Recent advances in precision oncology research

Abstract

Precision oncology has evolved into focusing on matching the most accurate and effective treatments based not only on the genetic profile of the patient and his/her cancer, but also on other unique characteristics that distinguish one patient from another. Each patient has a unique genome, proteome, epigenome, microbiome, lifestyle, diet, and other characteristics that all interact to influence oncogenesis, disease progression, effective treatment options, drug tolerance, remission, and relapse. Cancer comprises several hundred heterogeneous diseases, meaning that differences exist not only between cancer cells from various patients, but also between cancer cells within a single patient. Cancer is constantly developing characteristics to evade death and this is why no single drug has been effective in “curing” cancer. Precision oncology now involves using a combination of the unique characteristics of each patient to direct immunotherapy and targeted therapies.1 Many advances in research over the past year reflect these ideologies of precision oncology. Here we describe a few recent policy and research advances in the field of precision oncology. Most recently, the focus has shifted from treating cancer based on type and histology to treating the specific cancer mutation. FDA policies have paved the way for the adoption of “big data” genetic profiling techniques to guide patient therapies, such as those described by the NCI-MATCH (Molecular Analysis for Therapy Choice) or the NCI-MPACT (Molecular Profiling-based Assignment of Cancer Therapy) initiatives. In June 2017, the FDA granted regular approvals for using a combination of dabrafenib (i.e., a BRAF inhibitor) and trametinib (i.e., a MEK inhibitor) to treat patients if they had metastatic non-small cell lung cancer (NSCLC) with the BRAF V600E mutation. This regimen was first approved by the FDA in 2014 to treat melanomas in patients with BRAF mutations, and in 2017, researchers reported that the combination of dabrafenib and trametinib could also help patients with later stage melanoma by lowering the risk for recurrence after surgery.2 The hope is that the genetic profile of tumors can match patients with the BRAF V600E mutation treatment regimens including this combination or another BRAF inhibitor. Broader applicability remains to be seen but seems promising. However, results of next-generation sequencing have shown that most patients do not have “actionable” mutations like the BRAF V600E. In other words, we do not yet have a drug that can target every specific mutation identified. Also cancers can have more than one “driver” mutation. However, combination therapies seem to hold promise in overcoming these issues. A major challenge in drug development has been the minimum 10-year time frame traditionally required to move a drug from Phase I through Phase II and III trials and eventually into FDA approval for use in the clinic. This time frame is no longer acceptable, and the FDA has developed the “Breakthrough Therapy Designation” (BTTD) and accelerated approval of protocols to speed up the process. The BTTD was first approved in 2012, and this strategy refers to a drug that can be used alone or in combination to treat a life threatening condition or disease. The drug must have preliminary clinical evidence indicating that its use could demonstrate substantial improvement over existing therapies on one or more clinically relevant endpoints. Drugs that are designated as breakthrough therapy are granted expedited review and development. Even though a therapeutic receives breakthrough designation, the drug must still be further assessed in additional trials to confirm its clinical benefit. If the additional trial confirms the initial result, then the FDA will grant regular approval. The FDA-accelerated approval program is one of four evidence-based strategies used to speed-up the evaluation of therapeutics to treat life-threatening diseases such as cancer. The accelerated approval is built around the assessment of the effect of a therapeutic drug at an earlier stage than usual by using a surrogate endpoint (i.e., a marker believed to predict clinical benefit, such as tumor shrinkage that is associated with longer overall survival or improved quality of life). In spite of these challenges, 2017 was a remarkable year in the field of precision oncology and therapeutic advances. Notably, the European Society for Medical Oncology (ESMO) published a Precision Medicine Glossary in the Annals of Oncology.3 This publication is extremely important for establishing standardized communication regarding precision medicine between oncologists, researchers, and patients.