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Research and Clinical Trials

Return to Triple-Negative Breast Cancers Challenge Researchers Overview

More on Triple-Negative Breast Cancers Challenge Researchers

Triple-Negative Breast Cancers Challenge Researchers

New York (Dec 17, 2010)

African-American woman wearing red scarf

Triple-negative breast cancers, which account for 10 to 20 percent of breast cancers, present a formidable clinical challenge. Because they lack estrogen and progesterone receptors, they do not respond to tamoxifen and aromatase inhibitors. Since they do not overexpress HER2, they cannot be treated with trastuzumab or lapatinib. Moreover, they tend to be quite aggressive and are more likely to recur.

Triple-negative breast cancers represent a form of the disease for which no targeted therapy is known. NewYork-Presbyterian Hospital laboratory scientists and clinical researchers are now scrutinizing the biology of triple-negative breast cancers and participating in clinical trials of new treatment approaches.

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About 90 percent of BRCA1 mutation carriers with breast cancer have triple-negative disease. Triple-negative breast cancers often arise earlier in life than other breast cancers. They are also more common among African-American and Hispanic women – groups that comprise a large segment of the Hospital's breast cancer patients. Indeed, a quarter of the women with breast cancer treated at NewYork-Presbyterian/Columbia's Herbert Irving Comprehensive Cancer Center (HICCC) have triple-negative disease.

"The only way we're going to make headway against these cancers and develop more effective treatments is to expand our understanding of their pathogenesis," said Ramon Parsons, M.D., Ph.D. Toward that goal, he and his colleagues have been deciphering the signaling pathways involved in breast cancer development.

Ramon Parsons, M.D., Ph.D.
Ramon Parsons, M.D.,

In 1997, Dr. Parsons and his team identified the PTEN tumor suppressor gene, mutations in which have been linked to breast cancer, as well as brain and prostate cancers. In 2007, they reported for the first time that when BRCA1 is altered, PTEN loses its ability to put the brakes on cancer cell growth. "Once a cell loses PTEN, it has a growth advantage over its neighbors and starts on the road to cancer," Dr. Parsons explained.

He and his fellow investigators at the HICCC are now studying the PI3 kinase enzyme in basal-like breast cancers, which account for most triple-negative tumors. "Since PI3 kinase is commonly mutated and PTEN is commonly inactivated in many breast cancers, we're seeking to develop a way to target this pathway with more effective therapies," said Dr. Parsons.

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Because triple-negative breast cancer is actually a group of heterogeneous diseases, no single therapy is likely to be effective for all women. Several clinical trials of new agents as well as combinations of existing agents are therefore underway.

A phase I study being conducted at NewYork-Presbyterian/Columbia is evaluating the combination of temsirolimus, erlotinib, and cisplatin. Cisplatin is a known active cytotoxic agent against breast cancer. Temsirolimus targets the mTOR signaling pathway, while erlotinib homes in on the epidermal growth factor receptor. It is hoped that cisplatin could trigger apoptotic death in a cell whose PI3 kinase survival pathways are effectively inhibited by temsirolimus and erlotinib. The Principal Investigator of the study is Matthew Maurer, M.D.

Xin-Yun Huang, Ph.D.
Xin-Yun Huang, Ph.D.

PARP inhibitors make up another promising group of drugs for women with triple-negative breast cancers. They are designed to inhibit poly (ADP-ribose) polymerase, an enzyme which cancer cells employ to repair the genetic damage inflicted by cytotoxic agents. Through the New York Cancer Consortium, investigators at both NewYork-Presbyterian Hospital campuses are participating in a clinical trial assessing the PARP inhibitor veliparib with the drug doxorubicin. A second trial via the California Cancer Consortium is assessing veliparib with and without carboplatin in women with BRCA1 and BRCA2 mutations and advanced breast cancers. And a clinical trial at NewYork-Presbyterian/Weill Cornell Medical Center is evaluating the PARP inhibitor ABT-888.

Linda T. Vahdat, M.D.
Linda T. Vahdat, M.D.

NewYork-Presbyterian/Weill Cornell researchers, led by Xin-Yun Huang, Ph.D., are leading the study of synthetic versions of migrastatin, a natural substance secreted by Streptomyces which is a potent inhibitor of metastatic tumor cell migration and invasion. They've shown that these migrastatin analogues target the actin-binding protein fascin to inhibit its activity. Fascin could potentially become a new molecular therapeutic target for triple-negative disease.

"We've seen the success that we've had in treating HER2-positive breast cancers with trastuzumab," said Linda Vahdat, M.D. "So a therapeutic approach targeting signaling pathways that drive triple-negative breast cancers also makes sense."

Contributing faculty for this article:

Ramon Parsons, M.D., Ph.D. is the Leader of the Breast Cancer Program at the Institute for Cancer Genetics at the Herbert Irving Comprehensive Cancer Center of NewYork-Presbyterian/Columbia University Medical Center. He is also the Avon Professor of Pathology and Medicine at Columbia University College of Physicians and Surgeons.

Xin-Yun Huang, Ph.D. is a Professor of Physiology and Biophysics at Weill Cornell Medical College.

Linda T. Vahdat, M.D. is an Attending Physician at NewYork-Presbyterian/Weill Cornell Medical Center and a Professor of Medicine at Weill Cornell Medical College.

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