Activating HER2 Mutations Found in HER2-Negative Patients

Phoebe Starr

Uncategorized

Approximately 4000 breast cancer patients in the United States harbor HER2 mutations amenable to treatment with anti-HER2 therapy but are not receiving it because they are not HER2-positive on fluorescence in situ hybridization or immunohistochemical testing. However, genomic sequencing can identify patients with these mutations, who are likely to benefit from existing anti-HER2 therapies. These are the implications of a genomic sequencing study reported at the 2012 CTRC-AACR San Antonio Breast Cancer Symposium.

“These patients are going to be missed by our routine testing for HER2-positive breast cancer, but the mutations can be identified by genomic sequencing,� said lead author Ron Bose, MD, PhD, assistant professor of medicine at Washington University School of Medicine in St. Louis, MO. “These mutations are not inherited,� he emphasized.

Bose explained that 1.5% to 2% of breast cancer patients will test negative for HER2 amplification (reflecting multiple copies of the gene) and have undetected HER2 mutations that drive tumor growth.

Bose and colleagues analyzed nearly 1500 patients who participated in 8 DNA sequencing studies; 25 patients were found to have HER2 mutations without HER2 gene amplification. These mutations clustered in 2 areas of the HER2 protein, he said: the tyrosine kinase area and the extracellular domain of the HER2 gene. Not all of the mutations were equally activating. Of 13 mutations that were analyzed, 7 were determined to drive cancer proliferation.

“The mutations stimulate the function of HER2, and we feel they are highly likely to drive the growth of cancers when they are present,� Bose continued.

Laboratory studies showed that activating HER2
mutations were sensitive to the drugs lapatinib and trastuzumab, with the exception of the L755S mutation and deletion of 755-759. Both mutations were resistant to lapatinib but sensitive to neratinib, a drug currently in phase 2 testing.

These findings led to the launching of a multi-institutional phase 2 trial in women with metastatic breast cancer who test negative for HER2 amplification and who harbor HER2 mutations found on genomic sequencing. The women will be treated with neratinib 240 mg/day and monitored every 2 weeks. Four institutions will participate in the phase 2 trial: Washington University, Dana-Farber Cancer Institute, Memorial Sloan-Kettering Cancer Center, and University of North Carolina.

The study was published online December 7, 2012, in Cancer Discovery, to coincide with the presentation of the data at the symposium.

“These results show how cancer genome sequencing can be directly applied to guide individual patient treatment. HER2 mutations are a target for breast cancer treatment, and gene sequencing is needed to identify these patients. If the phase 2 trial is successful, we estimate that 4000 women per year could benefit. This is the same size as the patient population with chronic myelogenous leukemia in the US,� Bose stated.

George Sledge, MD, Indiana University School of Medicine, Indianapolis, said that 1% to 2% of all breast cancer patients is comparable to the number of patients with lung cancer who are positive for the ALK gene.

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