New Developments on Horizon in HER2-Positive Breast Cancer

Anna Azvolinsky, PhD
Published: Monday, Mar 10, 2014

Sunil Verma, MD, MSEd, FRCPC

Sunil Verma, MD, MSEd, FRCPC

In the last decade, there have been tremendous improvements in the treatment of HER2-positive breast cancer with new HER2-targeted agents improving survival in both the adjuvant and metastatic settings. We spoke about this progress and the current focus of research in the HER2-positive breast cancer setting with breast cancer expert, Sunil Verma, MD, MSEd, FRCPC, an associate professor at the University of Toronto and chair of Breast Medical Oncology at the Sunnybrook Odette Cancer Centre in Toronto, Canada. In his presentation, Verma will review the state of treatment of HER2-positive disease.

What is the current state of HER2-targeted therapy in metastatic disease?

Verma: In metastatic disease, over the past decade, we have seen a nearly doubling of the overall survival (OS) for patients with metastatic HER2-positive breast cancer since the pivotal publication of Slamon et al, in 2001, which showed an improvement from a 20-month to 25-month survival with integration of trastuzumab, and now we are seeing an improvement in OS with the addition of pertuzumab with docetaxel in the CLEOPATRA study, which is beyond 45 months. This survival improvement has been fueled through integration of new agents, such as pertuzumab, and also through the continuation of HER2-positive therapy with trastuzumab and lapatinib. The other key achievement is the development of T-DM1. This is the first time in solid tumors that an antibody-drug conjugate has been shown to be associated with an improvement in OS with superior toxicity profile. And so having both an improved OS with less toxicity is a remarkable achievement for our patients with HER2-positive disease.

What about for HER2-positive therapies in the adjuvant setting?

In adjuvant disease, there are two camps of research moving forward. On one side, we are trying to see how we can improve outcomes of patients by integrating newer agents. On the other side, we are trying to see whether we can get away with giving a select group of patients less traditional chemotherapy and possibly even a total targeted approach. So with that in mind, and certainly in our patients who received neoadjuvant therapy, we have seen that the integration of pertuzumab and lapatinib can improve pathologic complete response (pCR) rate. The data by Martine Piccart-Gebhart showed that addition of lapatinib to trastuzumab improves pCR, and this improvement translates to a superior event-free survival. The FDA recently approved pertuzumab in the neoadjuvant setting. On the other hand, there is emerging evidence that certain groups of patients may not need intensive chemotherapy. The APT trial showed that node-negative patients who have tumor size up to 3 cm receiving weekly paclitaxel and trastuzumab regimen had excellent outcomes with a disease-free survival (DFS) >98%. There are ongoing efforts to understand if shorter duration of trastuzumab therapy may also be reasonable for certain patients. So over the next 5 years, I anticipate that not all HER2-positive patients will be treated the same way, with certain patients who will be able to receive less chemotherapy and trastuzumab or even a total targeted approach, but there are certainly patients who need the standard one-year treatment along with newer targeted agents like lapatinib or pertuzumab.

What are key developments in how advancements in new neoadjuvant therapies are approached as they relate to HER2-positive disease?

The FDA has taken the right step in informing the research community that they are willing to consider pCR as a surrogate endpoint for approval of new HER2 therapies, which was based on a meta-analysis of close to 12,000 patients. There was a clear signal that pCR is an effective marker for long-term outcomes when evaluating anti-HER2 therapies. I think this is an important step forward, allowing us to expedite drug approval and design trials with meaningful results, but in a shorter timeframe, rather than doing large and adjuvant trials with long follow-up that sometimes impacts how quickly effective therapies are adopted into clinical practice.

What are the new anti-HER2 agents in development that you can highlight?

The most exciting next class of agents are the PI3K inhibitors. There appears to be interest in ERnegative, HER2-positive patients. There is also significant interest in developing second-generation tyrosine kinase inhibitors with drugs like neratinib. There needs to be a significant focus on drugs that can penetrate the bloodbrain barrier, because brain metastases remain a very significant challenge for patients with metastatic HER2- positive breast cancer.

What is the status of biomarkers for either prognosis or diagnosis?

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