Triple-Negative Breast Cancer: Divide and Conquer

Understanding the molecular makeup of triple-negative breast cancer reveals new therapeutic targets.

People say that I’m a miracle, and I don’t know how to feel about it,” says 49-year-old Brenda Beguin, who received a diagnosis of triple-negative breast cancer (TNBC) in 2005. “They told me that this [disease] was going to take my life,” she recalls, “and the only thing I could do to treat it was chemotherapy.”

At the time, Beguin was going through a divorce and didn’t feel she had the emotional or physical support to cope with the rigors of chemotherapy. So, against her doctors’ recommendation, she had only a lumpectomy followed by 36 rounds of radiation therapy, which kept her cancer at bay for more than four years.

Beguin’s cancer returned in 2010 as an aggressive tumor on her right lung. Remarried but struggling with domestic abuse, she again rejected chemotherapy. But four weeks later, the cancer had spread to a lymph node attached to her trachea, and her oncologist told her to get her affairs in order. “It’s the hardest thing when someone who’s supposed to give you the answers tells you that it’s over,” Beguin recalls.

This time, she decided to try chemotherapy. In June 2011, she joined a phase 1 trial of the PARP inhibitor veliparib combined with cisplatin and vinorelbine. PARP, which stands for poly ADP-ribose polymerase, is an enzyme that is key to repairing defective DNA—particularly DNA that has been damaged by chemotherapy—so PARP inhibitors make cancer cells more vulnerable to treatment. Beguin’s tumors vanished within six months of her starting the trial, and she was declared cancer-free. While such a dramatic response to a trial is not typical, it illustrates how our growing understanding of the genetics of individual tumors could open more treatment options.

TNBC, which is more common among younger women and African-Americans, refers to breast cancers that lack overexpression of the estrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 (HER2). Because these tumors are not fueled by hormones or the HER2 protein, they do not respond to targeted breast cancer drugs, such as tamoxifen or Herceptin (trastuzumab), which target ER and HER2, respectively. Thus chemotherapy—before surgery (neoadjuvant) or after (adjuvant), or for metastatic disease—remains the standard treatment for these patients.

The good news is that TNBC is generally sensitive to chemotherapy, and a good predictor of longer survival in TNBC is lack of any detectable disease after neoadjuvant (prior to surgery) chemotherapy—a so-called pathological complete response—which happens in 20 to 40 percent of cases. Patients whose tumors respond poorly or continue to grow during chemotherapy have a poorer outlook.

“These tumors are difficult to treat and can be very aggressive if we can’t find an effective therapy,” says Jennifer Litton, a breast cancer specialist at the MD Anderson Cancer Center in Houston.

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