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Thoracic 2017: Genetic Profile of Treatment-Resistant Lung Cancer More Variable Than Previously Thought

Key Points

  • All patients received at least one biopsy at first resistance to EGFR inhibitors. Nearly 1 in 5 of these 221 biopsies (19%) demonstrated more than one resistance mechanism simultaneously.
  • The T790M mutation was found in 61% of patients, and the proportions of other mutations were as expected. Specifically, 18% of patients had EGFR amplification; 2% acquired PIK3CA mutations; 5% had amplification of the MET gene, 3% had transformed non–small cell to small cell disease; and 1% acquired BRAF mutations.

The genetic mutations underlying treatment resistance in non–small cell lung cancer (NSCLC) are more complex and dynamic than previously thought. Analysis of 355 biopsied tumors from patients who acquired resistance to epidermal growth factor receptor (EGFR) inhibitors, the most common form of targeted therapy for NSCLC, found that mutations frequently varied between biopsies and that nearly one in five patients harbored more than one type of genetic resistance to treatment. Findings were presented by Piotrowska et al at the 2017 Multidisciplinary Thoracic Cancers Symposium in San Francisco, California (Plenary Abstract 1).

Between 10% and 30% of NSCLC cases are driven by mutations in the EGFR gene. These patients typically are treated with drugs that inhibit activation of the gene, but nearly all tumors eventually develop resistance to these therapeutic agents. Currently, many patients who acquire resistance to EGFR-targeted therapy undergo a tumor biopsy and are designated as either positive or negative for specific secondary mutations. This prognosis guides decisions for subsequent courses of targeted therapy, and further biopsies are not routinely obtained, given the invasive nature of rebiopsy in the lungs. Recent studies have indicated, however, that resistance in EGFR-mutant NSCLC can vary and that a permanent designation based on a single biopsy may be insufficient.

“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,” said Zofia Piotrowska, MD, lead author of the study and a thoracic oncologist at Massachusetts General Hospital Cancer Center.

“In an era where cancer treatment is increasingly personalized to the biology of each individual patient, our findings highlight the importance of molecular testing and the need for improved, noninvasive methods for serial testing.”

Study Findings

To better understand the biologic diversity of EGFR-resistant NSCLC, researchers retrospectively analyzed 355 biopsies of NSCLC tumors obtained from 221 patients after they acquired resistance to first-line EGFR inhibitor therapy. All patients were seen at a single institution between April 2008 and May 2016. The median patient age was 59 years (range 28–88 years), and 69% of patients were female. Researchers examined tumor samples for various genetic causes of EGFR resistance, including T790M, the most common secondary mutation.

All patients received at least one biopsy at first resistance to EGFR inhibitors. Nearly 1 in 5 of these 221 biopsies (19%) demonstrated more than one resistance mechanism simultaneously. The overall distribution of resistance mechanisms was consistent with previous research. The T790M mutation was found in 61% of patients, and the proportions of other mutations were as expected. Specifically, 18% of patients had EGFR amplification; 2% acquired PIK3CA mutations; 5% had amplification of the MET gene, 3% had transformed NSCLC to small cell disease; and 1% acquired BRAF mutations.

Eighty-three patients (37%) underwent two biopsies during postresistance treatment. For half of these patients (49%), resistance mechanisms varied between biopsies, including both “gain” and “loss” of the T790M mutation (20% and 11% of two-biopsy patients, respectively). Of the 17 patients who “lost” T790M, 3 demonstrated a new resistance mechanism on the second biopsy.

Researchers also sought to determine whether serial biopsies were safe and feasible for patients with NSCLC. Of the 307 biopsies, 2 biopsies (0.7%) resulted in clinically significant complications, and 13% of patients (n = 28) underwent 3 or more postresistance biopsies.

“As much as half of the time, the dominant resistance mechanisms observed on one biopsy may no longer be relevant on a second biopsy, and that second biopsy may uncover a new, potentially targetable, resistance mechanism,” said Dr. Piotrowska. “We hope that these findings will prompt clinicians to consider rebiopsy when selecting a new therapy. While we observed that biopsies were generally safe and feasible, noninvasive testing methods, such as liquid biopsies that analyze tumor DNA circulating in the patient's blood, may provide another method to more easily characterize resistance over time.”

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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