Exploiting Oncogene Addiction and Immunogenicity May Be Path to Improved Results in HER2-Positive Breast Cancer

Martine J. Piccart, MD, PhD

The approval of trastuzumab, targeted directly to the human epidermal growth factor receptor (HER2)-positive, was a major advance in extending the lives of women with HER2-positive breast cancer. More good news may be on the horizon for this group of women, as researchers identify how to best combine trastuzumab with other HER2 inhibitors.

"I want to share a dream with you, that excellent clinical and translational research may identify a subgroup of women with HER2-positive breast cancer who can be cured with dual HER2 inhibition and little chemotherapy," Martine J. Piccart, MD, PhD, told attendees at the Chemotherapy Foundation Symposium held in New York City. Piccart is president-elect of the European Society for Medical Oncology (ESMO), past-president of the European Organisation for Research and Treatment of Cancer (EORTC), and is professor of Oncology at the Université Libre de Bruxelles and director of the Medicine Department at the Institut Jules Bordet in Brussels, Belgium.

Listing achievements so far in HER2-positive breast cancer, she cited a survival gain in metastatic breast cancer with trastuzumab in 1999, and a disease-free survival in early breast cancer with trastuzumab in 2005. In 2010, dual HER2 blockade achieved double the rate of pathological complete response (pCR) seen with trastuzumab alone.

"HER2-positive breast cancer is unique because of two features: oncogene addiction and immunogenicity of HER2 overexpression," Piccart told listeners. It is these 2 features that may enable the dream she talked about to become a reality. "Exploiting these two features may help us develop chemo-light treatments," she stated.

Oncogene addiction refers to targeting the same pathway with different inhibitors. In HER2-positive breast cancer, anti-HER2 drugs such as trastuzumab, lapatinib, and pertuzumab act differently on the same pathway, and these drugs are being studied in various combinations to see if outcomes can be improved.

"Two anti-HER2 agents in combination can lead to profound apoptosis in a subset of women with HER2-positive breast cancer. We don't know who they are yet, but this strategy will allow us to use very little chemotherapy," Piccart said.

The Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation (NeoSPHERE) and Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (NeoALTTO) trials are looking at combinations of HER2 inhibitors in the neoadjuvant setting. Both trials had 1 arm that included 2 different anti-HER2 drugs with no chemotherapy.

NeoSPHERE enrolled 417 women with HER2-positive breast cancer and randomized them to receive: docetaxel/trastuzumab; docetaxel/trastuzumab/pertuzumab; docetaxel/pertuzumab; or trastuzumab/pertuzumab alone. This trial found that the rate of pCR was 46% for the dual antibody arm, which was much higher than the other 3 arms.

NeoALTTO randomized 450 women with HER2-positive breast cancer to lapatinib/paclitaxel, trastuzumab/paclitaxel, or concomitant lapatinib/trastuzumab for 1 year. In this study, the rate of pCR was 51% for the dual antibody arm, again much higher than the other 2 arms.

These trials had different results according to hormonal status. In general, pCR was lower in the estrogen receptor (ER)-HER2-positive patients. However, in NeoSPHERE, very little gain was observed for dual antibody therapy in the ER-positive patients, while in NeoALTTO both ER-negative and ER-positive patients had benefit. In NeoSPHERE, pertuzumab added little benefit to trastuzumab in the ER-positive subset.

"It is primarily the ER-negative women who gain benefit from dual antibody blockade," Piccart stated. More research is needed to identify the subset that will benefit from dual HER2 inhibition.

Biomarkers were incorporated in NeoALTTO, and also in the large Adjuvant Lapatinib and/or Trastuzumab Treatment Optimisation (ALTTO) study of adjuvant dual HER2 blockade. When these results are analyzed, there may be more clues as to which women can be treated with dual blockade and very little chemotherapy.

A large registry trial, Adjuvant Pertuzumab and Herceptin in Initial Therapy of Breast Cancer (APHINITY), will enroll 3800 patients with HER2-positive breast cancer and randomize them to placebo/trastuzumab versus trastuzumab/pertuzumab.

Three independent studies in HER2-positive breast tumors have shown that high expression of immunogenetic genes is associated with improved prognosis. It has been shown that trastuzumab generates CD8-dependent adaptive antitumor immunity. Perhaps only patients who can generate this immunity may be the ones who achieve durable responses, Piccart said.

"We need to understand which immune cells are important, but this research tells us that the microenvironment of the tumor matters," Piccart said.