Debu Tripathy, MD
In 1998, the first targeted therapy for the treatment of breast cancer entered broad clinical practice when the FDA approved trastuzumab (Herceptin) for patients with metastatic tumors that overexpress the human epidermal growth factor receptor 2 (HER2) protein.
Yet although HER2 has become one of the best-known biomarkers in oncology, continuing exploration of the molecular nature of tumor biology has yielded fresh insights and some surprises about HER2 signaling in breast cancer.
The latest research into HER2
gene mutations was among the highlights that Debu Tripathy, MD, emphasized in his presentation on “ASCO and San Antonio Updates” as the 30th Annual Miami Breast Cancer Conference (MBCC) opened Thursday.
Tripathy’s review of key abstracts presented at the 2012 American Society of Clinical Oncology (ASCO) annual conference and the San Antonio Breast Cancer Symposium (SABCS) has become a staple of MBCC. Tripathy, coleader of the Women’s Cancers Program and a professor of Medicine at the Norris Comprehensive Cancer Center at the University of Southern California in Los Angeles, is one of the program directors of MBCC.
In addition to HER2 research, Tripathy summarized noteworthy results from clinical studies in local, adjuvant, and metastatic disease therapies. His presentation covered 15 abstracts. In this interview, Tripathy discussed some of the most noteworthy studies.
New HER2 Complexities Uncovered
Researchers from the Washington University School of Medicine in St. Louis, Missouri, used genome-sequencing data to more precisely identify the role of HER2
mutations in driving tumors. Some patients whose tumors are HER2- negative based on standard assays may harbor undetected HER2
gene mutations that are driving disease and may be sensitive to HER2-directed therapies, the researchers suggested in an abstract presented at SABCS1
and in an article in Cancer Discovery
Investigators compiled data from several genome sequencing projects to identify patients whose tumors exhibited HER2
somatic mutations but not HER2
gene amplification. They then used experimental techniques, including in vitro kinase assays and protein structure modeling, to characterize activating mutations and determine which anti-HER2 therapies might be effective.
Bose et al concluded that HER2
somatic mutations promote HER2 signaling activity, and that these mutations also can be anticancer targets. One drug that is being tested as a result of their research is neratinib, an oral dual HER1/HER2 inhibitor.
Based on these findings, Bose and colleagues also hypothesize that undetected HER2
mutations, as opposed to HER2
amplification, may be present in 1.5% to 2% of patients with breast cancer, which would translate to more than 4000 of the newly diagnosed patients annually in the United States.
Tripathy said the findings make diagnosing and treating HER2 breast cancers more complex, and that the implications for targeting driver mutations go beyond this particular gene.
“We have generally thought that the way HER2 drives breast cancer is when it is present in large amounts,” Tripathy said. “Now we’re also discovering that another way HER2 can activate cancer is when it is present in normal amounts but when the gene itself is mutated in such a way that turns it on. This is a fundamentally different way that a gene can cause cancer.”
Tripathy said one challenging aspect of the knowledge gained through genome sequencing and other novel methods is that many of the mutations being discovered are relatively uncommon.
Untreated breast cancer cells with HER2 mutations, top image. Cells shrink after treatment with neratinib, bottom.
“We find many mutations that are only present in 1%, 2%, or 3% of cancers, which means that if we try to design therapy that counteracts the effects of these mutations with new therapies that are really targeted to these mutations, we’re going to have to come up with a whole panel, a whole set of therapies,” Tripathy said.
“Moreover, we’re finding that any given cancer has not only one mutation in it but may contain several—up to 40—and that would suggest that we’re going to have to develop cocktails of drugs, and that we are going to have to create a customized one for each patient depending on the sequence of their tumor,” he said.