Meta-analysis Supports Ovarian Suppression in Breast Cancer

Zosia Chustecka

September 28, 2015

VIENNA — Being diagnosed with breast cancer at a young age is devastating enough, but the prospect that the chemotherapy needed could push the ovaries into failure and result in infertility adds extra heartbreak.

In the last year, two major clinical trials have shown that using a hormone therapy to suppress ovarian function temporarily during cancer treatment can preserve fertility, with the results hailed as practice-changing. However, this strategy has not yet been incorporated into management guidelines.

A new meta-analysis of all the available clinical trial data — the largest so far — adds support for this approach. It involves the use of a luteinizing hormone-releasing hormone analogue (LHRHa), which is given during chemotherapy for the breast cancer.

The meta-analysis was presented in a poster session here at the European Cancer Congress (ECC) 2015, and was published simultaneously in the Annals of Oncology.

"In breast cancer patients, we believe there is now sufficient evidence to suggest that the administration of LHRHa could be considered a potential standard strategy to preserve ovarian function and might also play a role in increasing the likelihood of pregnancy after chemotherapy," said lead author Matteo Lambertini, MD, a medical oncologist at the IRCCS AOU San Martino-IST, Genoa, Italy.

Dr Matteo Lambertini

"Pharmacological protection of the ovaries with LHRHa during chemotherapy is an attractive option to preserve ovarian function and fertility," he said in an ECC press statement. "The agents are widely available, do not require any invasive procedure, and cause no delay in the initiation of anticancer therapies. Moreover, it is possible to use this technique in combination with other fertility preservation options, including cryopreservation strategies, thereby increasing the chance of fertility preservation as well as ovarian function after cancer therapies."

"With the rising trend of delaying childbearing, more breast cancer patients are diagnosed without having completed their families and, thus, it is vital to provide reliable fertility preservation methods for these young women," he added.

Meta-analysis Included Recent Trials

The meta-analysis included 12 randomized trials and a total of 1231 breast cancer patients receiving chemotherapy, with or without LHRHa.

It included two recently reported major trials. One is the POEMS trial of goserelin, which was hailed as practice-changing when presented at the 2014 annual meeting of the American Society of Clinical Oncology, and was subsequently published in the New England Journal of Medicine. The other is a study by Dr Lambertini and colleagues of the long-term outcomes from the phase 3 PROMISE-GIM6 trial, also presented at ASCO 2014 (J Clin Oncol. 32[26]:abstract 105).

 

In the meta-analysis, an initial calculation found that rates of chemotherapy-induced premature ovarian failure were reduced by 64% in patients who received LHRHa (odds ratio [OR], 0.36; 95% confidence internal [CI], 0.23 – 0.57; P < .001). However, the studies used different definitions of premature ovarian failure, and results ranged widely, Dr Lambertini noted.

The analysis was then restricted to eight trials that included specific data on whether menstruation had restarted 1 year after chemotherapy, in line with the World Health Organization's definition of menopause. When this stricter definition was used, there was close agreement in results from all the studies, he noted. This calculation showed a 45% reduction in chemotherapy-induced premature ovarian failure when an LHRHa was used (OR, 0.55; 95% CI, 0.41 - 0.73; P < .001).

Only five of the 12 studies included in the meta-analysis reported on pregnancies after breast cancer treatment. These five studies involved 359 patients treated with LHRHa during chemotherapy, of whom 33 (9.2%) became pregnant, compared with 19 (5.5%) among 347 women undergoing chemotherapy-alone use (OR, 1.83; 95% CI, 1.02 - 3.28; P = .041). The rates were similar across the five studies. Although the numbers are small, this suggests that the use of LHRH almost doubled the chance of achieving subsequent pregnancies, the researchers write in their study.

In addition, three of the studies reported data on breast cancer progression, and found no difference between women who took LHRHa and those who did not (hazard ratio, 1.00; 95% CI, 0.49 - 2.04; P = .939).

"In conclusion, temporary ovarian suppression with LHRHa during chemotherapy is associated with a reduced risk of chemotherapy-induced premature ovarian failure and seems to increase the pregnancy rate in young breast cancer patients, with no apparent negative impact on patients' prognosis," the authors write.

Another recent meta-analysis of 10 clinical trials published online June 5 in Obstetrics and Gynecology came to different conclusions, and said the use of these agents is not a reliable method of fertility preservation, as reported by Medscape Medical News. However, the lead author of the POEMS, Halle Moore, MD, from the Department of Hematology-Oncology at the Cleveland Clinic, told Medscape Medical News at the time that she questions the conclusions of that meta-analysis and remains convinced about this approach.

Incorporations Into Guidelines

The 2015 St. Gallen International Expert Consensus panel and the National Comprehensive Cancer Network guidelines have been updated to acknowledge the role of LHRHa in preventing ovarian failure induced by chemotherapy, but only in hormone-receptor-negative cancer.

Dr Lambertini said that the data now collected in the meta-analysis suggest that "this strategy could be useful and safe not only in women with hormone-receptor-negative breast cancer, but also in those with hormone-receptor-positive tumors, who account for two-thirds of new cases of breast cancer in young women."

Guidelines from ASCO and European Society for Medical Oncology have not been updated since 2013, and they consider the administration of LHRHa during chemotherapy an experimental strategy to preserve ovarian function and fertility.

"Other guidelines are hesitating to recommend this technique," Dr Lambertini said in an ECC press statement. "To date, the role of this approach in fertility preservation remains controversial."

Peter Naredi, MD, PhD, scientific cochair of the congress, who was not involved in the research, commented: "Thanks to a global collaboration with data available from several studies, it is possible to reinforce a benefit of LHRHa treatment for all the women with breast cancer who still want to have the option to become pregnant."

European Cancer Congress (ECC) 2015: Abstract 1957. Presented September 28, 2015.

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