Conference Coverage

Goserelin improves fertility in HR-negative breast cancer


 

AT THE ASCO ANNUAL MEETING 2014

CHICAGO – Use of the gonadotropin-releasing hormone agonist goserelin during chemotherapy for early hormone receptor–negative breast cancer was associated with lower rates of ovarian failure and more pregnancies in the phase III POEMS study.

At 2 years, 22% of women receiving standard neoadjuvant or adjuvant chemotherapy alone and 8% of those receiving chemotherapy plus goserelin (Zoladex) experienced ovarian failure, defined as amenorrhea for the prior 6 months and follicle-stimulating hormone (FSH) in the postmenopausal range.

Patrice Wendling/Frontline Medical News

Dr. Halle Moore

In logistic regression analysis that accounted for age and chemotherapy regimen, the risk of ovarian failure was reduced 70% with goserelin (odds ratio, 0.30; two-sided P = .04), Dr. Halle Moore reported at the annual meeting of the American Society of Clinical Oncology.

Risk was further reduced using the less stringent definition of ovarian failure of amenorrhea for the prior 6 months or FSH in the postmenopausal range (45% vs. 20%; OR, 0.29; P = .006).

The 2-year ovarian dysfunction rate was 33% with standard chemotherapy and 14% with chemotherapy plus goserelin (OR, 0.35; P = .03). Dysfunction was defined as amenorrhea for the prior 3 months and FSH, estradiol, and/or inhibin B levels in the postmenopausal range.

"For the 25 percent or so of women with breast cancer who are diagnosed under the age of 50, the induction of early menopause is a common and potentially devastating side effect of treatment," said Dr. Moore of the Cleveland Clinic.

Small studies have shown high rates of ovarian preservation in women with hematologic malignancies with the use of a luteinizing hormone release hormone (LHRH) analogue. Results of randomized trials in breast cancer have been mixed; the studies commonly used only return of menses as an endpoint, and few provided data on pregnancy outcomes, she said.

The intergroup POEMS/S0230 (Prevention of Early Menopause Study) randomly assigned 257 premenopausal women, aged 18-49 years, with operable stage I-IIIA estrogen or progesterone receptor–negative breast cancer to curative-intent standard cyclophosphamide containing neoadjuvant or adjuvant chemotherapy alone or with subcutaneous injections of goserelin 3.6 mg every 4 weeks starting at least 1 week prior to the first chemotherapy dose and ending within 2 weeks of the final dose. The average age of the groups was 38.7 and 37.6 years, respectively.

The study was closed prior to full accrual of the target 416 patients, with 218 women evaluable for pregnancy and survival outcomes and 135 for ovarian failure.

In all, 18 of 113 evaluable controls and 25 of evaluable 105 women given goserelin reported attempting pregnancy, with 12 and 22 women, respectively, becoming pregnant over the 5-year study period (OR, 2.45; P = .03), Dr. Moore said.

Compared with controls, women given goserelin were twice as likely to have a successful delivery (8 vs. 16; OR, 2.51; P = .05) and to have a successful delivery or an ongoing pregnancy at the time of the analysis (10 vs. 19; OR, 2.45; P = .04).

Twelve babies were born to women on chemotherapy alone and 18 to those given goserelin, with 3 and 5 pregnancies, respectively, ongoing.

Importantly, there was no evidence goserelin increased adverse pregnancy events such as miscarriage (5 controls vs. 4 goserelin), elective termination (3 vs. 2), and delivery complications (2 vs. 2), she said.

Grade II-IV endocrine toxicity was reported in 24% of the chemotherapy-alone arm and 48% of the goserelin arm (P = .006). One grade IV thromboembolic event occurred with goserelin, Dr. Moore said. The most common added toxicities with goserelin were hot flashes, mood changes, vaginal dryness, and headache.

A planned exploratory analysis revealed that 89% of women on goserelin versus 78% on chemotherapy alone were disease-free at 4 years, with a hazard ratio of 0.47 after controlling for age and regimen (P = .04) and 0.49 after further adjusting for cancer stage (P = .04).

Overall survival at 4 years was 92% with goserelin and 82% with chemotherapy alone, with hazard ratios of 0.45 (P = .06) and 0.43 (P = .05), respectively.

The favorable survival outcomes with the addition of goserelin are intriguing and reassuring regarding the safety of the approach, Dr. Moore said. One possible explanation for the finding is that there are a high number of LHRH receptors on hormone receptor–negative breast cancers.

"Premenopausal women beginning curative-intent chemotherapy should consider this new option to prevent premature ovarian failure," she concluded.

Discussant Dr. Sharon Giordano, chair of health services research at the University of Texas MD Anderson Cancer Center in Houston, praised POEMS for providing pregnancy information and reassuring outcome data, but said there were several limitations. The most worrisome of these was missing endpoint data for 38% of participants. The study was also hampered by early close and low accrual, and excluded women with more than 10% estrogen or progesterone receptor positivity.

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