Leading Oncologists Analyze Impact of New HER2 Research on Clinical Practice

Martine J. Piccart, MD, PhD

Although recent research findings suggest some patients with HER2-negative breast cancer would benefit from therapies directed against overexpression of the protein, two leading oncologists do not see an immediate impact on clinical practice as further validation is needed. Yet, they say major changes may be on the horizon.

OncologyLive asked Martine J. Piccart, MD, PhD, president of the European Society for Medical Oncology, and Debu Tripathy, MD, co-leader of the Women’s Cancers Program at the Norris Comprehensive Cancer Center at the University of Southern California in Los Angeles, to put the findings into perspective for practicing oncologists.

Both oncology leaders, who spoke at the 30th Annual Miami Breast Cancer Conference in March, have conducted key research into trastuzumab (Herceptin), the first HER2-directed therapy. Piccart helped lead the HERA trial, which has solidified one year of trastuzumab treatment as the standard of care for HER2-positive, early-stage patients after initial therapy. Tripathy’s work contributed to the development of trastuzumab in the mid- to late 1990s.

Fresh insights into HER2 include research from the Siteman Cancer Center and The Genome Institute at Washington University in St. Louis, Missouri, demonstrating that rare activating mutations in the HER2 gene can drive breast cancers among patients who would be considered HER2-negative by standard testing (Cancer Discov. 2013;3(2):224-237).

Meanwhile, investigators at the University of Michigan Comprehensive Cancer Center in Ann Arbor suggested that cancer stem cells and the bone microenvironment help drive HER2 activity even in patients who test negative for overexpression (Cancer Res. 2013;73(5):1635-1645).

Martine J. Piccart, MD, PhD

Here are the comments from Piccart and Tripathy:“Until now, we thought we had a very clear picture⎯that only patients with tumors showing HER2 amplification or overexpression benefit from anti-HER2 therapies. It is true that this belief has been shaken a little bit by some recent observations, but, to me, this is rather good news because we could offer anti-HER2 therapies to a larger proportion of women with breast cancer. These treatments are usually very well tolerated.

“The first interesting subgroup of patients where we are currently examining whether an anti-HER2 treatment could be beneficial are women with HER2-negative cancers who have circulating tumor cells at completion of standard chemotherapy. We have the notion that most of the circulating tumor cells are HER2-positive, so there is an interesting trial that is starting now by the EORTC [European Organisation for Research and Treatment of Cancer], which is going to randomize patients with HER2-negative test results but with HER2- positive circulating tumor cells detectable in the blood, between six months of trastuzumab or no treatment [NCT01548677].”

Debu Tripathy, MD

Debu Tripathy, MD

Piccart said the discovery of a driver HER2 mutation in patients who test negative for HER2 expression is not something that can be translated to practice at this time. “The mutation is too rare to imagine that medical oncologists outside big cancer centers would start to ask for this gene to be screened,” she said. “It doesn’t make sense at this point in time, but, clearly, it’s totally possible that in the not-too-distant future, we completely change the way we do oncology. It is possible that we will be able to screen the tumors of all patients for a wide pattern of gene mutations with very powerful diagnostic tests. Then it will be much easier, of course, to identify patients with rare abnormalities that are potentially actionable.”“For now, it’s important to understand how to deploy the therapeutics we do have for breast cancer. Certainly, trastuzumab is the standard of care for early-stage HER2-positive breast cancer or for metastatic cancer in patients who previously have not been treated with trastuzumab.

“We now have newer drugs that are not perfect but they certainly have a clinical impact. In the first-line setting, the addition of pertuzumab to trastuzumab, which inhibits dimerization of the receptor, has yielded a significant improvement on disease-free and overall survival, and is now approved for use in combination with docetaxel as firstline therapy. Just very recently, T-DM1, an immunoconjugate that uses in part the trastuzumab antibody bound to a toxin, seems to outperform the prior standard for second-line therapy, which is lapatinib and capecitabine.

“These advances are important. They extend survival, they do so with minimal impact on toxicity, and really represent new standards that help our patients. They do have their limitations. We’re still not curing these patients, and not all of them respond.”

Tripathy said the discovery of rare mutations offers opportunities for practicing oncologists to help their patients by participating in clinical trials. “Clinical trials are becoming increasingly available to the oncology general community,” Tripathy said. “For oncologists who don’t have clinical trials open, they should look to see if they can either open them on their own or maybe partner with another institution. This is a new era for engaging oncologists in the community in clinical trials, and what I’d like to see is that most patients who are being seen in the community setting can stay in the same setting but still have access to investigational drugs.

“Increasingly, it is relevant to the practicing oncologist to be aware of these molecular changes. It’s still mostly in the investigational setting, but the field is moving very quickly.”