A proportion of patients with breast cancer whose tumors test HER2-negative for gene amplification on fluorescence in situ hybridization or immunohistochemistry harbor HER2 mutations that are amenable to treatment with anti-HER2–targeted therapy, according to a gene-sequencing study presented at the 2012 San Antonio Breast Cancer Symposium.
13 Different Somatic Mutations
“HER2 mutations predominantly occur in patients who are HER2-negative, and our work suggests that many of these mutations are activating events that cause oncogenic transformation; thus, they are highly likely to be driver events in these breast cancers,” stated Ron Bose, MD, PhD, Assistant Professor of Medicine, Washington University School of Medicine, St. Louis.
Dr. Bose explained that progress in genome sequencing has led to the identification of HER2 somatic mutations that occur in the DNA of breast cancer, but not in normal DNA. “These are not inherited mutations,” he said.
He and his colleagues analyzed eight genomic sequencing studies that included data on nearly 1,500 patients with breast cancer. They identified 25 patients with 13 different HER2 somatic mutations. Only one of the patients who harbored these mutations also had HER2 amplification, which is the hallmark of HER2-positive breast cancer.
“Our study showed that the mutations were being expressed and occur predominantly in patients with normal HER2 gene copy numbers,” he noted.
These mutations occur in an estimated 1% to 2% of patients with breast cancer, he estimated, but there may be subgroups where they are expressed more frequently. “This translates to about 4,000 women in the United States with these activating mutations, about the same number of people with chronic myelogenous leukemia,” he said.
Two Domains
The investigators did extensive testing on the 13 mutations. Their findings were published in Cancer Discovery,2 to coincide with Dr. Bose’s presentation at the San Antonio meeting.
The mutations occurred mainly in two regions: the extracellular domain and the kinase domain. Mutation-bearing cells grown in culture formed irregular growths. Many of the growths were reversible with approved anti-HER2 therapies including trastuzumab (Herceptin) or lapatinib (Tykerb). However, all of the mutations, including two mutations associated with lapatinib resistance, were sensitive to neratinib.
Based on these preclinical results, a multi-institutional phase II trial has been initiated. Patients with stage IV, HER2-negative breast cancer will be screened by sequencing DNA from their cancer, and those who have somatic HER2 mutations will be treated with neratinib. Tumor response to neratinib will be measured by RECIST criteria.
Press conference moderator C. Kent Osborne, MD, Professor of Medicine and Director of both the Lester and Sue Smith Breast Center and Dan L. Duncan Cancer Center at Baylor College of Medicine in Houston, said that these preliminary findings have limited clinical utility at present. “But if you are a patient with one of these mutations, it is important for you to know. Now that Bose et al have identified these mutations, it is possible that they will be found in other types of cancer, heightening their importance.”
Addition of Trastuzumab
Formal discussant of the trial, Maccon M. Keane, MD, Consultant Oncologist at Galway University Hospitals, Galway, Ireland, raised the issue of whether adding trastuzumab to neratinib could improve outcomes.
Dr. Bose said that in tissue culture, no benefit was observed for adding trastuzumab to neratinib. “But we don’t know what the situation will be in actual patients,” Dr. Bose commented.
If the phase II study shows that targeting the mutations with neratinib improves outcomes, it is more likely that genomic sequencing of HER2 will move to the clinic, Dr. Bose said. Although genomic sequencing is not yet used to guide breast cancer treatment, it is being used increasingly in lung cancer and other cancers. ■
Disclosure: Drs. Bose, Osborne, and Keane reported no potential conflicts of interest.
References
1. Bose R, Kavuri SM, Searleman AC, et al: Activating HER2 mutations in HER2 gene amplification negative breast cancers. 2012 San Antonio Breast Cancer Symposium. Abstract S5-6. Presented December 7, 2012.
2. Bose R, Kavuri SM, Searleman AC, et al: Activating HER2 mutations in HER2 gene amplification negative breast cancer.Cancer Discovery. December 7, 2012 (early release online).
