“Developing predictive biomarkers will be key to treating patients with triple-negative breast cancer (TNBC), especially when choosing a targeted therapy, said Banu K. Arun, MD.
“In a presentation during the 2018 OncLive® State of the Science Summit™ on Breast Cancer, Arun said there is evidence that PARP inhibitors as well as immunotherapy in combination with various agents may be effective in women with TNBC and BRCA1-related breast cancers, but the science isn’t there yet.”
“U.S. regulators have granted a priority review to AstraZeneca’s ovarian cancer drug Lynparza as a treatment for breast cancer, putting it on track for potential approval in the new disease area during the first quarter of 2018.
“The medicine, which is being jointly developed and marketed with Merck under a deal struck in July, is the first poly ADP-ribose polymerase (PARP) drug to be considered for use outside ovarian cancer.”
Non-metastatic breast cancers are most often treated with surgery, but if the tumors are fairly large, or involve nearby lymph nodes, neoadjuvant (pre-operative) treatments with chemotherapy (NAC) are done first. NAC often reduces the tumor size and kills cancer cells in lymph nodes, if present, prior to surgery, improving the outcome. The best possible result of neoadjuvant treatment is pCR (pathologic compete response), when the tumor is no longer visible in imaging studies. Here, I review the new directions in which neoadjuvant treatments are evolving.
Today, treatments for metastatic breast cancers are tailored for specific subtypes. Starting with the introduction of the drug trastuzumab (Herceptin) for HER2-positive cancers, new, more specific treatment options were eventually developed and approved for other types as well. Estrogen deprivation endocrine therapies, lately prescribed in combination with CDK4/6 inhibitors, are used in estrogen receptor (ER)-positive cancers. Triple negative cancers (TNBC) are still treated mostly with chemotherapy, but immune checkpoint drugs and PARP inhibitors are explored in clinical trials, with some successes reported.
However, neoadjuvant treatments (except for HER2+ cancers) remain largely limited to chemotherapy regimens. This is starting to change now, with new approaches tailored to the cancer type being investigated in clinical trials.
In this regard, it is important to mention the I-SPY2 trial, NCT01042379, which started in 2010 and is for women with stage II-III breast cancer. It offers about a dozen drugs that are chosen based on particular features of the newly diagnosed cancers. This trial has a unique design and has produced some important results. Additional treatments and trials for various types of breast cancer are discussed below. Continue reading…
“Pfizer Inc. (NYSE:PFE) today announced Phase 2 data showing that its investigational, dual-mechanism poly ADP ribose polymerase (PARP) inhibitor, talazoparib, demonstrated anti-tumor activity in patients with germline (inherited) BRCA1/2-positive (gBRCA+) advanced breast cancer. Results from the Phase 2 ABRAZO trial were presented during an oral session at the 53rd Annual Meeting of the American Society of Clinical Oncology (ASCO) in Chicago.”
“The field of prostate cancer is rapidly progressing on several different fronts, says Celestia Higano, MD, who discussed several of the the latest advances at the 2017 Interdisciplinary Prostate Cancer Congress (IPCC).
” ‘I want the community to have a sense of the very rapid change of pace of prostate cancer therapy. I hope to spread the message of what is changing, why is it is changing, what has been shown in evidence-based therapies, and what is still experimental,’ said Higano, MD, professor of medicine and urology at the University of Washington, and a member of the Clinical Research Division at Fred Hutchinson Cancer Research Center.”
“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.”
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“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.’ “