Genetic Variations and Therapy Resistance in EGFR-mutant NSCLC

Genetic variants underlying resistance to targeted therapies in non-small cell lung cancer (NSCLC) are more heterogeneous and complicated than originally thought. An analysis of 355 biopsies from 223 patients with EGFR-mutant NSCLC who acquired resistance to EGFR inhibitors demonstrated variation in acquired mutations between biopsies. Almost 20% of patients, furthermore, harbored at least 2 types of genetic resistance to treatment, according to research presented at the 2017 Multidisciplinary Thoracic Cancers Symposium.¹

EGFR mutations drive between 10% and 30% of cases of NSCLC. After acquisition of resistance to EGFR-targeted treatment, most patients undergo a single biopsy to guide subsequent treatment.

Resistance to EGFR-targeted therapies may not, however, be permanent, and a single biopsy, though less invasive, is insufficient for fully understanding the nature of therapy resistance.

Researchers biopsied tumors after acquired resistance. They examined tumor tissue for genetic variants causing therapy resistance, including T790M, the most frequent secondary mutation.

In total, 19% of biopsies demonstrated more than 1 genetic resistance to therapy; 61% of patients harbored the T790M mutation.

Eighty-three patients (37%) underwent 2 biopsies. In 49% of these patients, resistance mechanisms varied from the first biopsy to the second. For example, 20% of patients who underwent 2 biopsies gained a T790M mutation between the first and second biopsy, and 11% lost the mutation.

In 307 biopsies, 2 resulted in clinically significant complications. Thirteen percent of patients underwent 3 or more biopsies.

“In the past, resistance mechanisms were usually thought of as static. Our study demonstrates, conversely, that a binary designation of resistance may oversimplify cancer’s true biology. These genetic mutations can fluctuate over time, and some patients can harbor more than one mutation,” explained lead author Zofia Piotrowska, MD, a thoracic oncologist at the Massachusetts General Hospital Cancer Center in Boston.

Reference

1. Piotrowska Z, Stirling K, Heist R, et al. Heterogeneity and variation in resistance mechanisms among 223 EGFR-mutant NSCLC patients with > 1 post-resistance biopsy. Paper presented at: 2017 Multidisciplinary Thoracic Cancers Symposium; March 16-18, 2017; San Francisco, CA.