Endocrine treatment for breast cancer finds potential support from leukemia drug
Endocrine treatment for breast cancer finds potential support from leukemia drug
16/12/2013
Metastatic breast cancer patients starting endocrine therapy had delayed disease progression after taking the leukemia drug dasatinib (Sprycel), however, the drug failed to affect clinical response. This is according to an early-phase trial.
The median progression-free survival reached 20.1 months with addition of dasatinib compared with 9.9 months on letrozole (Femara) alone, Devchand Paul, DO, PhD, a breast oncologist at U.S. Oncology and Rocky Mountain Cancer Centers in Denver, and colleagues found.
The trial failed, though, for lack of impact on the primary endpoint of clinical benefit rate, which came in at 71% compared with 66% on letrozole alone, the researchers reported here at the San Antonio Breast Cancer Symposium.
Even though the trial wasn't powered to make comparisons between arms, the progression-free survival results were "pretty impressive" and warrant further study, commented Aditya Bardia, MD, MPH, a medical oncologist at Massachusetts General Hospital in Boston.
Carlos L. Arteaga, MD, breast cancer program director at the Vanderbilt-Ingram Comprehensive Cancer Center in Nashville, Tenn., agreed but noted that dasatinib would be fighting an uphill battle.
Dasatinib blocks the activity of a protein called Src, which plays a role in breast cancer invasion, proliferation, and survival but also is part of a complex with PI3 kinase and membrane estrogen receptor-alpha to drive endocrine therapy resistance.
"The problem with the Src field is we don't have very specific and very potent inhibitors," Arteaga said in an interview. "Dasatinib is not considered a specific inhibitor."
Moreover, there's a lot of competition in terms of pathways and agents to tackle resistance to endocrine therapy, he told MedPage Today.
"There are many mechanisms that mediate that resistance," he noted. "I think eventually we may need to be treating by trying to treat that resistance with not two, but three and four drugs. We're not there yet, but we may need a PI3K inhibitor, an Src inhibitor, and everything else."
Two points on which dasatinib stood out were use early in the natural history of metastatic disease, before resistance had emerged, and its benefits for bone, said Arteaga, who is also president-elect of the American Association for Cancer Research.
Bone mineral density improved with dasatinib during the study, with the proportion of patients with T-scores in the osteopenic range, below -1.5, falling from 32% at baseline to 14%. The rate remained about the same in the letrozole-only group (38% at baseline, 32% during the study).
That was despite a similar proportion being on bisphosphonate treatment during the study.
"It's probably a combination of stopping that destruction of bone and a direct anti-tumor effect because you have tumor cells in the bone," Arteaga suggested.
The phase II trial included 120 postmenopausal women with estrogen receptor (ER)-positive, HER2-negative disease.
Adjuvant aromatase inhibitor use more than a year prior was allowed, as was up to one prior chemotherapy regimen for metastatic disease. Use of other aromatase inhibitors in the metastatic setting was an exclusion criterion.
Women were randomized to once daily letrozole (2.5 mg) alone or with dasatinib (100 mg), with crossover allowed upon disease progression in the letrozole-only arm.
No complete responses occurred. Other components of the clinical benefit rate with the combination versus letrozole alone were partial response in 21% versus 25% and stable disease for at least 6 months in 57% versus 26%.
The exploratory hazard ratio for comparison between groups was 0.69, indicating better progression-free survival with dasatinib plus letrozole.
The lack of tumor shrinkage wasn't unexpected, according to Bardia. He cited everolimus (Afinitor) with exemestane (Aromasin) and single-agent fulvestrant (Faslodex) as examples of endocrine regimens that didn't yielded a high response rate but were effective on outcomes.
There was no unexpected or grade 4 toxicity, Paul noted. Adverse events that were more common with the addition of dasatinib were rash, fatigue, and some pleural effusion. Altogether the picture was one of benefit for dasatinib in initial aromatase inhibitor treatment to prevent acquired resistance, whereas prior studies showed no benefit to combinations after patients had already progressed on nonsteroidal aromatase inhibitors, Paul explained.
However, Bardia cautioned about the possibility of crossover effects, selection bias, and other problems with phase II studies.
"We have been fooled before," he told MedPage Today. "A couple years ago in randomized phase II, PARP inhibitors clearly showed an improvement in progression-free survival and it was felt that would be the next big thing in triple-negative breast cancer. But the randomized phase III trial was negative, so we have to be cautious about phase II trials."
Source: MedPage Today: http://www.medpagetoday.com/MeetingCoverage/SABCS/43426