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."
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:

Does MRI plus mammography improve detection of new breast cancer after breast conservation therapy?
A new article published by JAMA Oncology compares outcomes for combined mammography and MRI or ultrasonography screenings for new breast cancers in women who have previously undergone breast conservation surgery and radiotherapy for breast cancer initially diagnosed at 50 or younger.
Blood test offers improved breast cancer detection tool to reduce use of breast biopsy
A Clinical Breast Cancer study demonstrates Videssa Breast can inform better next steps after abnormal mammogram results and potentially reduce biopsies up to 67 percent.
Surgery to remove unaffected breast in early breast cancer increases
The proportion of women in the United States undergoing surgery for early-stage breast cancer who have preventive mastectomy to remove the unaffected breast increased significantly in recent years, particularly among younger women, and varied substantially across states.
Breast cancer patients with dense breast tissue more likely to develop contralateral disease
Breast cancer patients with dense breast tissue have almost a two-fold increased risk of developing disease in the contralateral breast, according to new research from The University of Texas MD Anderson Cancer.
Some early breast cancer patients benefit more from breast conservation than from mastectomy
Breast conserving therapy (BCT) is better than mastectomy for patients with some types of early breast cancer, according to results from the largest study to date, presented at ECC2017.
One-third of breast cancer patients not getting appropriate breast imaging follow-up exam
An annual mammogram is recommended after treatment for breast cancer, but nearly one-third of women diagnosed with breast cancer aren't receiving this follow-up exam, according to new findings presented at the 2016 Annual Clinical Congress of the American College of Surgeons.
Low breast density worsens prognosis in breast cancer
Even though dense breast tissue is a risk factor for breast cancer, very low mammographic breast density is associated with a worse prognosis in breast cancer patients.
Is breast conserving therapy or mastectomy better for early breast cancer?
Young women with early breast cancer face a difficult choice about whether to opt for a mastectomy or breast conserving therapy (BCT).
Breast density and outcomes of supplemental breast cancer screening
In a study appearing in the April 26 issue of JAMA, Elizabeth A.
Full dose radiotherapy to whole breast may not be needed in early breast cancer
Five years after breast-conserving surgery, radiotherapy focused around the tumor bed is as good at preventing recurrence as irradiating the whole breast, with fewer side effects, researchers from the UK have found in the large IMPORT LOW trial.

Related Breast Cancer Reading:

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

Digital Manipulation
Technology has reshaped our lives in amazing ways. But at what cost? This hour, TED speakers reveal how what we see, read, believe — even how we vote — can be manipulated by the technology we use. Guests include journalist Carole Cadwalladr, consumer advocate Finn Myrstad, writer and marketing professor Scott Galloway, behavioral designer Nir Eyal, and computer graphics researcher Doug Roble.
Now Playing: Science for the People

#529 Do You Really Want to Find Out Who's Your Daddy?
At least some of you by now have probably spit into a tube and mailed it off to find out who your closest relatives are, where you might be from, and what terrible diseases might await you. But what exactly did you find out? And what did you give away? In this live panel at Awesome Con we bring in science writer Tina Saey to talk about all her DNA testing, and bioethicist Debra Mathews, to determine whether Tina should have done it at all. Related links: What FamilyTreeDNA sharing genetic data with police means for you Crime solvers embraced...