Chemotherapy-induced amenorrhea in premenopausal women being treated for early stage breast cancer was associated with significantly improved patient survival, according to a study published this week in the New England Journal of Medicine by the National Surgical Adjuvant Breast and Bowel Project (NSABP) in collaboration with leading US cancer centers and cooperative cancer research groups. The NSABP is led by oncologists from Allegheny General Hospital (AGH) in Pittsburgh. The study also showed that a sequential administration of chemotherapeutic drugs significantly improves survival in women with early breast cancer compared to delivering the drugs concurrently.
According to Charles Geyer, MD, an AGH breast medical oncologist and one of the study’s lead authors, the development of amenorrhea during and after adjuvant chemotherapy is associated with clinically important side effects and impacts on the quality of life in premenopausal women with early breast cancer. Chemotherapy-induced amenorrhea occurs in 40-90% of premenopausal breast cancer patients depending on their age and the type of chemotherapy regimen.
Estrogen promotes the growth of endocrine responsive breast cancers, which comprise approximately three quarters of breast cancers. Studies focusing on premenopausal women with endocrine responsive tumors have previously shown an association between chemotherapy-induced amenorrhea and improved outcomes.
Amenorrhea occurs because the chemotherapy suppresses ovarian function which results in substantial declines in estrogen levels. Some of the benefit of chemotherapy in premenopausal women is thought to be related to this form of endocrine therapy. Such findings have led to specific clinical trials in premenopausal women with endocrine responsive breast cancers designed to evaluate the potential benefit of more specific suppression of ovarian function with drugs that inhibit production of the critical pituitary hormones that drive ovarian function. These studies are completing accrual, but results will not be known for several years.
“The new and surprising observation in our study was that chemotherapy-induced amenorrhea was associated with improved survival among premenopausal women with estrogen negative breast cancers as well as those with endocrine responsive breast cancers. This would suggest that the ovaries may be playing an important role beyond estrogen production that is influencing the disease process,” said Dr. Geyer, who also serves as Director of the AGH Cancer Center and Director of Medical Affairs for the NSABP.
As an important secondary endpoint of the trial, the research team prospectively documented menstrual status at baseline and after therapy in premenopausal women in order to assess the effect of amenorrhea on patient outcomes. Both overall survival and disease-free survival were significantly better among patients who had no menstrual activity for at least six months as compared to those who continued with normal menstrual patterns. The results were consistent regardless of age, regimen used and estrogen receptor status.
Dr. Geyer said the finding underscores the need to further study the role of induced amenorrhea, and ultimately to consider a future randomized clinical trial evaluating ovarian suppression as a specific intervention in premenopausal women with estrogen receptor negative breast cancers.
The study’s primary endpoint conclusion, however, could have a more immediate impact on the standard of care, said Norman Wolmark, MD, the paper’s senior author and principal investigator for the National Cancer Institute Grant that funded the research. Dr. Wolmark is Chair of both the NSABP and the Department of Human Oncology at Allegheny General Hospital.
Following primary surgery with total mastectomy or lumpectomy plus axillary nodal dissection, a total of 5,351 premenopausal and postmenopausal women with operable, lymph node-positive, early stage breast cancer were enrolled in the clinical trial and randomly assigned to receive either four cycles of doxorubicin and cyclophosphamide followed by four cycles of docetaxel (sequential ACT); four cycles of doxorubicin and docetaxel (doxorubicin-docetaxel); or four cycles of doxorubicin, cyclophosphamide and docetaxel (concurrent ACT).
At a median follow-up of 73 months, eight year overall patient survival was improved in the sequential ACT group (83%) as compared to both the doxorubicin-docetaxel group (79%) and the concurrent ACT group (79%). Eight-year disease free survival (factoring local, regional or distant breast cancer recurrence, second primary cancer or death from any cause before recurrence) was improved in the sequential ACT group (74%) compared to the doxorubicin-docetaxel group (69%) and the concurrent ACT group (69%).
“This trial showed that the sequential administration of ACT in the adjuvant treatment of operable node positive breast cancer provided a significant 17% reduction in mortality over doxorubicin-docetaxel and a clear advantage over both concurrent treatment approaches in terms of disease free survival,” Dr. Wolmark said.
In addition to Drs. Geyer and Wolmark, other AGH oncologists contributing to the study included D. Lawrence Wickerham, MD, AGH surgical oncologist and Associate Chair of the NSABP and Thomas Julian, MD, Associate Director of the AGH Breast Center and a Principal Investigator for the NSABP at AGH.