NEW YORK (Reuters Health) - Nearly 40% of breast cancer patients in their 40s who received adjuvant chemotherapy and stopped menstruating for at least a year after chemotherapy subsequently regained ovarian function and estrogen production when they were given an aromatase inhibitor (AI), a new study shows.
"The clinical implication is that women in their 40s with intact ovaries should not be treated with aromatase inhibitors because the risk of their having recovery of ovarian function, leading to estrogen production and decreased AI effectiveness, is high," Dr. Joyce O'Shaughnessy of Texas Oncology-Baylor Charles Sammons Cancer Center, in Dallas, told Reuters Health by email.
The study adds to accumulating evidence indicating that AI therapy is contraindicated for such women, she said.
In postmenopausal women who have hormone-positive breast cancer, AIs reduce recurrence and boost survival rates. In these women, estrogen is produced mostly by aromatase activity in peripheral tissues, and AI treatment reduces nearly all circulating estrogen.
But for a subset of premenopausal breast cancer patients who undergo chemotherapy-induced amenorrhea but who have residual ovarian function, AI therapy stimulates ovarian production of estrogen.
"The concern is that ovarian estrogen production will decrease the effectiveness of AI therapy because some early studies suggest that the lower the blood estrogen levels, the more effective AI therapy may be in preventing breast cancer recurrence," Dr. O'Shaughnessy noted.
The prospective open-label study assessed two years or more of AI therapy in 177 women 40 to 49 with estrogen-positive breast cancer. All participants had stopped menstruating after receiving adjuvant cyclophosphamide therapy, had postmenopausal serum estradiol (E2) levels, and had taken tamoxifen for a year or more without menses.
Serum follicle stimulating hormone (FSH) levels and E2 levels were measured at baseline and over two years. The primary objective was to learn whether serial FSH levels during AI therapy were predictive of recovery of ovarian function (resumption of menses or return to premenopausal E2 levels).
Of 173 evaluable participants, 67 (39%) regained ovarian function, 11 of whom (6%) resumed menstruating and 56 of whom (32%) developed premenopausal E2 without menses, the researchers noted in a report online February 16 in the Journal of Clinical Oncology.
Analysis with a general linear model to assess serial FSH by ovarian function recovery found that serial FSH increased significantly among AI-naive patients over time (p=0.001), but did not vary significantly by recovery of ovarian function status.
Significant multivariable baseline predictors of ovarian function recovery included age less than 45 years and levels of inhibin B. Studies have suggested that declining inhibin B is a more direct marker of ovarian aging than FSH.
"We were surprised that the rate of ovarian function recovery on AI therapy was so high both in women under age 45 and in those 45 years or older," said Dr. O'Shaughnessy. "We learned that the ovaries in women in their 40s after cyclophosphamide-based chemotherapy and cessation of menses are still functional in a high percentage of women."
"These findings represent an important cautionary note for oncologists who are treating young women with breast cancer," Dr. N. Lynn Henry, of the University of Michigan, Ann Arbor, told Reuters Health by email.
"Considering the high overall risk of recurrence of ovarian function in this population, the inability to predict ahead of time which women will experience recovery of their ovarian function, and the technical challenges with monitoring ovarian function, the authors reasonably conclude that amenorrheic women in their 40s with at least one ovary in place should not receive aromatase inhibitor therapy by itself," noted Dr. Henry, who was not involved in the study.
Treatment alternatives for such women include either tamoxifen or AI therapy in conjunction with ovarian function blockade. "If aromatase inhibitor therapy alone must be used, then patients should be made aware of the risk and should be very closely monitored with blood tests," she said.
To optimize management of young women with hormone-receptor positive breast cancer, additional research is needed to determine who is at highest risk of ovarian function recovery following chemotherapy, as well as determining the best tests (and when to give them) for monitoring ovarian function, Dr. Henry said.
The study was supported by a research grant from Novartis, which manufactures the aromatase inhibitor letrozole. Dr. O'Shaughnessy and some of her coauthors disclosed consulting or other relationships with Novartis and other companies that market aromatase inhibitors.
J Clin Oncol 2016.