When Should Tumor Genomic Profiling Prompt Consideration of Germline Testing?

Kim DeLeonardis, MS; Lauren Hogan, MS; Stephen A. Cannistra, MD; Deepa Rangachari, MD; Nadine Tung, MD


J Oncol Pract. 2019;15(9):465-473. 

In This Article

Abstract and Introduction


Somatic genomic testing is rapidly becoming an integral part of care for patients with metastatic cancer. Extrapolation of these results beyond personalized cancer therapy is a skill being demanded of practicing oncologists without prior specialty in genetics. Up to 12% of tumor genomic profiling reports will reveal a germline pathogenic variant. Recognition of these germline variants is essential not only for optimal care of the patient with cancer but also to initiate cascade genetic testing in at-risk family members who also may carry the familial mutation. This article provides a concise and methodical, evidence-based strategy to guide oncology providers about how to identify genes associated with an inherited predisposition for cancer, determine the pathogenicity of variants reported within those genes, and understand the likelihood that these variants are of germline origin in a particular patient with cancer. Case examples are provided to illustrate clinical scenarios and facilitate application of the proposed approach.

Introduction: Somatic Genetic Testing in the Context of Known Cancer

Personalized medicine is heralded by the evolving effort to optimally match patient- and disease-specific characteristics with effective therapies. In oncology, this is characterized more specifically as precision oncology, whereby tumor-specific acquired (somatic) genetic changes identified through tumor genomic testing are matched with targeted therapies that aim to abrogate specific cancer-promoting pathways or exploit tumor vulnerabilities. Testing for somatic mutations in tumors is an evolving standard of care across many cancer types. However, the enthusiasm that surrounds the promise of precision medicine must be tempered by the limited success of these targeted therapies in most patients thus far, especially in the setting of off-label use.[1] Increasing use of tumor genomic profiling is associated with the possibility of identification of (potentially unexpected) germline aberrations, so genetic awareness on the part of oncology providers is a growing mandate in the landscape of modern oncology.

In most cases, current standards for evidence-based tumor genomic profiling are focused in the arena of advanced-stage disease. Tumor genomic testing is requested by the treating oncologist and may include either tissue-based assays (ie, performed on tumor samples) or peripheral blood–based assays (ie, circulating tumor DNA). The specific objective of such assays is to identify genetic determinants of disease that may afford key predictive information about optimal treatment options. In contrast, germline genetic testing is most often conducted on peripheral blood or saliva samples and requested by a genetic counselor or other genetics provider with the purpose of identifying potential inherited (germline) genetic changes that may predict future risk of developing cancer—in either a cancer-affected or -unaffected individual. However, in some cases, detection of a germline pathogenic variant may also inform decisions about cancer-directed therapy.

This review is intended to provide a systematic approach to guide clinicians about how to recognize genetic variants identified through tumor genomic profiling that may be germline and thus prompt consideration of germline genetic testing. In accordance with expert consensus, the terms mutation, pathogenic variant, deleterious variant, likely pathogenic variant, and suspected deleterious variant will be used in this review to describe a genetic variant that disrupts the function of encoded protein and is associated with an increased risk for cancer. In addition, the terms somatic and tumor are used interchangeably to contrast with germline (hereditary) genetic changes.

Although a list of hereditary cancer genes is included in this review, we recognize that consensus on which genes have sufficient clinical validity to be considered cancer susceptibility genes is still evolving. Likewise, the clinical utility of identifying moderate-risk cancer susceptibility genes (eg, CHEK2, BRIP1) and of modifying surveillance and prevention practices on the basis of mutations in these genes is not as established as it is for mutations in high-risk genes, although published guidelines exist.[2] Similarly, cancer risks associated with the incidental identification of a mutation in a high-penetrance gene (eg, BRCA1/2) in a patient without a suggestive personal or family history are not fully known. A stepwise framework is presented below, followed by case presentations that provide guidance for real-world examples.