Pairing Cancer Biomarkers to Biomedicine

On May 23, 2017, the US Food and Drug Administration (FDA) approved pembrolizumab for the treatment of any solid tumors with certain specific genetic features or biomarkers, namely microsatellite instability-high (MSI-H) or mismatch repair deficient (dMMR). This was the first time that the FDA approved a cancer treatment based on a common biomarker, rather than the organ site or histology. Pembrolizumab binds to the programmed death 1 (PD-1) protein, preventing its ligands from binding. The PD-1/ligand interaction causes immune suppression, thus blocking this interaction helps restore the body's immune response against the cancer. Pembrolizumabwas previously approved by the FDA for treatment of certain cancer types including metastatic melanoma, metastatic non-small cell lung cancer (NSCLC) and refractory classical Hodgkin lymphoma. It was approved for this new biomarker based indication using the Accelerated Approval pathway, underwhich the FDA can approve drugs for serious conditions where there is unmet medical need and a drug has certain effects that are reasonably likely to predict a clinical benefit to patients. Simple genetic tests that allow clinicians to prescribe tailored treatments to cancer patients that take into account their genetic background, are becoming a reality. Theoretically this could allow clinicians to maximize therapeutic efficacy, while minimizing adverse effects. Precision oncology thus holds great promise for cancer research. Important biomarkers formany types of cancer have already been identified, allowing patients to benefit from analysis of their genetic traits. For example, the mutational status of the gene Kras, can help predict the efficacy of treatments for metastatic colorectal cancer patients with epidermal growth factor receptor (EGFR) inhibitors. Patients with colorectal tumors expressing wild type Kras benefit from cetuximab, an anti-EGFR antibody, while patients with colorectal tumors with mutated Kras exhibit resistance to EGFR inhibitors. Likewise, Braf mutants are also reported to confer resistance to EGFR inhibitor treatment in colon cancer patients. Checking the mutational status of specific, pertinent genes in patients, could thus help in choosing more effective treatments for individual patients in the clinic. In most cases, however, the criteria that can predict drug responses are complicated. Finding appropriate and effective biomarkers for treatment is not easy. In cancer immunotherapy, for example, the expression level of programmed death-ligand 1 (PD-L1) is critical for determining the efficacy of treatments with the PD-1 inhibitors like pembrolizumab and nivolumab. A randomized controlled trial published in April 2016 in The Lancet showed that pembrolizumab prolonged overall survival in NSCLCpatientswhere at least 50%of tumor cells expressed PD-L1, as determined by immunohistochemistry. However, another randomized clinical trial published in June 2017 in the New England Journal of Medicine, found that nivolumab was not associated with longer progressionfree survival for late stage or recurrent NSCLC patients with a PD-L1