LHRHa Preserves Ovarian Function in Breast Cancer Chemo

Fran Lowry

December 22, 2015

Another large study has shown that the concurrent administration of a luteinizing hormone-releasing hormone analogue (LHRHa) and chemotherapy might help premenopausal women with breast cancer retain ovarian function and go on to become pregnant.

This phase 3 trial — Prevention of Menopause Induced by Chemotherapy: A Study in Early Breast Cancer Patients – Gruppo Italiano Mammella 6 (PROMISE-GIM6) — assessed the LHRHa triptorelin in patients with hormone-receptor-positive or hormone-receptor-negative breast cancer.

The results, which were published in the December 22/29 issue of JAMA, show that triptorelin added to chemotherapy improved the long-term probability of ovarian function recovery, compared with chemotherapy alone.

More patients treated with triptorelin than with chemotherapy alone achieved pregnancy, although the difference was not significant. There was no significant difference in disease-free survival between triptorelin and chemotherapy alone.

Similar findings were reported in the Prevention of Early Menopause Study (POEMS), which assessed the LHRHa goserelin. Those results were presented at the 2014 Annual Meeting of the American Society of Clinical Oncology, as previously reported by Medscape Medical News.

Results from the PROMISE trial, together with the results from the POEMS-SWOG S0230 study, show that "in addition to fertility preservation strategies, such as embryo and oocyte cryopreservation, temporary ovarian suppression with an LHRHa is a valid option to preserve ovarian function in premenopausal women with early-stage breast cancer receiving adjuvant or neoadjuvant chemotherapy," said senior PROMISE author Lucia Del Mastro, MD, from the Istituto Nazionale per la Ricerca sul Cancro in Genova, Italy.

For a person who is very invested in having a future biological child, this is a new and emerging alternative that can be considered.

"These aren't home runs — the numbers are relatively small — but for a person who is very invested in having a future biological child, this is a new and emerging alternative that can be considered," said Ann Partridge, MD, from the Dana-Farber Cancer Institute, Brigham and Women's Hospital, and Harvard Medical School in Boston, who was not involved in either trial.

Loss of Ovarian a Serious Problem for Breast Cancer Survivors

"Ovarian function loss and impaired fertility are possible consequences of anticancer treatment and have a negative impact on the global health of young breast cancer survivors," Dr Del Mastro told Medscape Medical News.

Currently, embryo and oocyte cryopreservation is the standard for fertility preservation in cancer patients. "But to date, no proven methods for preservation of ovarian function are available. The PROMISE-GIM6 study is the largest study so far aiming to evaluate the role of temporary ovarian suppression with an LHRHa as a possible strategy to preserve ovarian function in these young breast cancer patients," she explained.

Not only is PROMISE the largest study, "it has longer follow-up and, unlike POEMS, it included patients with hormone-receptor-positive and those with hormone-receptor-negative disease. Our data suggest that this strategy could be useful and safe, not only in women with hormone-receptor-negative breast cancer, as was recently endorsed by the 2015 St. Gallen International Expert Consensus panel and the National Comprehensive Cancer Network guidelines, but also for those with hormone-receptor-positive tumors, who account for the majority — more than 65% — of new cases of breast cancer in young women," Dr Del Mastro said.

Details of PROMISE Results

The PROMISE study involved 281 premenopausal women 24 to 45 years of age (median age, 39 years) with stage I to III hormone-receptor-positive or hormone-receptor-negative breast cancer. Dr Del Mastro and her colleagues randomly assigned 148 women to chemotherapy plus the LHRHa triptorelin and 133 to chemotherapy alone (control group).

The trial was conducted at 16 sites in Italy. Enrollment took place from October 2003 to January 2008, and the last follow-up was in June 2014. Median follow-up was 7.3 years (interquartile range, 6.3 - 8.2 years).

The long-term probability of menstrual resumption, defined as the occurrence of at least one menstrual cycle, was higher in the LHRHa group than in the control group.

The 5-year cumulative incidence estimate of menstrual resumption was 72.6% (95% confidence interval [CI], 65.7% - 80.3%) in the LHRHa group and 64.0% (95% CI, 56.2% - 72.8%) in the control group.

Table. Menstrual Resumption in the Study Cohort

Tumor Type LHRHa Group, % Control Group, %
Hormone-receptor-negative 86.2 81.0
Hormone-receptor-positive 69.3 60.7


There were more pregnancies in the LHRHa group than in the control group (8 vs 3). The 5-year cumulative incidence estimate of pregnancy was 2.1% (95% CI, 0.7% - 6.3%) in the LHRHa group and 1.6% (95% CI, 0.4% - 6.2%) in the control group.

Of the five pregnancies that occurred more than 5 years after the end of chemotherapy, four were in the LHRHa group and one was in the control group.

Five year disease-free survival was 80.5% in the LHRHa group and 84% in the control group. This increased but statistically nonsignificant risk appears to be specific to women with hormone-receptor-negative tumors.

For patients with hormone-receptor-positive tumors, the hazard ratio (HR) was 0.96 (95% CI, 0.55 - 1.70); for those with hormone-receptor-negative tumors, the HR was 2.11 (95% CI, 0.74 - 5.98).

"The results of our study can help doctors counsel their young patients on what they can do to preserve their ovarian function and fertility during chemotherapy," Dr Del Mastro said.

"Particularly, doctors can say that the use of temporary ovarian suppression with LHRHa during chemotherapy is associated with approximately a 15% absolute reduction in the number of patients developing chemotherapy-induced premature ovarian failure, a higher long-term probability of ovarian function recovery, a higher likelihood of becoming pregnant after the end of chemotherapy, and no negative impact on their prognosis," she said.

The PROMISE findings suggest modest benefits regarding the potential prevention of treatment-associated infertility, Dr Partridge writes in an accompanying editorial.

Both this and the POEMS trial "reflect the emerging importance of understanding and improving such critical quality-of-life issues, offering patients new treatment and supportive care options, and ultimately providing hope regarding an issue that is highly valued by many young patients diagnosed with cancer," she reports.

PROMISE is one of the two largest studies to date that have demonstrated that in both estrogen-receptor (ER)-positive and ER-negative breast cancers, ovarian function suppression with an LHRHa plus chemotherapy "is associated with fewer women going through premature menopause after chemotherapy," Dr Partridge told Medscape Medical News.

"There is also a modest incremental increase in the number of babies born in the population that received the ovarian suppression, which is consistent with the POEMS-SWOG trial. The evidence now is suggesting that there are small benefits in terms of prevention of premature menopause, as well as the potential preservation of fertility through the use of ovarian suppression treatments," she said.

The study was supported by the Istituto Nazionale per la Ricerca sul Cancro and the Associazione Italiana per la Ricerca sul Cancro (AIRC). The triptorelin used in the study was provided by Ipsen. Dr Del Mastro reports receiving honoraria from Takeda and personal fees from Ipsen and Takeda. Dr Partridge has disclosed no relevant financial relationships.

JAMA. 2015;314:2625-2627, 2632-2640. Editorial, Abstract


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