News Reports: April 2007

By Querida Anderson and Prachi Patel-Predd
Published: Thursday, Aug 12, 2010

%u25BA New Clues to Herceptin Resistance

Researchers at Harvard and Yale Universities discovered markers in breast cancer tumors associated with resistance to Herceptin® (trastuzumab, Genentech). “Herceptin has revolutionized the care of HER2-positive breast cancer for many patients, but unfortunately, not for some,” noted Lyndsay Harris, MD, the study’s lead author and associate professor and director of the Breast Cancer Disease Unit at Yale University Medical Center. “This research is important in that it has generated a hypothesis of certain markers that are associated with resistance. A second study is required to validate these markers to tell us which ones are truly causative.”

Most importantly, Dr. Harris said, “We were the first to discover that HER2 tumors have a basal subgroup.” The non-responding tumors were observed to be more likely to express genes associated with basal-like breast cancer. This is surprising because most basal-like tumors are HER2-negative, she explained. Such cancers are often more aggressive and have unique features, making them resistant to therapy.

About a quarter of patients newly diagnosed with breast cancer annually have the HER2 class of tumor. Response rates for Herceptin, although hard to accurately determine, seem to be only about 30%, noted Dr. Harris. Along with chemotherapy, however, the response rates double, she added. The Herceptin plus chemotherapy regimen, though, can cause heart damage, according to Dr. Harris. “Hence, one reason we decided to do this study was to find a less toxic regimen than Herceptin and chemotherapy. Another focus was to try and define molecular markers associated with Herceptin resistance.”

Navelbine®(vinorelbine, Glaxo Wellcome), approved for lung cancer, has been shown to be very effective and less toxic in  breast cancer than standard chemotherapy. “Thus, we decided to study the Herceptin/Navelbine combination and use that to assess markers for resistance,” she explained.

In the February 15 issue of Clinical Cancer Research, the researchers report that the combination was well tolerated. The non-responsive tumors showed a continued overexpression of HER2. “That tells us that the cancer cells are still creating HER2 surface proteins even as Herceptin is being used, and that means HER2 loss does not appear to be a mechanism of resistance in earlystage breast cancer,” Dr. Harris remarked.

The researchers derived about 50 to 60 markers that were either up-regulated or down-regulated in the Herceptin-resistant tumors, including certain basal markers, growth factors and growth factor receptors. Insulin-growth factor receptor 1 (IGF-1R) was associated with a Herceptin response rate that was half that of tumors that did not express IGF-1R. Similar association of IGF-1R to Herceptin resistance has been reported in three previous studies, noted Dr. Harris. Herceptin-resistant tumors were

also more likely to express a variety of growth factors, suggesting that “activation of parallel pathways may release tumors from dependence on HER2 proliferation and survival.”

If additional studies validate these findings, it may be possible to select those patients that will be resistant to Herceptin and treat them with additional drugs to restore sensitivity. “Our goal is to see what the tumor tells us before any treatment starts and tailor therapy accordingly.”

Dr. Harris plans to conduct a bigger study to compare the Navelbine/Herceptin regimen and standard paclitaxel/carboplatin/ Herceptin regimen for tolerance. She will also test the profile of markers found in the current study in its ability to predict outcome in the second study. Additionally, she plans to study IGF-R1 and inhibitors of IGF-R1.

                                                                                                                                                                                           —Querida Anderson


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