Integration of Germline Pharmacogenetics Into a Tumor Sequencing Program.

Evidence-based guidelines inform treatment decisions for patients for whom germline genetic information is available. Our real-time tumor sequencing program, which makes precision treatment decisions for patients with cancer, produces matched germline information, providing a unique opportunity to efficiently implement pharmacogenetics and benefit patients.

The germline genetic database from the Michigan Oncology Sequencing (MI-Oncoseq) program was searched for 21 clinically actionable polymorphisms in five cancer-relevant genes: <i>TPMT</i>, <i>DPYD</i>, <i>CYP2C19</i>, <i>CYP3A5</i>, and <i>UGT1A1</i>. Residual germ line DNA was sent to an external Clinical Laboratory Improvement Amendments-approved laboratory for confirmatory genotyping. The medical records of MI-Oncoseq patients with actionable phenotypes were searched for receipt of relevant drugs and to determine whether having genetic information at the time of treatment would have led to a treatment recommendation.

All nine variants in <i>TPMT</i>, <i>DPYD</i>, and <i>CYP2C19</i> that were detected in MI-Oncoseq were confirmed by external genotyping. Genotype determinations could not be made for <i>CYP3A5*3</i>, <i>UGT1A1*28</i>, or <i>UGT1A1*80</i>. On the basis of retrospective assessment of 115 adult and pediatric patient records, 4.3% (n = 5) had a potentially clinically actionable phenotype for <i>TPMT</i>, <i>DPYD</i>, or <i>CYP2C19</i> and received a relevant medication. After accounting for differences in adult and pediatric recommendations, three of these patients could have received a treatment recommendation at the time of prescribing.

Germline genotype determinations for <i>TPMT</i>, <i>DPYD</i>, and <i>CYP2C19</i> can be used to make evidence-based treatment recommendations in MI-Oncoseq patients. Although the proportion of patients for whom recommendations can be made is small, this added value to MI-Oncoseq and patient care comes at no additional genotyping cost. Pharmacogenetic assessment should be integrated into tumor sequencing programs that genotype matched germline DNA; however, the complexity and additional cost of implementing pharmacogenetics remain challenging.

Anderson B, Chinnaiyan A, Frank K, Glatz A, Hertz DL, Lonigro RJ, Mody RJ, Mora E, Pasternak AL, Rabban E, Robinson DR, Vats P, Wu YM

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JCO Precis Oncol, 2018, 2

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