Therapeutic Implications of Germline Testing in Patients With Advanced Cancers
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Published:2021-08-20
Issue:24
Volume:39
Page:2698-2709
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ISSN:0732-183X
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Container-title:Journal of Clinical Oncology
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language:en
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Short-container-title:JCO
Author:
Stadler Zsofia K.1ORCID, Maio Anna1ORCID, Chakravarty Debyani2, Kemel Yelena2ORCID, Sheehan Margaret1, Salo-Mullen Erin1, Tkachuk Kaitlyn1, Fong Christopher J.3, Nguyen Bastien3ORCID, Erakky Amanda4, Cadoo Karen1ORCID, Liu Ying1ORCID, Carlo Maria I.1ORCID, Latham Alicia1ORCID, Zhang Hongxin5, Kundra Ritika5ORCID, Smith Shaleigh5, Galle Jesse1, Aghajanian Carol1, Abu-Rustum Nadeem6, Varghese Anna1ORCID, O'Reilly Eileen M.14ORCID, Morris Michael1ORCID, Abida Wassim1ORCID, Walsh Michael1ORCID, Drilon Alexander1ORCID, Jayakumaran Gowtham2ORCID, Zehir Ahmet25ORCID, Ladanyi Marc2ORCID, Ceyhan-Birsoy Ozge2, Solit David B.15ORCID, Schultz Nikolaus35, Berger Michael F.25ORCID, Mandelker Diana2ORCID, Diaz Luis A.1ORCID, Offit Kenneth1ORCID, Robson Mark E.1ORCID
Affiliation:
1. Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 2. Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 3. Computational Oncology, Department of Epidemiology and Statistics, Memorial Sloan Kettering Cancer Center, New York, NY 4. David M. Rubinstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 5. Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 6. Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY
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.
Publisher
American Society of Clinical Oncology (ASCO)
Subject
Cancer Research,Oncology
Cited by
77 articles.
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