January 9, 2014 | by City of Hope
Of the estimated 230,000 new cases of breast cancer diagnosed annually in the U.S., approximately 12,000 patients carry harmful mutations on either the BRCA1 or BRCA2 genes.
Cancer cells carrying these mutations are unable to properly repair double-strand DNA. Because specific enzymes – poly ADP-ribose polymerase 1 and 2 (known as PARP1 and PARP2) – are needed for DNA repair in malignant (as well as normal) cells, drugs known as PARP inhibitors often are used to help kill the cells.
As George Somlo, M.D., professor in City of Hope's Department of Medical Oncology & Therapeutics Research, puts it: In BRCA1- or BRCA2-related breast cancer, exposing the cancer cells to PARP inhibitors greatly enhances the potential for irreversible single- or double-strand DNA damage.
In the fight against cancer, that kind of DNA damage is ideal.
Now Somlo and his colleagues are learning even more about how a specific PARP inhibitor, called veliparib (or ABT-888), could improve cancer treatment.
In a previous phase I trial of 28 patients with Stage IV metastatic BRCA-associated breast cancer, City of Hope researchers had found that the combination of carboplatin (a chemotherapy drug) and veliparib yielded a response rate of 57 percent, and a clinical benefit ratio of 71 percent. Based on these results, the researchers planned – in the next phase of study – to randomize patients to the combination of drugs instead of to veliparib alone.
First, however, the single-agent activity of veliparib has to be demonstrated.
At the San Antonio Breast Cancer Symposium in December, City of Hope researchers presented preliminary results of a multicenter study exploring the single-agent effectiveness of the PARP-inhibitor veliparib in patients with Stage IV metastatic BRCA-associated breast cancer. Thirty-nine patients with BRCA-associated Stage IV metastatic breast cancer have enrolled in the study so far. They range in age from 32 to 66, with the median age of 45. An additional five patients are still being accrued into the trial.
“We successfully demonstrated clinically relevant activity with veliparib in patients with both BRCA1 or BRCA2 mutation-associated advanced breast cancers,” said Somlo, first author of the study.
At the time of disease progression on veliparib alone, the chemotherapeutic agent carboplatin was prescribed in addition to continuing with veliparib.
“It is too early to assess the benefit of crossing over to the combination of veliparib and carboplatin after progression on veliparib alone,” Somlo said. “The strategy of administering veliparib alone followed by veliparib and carboplatin on progression needs to be compared to combination therapy with veliparib and carboplatin first, followed by veliparib maintenance.”
Somlo and Jeffrey Weitzel, M.D., senior author of the study and director of the Division of Clinical Cancer Genetics at City of Hope are co-chairing the study. Co-authors at City of Hope include: Joanne Mortimer, M.D., Arti Hurria, M.D., Paul Frankel, Ph.D., and Thehang Luu, M.D.
Other participating researchers included: Cynthia Ma, M.D., Ph.D., Washington University School of Medicine, St. Louis; Banu Arun, M.D., University of Texas MD Anderson Cancer Center, Houston; Agustin Garcia, M.D., USC Norris Comprehensive Cancer Center, Los Angeles; Tessa Cigler, M.D., Weill Cornell Medical College, New York; Gina Fleming, M.D., University of Chicago, Chicago; Rita Nanda M.D: University of Chicago; Helen Chew, M.D., University of California, Davis Cancer Center, Sacramento, Calif.; Timothy Moynihan, M.D., Mayo Clinic, Rochester, Minn.; Linda Vahdat, M.D: Weill Cornell Medical College, New York; Matthew Goetz M.D: Mayo Clinic; David Gandara M.D., University of California, Davis Cancer Center; Alice Chen, M.D., National Cancer Institute, Bethesda, Md.; Harold Harvey, M.D., Milton Hershey Medical Center, Hershey, Pa., and Joseph Sparano, M.D., Einstein Montefiore Medical Center, New York.
Research reported in this study was supported in part by the National Cancer Institute of the National Institutes of Health under grant number NIH-NCI CA 137684. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.