Nav: Home

Frontline PARP inhibitor shrinks tumors in BRCA-positive breast patients

October 05, 2016

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.

Results of the study (abstract 153PD) will be presented Saturday at a breast cancer poster discussion session of the 2016 European Society for Medical Oncology (ESMO) Congress in Copenhagen.

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.

"Acknowledging that this is a small study, I can't think of any systemic therapy that gives results this consistently strong in only two months," said Jennifer Litton, M.D., associate professor of Breast Medical Oncology and leader of the study. An extension of the trial is under way.

Previously untreated patients agreed to undergo the targeted therapy treatment before proceeding to standard-of-care chemotherapy and then surgery. Patients with HER2-positive disease were excluded from the study because approved targeted agents exist for those breast cancers.

PARP inhibitors block a DNA repair pathway that tumors can use to survive DNA damage, both intrinsic and caused by therapy. BRCA1 and BRCA2 are tumor-suppressing genes that, when mutated, account for 5 to 10 percent of all breast cancers. BRCA-related cancers are thought to be vulnerable to PARP inhibitors.

Litton is principal investigator of an international phase III clinical trial of talazoparib for patients with advanced or metastatic breast cancer. Talazoparib and other PARP inhibitors already have been through phase I safety and phase II/III efficacy clinical trials.

A first step testing drug as initial treatment

Given these early results for PARP inhibitors, Litton designed a stepwise approach to more quickly move talazoparib into the presurgical treatment setting for patients newly diagnosed with BRCA-positive breast cancer. She proposed an investigator-initiated pilot study to the drug company, to be supported by MD Anderson's Moon Shots Program, an ambitious effort to reduce cancer deaths by more rapidly developing and implementing advances in prevention, early detection and treatment based on scientific discoveries.

Litton originally expected the study to take two years to sign up 20 patients. Instead, 13 enrolled in eight months, and the results were striking enough that the study was stopped. Complete results, including pathological response after the full course of treatment through surgery, are being prepared for publication.

None of the 13 patients had to withdraw from the talazoparib treatment due to side effects, which were limited mainly to fatigue and low blood counts. There were no grade 4 toxicities. Eight of the 13 had triple-negative disease, breast cancer that does not have HER2 or hormonal targets for treatment.

"After we saw the extensive clinical response, confirmed by ultrasound, and with a favorable toxicity profile, we really wanted to move forward into an extension to evaluate pathological response for this drug as a single treatment," Litton said.

Next study, presurgical talazoparib alone

An extension of the pilot study opened in August for 20 more patients who will take only talazoparib for six months before proceeding to surgery. Six patients have enrolled. Patients whose disease progresses will proceed to chemotherapy and then surgery.

"If this study produces similarly strong results, the next step would be to directly compare talazoparib to chemotherapy in the presurgical, curative setting," Litton said. "We might be able to delay or replace chemotherapy if we can get similar efficacy with less toxicity from treatment."

Litton noted that institutional support through the Moon Shots Program helped convince the company to provide the drug for Litton's investigator-initiated trials.

Extensive, unique biomarker research

In addition to evaluating the feasibility of enrolling patients before standard neoadjuvant therapy and the drug's toxicity profile, as well as a first estimate of clinical response, the pilot study also tapped Moon Shots Program resources for extensive biomarker evaluation.

Biopsies taken before and after PARP inhibition are evaluated for DNA and RNA changes, proteomics and immune response by Gordon Mills, M.D., Ph.D., chair and professor of Systems Biology.

Patient-derived xenografts of tumors are developed by Helen Piwnica-Worms, Ph.D., vice provost for research and professor of Experimental Radiation Oncology, and colleagues, for use in mouse models to further study tumor response to treatment.

"We will be able to learn a great deal, and not only from the tissue," Litton said. "We also have paired PDXes before and after treatment in previously untreated breast cancer. I don't know anywhere else in the world that has these types of exciting reagents."
-end-
The drug's owner, Medivation, recently acquired by Pfizer, provided talazoparib for the study, which was otherwise supported by the Moon Shots Program Breast Cancer Moon Shot and the Toomim Breast Cancer Research Fund.

Co-investigators with Litton, Mills and Piwnica-Worms are David Ramirez, M.D., Rashmi Murthy, M.D., Stacy Moulder, M.D., Carlos Barcenas, M.D., Vicente Valero, Daniel Booser, M.D., Jill Schwartz Gomez and Banu Arun, M.D., all of Breast Medical Oncology; Marion Scoggins, M.D., Gary Whitman, M.D., and Beatriz Adrada, M.D., of Diagnostic Radiology; Kenneth Hess, Ph.D., of Biostatistics.

University of Texas M. D. Anderson Cancer Center

Related Breast Cancer Articles:

Partial breast irradiation effective treatment option for low-risk breast cancer
Partial breast irradiation produces similar long-term survival rates and risk for recurrence compared with whole breast irradiation for many women with low-risk, early stage breast cancer, according to new clinical data from a national clinical trial involving researchers from The Ohio State University Comprehensive Cancer Center - Arthur G.
Breast screening linked to 60 per cent lower risk of breast cancer death in first 10 years
Women who take part in breast screening have a significantly greater benefit from treatments than those who are not screened, according to a study of more than 50,000 women.
More clues revealed in link between normal breast changes and invasive breast cancer
A research team, led by investigators from Georgetown Lombardi Comprehensive Cancer Center, details how a natural and dramatic process -- changes in mammary glands to accommodate breastfeeding -- uses a molecular process believed to contribute to survival of pre-malignant breast cells.
Breast tissue tumor suppressor PTEN: A potential Achilles heel for breast cancer cells
A highly collaborative team of researchers at the Medical University of South Carolina and Ohio State University report in Nature Communications that they have identified a novel pathway for connective tissue PTEN in breast cancer cell response to radiotherapy.
Computers equal radiologists in assessing breast density and associated breast cancer risk
Automated breast-density evaluation was just as accurate in predicting women's risk of breast cancer, found and not found by mammography, as subjective evaluation done by radiologists, in a study led by researchers at UC San Francisco and Mayo Clinic.
More Breast Cancer News and Breast Cancer Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Rethinking Anger
Anger is universal and complex: it can be quiet, festering, justified, vengeful, and destructive. This hour, TED speakers explore the many sides of anger, why we need it, and who's allowed to feel it. Guests include psychologists Ryan Martin and Russell Kolts, writer Soraya Chemaly, former talk radio host Lisa Fritsch, and business professor Dan Moshavi.
Now Playing: Science for the People

#537 Science Journalism, Hold the Hype
Everyone's seen a piece of science getting over-exaggerated in the media. Most people would be quick to blame journalists and big media for getting in wrong. In many cases, you'd be right. But there's other sources of hype in science journalism. and one of them can be found in the humble, and little-known press release. We're talking with Chris Chambers about doing science about science journalism, and where the hype creeps in. Related links: The association between exaggeration in health related science news and academic press releases: retrospective observational study Claims of causality in health news: a randomised trial This...