NATIONAL HARBOR, MD—The link between BRCA mutations and triple-negative breast cancer is leading to new insights into the management of women whose breast cancer lacks receptors for estrogen, progesterone, and HER2, according to research presented here at the Breast Cancer Symposium. Women with this subtype of breast cancer—which is more common in younger women, especially African Americans—make up about 15% of breast cancer cases, and have a poor prognosis.
In a series of 77 unselected patients with triple-negative breast cancer, 19.5% of the women were found to have BRCA1 or BRCA2 mutations. Lead author Ana Maria Gonzalez-Angulo, MD, MSc, Associate Professor of Breast Medical Oncology at the University of Texas MD Anderson Cancer Center, said that of the 77 patients, 12 were BRCA1 mutation carriers and three were BRCA2 mutation carriers. The mean age of the patients was 51; the number of BRCA mutations tended to be higher in the younger women.
“In patients younger than 50, the number of mutations is even higher,” said Dr. Gonzalez-Angulo, who also participated in a pre-symposium webcast of selected study findings hosted by the American Society of Clinical Oncology, one of the meeting's six cosponsors.
In this study all triple-negative patients except for one received anthracycline and taxane-based adjuvant chemotherapy; those with BRCA mutations had a significantly lower risk of relapse.
Dr. Gonzalez-Angulo said it is known that women with BRCA mutations have a high rate of triple-negative breast cancer, so it is not surprising that these women have more BRCA mutations. It is somewhat surprising, though, she said, that BRCA mutation carriers have a higher rate of relapse-free survival, for as yet unknown reasons.
She and her co-researchers estimated that about 48% of the women without a BRCA mutation would have their breast cancers return within five years after diagnosis, compared with only about 14% of the women with BRCA mutations.
The researchers also estimated that about 53% of the patients without a BRCA mutation would live at least five years after diagnosis, compared with about 73% of the women with a BRCA mutation.
Genetic Testing & Counseling Should Be Considered
What this means for patient management in the challenging setting of triple-negative breast cancer is that genetic testing and counseling should be considered for women with triple-negative breast cancer, Dr. Gonzalez-Angulo said, adding, however, that the study findings do need to be confirmed by additional research.
Jennifer C. Obel, MD, a member of ASCO's Cancer Communications Committee, commented that knowing whether a woman with triple-negative breast cancer has a BRCA mutation could ultimately affect the type of treatment given.
Dr. Obel, a medical oncologist at North Shore University Health System and Assistant Clinical Professor of Medicine at the University of Chicago, pointed out that the investigational PARP inhibitors now in development are showing promise in treating women with BRCA1 and BRCA2 mutations. Poly (ADP-ribose) polymerase 1 (PARP-1) is a key enzyme in cell proliferation and DNA repair, and several PARP-1 inhibitors have been tested preclinically as enhancers of chemotherapy and radiation therapy.
Olaparib is a new PARP inhibitor that has shown efficacy in patients with breast and ovarian cancers with BRCA mutations in Phase I and II studies, and Phase II studies of other PARP inhibitors are ongoing.
Disproportionately in Stage IV Cases
In a general session on triple-negative breast cancer at the symposium, Lisa A. Carey, MD, Medical Director of the University of North Carolina Breast Center, Lineberger Comprehensive Cancer Center, said that although that type of breast cancer makes up only about 15% of all breast cancer cases, because it carries a poor prognosis it is disproportionately represented among Stage IV cases.
As yet there are no known targeted agents for triple-negative breast cancer, and therapy consists of chemotherapy, Dr. Carey explained. Fortunately, though, “conventional chemotherapy is effective and remains the adjuvant standard of care; moreover, modern advances in chemotherapy have particularly benefited this breast cancer subtype.”
Dr. Carey noted that the PARP inhibitor olaparib appears primarily to benefit germline BRCA1 and BRCA2 mutation carriers and not women with sporadic triple-negative breast cancer.
She cited a randomized Phase II study of the PARP inhibitor iniparib, which suggests that when it is added to gemcitabine and carboplatin in treating women with metastatic triple-negative breast cancer (TNBC), PARP inhibition increases progression-free and overall survival. She noted that a confirmatory Phase III study of these Phase II findings should be reported next year, and that “if its findings are positive, it will identify DNA damage response aberration as the first unique target in TNBC.”
Molecular subclassification of triple-negative breast cancer offers the hope of better understanding the underlying biologic processes of the disease and the mechanisms controlling tumor behavior, with a goal of developing more effective therapies, said Anne-Lise Børresen-Dale, MD, PhD, Professor and Head of the Department of Genetics at the Institute for Cancer Research at the Norwegian Radium Hospital.
She pointed out that while the majority of triple-negative breast cancers are basal-like tumors, some basal-like tumors are not triple negative, and triple-negative breast cancer also can be found among other expression subclasses, in particular among the luminal B and normal-like groups.
“Thus, advances in further subclassification of TNBC using various ‘omics' technologies are needed to design optimal strategies for treatment,” she said, describing two algorithms that she and her colleagues have developed to explore genomic architectural distortions in breast cancer.
“By applying these algorithms to data from 595 patients with breast cancer, we were able to separate the cases into eight subgroups with different distribution of genomic distortion,” she said. “Large prospective trials are needed to validate the different gene signatures identified in various studies, and in time, we hope to arrive at molecular signatures for TNBC that can be used in clinical practice.”
A related preclinical study from the University of Alabama at Birmingham presented at the symposium highlighted the role of the investigational monoclonal antibody TRA-8 alone or combined with chemotherapy as a possible new treatment for triple-negative breast cancer.
TRA-8 was tested against breast cancer cell lines and isolated stem cells of known genotype, and is being evaluated in vivo in a xenograft model. The monoclonal antibody targets death receptor 5, a major component in the extrinsic apoptotic pathway.
“Death receptor 5 represents an attractive therapeutic target that may lead to a new therapeutic strategy for TNBC,” the researchers concluded.
Triple Negative Breast Cancer Foundation
The Triple-Negative Breast Cancer Foundation http://www.tnbcfoundation.org was started by a group of young women with the cancer in the hopes of increasing funding and research for the disease.
This is the fourth annual Breast Cancer Symposium, and it is cosponsored by the American Society of Breast Disease, American Society of Breast Surgeons, ASCO, the American Society for Radiation Oncology, the National Consortium of Breast Centers, and the Society of Surgical Oncology. The organizers note that Susan G. Komen for the Cure is the primary supporter of the symposium.