91P - Prevalence of HR-/DDR-genes alterations across sarcoma histologies: Insights from a cBioPortal comprehensive analysis

Background

Sarcomas represent a broad spectrum of mesenchymal malignancies, displaying several targets suitable for clinical actionability, including alterations in Homologous recombination (HR) and DNA-damage response (DDR) genes. Yet, limited data is available concerning the prevalence of these latter across sarcoma histologies.

Methods

cBioPortal was queried to include sarcoma pan-histology studies. HR-/DDR-genes included BRCA1, BRCA2, ATM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2, RAD51C, RAD51D, RAD50, ATR. Only pathogenic and likely pathogenic alterations (alt) were included according to OncoKB. Data retrieval and statistical analysis were conducted using R Software 4.2.2.

Results

Among 2389 cases, 127 HR-/DDR-gene^alt were identified, with BRCA2 showing the highest frequency (32 of 127, 25.2%), followed by ATM (25 of 127, 19.7%). BRCA1/2^alt distribution significantly differed across histologies, with the highest rate found in uterine leiomyosarcoma (uLMS) (14 of 189, 7.41%), followed by LMS (7 of 206, 3.40%) (P=0.004). Conversely, no difference was observed in non-BRCA1/2 HR-/DDR-genes^alt distribution (P=0.170). BRCA2^alt accounted for most BRCA1/2^alt (84.6%, 33 of 39), with most consisting in deep deletions (deepDel) (25 of 33, 75.8%), followed by Indels (5 of 33, 15.2%) and missense point mutations (3 of 33, 9.09%) (P<.001). uLMS exhibited 42.4% of all BRCA2^alt, which were found to a higher frequency compared to LMS (P=0.04). In our sample, tumors carrying BRCA2 deepDel (n=25) exhibited higher Fraction Genome Altered (FGA) (0.391 [IQR .274-.525]) compared to non-BRCA2 deepDel (n=56, 0.295 [.127-.538]; P=.482), non-deepDel BRCA2^alt (n=8, 0.196 [.116-.338]; P=.459), other HR-/DDR-gene alterations (n=39, 0.253 [.103-.424]; P=.245) and Wild-type tumors (n=2272, 0.164 [.016-.311]); P=.0192).

Conclusions

Sarcomas display a heterogeneous distribution of HR-/DDR-alterations, warranting refined patient selection for clinical trials testing the use of PARP-i. Somatic BRCA2 deep deletions yield high genomic instability and are particularly enriched among uLMS. As such, further investigation to test the use of PARP-i in uLMS is required.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Has not received any funding.

Disclosure

M. Repetto: Financial Interests, Personal, Other, Travel expenses: Sanofi. E. Guerini Rocco: Financial Interests, Personal, Other: AstraZeneca, Exact Sciences, GSK, LCM, Genentech, Novartis, Ruche, Thermo Fisher Scientific. G. Curigliano: Financial Interests, Personal, Invited Speaker: Roche, AstraZeneca, Daiichi Sankyo, Novartis, Pfizer, Pfizer; Financial Interests, Personal, Advisory Board: Roche, AstraZeneca, Daiichi Sankyo, Lilly, Pfizer, Veracyte, BMS, Merck, Exact Sciences, Celcuity; Financial Interests, Personal, Advisory Board, Advisory Board: Menarini, Gilead; Financial Interests, Personal, Other, Advisory Board: Ellipsis; Financial Interests, Institutional, Research Grant, Investigator Initiated Trial: Merck; Financial Interests, Institutional, Funding, Phase I studies: BMS, Novartis, AstraZeneca, Daiichi Sankyo, Roche, Blueprint Medicine, Kymab, Astellas, Sanofi, Philogen; Financial Interests, Institutional, Invited Speaker, Phase I clinical basket trial: Relay Therapeutics; Non-Financial Interests, Personal, Officer, Italian National Health Council as Advisor for Ministry of Health: Consiglio Superiore di Sanità; Non-Financial Interests, Personal, Advisory Role, Member of the Scientific Council. Patient advocacy association: Europa Donna; Non-Financial Interests, Personal, Advisory Role, Cancer Research Foundation: Fondazione Beretta; Non-Financial Interests, Personal, Member of Board of Directors, No compensation for this role. This a public national company for cancer prevention: Lega Italiana Lotta ai Tumori; Non-Financial Interests, Personal, Officer, Member of the Advisory Council: EUSOMA; Non-Financial Interests, Personal, Officer, ESMO Clinical Practice Guidelines Chair: ESMO; Non-Financial Interests, Personal, Member of Board of Directors, Chair of Clinical Practice Guidelines Committee: ESMO. All other authors have declared no conflicts of interest.