ERCC1: Signals of Needed Research

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Challenges persist in identifying predictive biomarkers for targeted chemotherapy, but new technologies offer potential.
Challenges persist in identifying predictive biomarkers for targeted chemotherapy, but new technologies offer potential.

Results of a phase 3 randomized prospective trial indicate that a promising biomarker, excision repair cross complementing group 1 (ERCC1), may not help to target chemotherapy for non-small cell lung cancer (NSCLC).1

The trial's results highlight the challenges surrounding the development of reliable biomarkers for targeted chemotherapy. A suite of new and developing technologies, however, may offer new methods for identifying biomarkers that could transform targeted chemotherapy.

ERCC1, which forms an enzyme complex with xeroderma pigmentosum F (XPF) to repair double-strand breaks in DNA, has shown promise as a potential biomarker. Previous retrospective studies have found that ERCC1 protein expression is associated with platinum resistance and survival in NSCLC.2 But while preclinical and clinical data indicate that it does play an important role in platinum sensitivity, the biomarker did not have predictive influence for choice of chemotherapy.3

The ERCC1 trial was intended to include 1272 patients, but accrual of patients with non-squamous NSCLC was halted prematurely after a worse overall survival (OS) for non-platinum therapy was observed (median OS 7.6 months vs 10.7 months). Ultimately, 648 patients were recruited: 177 with squamous NSCLC and 471 with non-squamous NSCLC. Nearly 55% of patients with squamous NSCLC were positive for ERCC1 protein, compared to nearly 77% of patients with non-squamous NSCLC. The corresponding rates of patients who were positive for XPF were 70.5% and 68.5%, respectively.

Patients with non-squamous NSCLC who were ERCC1-positive had a median OS of 8.0 months when treated with platinum therapy compared to 9.6 months for patients treated with non-platinum therapy. Patients with non-squamous NSCLC who were ERCC1-negative had a median OS of 10.3 months with platinum therapy and 11.6 months with non-platinum therapy.

Neither ERCC1 nor XPF were predictive of survival benefit.

“Our study illustrated the difficulty of conducting a trial for cytotoxic chemotherapy using only a single immunohistochemistry-based cytotoxic resistance biomarker, unlike that for oncogenic addicted NSCLC such as EGFR mutation and ALK re-arrangements,” said lead author Siow Ming Lee, MD, PhD, of the University College London Hospitals, United Kingdom, in an email to Cancer Therapy Advisor. “It is very disappointing that our results were negative, as ERCC1 represents the most promising biomarker for customizing platinum chemotherapy treatment.”

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