Molecular Diagnostics in Cancer
Authors: Coyne Zachary L. , Kalachand Roshni D. , Bast Robert C. , Mills Gordon B. , Hennessy Bryan T. 
Published: October 2022

OverviewMolecular diagnostics refers to the use of molecular alterations that are associated with cancers to facilitate detection, diagnosis, monitoring, and/or treatment selection. Molecular biomarkers have primarily been studied in cancer tissue but can potentially be assayed in readily available patient samples (saliva, sputum, blood, urine, feces), thereby minimizing the need for invasive biopsies. Traditional blood biomarkers—CEA, PSA, hCG, AFP, CA125, and CA15‐3—have been used to monitor response to treatment and to detect disease recurrence. Their clinical utility often depends upon the availability of effective treatment for residual or recurrent disease. Early detection requires biomarkers with high sensitivity to detect preclinical and ideally premetastatic disease, as well as high specificity to permit efficient, cost‐effective screening. Two‐stage strategies are often most promising where rising biomarkers trigger imaging or results of imaging are combined with biomarkers to improve positive predictive value. Cancer‐specific genomic aberrations have been identified which guide therapy and predict outcomes in subgroups of patients. Targeting HER2 has dramatically altered the outcomes of patients withHER2amplified breast cancers, as have EGFR inhibitors in the treatment of metastaticEGFRmutation‐positive non‐small‐cell lung cancer. As single driver gene aberrations are frequently not sufficient to predict therapeutic responses, gene signatures, and multi‐marker panels incorporating DNA, RNA, and/or protein aberrations are being evaluated as potential effective biomarkers. A panel of multiple biomarkers (OncoType Dx®) has proven useful in predicting the need for chemotherapy in addition to hormonal therapy in hormone receptor‐positive breast cancer. As targeted therapies are becoming a reality, so is the predictable emergence of resistance to these therapies, often occurring through gene amplification, secondary mutations, or re‐activation of signaling mechanisms downstream from the targeted molecular aberration. The search for molecular biomarkers, so‐called companion diagnostics, predictive of first‐line therapy resistance and of second‐line therapy response is now inherent to targeted drug development. However, these emerging integrative technologies have yet to benefit the majority of patients with cancer. Progress is being made in particular with liquid biopsies that sequence ctDNA in peripheral blood‐seeking evolving resistance mechanisms or germline mutations. Interpretation of the extensive number of aberrations identified by high‐throughput technologies, availability of adequate high‐quality tissue, integrative analysis across different analytics including DNA, RNA and protein, intra‐ and intertumoral heterogeneity, cost, and clinical validation remain significant challenges to developing and implementing effective biomarkers. Strategic use of bioinformatics, international collaboration, development of prospectively collected clinically annotated biobanks containing fresh frozen tissue, and clinical validation in large prospective datasets are key to bringing useful molecular biomarkers into clinical practice.