New drug combination delayed disease progression for subgroup of women with metastatic breast cancer

December 12, 2013

SAN ANTONIO -- Adding the drug dasatinib to a standard antihormone therapy, letrozole, doubled the time before disease progressed for women with hormone receptor-positive, HER2-negative metastatic breast cancer, according to results of a phase II clinical trial presented here at the 2013 San Antonio Breast Cancer Symposium, held Dec. 10-14.

Dasatinib is approved by the U.S. Food and Drug Administration for the treatment of chronic myelogenous leukemia. One of the ways it works is by blocking the activity of a protein called Src, which has been recently implicated in the spread of breast cancer to bones.

"Patients with metastatic breast cancer desperately need new treatment options that can lengthen and improve the quality of their lives," said Dev Paul, D.O., Ph.D., breast oncologist at U.S. Oncology and Rocky Mountain Cancer Centers in Denver, Colo. "Because several studies have linked high levels of Src activity to breast cancer metastasis to the bone, we wanted to see whether combining letrozole and dasatinib as first-line treatment for metastatic breast cancer would improve the clinical-benefit rate and progression-free survival compared with letrozole alone.

"We are encouraged to see that the combination doubled progression-free survival time," he added. "But this was a small study, and we really need a biomarker to measure Src activity in breast tumors, so that we can better determine which patients will be most likely to benefit from the addition of dasatinib to letrozole."

Paul and colleagues enrolled 120 postmenopausal women with locally recurrent or metastatic hormone receptor-positive, HER2-negative breast cancer in the phase II clinical trial. They randomly assigned 63 participants to letrozole and 57 to letrozole plus dasatinib. The primary aim of the study was to determine whether adding dasatinib to letrozole increased the clinical-benefit rate. The clinical-benefit rate is the number of patients who had a complete response, plus the number who had a partial response, plus the number who had stable disease for six or more months.

The researchers found that adding dasatinib to letrozole did not increase the clinical-benefit rate compared with letrozole alone. When a second measure of the study's outcome was analyzed, the combination therapy was shown to dramatically improve progression-free survival. Progression-free survival for patients receiving dasatinib and letrozole was 20.1 months compared with 9.9 months for letrozole alone.

Patients receiving dasatinib plus letrozole did experience additional side effects but none were considered severe adverse events, according to Paul, and most patients tolerated the full dose of dasatinib.

"Although these data suggest that adding dasatinib to letrozole improves progression-free survival for postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer, we would like to find a biomarker for Src activity in the breast before conducting larger clinical studies of this drug combination," said Paul.
-end-
This study was supported by funds from Bristol-Myers Squibb. Paul declared no conflicts of interest.

This research will be presented at the 2013 San Antonio Breast Cancer Symposium Thursday, Dec. 12, 7:30 a.m. CT, during a press conference hosted by Carlos L. Arteaga, M.D., president-elect of the AACR and associate director for translational/clinical research and director of the Breast Cancer Program at Vanderbilt-Ingram Comprehensive Cancer Center. Press conferences will be held in Room 217D of the Henry B. Gonzalez Convention Center, San Antonio, Texas.

Reporters who cannot attend in person can call into the press conferences using the following information: To interview Dev Paul, contact Liz May at liz.may@usoncology.com or 303-518-9860. For other inquiries, contact Jeremy Moore at jeremy.moore@aacr.org or 215-446-7109.

The mission of the 2013 San Antonio Breast Cancer Symposium is to produce a unique and comprehensive scientific meeting that encompasses the full spectrum of breast cancer research, facilitating the rapid translation of new knowledge into better care for patients with breast cancer. The Cancer Therapy & Research Center (CTRC) at The University of Texas Health Science Center at San Antonio, the American Association for Cancer Research (AACR), and Baylor College of Medicine are joint sponsors of the San Antonio Breast Cancer Symposium. This collaboration utilizes the clinical strengths of the CTRC and Baylor and the AACR's scientific prestige in basic, translational, and clinical cancer research to expedite the delivery of the latest scientific advances to the clinic. For more information about the symposium, please visit http://www.sabcs.org.

Publication Number: S3-07

Presenter: Dev Paul, D.O., Ph.D.

Title: Letrozole plus dasatinib improves progression-free survival (PFS) in hormone receptor-positive, HER2-negative postmenopausal metastatic breast cancer (MBC) patients receiving first-line aromatase inhibitor (AI) therapy

Authors: Devchand Paul1,2, Sasha J Vukelja1,3, Frankie Ann Holmes1,4, Joanne Blum1,5, Kristi J McIntyre1,6, Aparna R Kumar1,3, Deborah L Lindquist1,7, Cynthia R Osborne1,5, Ines J Sanchez1,8, Jerome H Goldschmidt1,9, Yunfei Wang1, Lina Asmar1, Michael E Lee1,10, Nini Wu1,11, Keith Logie1,12 and Joyce O'Shaughnessy1,5. 1US Oncology Research, McKesson Specialty Health, The Woodlands, TX; 2Rocky Mountain Cancer Center, Denver, CO; 3Texas Oncology - Tyler, Tyler, TX; 4Texas Oncology - Houston Memorial City, Houston, TX; 5Texas Oncology-Baylor Sammons Cancer Center, Dallas, TX; 6Texas Oncology - Dallas Presbyterian Hospital, Dallas, TX; 7Arizona Oncology Associates, Sedona, AZ; 8Texas Oncology - El Paso West, El Paso, TX; 9Blue Ridge Cancer Care- Christiansburg Office, Christiansburg, VA; 10Virginai Oncology Associates, Norfold, VA; 11New York Oncology Hematology -Albany Medical Center, Albany, NY and 12Central Indiana Cancer Centers, Fishers, IN.

Introduction Dasatinib inhibits the protein tyrosine kinase, Src, which can support the development of bone metastases in patients with ER+breast cancer. The primary objective of this study is to determine if letrozole plus dasatinib increases the clinical benefit rate (CBR) (CR+PR+SD ≥6mo) in first-line MBC patients compared with letrozole alone. Secondary objectives include overall response; progression-free survival; time to treatment failure (TTF); and toxicity.

Methods This is a Phase II randomized, noncomparative study of postmenopausal women with locally recurrent or metastatic, measurable or nonmeasurable BC, ER+, HER2-. Patients are allowed to have had prior non-AI endocrine therapy for MBC; prior adjuvant AI therapy if completed at least 1 year prior to study entry; and up to 1 prior chemotherapy regimen for MBC. Patients are stratified by ≤2 yrs vs >2 years disease-free interval (DFI) from initial breast cancer diagnosis (date of definitive surgery) to first locally recurrent or MBC and by prior tamoxifen for MBC. Patients were randomly assigned to Arm 1 (letrozole 2.5mg PO QD + dasatinib 100mg PO QD) or Arm 2 (single-agent letrozole 2.5mg PO QD) on 28-day cycles. Arm 1 patients who experienced intolerable toxicity related to dasatinib discontinued dasatinib and continued single-agent letrozole. Arm 2 patients who developed progressive disease (PD) on letrozole had the option to receive dasatinib plus letrozole. The primary endpoint of CBR was assessed when patients developed progressive disease on their randomly assigned therapies before any crossover therapy.

Results Patients with prior adjuvant AI/tamoxifen were 39%/32% Arm 1 and 44%/37% Arm 2; prior metastatic endocrine therapy Arm 1/Arm 2 was 9%/5%; and prior metastatic chemotherapy Arm 1/Arm 2 was 11%/6%. Median DFI Arm 1/Arm 2 was 27.5/21.2 months; patients presenting with de novo MBC Arm 1/Arm 2 was 42%/32%, respectively; measureable disease by RECIST Arm 1/Arm 2 was 58%/75%. The ITT population comprised 120 patients; 57 in Arm 1 and 63 in Arm 2. Clinical benefit rate (CBR) in 116 evaluable patients in Arm 1(55)/Arm 2(61), respectively, was 64% (95% CI, 50-76) and 61% (95% CI, 47-73). Median PFS time was 22 months with letrozole/dasatinib and 11 months with letrozole alone, p=.05. PFS at 6 and 12 months for Arms 1 and 2, respectively, was 78%/66% and 66%/43%. The most common toxicities observed with dasatinib on Arm 1 were fatigue (38%), nausea (38%), anemia (25%), rash (23%), pleural effusion (16%), and edema (13%). 27% of patients required dasatinib dose reduction.

Conclusion The addition of dasatinib to letrozole in MBC patients receiving their first AI therapy for metastatic disease did not improve CBR compared with letrozole alone. Median PFS improved from 11 to 22 months (p=.05) with the addition of dasatinib, suggesting dasatinib improved duration of disease control combined with letrozole. Most patients tolerated full dose dasatinib until PD. 25% of patients remain on study therapy; final results will be available at SABCS 2013.

American Association for Cancer Research

Related Breast Cancer Articles from Brightsurf:

Oncotarget: IGF2 expression in breast cancer tumors and in breast cancer cells
The Oncotarget authors propose that methylation of DVDMR represents a novel epigenetic biomarker that determines the levels of IGF2 protein expression in breast cancer.

Breast cancer: AI predicts which pre-malignant breast lesions will progress to advanced cancer
New research at Case Western Reserve University in Cleveland, Ohio, could help better determine which patients diagnosed with the pre-malignant breast cancer commonly as stage 0 are likely to progress to invasive breast cancer and therefore might benefit from additional therapy over and above surgery alone.

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.

Blood test can effectively rule out breast cancer, regardless of breast density
A new study published in PLOS ONE demonstrates that Videssa® Breast, a multi-protein biomarker blood test for breast cancer, is unaffected by breast density and can reliably rule out breast cancer in women with both dense and non-dense breast tissue.

Study shows influence of surgeons on likelihood of removal of healthy breast after breast cancer dia
Attending surgeons can have a strong influence on whether a patient undergoes contralateral prophylactic mastectomy after a diagnosis of breast cancer, according to a study published by JAMA Surgery.

Young breast cancer patients undergoing breast conserving surgery see improved prognosis
A new analysis indicates that breast cancer prognoses have improved over time in young women treated with breast conserving surgery.

Read More: Breast Cancer News and Breast Cancer Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.