests, Institutional, Invited Speaker, NCT02690350: Daiichi Sankyo; Financial Interests, Institutional, Invited Speaker, NCT04839991: Crescendo; Financial Interests, Institutional, Invited Speaker, NCT05104515: Oxford Vacmedix Ltd.; Financial Interests, Institutional, Invited Speaker, NCT05278975: RS Oncology LLC; Financial Interests, Institutional, Invited Speaker, NCT03697824, NCT03391778: GSK; Financial Interests, Institutional, Invited Speaker, NCT04140500, NCT04857138, NCT04826003: Roche; Financial Interests, Institutional, Invited Speaker, NCT04272203: AbbVie; Financial Interests, Personal, Invited Speaker, NCT05008913, NCT04949425, NCT0331509, NCT03313557: AstraZeneca; Financial Interests, Institutional, Invited Speaker, NCT03829501: Kymab Ltd./Sanofi; Financial Interests, Institutional, Invited Speaker, EudraCT ID No: 2019-003329-11: Chugai; Financial Interests, Institutional, Invited Speaker, NCT05430555: T-Knife Therapeutics; Financial Interests, Institutional, Invited Speaker, NCT03621982: ADCT Therapeutics; Financial Interests, Institutional, Research Grant, IRAS Project ID: 227414: Novartis; Non-Financial Interests, Personal, Other, Panel member for a funding committee (MRC is a UK government NFP organisation): MRC DPFS panel member; Non-Financial Interests, Personal, Advisory Role, Sarcoma UK is a not-for-profit charity. I act as an advisor on their Research Strategy Committee. This role is not compensated: Sarcoma UK; Non-Financial Interests, Personal, Leadership Role, Funding is from not-for-profit government bodies. Role is not compensated: Chair of the Independent Steering Committee for NIHR Blood & Transplant Research Unit, Oxford; Non-Financial Interests, Personal, Advisory Role, Funding panel member for CRUK (not-for profit charity). Role is not compensated: CRUK New Agents Committee Member; Non-Financial Interests, Personal, Leadership Role, Chair of Cell therapy subgroup. MRC is a not-for-profit organisation. Role is not compensated: MRC Advanced Therapies Task Group. L. Carter: Financial Interests, Personal, Other, Consultancy: Bicycle Therapeutics, Boehringer Ingelheim, Athenex; Financial Interests, Personal, Full or part-time Employment, Medical Advisor: Cancer research UK Centre for Drug Development; Financial Interests, Institutional, Invited Speaker: Boehringer Ingelheim, Bicycle Therapeutics, Cellcentric, Eli Lilly, Athenex, Lupin Limited, Repare Therapeutics, Cytomx therapeutics, EMD Serono/Merck KGaA, Sierra Oncology. All other 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.

Background

Adrenocortical carcinoma (ACC) is a rare cancer that can arise sporadically or in the context of hereditary syndromes. Germline variants (GVs) of cancer-associated genes are traditionally associated with cancer risk but they also show potential as prognostic factors. Data on GVs in patients (pts) with sporadic ACC are limited.

Methods

Germline DNA was extracted from 150 adult European-non Finnish pts with sporadic ACC. For NGS analysis we used a custom panel of 17 genes involved in the pathogenesis of ACC: AIP, APC, ARMC5, ARNT, BRCA1, BRCA2, CTNNB1, IGF2, MEN1, MSH2, MSH6, PDE8B, PDE11A, PRKACA, PRKACB, PRKAR1A, and TP53. All variants were studied using effect predictor tools and classified according to the ACMG criteria. GVs interpreted as pathogenic (P) or likely pathogenic (LP) were considered positive. Clinico-pathological and genomic data were analyzed in different Cox models to study prognostic impact of covariates for disease-free survival (DFS), progression-free survival (PFS) and overall survival (OS).

Results

Overall, we identified 21 unique GVs in 24/150 (16%) pts. GVs were found in 9 genes including: APC (n=3), ARMC5 (n=3), MSH2 (n=3), PDE11A (n=3), TP53 (n=3), MSH6 (n=2), PDE8B (n=2), AIP (n=1) and CTNNB1 (n=1). Eight P/LP GVs and 3 GVs with deleterious potential were found in 14/150 (9.3%) of pts. Some variants were particularly enriched, with a frequency of 0.02% compared to an overall frequency of 0.001-0.004% in the gnomAD database. Of note, we found a new GV in TP53 (G105D) and 3 GVs in ARMC5 (P731R) for the first time in ACC pts. Clinico-pathological features did not differ significantly in pts carrying or not P/LP GVs but pts with ARMC5 GVs had large cortisol-secreting tumors. P/LP GVs were associated with a shorter OS (50 vs 142 months [mo], HR 1.81 95%CI.86-3.82, p.118) and PFS (8 vs 30 mo, HR 3.11 95%CI 1.57-6.16, p.001) but not DFS (27 vs 32 mo, HR 1.07 95%CI.52-2.22, p.845). At multivariate analysis GVs remained independent predictors of PFS and OS in metastatic pts.

Conclusions

We found a 9.3% prevalence of P/LP GVs which is comparable to the 9.9% from the TCGA. The findings of GVs in genes involved in DNA repair and that GVs can affect ACC progression and survival could open new therapeutic strategies in ACC.

Legal entity responsible for the study

Massimo Terzolo, MD.

Funding

Associazione Italiana Ricerca sul Cancro (AIRC).

Disclosure

All authors have declared no conflicts of interest.