Platinum agent combination treatment for triple-negative breast cancer well tolerated in phase II clinical trial

Triple-negative breast cancer is characterized by the absence of estrogen and progesterone receptors and the HER2/neu protein in breast cancer cells. That in itself presents a challenge in treating the disease, as it does not respond to hormonal- or HER2-targeted therapies that provide for positive outcomes in other subtypes of breast cancer. Triple-negative breast cancers are often deficient in DNA repair and other specific cellular pathways that make them susceptible to DNA damage. There is growing evidence that suggests platinum-based agents may offer improved outcomes in treating the subset of triple-negative breast cancer because of their specificity for causing DNA damage. Investigators at the Cancer Institute of New Jersey further examined a platinum-based drug regimen as part of a combination therapy.

From 2008 to 2012, 31 patients with previously untreated metastatic, triple-negative breast cancer participated in a Phase II clinical trial at the Cancer Institute. Participants were given a combination of doxil, bevacizumab and the platinum agent carboplatin every four weeks. Patients received a median of 5.6 treatment cycles.

Nearly 39 percent of participants experienced a clinical benefit that lasted at least six months. Taxane therapy was included as part of the treatment of primary disease, i.e. localized disease before recurrence at distant sites, in 41.9 percent of patients. Nearly 31 percent of participants who received prior taxane therapy experienced a clinical benefit of greater than six months. Median time without progression of disease was 5.6 months, while the percentage of patients without progression at six-months was 41.9 percent. Median overall survival was 11.9 months and the one-year survival rate was 47.3 percent with 13 patients alive at 10 months or longer. Bevacizumab was discontinued from the treatment regimen after two patients experienced severe hypertension and one patient experienced a symptomatic blood clot.

"While the regimen demonstrated a clinical benefit, it was also well tolerated, as women experienced minimal nausea and did not experience hair loss. That speaks to an improved quality of life," says the study's principal investigator and Cancer Institute Chief Medical Officer Deborah Toppmeyer, MD, who is also director of the Cancer Institute's Stacy Goldstein Breast Cancer Center and LIFE Center as well as a professor of medicine at Rutgers Robert Wood Johnson Medical School.

"With up to 20 percent of breast cancer cases diagnosed as triple-negative, additional treatment options are needed for this population," notes lead author and co-investigator Kim M. Hirshfield, MD, PhD, breast medical oncologist at the Cancer Institute. "By exploring non-traditional agents and integrating genomic analysis, we have an opportunity to expand our arsenal of therapies against this disease."

As part of the study, tumors were analyzed using Next Generation Sequencing technology, which revealed alterations in the p53 gene to be the most common. For three patients, tumors analyzed both before and after having treatment that included the platinum agent, there was an increase in the number of genomic alterations observed at the time of disease progression (five months, eight months and 20 months). Although the third patient was only on study for eight months, the patient was able to receive reduced doses of doxil and carboplatin off study until disease progression at 20 months.

"By uncovering specific genomic abnormalities, we can identify molecularly targeted cancer treatments. In this particular case, our data may provide a better understanding about p53 biomarkers in terms of their sensitivity to platinum-based agents and how we can use that information to tailor therapy regimens for triple-negative breast cancer patients," says Dr. Hirshfield, who is also an assistant professor of medicine at Robert Wood Johnson Medical School.

Along with Hirshfield and Dr. Toppmeyer, authors include Shridar Ganesan, MD, PhD, Cancer Institute and Robert Wood Johnson Medical School; Shou-En Lu, PhD and Weichung Shih, PhD, both Cancer Institute and Rutgers School of Public Health; Serena Wong, MD, Cancer Institute and Robert Wood Johnson Medical School; Antoinette Tan, MD, formerly at both Cancer Institute and Robert Wood Johnson Medical School; Laurie Kirstein, MD, FACS and Thomas Kearney, MD, FACS, both Cancer Institute and Robert Wood Johnson Medical School.