“The treatment landscape for triple-negative breast cancer (TNBC) is transforming, experts say, with the potential additions of immunotherapy and PARP inhibitors. These agents are being explored both as monotherapy and in combination regimens with standard chemotherapy options.
“At the 2016 San Antonio Breast Cancer Symposium, treatment with pembrolizumab (Keytruda) continued to show a consistent durable benefit with an additional year of follow-up for heavily pretreated patients with recurrent PD-L1–positive TNBC, according to findings from the phase Ib KEYNOTE-012 trial.”
“All 13 newly diagnosed breast cancer patients with BRCA mutations had their tumors shrink significantly when treated with a PARP inhibitor ahead of frontline presurgical chemotherapy in a pilot study at The University of Texas MD Anderson Cancer Center.
“Tumor shrinkage after two months of treatment with the PARP inhibitor talazoparib, measured by ultrasound, ranged from 30 to 98 percent with an average reduction in tumor volume of 78 percent among the 13 patients.”
“The loss of CHD1, one of the most frequently mutated genes in prostate tumors, sensitizes human prostate cancer cells to different drugs, including PARP inhibitors. This suggests CHD1 as a potential biomarker for targeted prostate cancer therapy. These are the results of a study published in EMBO Reports.
“A team of researchers in Germany and Denmark led by Steven Johnsen, Professor at the University Medical Center Göttingen, Germany, used human prostate cancer cell lines and depleted them of the DNA-binding protein CHD1. The CHD1 gene is mutated in 15-27% of all prostate tumors, and such mutations correlate with chromosomal instability and poor prognosis for prostate cancer patients. The researchers could demonstrate that CHD1-depleted cells have defects in homologous recombination (HR), an important mechanism for repairing breaks in the DNA molecule. The data indicate that CHD1’s normal function is the loosening of DNA around break sites in order to facilitate the access of HR repair proteins. Importantly, like cancer cells with other mutations in the HR repair pathway, CHD1-depleted prostate cancer cells proved to be hypersensitive to chemotherapeutic drugs causing DNA breaks, such as Mitomycin C, Irinotecan and PARP inhibitors.”
Do you have questions about this story? Let us know in a comment below. If you’re wondering whether this story applies to your own cancer case or a loved one’s, we invite you to use our Ask Cancer Commons service.
“A combination treatment composed of the PARP inhibitor olaparib and the investigational PI3K inhibitor BKM120 demonstrated activity and safety for women with triple-negative breast cancer or high-grade serous ovarian cancer, according to study findings presented at the American Association for Cancer Research Annual Meeting.
“High-grade serous ovarian cancer and triple-negative breast cancer are similar in that they often have germline BRCA mutations, have a sensitivity to platinum agents and have high copy number alterations based on The Cancer Genome Atlas, according to study background. Further, preclinical data have suggested olaparib (Lynparza, AstraZeneca) is synergistic with BKM120 (Novartis) and BYL719 (Novartis) in both cancers.
“Ursula A. Matulonis, MD, medical director of gynecologic oncology at the Susan F. Smith Center for Women’s Cancers at Dana-Farber Cancer Institute and associate professor of medicine at Harvard University Medical School, and colleagues evaluated olaparib plus BKM120 in 12 patients with triple-negative breast cancer and 34 patients with high-grade serous ovarian cancer. Thirty-five patients had germline BRCA mutations.
“ ‘This is one area where we in ovarian cancer are in the forefront,’ Matulonis said during a press conference. ‘We are using an FDA-approved biomarker through germline BRCA status to basically say when a patient is eligible to receive olaparib.’ “
The gist: Breast cancer patients with BRCA mutations could potentially be treated with new drugs called PARP inhibitors. In many cases, BRCA mutations are inherited, and are therefore found in all cells in the body. But a patient who did not inherit a BRCA mutation might still develop a mutation in a small number of cells, which might grow into a breast cancer tumor. Indeed, patients with ovarian and breast cancers have been identified who have BRCA mutations in their tumors only, but not in normal cells. Testing for BRCA mutations in tumor tissues could help identify more people who might benefit from treatment with PARP inhibitors.
“A comparison of germline BRCA mutation testing against a new diagnostic developed by Myriad Genetics that can gauge somatic mutations revealed that the latter was able to pick up 44 percent more deleterious markers in women with ovarian cancer.
“In identifying additional mutation carriers, Myriad hopes its so-called Tumor BRACAnalysis CDx will be able to identify more responders PARP inhibitors. The company has long-term plans to launch somatic BRCA mutation testing as a companion diagnostic first in Europe and then in the US.
“Germline mutations show up in all cells of the body, but a blood test that gauges just these mutations can miss some patients who acquire mutations only in their tumor. Gauging somatic mutations usually requires a test that analyzes markers in tumor tissue samples.
“At the European Society for Medical Oncology’s annual meeting in Madrid, Spain this week, researchers from Myriad and MD Anderson Cancer Center described a study analyzing approximately 130 previously untreated, high-grade ovarian cancer patients for germline BRCA mutations in blood samples and somatic mutations in tissue samples. In the study, the researchers also tested patients undergoing surgery for both of these types of mutations, and they performed germline testing using a custom amplicon assay and next-generation sequencing.”
The gist: Researchers are conducting a clinical trial with volunteer patients to test a new breast cancer treatment called BMN673. BMN673 is a “PARP inhibitor” drug that may benefit patients who have hereditary mutations in the BRCA genes. Patients involved in the trial must have locally advanced and/or metastatic breast cancer, and must have undergone no more than two prior chemotherapy treatments for metastatic disease.
” ‘We are excited to collaborate with BioMarin on this landmark trial to increase the treatment opportunities for patients with BRCA related breast cancer,’ said Dr Alison Jones, Consultant Medical Oncologist and Principal Investigator for the EMBRACA Phase 3 trial at Sarah Cannon Research Institute UK.
” ‘This study is an important milestone for both organizations to foster future collaborations,’ highlighted Dr Hendrik-Tobias Arkenau, FRCP, PhD, Medical Oncologist and Medical Director at Sarah Cannon Research Institute UK.
” ‘Sarah Cannon Research UK has a long history of pioneering significant advances in medical therapy, and we are thrilled to commence enrollment outside of the United States to evaluate the safety and efficacy of BMN 673 in patients with hereditary breast cancer,’ said Hank Fuchs, M.D., Chief Medical Officer of BioMarin. ‘Breast cancer patients with germline BRCA-associated tumors have no targeted treatment options. There is an unmet need for therapies that target specific molecular defects in tumors, and PARP inhibitors offer that potential in BRCA-related breast cancer.’
“The EMBRACA Phse 3 study began in the United states in the fall of 2013 and has expanded internationally. BioMarin plans to enroll patients from sites around the world and to work with partners outside of the United States. The EMBRACA Phase 3 study is an open-label, randomized, parallel, two-arm, multi-center study of BMN 673 versus physician’s choice in approximately 430 germline BRCA mutation patients with locally advanced and/or metastatic breast cancer, who have received no more than two prior chemotherapy regimens for metastatic disease. The primary objective of the study is to measure progression free survival (PFS). Secondary objectives include evaluating the objective response rate (ORR) and the overall survival (OS).”
The gist: With the participation of volunteer patients, researchers are testing a potential new treatment approach for locally advanced pancreatic cancer, which is difficult to treat. The treatment combines radiation, chemotherapy, and a specific drug known as a PARP inhibitor, which keeps cancer cells from being able to undo the damage caused by radiation and chemotherapy. The treatment is being tested in a clinical trial. The researchers are also interested in investigating certain molecules, or “biomarkers,” found in patients’ tumors that could be used to predict how well the new treatment will work for different patients.
“Investigators at the Cedars-Sinai Samuel Oschin Comprehensive Cancer Institute are developing a novel, multistep investigational treatment for one of the most complex and difficult-to-treat forms of the disease, locally advanced pancreatic cancer.
“Locally advanced pancreatic cancer has the lowest survival rate of any solid tumor, with a cumulative five-year survival rate of only 4 percent for all stages of disease. Surgery is rarely an option for patients because tumors often involve vital blood vessels. Chemotherapy and radiotherapy given concurrently remain the mainstay treatment, yet to-date, no treatment has had a significant impact on improving outcomes.
” ‘To move the needle forward toward prolonged survival and better treatment outcomes, our research team created a combined investigational regimen for patients with locally advanced pancreatic cancer,’ said Richard Tuli, MD, PhD, a radiation oncologist in the Department of Radiation Oncology and a member of the Samuel Oschin Comprehensive Cancer Institute. ‘Coupled with this research treatment, we are also looking to identify patient biomarkers, or molecular signatures, that may provide clues to how, and why, some patients respond better than others.’ “
“The drug, called olaparib – a type of treatment called a PARP inhibitor – will be given after chemotherapy to patients with non-small cell lung cancer (NSCLC) to see if it delays the growth of their tumour.
“The phase II trial will recruit over 100 people with advanced non-small cell lung cancer at 25 hospitals around the UK. It is funded by Cancer Research UK and AstraZeneca through a National Cancer Research Network initiative and is being co-ordinated by Cancer Research UK’s Wales Cancer Trials Unit at Cardiff University and Velindre NHS Trust in Cardiff.”
Editor’s Note: More and more, scientists are finding that different types of cancer (breast and lung cancer, for instance) can sometimes have similarities, meaning that a treatment that works for one type might also work for another type. This study is exploring once such treatment.
Cardnell RJG, Feng Y, Diao L, Fan YH, et al. Clinical Cancer Research. Sept 27, 2013.
Here, we evaluate activity of a novel, potent PARP inhibitor, BMN 673, and identify markers of response as a basis for developing predictive markers for clinical application.
Elevated expression of multiple DNA repair proteins, as well as a corresponding “DNA repair protein score,” predict response to BMN 673 in in vitro SCLC models. These observations complement recent work in which PI3K inhibition sensitizes breast cancer models to PARP inhibition, suggesting cooperation between DNA repair and PI3K pathways.