CHICAGO, IL USA (UroToday.com) - Cisplatin-based chemotherapy regimens are the backbone of treatment of metastatic and muscle-invasive urothelial cancer. Evidence suggests a survival benefit with neoadjuvant cisplatin-based chemotherapy among patients with muscle-invasive disease. In spite of that, cisplatin-based chemotherapy can be difficult to give to patients with urothelial cancer, especially because they frequently have poor performance status and renal insufficiency. Having a biomarker that could predict response to cisplatin chemotherapy could allow clinicians to spare patients who would be unlikely to respond, and push forward with patients who might have more significant benefit. Presently, such a biomarker does not exist.
ERCC2 is a nucleotide excision-repair gene. Preclinical data suggests that defects in this gene may mediate cisplatin sensitivity. Importantly, up to 7-12% of bladder tumors have somatic mutations in ERCC2. In this study, investigators sought to determine whether mutations in ERCC2 might be associated with improved response to neoadjuvant cisplatin-based chemotherapy.
Rosenberg and colleagues performed whole exome sequencing of 51 urothelial tumors, prior to treatment with cisplatin neoadjuvant chemotherapy, and germline DNA from the associated patients. All patients included in the study were treated with neoadjuvant chemotherapy and ultimately proceeded to radical cystectomy. Of the 51 patient samples evaluated, 26 had pT0/pTis (non-invasive) disease at cystectomy and were termed “responders,” and 25 had pT2+ (muscle-invasive) disease at cystectomy and were labeled “non-responders.” The investigators used computational methods to identify somatic mutations that were present in the responder tissues but were lacking in the non-responder samples. They then used functional assays, cellular cisplatin, and UV sensitivity assays, to validate their findings.
When comparing responders to non-responders, somatic ERCC2 mutations were present in 38.5% of responder samples and 0% of non-responder samples. Importantly, ERCC2 was the only gene the investigators identified that was enriched in the responder but not in the non-responder samples. When expressed in an ERCC2-deficient cell line, ERCC2 mutants were unable to rescue cisplatin and UV sensitivity compared to wild-type ERCC2.
They concluded that somatic ERCC2 mutations appeared to be associated with sensitivity to cisplatin in this group of patients with muscle-invasive urothelial cancer. This finding may ultimately provide clinical utility if patient samples are tested prior to neoadjuvant chemotherapy in practice. However, prior to incorporating this test into clinical practice, several criteria must be met. First, the results will need to be verified in a secondary cohort, ideally in a prospective study. Second, there must be a valid and reliable assay that can accurately identify ERCC2 mutations in clinical specimen. Finally, an ideal biomarker for clinical care would predict clinically relevant outcomes, such as overall survival, rather than simply intermediate outcomes like pathologic response. Overall the results present some provocative data that may ultimately make their way to clinical practice, but are not quite ready to direct clinical care at this point.
Presented by Jonathan E. Rosenberg, MD at the American Society of Clinical Oncology (ASCO) 50th Annual Meeting - May 30 - June 3, 2014 - Chicago, Illinois USA
Memorial Sloan‑Kettering Cancer Center, New York, NY USA
Written by Alicia K. Morgans, MD, assistant professor of medicine and medical oncologist at Vanderbilt-Ingram Cancer Center, and medical writer for UroToday.com