Lung adenocarcinoma can harbor both ALK fusions and EGFR driver mutations

In recent years it has become apparent that intratumoral heterogeneity is an inherent property of many types of cancer, including lung adenocarcinoma (LADC). Although previous studies have shown coexistence of ALK fusions with EGFR mutations in patients with LADC, Dr. Cai and associates have taken these observations further: In two patients with both ALK fusions and EGFR mutations, they examined four separate areas within one tumor. In different tumor regions, one, both, or neither mutation was present. In tumor regions with evidence of both mutations present, they found the relative abundance of ALK fusions and EGFR mutations differed, suggesting that at least some cancer cells did not harbor both mutations. It appears ALK fusions and EGFR mutations may not coexist in the same cancer cell population and may be later branched events in the evolution of the tumor. The specific EGFR mutations observed were inconsistent as well, either R832H or L858R.

If EGFR mutation–positive subclones within ALK-rearranged tumors cause relapse in a subset of patients, these patients may be candidates for subsequent treatment with anti-EGFR therapies. These findings support a role for repeated tumor analysis during the evolution of disease in patients who progress after ALK inhibitor therapy despite a prior EGFR-negative biopsy. Recognition of the limits of diagnostic assays and the influence that a minority of cells harboring oncogenic drivers may have on disease is important to advance precision medicine.

This study highlights the importance of evolutionary precision medicine in LADC and the need for genomic evaluations throughout the disease course. Advances in cell-free DNA detection may circumvent problems of tumor sampling and enable us to monitor evolving subclonal driver events in the tumor and in metastatic lesions so that therapy can be adapted accordingly.

Dr. Nicolai Juul Birkbak is a principal research associate at University College London. Dr. Crispin T. Hiley is a research fellow at University College London. Dr. Charles Swanton is a senior clinical research fellow and group leader of the translational cancer therapeutics laboratory at the London Research Institute and consultant medical oncologist at the Royal Marsden Hospital. These remarks were part of an editorial accompanying the report (J Clin Oncol. 2015 Sep 28. doi: 10.1200/jco.2014.58.8293). Dr. Birkbak disclosed stock or other ownership in Onxeo and royalties from Myriad Genetics. Dr. Hiley reported stock or other ownership in Bristol-Myers Squibb. Dr. Swanton reported stock or other ownership in Epic Sciences and Apogen Biotechnologies and honoraria or research funding from Roche, Boehringer Ingelheim, Novartis, and GlaxoSmithKline.