Sep. 30, 2008 A genetic fingerprint identified in patients with a gynecologic cancer may reveal candidates for targeted therapy. In a study in the journal Gynecologic Oncology, investigators from the Massachusetts General Hospital (MGH) Obstetrics and Gynecology Service report that women with vulvar carcinoma whose tumors have extra copies of the epidermal growth factor receptor (EGFR) gene are at increased risk of dying from their cancer.
The EGFR pathway is known to be critical in several types of cancer, but this is the first association of an EGFR gene alteration with this tumor.
"Treatment for vulvar carcinoma has changed little over the years." says Bo Rueda, PhD, of the Vincent Center for Reproductive Biology in the MGH Obstetrics and Gynecology Service, co-senior author of the report. "Through a better understanding of the specific mechanisms that underlie the tumorigenic process, we hope to expand treatment options for these patients with molecularly targeted therapies." The study was a collaboration with MGH Cancer Center investigators.
Although cancer of the vulva – women's exernal genital structures – is rare, it frequently recurs after standard treatment, and little has been known about factors leading to its development. Changes in the expression or activity of EGFR have been associated with many solid tumors, and patients whose cancers have EGFR mutations often can be successfully treated with drugs targeting the molecular pathway controlled by that receptor. The current study, which has been released online, was designed to investigate whether EGFR activity is also altered in vulvar tumors.
Using samples from the hospital's Tumor and Pathology Banks, the team analyzed data from 51 patients treated for vulvar carcinoma at the MGH Cancer Center from 1994 to 2007. Tumor samples were first evaluated for presence of the EGFR molecule, which revealed that the highest levels were found in more advanced tumors from patients with poorer survival.
Chromosomal analysis of the tumors showed that additional copies of the EGFR gene in tumor cells – seen in 6 of the 51 samples analyzed – likely contributed to overproduction of the protein in those patients. No mutations in the EGFR gene itself were seen; and although infection with the human papilloma virus (HPV) is a known risk factor for vulvar cancer, there was no evidence of HPV infection in the EGFR-amplified tumors. Overall, patients with EGFR-amplified tumors were twice as likely to die from their cancer as were those without gene amplification.
"The increased risk of death associated with EGFR amplification was independent of other known factors – such as age, stage of disease and spread to lymph nodes," says Whitfield Growdon, MD, the study's lead author and an MGH Gynecologic Oncology fellow. "EGFR amplification is now being used to identify patients eligible for clinical trials of novel EGFR-targeted therapies for several types of tumors."
Daniel Haber, MD, PhD, director of the MGH Cancer Center, adds, "This analysis shows that high levels of EGFR amplification are present in a variety of different cancers that have not been analyzed to date, raising the possibility of more therapeutic opportunities for the emerging array of EGFR-directed agents"
Along with Rueda – an associate professor of Obstetrics, Gynecology and Reproductive Biology at Harvard Medical School (HMS) – the co-senior author is Darrell Borger, PhD, co-director of the Translational Research Laboratory in the MGH Cancer Center and instructor in Medicine at HMS. Additional co-authors are Susan Boisvert, MGH Cancer Center; and Sara Akhavanfard, Esther Oliva, MD, Dora Dias-Santagata, PhD, Sakiko Kojiro, MD, PhD, and John Iafrate, MD, PhD, MGH Pathology; and Neil Horowitz, MD, Brigham and Women's Hospital. The study was supported by grants from the Advanced Medical Research Foundation, Vincent Memorial Research and the MGH Cancer Center.
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