Therapeutic Implications of Germline Testing in Patients With Advanced Cancers. Issue 24 (20th August 2021)

• Record Type: Journal Article
• Authors: Stadler, Zsofia K.; Maio, Anna; Chakravarty, Debyani; Kemel, Yelena; Sheehan, Margaret; Salo-Mullen, Erin; Tkachuk, Kaitlyn; Fong, Christopher J.; Nguyen, Bastien; Erakky, Amanda; Cadoo, Karen; Liu, Ying; Carlo, Maria I.; Latham, Alicia; Zhang, Hongxin; Kundra, Ritika; Smith, Shaleigh; Galle, Jesse; Aghajanian, Carol; Abu-Rustum, Nadeem; Varghese, Anna; O'Reilly, Eileen M.; Morris, Michael; Abida, Wassim; Walsh, Michael; Drilon, Alexander; Jayakumaran, Gowtham; Zehir, Ahmet; Ladanyi, Marc; Ceyhan-Birsoy, Ozge; Solit, David B.; Schultz, Nikolaus; Berger, Michael F.; Mandelker, Diana; Diaz, Luis A.; Offit, Kenneth; Robson, Mark E.;
• Is Part Of: Journal of clinical oncology. Volume 39:Issue 24(2021)
• Page Start: 2698
• Page End: 2709
• Publication Date: 2021-08-20
• Subjects: Oncology -- Periodicals; Cancer -- Periodicals; Oncology; Medical Oncology; Cancérologie -- Périodiques; Cancer -- Périodiques; Cancérologie; Cancer; Oncology; Oncologia; Càncer; Periodicals; 616.994
• DOI: 10.1200/JCO.20.03661
• Languages: English
• ISSNs: 0732-183X

Abstract

Abstract : PURPOSE: Tumor mutational profiling is increasingly performed in patients with advanced cancer. We determined the extent to which germline mutation profiling guides therapy selection in patients with advanced cancer. METHODS: Patients with cancer undergoing tumor genomic profiling were prospectively consented for germline cancer predisposition gene analysis (2015-2019). In patients harboring germline likely pathogenic or pathogenic (LP/P) alterations, therapeutic actionability was classified using a precision oncology knowledge base. Patients with metastatic or recurrent cancer receiving germline genotype–directed therapy were determined. RESULTS: Among 11, 947 patients across > 50 malignancies, 17% (n = 2, 037) harbored a germline LP/P variant. By oncology knowledge base classification, 9% (n = 1042) had an LP/P variant in a gene with therapeutic implications (4% level 1; 4% level 3B; < 1% level 4). BRCA1/2 variants accounted for 42% of therapeutically actionable findings, followed by CHEK2 (13%), ATM (12%), mismatch repair genes (11%), and PALB2 (5%). When limited to the 9, 079 patients with metastatic or recurrent cancer, 8% (n = 710) harbored level 1 or 3B genetic findings and 3.2% (n = 289) received germline genotype–directed therapy. Germline genotype–directed therapy was received by 61% and 18% of metastatic cancer patients with level 1 and level 3B findings, respectively, and by 54% of BRCA1/2, 75% of mismatch repair, 43% of PALB2, 35% of RAD51C/D, 24% of BRIP1, and 19% of ATM carriers. Of BRCA1/2 patients receiving a poly(ADP-ribose) polymerase inhibitor, 45% (84 of 188) had tumors other than breast or ovarian cancer, wherein the drug, at time of delivery, was delivered in an investigational setting. CONCLUSION: In a pan-cancer analysis, 8% of patients with advanced cancer harbored a germline variant with therapeutic actionability with 40% of these patients receiving germline genotype–directed treatment. Germline sequence analysis is additive to tumor sequence analysis for therapy selection and should be considered for all patients with advanced cancer.