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Genes predict adjuvant trastuzumab outcomes in HER2-positive breast cancer


 

AT THE SAN ANTONIO BREAST CANCER SYMPOSIUM

SAN ANTONIO – Researchers have taken a first stride toward the goal of developing a gene test that predicts a breast cancer patient’s likelihood of a favorable clinical outcome in response to adjuvant trastuzumab.

A massive gene expression profiling analysis of baseline pretreatment tumor specimens obtained from 372 breast cancer patients identified 32 genes that correlated strongly with 5-year relapse-free survival, each with a P value less than .001, Dr. Edith A. Perez reported at the San Antonio Breast Cancer Symposium.

The ideal thing would be to find a gene that, if highly expressed, predicts for benefit or not of Herceptin [trastuzumab]. We are on our way to developing a predictive test that can define the right treatment for individual patients, and that is very exciting," declared Dr. Perez, deputy director at large of the Mayo Clinic Comprehensive Cancer Center and director of the breast cancer translational genomics program at the Mayo Clinic in Jacksonville, Fla.

In all, 27 of the genes were associated with good outcome, while the other 5 correlated with poor outcome. The major functional categories these genes are involved in have been identified: cell receptor signaling, chromatin structure and transcription, control of cell death, cell cycle, Wnt/beta-catenin signaling, and lipid signaling. It’s not yet known whether these 32 genes are expressed in the epithelial or the stromal component of the tumors, and it will be challenging to figure that out, she said.

All 372 specimens in this analysis came from women randomized to adjuvant chemotherapy plus concurrent trastuzumab in the previously reported North Central Cancer Treatment Group N9831 trial. The N9831 trial was one of the pivotal studies that led to adjuvant trastuzumab plus chemotherapy becoming established as the standard of care in treating HER2-positive breast cancer

Dr. Perez and her coinvestigators have also just completed a gene expression profiling analysis of baseline tumor samples from an additional 910 women in the N9831 trial who were randomized to either chemotherapy alone or chemotherapy followed sequentially by trastuzumab. The plan is to identify similarities and differences in the patterns of gene expression in the chemotherapy-only and the two chemotherapy-plus-trastuzumab groups in order to home in more specifically on genes associated with the outcome of trastuzumab therapy. Those data weren’t ready for presentation at the symposium.

The study used the DNA-mediated DASL (annealing, extension, selection, and ligation) assay marketed by Illumina to scrutinize the activity of more than 29,000 genes in tumor specimens from 1,262 N9831 trial participants.

In addition, Dr. Perez and her coworkers are collaborating with other investigators around the world who also conducted adjuvant trastuzumab trials with collections of tumor samples, including the HERA (Herceptin Adjuvant) and FinHer studies, in order to carry out a validation study.

Discussant Dr. Dennis C. Sgroi called this work tremendously exciting. He noted that trastuzumab is a very expensive drug, and roughly 25% of treated patients relapse within 5 years. Trastuzumab also carries a risk of cardiotoxicity, and he was intrigued by Dr. Perez’ suggestion that the investigators believe they may have identified baseline tumor gene activity signatures predisposing to symptomatic cardiomyopathy and transient asymptomatic drops in left ventricular ejection fraction.

A noteworthy aspect of this study is that many of the 32 predictive genomic markers that were identified function in domains other than proliferation. Genes that figure in proliferation are the predominant drivers of the prognostic performance of Genomic Health’s Oncotype DX and all the other molecular biomarker assays developed to date. So the work of Dr. Perez and her coinvestigators is definitely next-generation in the molecular profiling arena, said Dr. Sgroi of Massachusetts General Hospital, Boston.

This study was funded by the National Cancer Institute, the Breast Cancer Research Foundation, and the 26.2 with Donna Foundation. Dr. Perez reported no financial conflicts.

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