Abstract 20P
Background
There is a growing utilization of comprehensive cancer genome profiling (CGP) to assess patients’ eligibility for target therapies. Potential pathogenic germline variants (PPGVs) may be identified via CGP. Large series indicate that PPGVs in cancer risk genes are found in 10-23% of patients tested by CGP and 3-7% were confirmed to be germline. The present study reports the frequency of PGVs in a cohort of gynaecologic cancers patients on a prospective CGP programme.
Methods
PPGVs were indicated for 1.069 tumor samples of ovarian (OC, n=632) and endometrial (EC, n=437) cancer patients analyzed by TruSight Oncology 500 High-Throughput (TSO500HT) solution from January 2022 to June 2023. PPGVs focused on 40 cancer risk genes as indicated by the European Society for Medical Oncology recommendations.
Results
Overall, 22.5% of patients (29.3% of OC and 12.8% of EC) had at least one PPGVs in cancer risk genes; in detail, 71 PPGVs were identified for EC and 206 for OC. Considering the association between variants and tumor type, 46.5% of PPGVs in EC and 65% in OC were referred to genes involved in well-known hereditary conditions (MLH1, MSH2, MSH6, PMS2 in EC and BRCA 1/2 in OC). Data on germinal confirmation are available for 207/277 variants (74.7%). 153 out of 207 variants (73.9%, of which 64.4% for EC and 76.5% for OC) were confirmed of germline origin. 30.7% (9/29 of EC and 38/124 of OC) of the confirmed PGVs were not related to Lynch syndrome and BRCA1/2 genes in EC and OC, respectively (Table). Table: 20P
| Gene | OC | EC | ||
| PPGV (n) | Confirmed PGV (n) | PPGV (n) | Confirmed PGV (n) | |
| ATM | 5 | 4 | 7 | 1 |
| BRCA1 | 97 | 59 | 3 | 0 |
| BRCA2 | 37 | 27 | 5 | 1 |
| BRIP1 | 5 | 3 | 1 | 1 |
| CHEK2 | 1 | 1 | 4 | 0 |
| DICER1 | 2 | 0 | 1 | 0 |
| MLH1 | 4 | 3 | 6 | 2 |
| MSH2 | 3 | 1 | 18 | 10 |
| MSH6 | 6 | 3 | 8 | 7 |
| MUTYH | 11 | 6 | 5 | 3 |
| NF1 | 8 | 0 | 1 | 0 |
| PALB2 | 7 | 6 | 2 | 1 |
| PMS2 | 1 | 1 | 1 | 1 |
| POLD1 | 1 | 0 | 1 | 0 |
| POLE | 1 | 1 | 3 | 0 |
| PTCH1 | 2 | 0 | 1 | 0 |
| PTEN | 0 | 0 | 1 | 0 |
| RAD51C | 9 | 6 | 0 | 0 |
| RAD51D | 3 | 2 | 1 | 1 |
| RET | 0 | 0 | 1 | 0 |
| SDHA | 2 | 1 | 1 | 1 |
| SMARCB1 | 1 | 0 | 0 | 0 |
| Total | 206 | 124 | 71 | 29 |
Conclusions
Besides therapeutic and prognostic implications, CGP can identify variants related to hereditary cancer predisposition conditions allowing cascade prevention and identification of affected relatives. Approximately one-third of gynecological cancer patients were discovered to have PGVs in genes other than those commonly recommended.
Clinical trial identification
NCT06020625.
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
C. Nero: Financial Interests, Personal, Other, travel support: MSD, Illumina; Financial Interests, Personal, Other, honoraria: Veeva, GSK, MSD, AZ, Altems, Illumina. A. Fagotti: Financial Interests, Personal, Advisory Board, Advisory Board AstraZeneca: AstraZeneca & MSD; Financial Interests, Personal, Invited Speaker, Speaker: PharmaMar, Johnson & Johnson, Fondazione Internazionale Menarini; Financial Interests, Personal, Invited Speaker, Moderator: GSK; Financial Interests, Institutional, Invited Speaker, NUVOLA trial-NCT04261465: AstraZeneca; Financial Interests, Institutional, Invited Speaker, ENSEAL® X1 Curved Jaw Tissue Sealer: Johnson & Johnson; Financial Interests, Institutional, Invited Speaker, PROTOCOL ID: Microvesicles INnovative OvaRian CAncer (MINORCA). ID2368Studio osservazionale valutante gli esosomi e le microvescicole circolanti con tecnologie innovative in qualità di potenziali biomarcatori per personalizzare il trattamento del carcinoma sieroso di alto grado ovarico: Roche. G. Scambia: Financial Interests, Personal, Advisory Role: AstraZeneca, MSD, Covidien AG; Financial Interests, Personal, Speaker’s Bureau: Olympus Europa SE & CO. KG, Baxter Healthcare SA, Intuitive Surgical Inc., GSK S.p.A.; Financial Interests, Personal, Other: Clovis Oncology Italy S.r.l.; Financial Interests, Personal, Advisory Board: TESARO Bio Italy S.r.l., Johnson & Johnson. All other authors have declared no conflicts of interest.