Study Suggests Approach to Reduce Ovarian Toxicity While Fighting Breast Cancer

Ovarian toxicity is a significant concern for women undergoing chemotherapy treatment for breast cancer — especially those of child-bearing age who wish to preserve their fertility.

Damage from such toxicity can include premature ovarian failure, marked by amenorrhea, sexual dysfunction and infertility. But a new study in the New England Journal of Medicine suggests that ovarian failure may be preventable in some patients, potentially altering the ways in which clinicians care for these women.

Redefining fertility benchmarks

The Prevention of Early Menopause Study (POEMS) was a Phase III clinical trial developed to assess whether ovarian failure could be prevented by temporarily suppressing ovarian function by including goserelin, a gonadotropin hormone-releasing hormone (GNRH) agonist, with standard chemotherapy.

Previous investigations of this approach have yielded mixed results and typically only used return of menstruation as an indicator of ovarian function. But this can be misleading, says Halle Moore, MD — chair of the Taussig Cancer Institute Survivorship Program and the study’s lead author — because regular menstrual bleeding is not equivalent to fertility in cancer survivors.

POEMS used a rigorous definition for ovarian failure that included absence of menses at two years and menopausal hormone levels. Furthermore, previous studies did not comprehensively track future pregnancies as an outcome — a clear benchmark for fertility. POEMS sought to resolve these limitations.

“The only way to evaluate fertility in breast cancer survivors is to focus on the meaningful endpoints of pregnancy and live birth rates, and that is a real strength of this study,” notes Rebecca Flyckt, MD, Director of the Fertility Preservation Program in the Ob/Gyn & Women’s Health Institute.

Improved fertility prospects

The study randomized 218 eligible female breast cancer patients whose cancers were estrogen-receptor and progesterone-receptor-negative to receive either cyclophosphamide-containing chemotherapy alone or with goserelin added.

The researchers found that among 135 participants for whom ovarian function was assessable at two years, only 8 percent of those receiving the goserelin-supplemented treatment experienced ovarian failure, compared to 22 percent of the women who did not (OR = 0.30, p = 0.03).

Furthermore, among all 218 eligible participants, almost twice as many women in the co-treatment group were able to achieve pregnancy compared to those in the control group (21 percent versus 11 percent of women, respectively; OR = 2.45, p = 0.03).

“Disease-free survival and overall survival also were higher among the women receiving goserelin,” Dr. Moore says. She adds that the study’s findings offer the first demonstration of improved fertility prospects using goserelin along with chemotherapy — as well as demonstration of the safety of the approach.

Dr. Flyckt points out that “this GnRH regimen is one of the few options available for preventing chemotherapy-induced amenorrhea and infertility. GnRH agonists do have side effects, however, and their use has been a topic of controversy for years.

“I believe that many reproductive-aged women would choose to exchange transient symptoms for an increased pregnancy rate following cancer treatment. This study offers clear evidence in support of ovarian protection with GnRH agonists for women with hormone-receptor-negative breast cancers, and these findings may be applicable to other cancers as well.”

A look at other breast cancers

Dr. Moore and her colleagues are following up on their novel findings by participating in a meta-analysis examining all randomized controlled trials in both hormone receptor-negative and hormone receptor-positive breast cancer patients. The goal: to increase the overall sample size and to better determine the impact of this ovarian protection strategy.

Even with larger-scale data yet to come, results from the current study are anticipated to significantly affect treatment approaches for breast cancer. They also may affect other types of malignancies treated with similar chemotherapy, including non-Hodgkin lymphoma.

For some young women with breast cancer, the prospect of treatment with chemotherapeutic agents that could prolong survival at the potential cost of fertility is a heartbreaking decision — and one that sometimes leads patients to turn down the therapy. Outcomes from POEMS may help diminish these fears and help women preserve their lives and their reproductive abilities.

Spreading the word

“I believe many clinicians have already started implementing this strategy to protect ovarian functioning for young women being treated for breast cancer,” Dr. Moore says.

In addition to the study’s publication in the New England Journal of Medicine, the American Society of Clinical Oncology (ASCO) included this report in the recently published report Clinical Cancer Advances 2015: ASCO’s Annual Report on Progress Against Cancer.

“This information needs to be available to patients, primary care physicians, gynecologists, surgeons and other people helping women make decisions early on in the breast cancer diagnosis,” says Dr. Moore.

“This is an important long-term survivorship issue, and hopefully publication in a high-impact journal and citation by ASCO as an important clinical advancement will help to inform a broader base of people providing for these women.”

An inexpensive option

Dr. Flyckt notes that when reproductive-aged women present with breast cancer, fertility preservation options are not always discussed. And when they are, patients often decline them due to the urgent need for cancer treatment, and the costs of options such as egg and embryo freezing.

“Although egg and embryo freezing represent the gold standard in fertility preservation, this study should reinforce the availability of relatively simple, inexpensive options for preserving a young cancer patient’s fertility that will not delay chemotherapy,” she says.

“Patients need to be informed about the full range of options in order to make a decision that is right for them. Fertility specialists are available to help patients navigate the decision-making process and to work closely with the oncology team.”