Breast Cancer Genome Sequencing Identified HER2 Mutations as Targets for Drug Treatment

This abstract will be presented at a press conference hosted by C. Kent Osborne, M.D., director of the Lester and Sue Smith Breast Cancer Center at Baylor College of Medicine, on Friday, Dec. 7 at 7:30 a.m. CT in Room 217 A-C of the Henry B. Gonzales Convention Center. Reporters who cannot attend in person can call in using the following information:• U.S./Canada (toll free): 1 (800) 446-2782• International (toll call): 1 (847) 413-3235

Newswise — SAN ANTONIO — An analysis of data from a series of studies documenting breast cancer genome sequencing has confirmed that HER2 mutations may be ideal targets for breast cancer treatment. Further, the majority of these mutations are activating mutations that drive breast cancer cell growth in tissue culture.

Ron Bose, M.D., Ph.D., assistant professor in the division of oncology at the Washington University School of Medicine and the Siteman Cancer Center in St. Louis, Mo., presented these results at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium, held here Dec. 4-8. The data were also published in Cancer Discovery, a journal of the American Association for Cancer Research.

Bose and colleagues reviewed data from eight genome-sequencing studies that included nearly 1,500 patients. Twenty-five patients’ cancer had HER2 mutations, nearly all of which occurred in those who did not have HER2 gene amplification, the hallmark of HER2-positive breast cancer. Bose estimated that HER2 mutations occur in 1 percent to 2 percent of breast cancer cases, but there may be subgroups in which the frequency of this mutation is higher.

“Normally, patients with HER2 mutations would not qualify to receive drugs that target HER2, such as trastuzumab, because the HER2 gene amplification tests will come back as normal. This is because the current testing used to measure HER2 in breast cancer will not pick up HER2 mutations. DNA sequencing of HER2 is needed,” Bose said. “It is possible that patients with cancers containing HER2 mutations will benefit from receiving the same drugs that are currently used to treat patients with HER2-positive breast cancer.”

Analysis showed that HER2 mutations clustered in two regions of the HER2 gene. The researchers found one cluster in 20 percent of patients in the outside half of HER2, called the extracellular domain. Seventy percent of patients had mutations in the inside half of HER2, specifically in the tyrosine kinase domain. After testing 13 HER2 mutations, the researchers found a majority were activating mutations that were sensitive to the drugs lapatinib and trastuzumab. Two of the mutations, however, were resistant to lapatinib and sensitive to neratinib.

“The activating mutations are turning on HER2’s functioning and will probably result in abnormal, unregulated HER2 signaling, which is likely driving the cancer cell,” Bose said. “These mutations were sensitive to HER2 tyrosine kinase inhibitors. Many were sensitive to lapatinib, an FDA-approved drug, and all were sensitive to neratinib, a drug in phase II clinical trials.”

However, not all HER2 mutations were activating mutations. A few mutations appeared to be “silent events” occurring in the genome of the cancer. “Just because we see a mutation in the HER2 gene does not guarantee that every case is an activating mutation that is sensitive to drugs,” Bose said. “The best way to find out is to test individual mutations in the laboratory.”

Bose and his colleagues are now working on a multicenter, phase II clinical trial testing neratinib in patients who have HER2 mutations in their breast cancer.

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The mission of the 2012 CTRC-AACR San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for patients with breast cancer. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR) and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor and the AACR’s scientific prestige in basic, translational and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. For more information about the symposium, please visit www.sabcs.org.

Abstract:Publication Number: S5-6

Title: Activating HER2 mutations in HER2 gene amplification negative breast cancers.

Ron Bose1, Shyam M Kavuri1, Adam C Searleman1, Wei Shen1, Dong Shen2, Daniel C Koboldt2, John Monsey1, Shunqiang Li1, Li Ding2, Elaine R Mardis2 and Matthew J Ellis1. 1Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, MO and 2The Genome Institute and the Dept. of Genetics, Washington University School of Medicine, St. Louis, MO.

Body: Background: Breast cancer genome sequencing projects, performed by the genome sequencing centers in the U.S., Canada, and the U.K., are elucidating the somatic mutations and other genomic alterations that occur in human breast cancer. These studies recently identified somatic HER2 mutations in breast cancers lacking HER2 gene amplification.

Results: Compilation of data from seven sequencing studies documented 22 patients with somatic HER2 mutations. These mutations clustered in three regions. The first cluster was at amino acid (aa) 309-310 (exon 8), located in the extracellular domain. These aa residues form part of the HER2 dimerization interface. The second cluster was at aa 755-781, located in the kinase domain (exons 19-20). This was the most common location for HER2 mutations, with 17 out of 22 patients having somatic mutations here. The third region was at aa 835-896, also in the kinase domain (exons 21-22). Using multiple experimental approaches (cell line experiments, in vitro kinase assays, protein structure modeling, and xenograft experiments), we tested seven of these HER2 mutations and showed that 4 of them are activating mutations that are sensitive to lapatinib and trastuzumab. Another 2 mutations were found to be lapatinib resistant and we determined their sensitivity to neratinib, canertinib, and gefitinib.

Conclusions: These findings biologically validate somatic HER2 mutations as good targets for breast cancer treatment, but the appropriate choice of targeted drug is dependent on the precise mutation present. This study is among the first to functionally characterize mutations identified by breast cancer genome sequencing. A prospective, multi-institutional clinical trial has been launched to screen for HER2 mutation positive patients and determine the clinical outcome of treatment with HER2 targeted drugs.