Precision Oncology Medicine: The Clinical Relevance of Patient‐Specific Biomarkers Used to Optimize Cancer Treatment

Abstract

Precision medicine in oncology is the result of an increasing awareness of patient specific clinical features coupled with the development of genomic-based diagnostics and targeted therapeutics. Companion diagnostics designed for specific drug-target pairs were the first to widely utilize clinically applicable tumor biomarkers (e.g. HER2, EGFR), directing treatment for patients whose tumors exhibit a mutation susceptible to a FDA approved targeted therapy (e.g. trastuzumab, erlotinib). Clinically relevant germline mutations in drug metabolizing enzymes and transporters (e.g. TPMT, DPYD) have been shown to impact drug response, providing rationale for individualized dosing to optimize treatment. The use of multigene expression-based assays to analyze an array of prognostic biomarkers have been shown to help direct treatment decisions, especially in breast cancer (e.g. Oncotype DX). More recently, the use of Next-Generation Sequencing to detect many potential “actionable” cancer molecular alterations is further shifting the one gene-one drug paradigm towards a more comprehensive, multi-gene approach. Currently, many clinical trials (e.g. NCI-MATCH, NCI-MPACT) are assessing novel diagnostic tools with a combination of different targeted therapeutics, while also examining tumor biomarkers that were previously unexplored in a variety of cancer histologies. Results from ongoing trials like the NCI-MATCH will help determine the clinical utility and future development of the precision-medicine approach.

Next-Generation Sequencing in the Clinical Setting Clarifies Patient Characteristics and Potential Actionability

“…For example, targeted agents for the protein products of EGFR mutations have been extensively studied in non-small cell lung cancer with impressive results [7–8]. ERBB2 (HER2) positivity, frequently seen in invasive breast and gastric cancer, has been targeted effectively with a yield of improved outcomes [9–11, 15, 16]. However, other studies have suggested that some alterations cannot be targeted well, at least with single agents in the refractory metastatic setting.…”

The 100 000 Genomes Project: bringing whole genome sequencing to the NHS

“…Clinical testing for genomic changes (biomarkers) can define diagnostic subtypes; predict tumour behaviour, prognosis, and drug response; and enable monitoring for early recurrence of disease2223…”

Precision Medicine Requires Precision Laboratories

“…To date most of these companion diagnostic assays have focused on relatively few analyte targets. However, the total number of mutations that have evidence for activity as a driver of tumor progression and that can be specifically targeted by a specific drug has grown to several thousand, shifting the precision medicine paradigm from 1-gene-1 drug to a multigene-many drugs model [6]. Multiplex testing strategies are needed to be developed to increase the number of tests that can be performed on limited biopsy samples.…”