Controversial Breast Cancer Treatment Strategy May Protect Ovarian Function, Preserve Fertility

Results from a meta-analysis of data collected from 837 premenopausal women undergoing chemotherapy for early-stage breast cancer suggest that gonadotropin-releasing hormone analog (GnRHa) may preserve fertility and have a protective ovarian function.

Matteo Lambertini, M.D., medical oncologist and ESMO fellow at the Institut Jules Bordet in Brussels, Belgium, and his team found that women assigned to GnRHa had a 62 percent lower risk for developing premature ovarian insufficiency (POI) compared to those treated with chemotherapy alone. The premature ovarian insufficiency rate was 14.1 percent in the GnRHa group versus 30.9 percent in the control group.

Lambertini discussed findings from a review of five clinical trials during a Thursday morning press conference at the 2017 San Antonio Breast Cancer Symposium. Temporary ovarian suppression with GnRHa during chemotherapy has the potential to preserve ovarian function and fertility in premenopausal breast cancer patients. However, the practice is controversial and is still considered experimental by ASCO and ESMO. He said this study provides important evidence on the efficacy and safety of this strategy in both estrogen receptor [ER]-negative and ER-positive women.

“Taking these results into account, we believe that this strategy should be considered the standard option to reduce the likelihood of developing chemotherapy-induced premature ovarian insufficiency, and potentially improve future fertility in premenopausal early breast cancer patients undergoing adjuvant or neoadjuvant chemotherapy,” he said.

He said later that these findings should put the controversy to rest.

“It’s a systematic review and meta-analysis of the five major, randomized, controlled trials in this setting, so it’s the highest level of evidence that we can reach. Second, it is unlikely that we will have new randomized, controlled trials in this setting and, based on these results, I think it would be unethical to have randomized, controlled trials again in this setting.

“What researchers should do in the next year is to better understand how this strategy works. This is probably the main controversy right now because it’s not clear how this strategy works,” Lambertini said.

Women treated with GnRHa were slightly less likely to experience amenorrhea — absence of menstrual periods — at one year, but there was a significant difference at two years. Thirty-seven women (10.3 percent) in the GnRHa group had at least one post-treatment pregnancy during the follow-up period compared with 20 women (5.5 percent) in the control group.

Lambertini said those 57 pregnancies resulted in 50 live births. Because this was a meta-analysis, his research team did not know how many women in the cohort had hoped to become pregnant.

Temporary ovarian suppression with GnRHa during chemotherapy was mostly developed as a strategy to reduce the risk for developing treatment-induced premature ovarian insufficiency, not as a fertility-preserving procedure. As a result, most trials exploring this strategy have a very short follow-up and do not report on post-treatment pregnancies. Randomized clinical trials investigating efficacy have produced conflicting results, and some had very small patient populations, making it difficult to draw solid conclusions based on the results of individual studies.

To develop more conclusive clinical evidence, Lambertini and his colleagues performed meta-analysis on five randomized clinical trials—PROMISE-GIM6, POEMS/SWOG S0230, Angelo Celtic Group OPTION, GBG-37 ZORO, and a Moffitt Cancer Center-led trial — in which premenopausal women with early-stage breast cancer were randomly assigned to chemotherapy alone (n = 437) or chemotherapy with concurrent GnRHa (n = 436). Median patient age was 38 years, and more than two-thirds were younger than age 40 at diagnosis.

At five years, there were no significant differences in disease-free survival or overall survival between the two groups regardless of estrogen receptor status. Lambertini said this result suggests that administering GnRHa during chemotherapy can be considered safe.

Moderator Carlos L. Arteaga, MD, director of the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern Medical Center, noted that the difference in premature ovarian insufficiency was real, but small. He asked Lambertini how he would counsel patients who eventually hope to have children about their risk, and which women are likely to have the best chance for success?

“GnRHa does not avoid the risk for early menopause in all patients but does decrease significantly the number of patients who develop this side effect,” Lambertini said. “The best candidates for this procedure, first, are patients concerned about developing early menopause, patients who are concerned about the side effects related to early menopause, [and] patients who . . . want to preserve ovarian function.”