Mutation Detection in Patients With Advanced Cancer by Universal Sequencing of Cancer-Related Genes in Tumor and Normal DNA vs Guideline-Based Germline Testing.

Mandelker D1, Zhang L1, Kemel Y1,2, Stadler ZK1,3, Joseph V1,2,3, Zehir A1, Pradhan N1, Arnold A1, Walsh MF1,3, Li Y1, Balakrishnan AR1, Syed A1, Prasad M1, Nafa K1, Carlo MI1,3, Cadoo KA1,3, Sheehan M1, Fleischut MH1, Salo-Mullen E1, Trottier M1, Lipkin SM3, Lincoln A1, Mukherjee S1,2, Ravichandran V1, Cambria R1, Galle J1, Abida W1,3, Arcila ME1, Benayed R1, Shah R1,2, Yu K1,3, Bajorin DF1,3, Coleman JA1,3, Leach SD1,3, Lowery MA1,3, Garcia-Aguilar J1,2,3, Kantoff PW1,3, Sawyers CL1,2,3, Dickler MN1,3, Saltz L1,3, Motzer RJ1,3, O'Reilly EM1,3, Scher HI1,2,3, Baselga J1,2,3, Klimstra DS1,3, Solit DB1,2,3, Hyman DM1,3, Berger MF1,2,3, Ladanyi M1,2, Robson ME1,3, Offit K1,2,3.

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Abstract

IMPORTANCE:

Guidelines for cancer genetic testing based on family history may miss clinically actionable genetic changes with established implications for cancer screening or prevention.

OBJECTIVE:

To determine the proportion and potential clinical implications of inherited variants detected using simultaneous sequencing of the tumor and normal tissue ("tumor-normal sequencing") compared with genetic test results based on current guidelines.

DESIGN, SETTING, AND PARTICIPANTS:

From January 2014 until May 2016 at Memorial Sloan Kettering Cancer Center, 10 336 patients consented to tumor DNA sequencing. Since May 2015, 1040 of these patients with advanced cancer were referred by their oncologists for germline analysis of 76 cancer predisposition genes. Patients with clinically actionable inherited mutations whose genetic test results would not have been predicted by published decision rules were identified. Follow-up for potential clinical implications of mutation detection was through May 2017.

EXPOSURE:

Tumor and germline sequencing compared with the predicted yield of targeted germline sequencing based on clinical guidelines.

MAIN OUTCOMES AND MEASURES:

Proportion of clinically actionable germline mutations detected by universal tumor-normal sequencing that would not have been detected by guideline-directed testing.

RESULTS:

Of 1040 patients, the median age was 58 years (interquartile range, 50.5-66 years), 65.3% were male, and 81.3% had stage IV disease at the time of genomic analysis, with prostate, renal, pancreatic, breast, and colon cancer as the most common diagnoses. Of the 1040 patients, 182 (17.5%; 95% CI, 15.3%-19.9%) had clinically actionable mutations conferring cancer susceptibility, including 149 with moderate- to high-penetrance mutations; 101 patients tested (9.7%; 95% CI, 8.1%-11.7%) would not have had these mutations detected using clinical guidelines, including 65 with moderate- to high-penetrance mutations. Frequency of inherited mutations was related to case mix, stage, and founder mutations. Germline findings led to discussion or initiation of change to targeted therapy in 38 patients tested (3.7%) and predictive testing in the families of 13 individuals (1.3%), including 6 for whom genetic evaluation would not have been initiated by guideline-based testing.

CONCLUSIONS AND RELEVANCE:

In this referral population with selected advanced cancers, universal sequencing of a broad panel of cancer-related genes in paired germline and tumor DNA samples was associated with increased detection of individuals with potentially clinically significant heritable mutations over the predicted yield of targeted germline testing based on current clinical guidelines. Knowledge of these additional mutations can help guide therapeutic and preventive interventions, but whether all of these interventions would improve outcomes for patients with cancer or their family members requires further study.