1. Carlson, Robert H.

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NEW YORK CITY-There is a subgroup of women with HER2-positive breast cancer who appear to be particularly sensitive to HER2 blockade. Reinforcing that blockade by using two anti HER2 agents together may substantially reduce the need for anthracycline therapy. That was the conclusion of Martine J. Piccart, MD, PhD, speaking here at the Chemotherapy Foundation Symposium, giving the Ezra Greenspan Memorial Lecture, named after the meeting's founder.

Chemotherapy Foundat... - Click to enlarge in new windowChemotherapy Foundation Symposium

"Today the vast majority of women with breast cancer are treated in the adjuvant setting with anthracycline and taxane," said Dr. Piccart, Director of the Medicine Department at Jules Bordet Institute and Professor of Oncology at Universite Libre de Bruxelles in Belgium. "Emerging data might suggest that a subgroup of women with HER2-positive breast cancer might do very well with the use of two anti-HER2 therapies and only three months of paclitaxel weekly."


Dr. Piccart called this "chemotherapy light." She urged caution because the hypothesis obviously needs to be validated-"But it will not be easy to validate this. It is much easier to add new drugs on to existing standards of care, which we have been doing all the time, than to try to subtract drugs to show something less aggressive works just as well."


She said she was concerned about the difficulty of financing such trials when the goal of the trial is de-escalation of treatment-"It is not very interesting for Pharma, so we will have to look for help from foundations."


Dr. Piccart says researchers should nonetheless be thinking this way, because with the increase in the use of expensive agents there will come a point where society will not be able to afford them.


But she was far more optimistic about the science itself.


"If we do excellent clinical and translational research, in the next two years we may be able to identify a subgroup of women with HER2 positive breast cancer whom we are going to be able to cure with the smart use of two anti-HER2 drugs and very light chemotherapy," she said.


One of the Great Discoveries in Translational Research[horizontal ellipsis]

In her presentation, Dr. Piccart said one of the greatest discoveries in translation research in cancer, in 1987, was that tumors overexpressing HER-2 were overly aggressive. Only five years later a humanized anti HER2 monoclonal antibody was developed, trastuzumab. More recently, a combination of trastuzumab and chemotherapy showed a survival gain in metastatic disease, and it was reported in 2005 that trastuzumab and chemotherapy can reduce the risk of relapse of early HER2-positive breast cancer by approximately 50%.


"I think the next important progress we are going to make for these women with HER2-positive breast cancer is treatment with dual HER-2 blockade."


Two features make HER2-positive breast cancer unique, she said: oncogene addiction and immunogenicity of HER2 overexpression. "Exploitation of these two features will allow us to develop 'chemotherapy light' treatments for selected patients."


'Oncogene Addiction'

Oncogene addiction, a concept introduced in 2002, holds that despite genomic and epigenetic complexities, tumor regressions can occur with the inactivation of a single oncogene, she said. "Pathway dependence is immense, and dramatic regressions can happen if one treats with inhibitors of the same pathway." The effect is much more powerful when two HER2 inhibitors are used.


The concept of dual blockade has been tested in clinical trials, Dr. Piccart said. For example, the NEO-SPHERE trial included 417 patients randomly assigned to receive combined trastuzumab with or without pertuzumab and with or without docetaxel; and in the NEO-ALLTO trial, 450 patients received lapatinib with paclitaxel, trastuzumab with paclitaxel, or all three drugs. In both trials, these anti-HER2-based therapies were followed by surgery, chemotherapy, and further anti-HER2-based treatment.


And in both trials, she said, there were lower pathologic complete response rates in the ER-positive/HER2-positive subgroups.


Dr. Piccart reviewed what she said were exciting results presented at the 2011 meeting of the American Society of Clinical Oncology (Chang et al, Abstract 505), of a neoadjuvant trial giving women dual HER-2 blockade alone or with endocrine therapy.


"With the administration of dual HER-2 blockade with lapatinib and trastuzumab, the pCR rate was 40% in women with ER-negative disease," she said. "But with the addition of endocrine treatment [letrozole, with or without goserlin], Dr. Chang achieved a 21% pCR rate in the subgroup with ER-positive disease."

MARTINE J. PICCART, ... - Click to enlarge in new windowMARTINE J. PICCART, MD, PHD: "If we do excellent clinical and translational research, in the next two years we may be able to identify a subgroup of women with HER2 positive breast cancer whom we can cure with the smart use of two anti-HER2 drugs and very little chemotherapy."

To make chemotherapy light a reality, Dr. Piccart said researchers will have to understand who are the right candidates for dual HER2 blockade; better understand the role of the host immune system; start thinking about trials where the immune system receives a boost; and also perhaps conduct trials that combine dual HER2 blockade with modern immune therapies.