Use of the hormone-suppressing drug goserelin (Zoladex, AstraZeneca) during chemotherapy for breast cancer protects ovarian function and might help some women avoid the heartbreak of treatment-related infertility, according to results from a study published online March 4 in the New England Journal of Medicine.
When the study was first presented at the 2014 Annual Meeting of the American Society of Clinical Oncology (ASCO), it received a lot of professional and consumer media coverage. It can now be reviewed in greater detail.
In the Prevention of Early Menopause Study (POEMS), the chemotherapy regimens all contained cyclophosphamide, which can induce ovarian failure.
All study participants were premenopausal, younger than 50 years, and had stage I to IIIA hormone-receptor-negative breast cancer.
"Premenopausal women beginning chemotherapy for early breast cancer should consider this new option to prevent premature ovarian failure," lead study author Halle Moore, MD, from the Cleveland Clinic, reported at the ASCO meeting.
In their now-published study, Dr Moore and her coauthors expand on those comments.
They observe that current ASCO guidelines encourage female cancer patients interested in fertility preservation to see reproductive specialists for embryo cryopreservation.
But embryo cryopreservation is limited by cost, timing issues, and the need for a partner.
These limitations do not apply to goserelin, a gonadotropin-releasing hormone (GnRH) agonist, which temporarily shuts the ovaries down and protects them during chemotherapy.
"Coadministration of a GnRH agonist with chemotherapy may be a more accessible option for patients and can be used in conjunction with traditional fertility-preservation techniques," the study authors write.
Preventing Premature Ovarian Failure
The primary end point of the study was premature ovarian failure at 2 years, defined as amenorrhea for the preceding 6 months and postmenopausal levels of follicle-stimulating hormone.
The team planned to enroll 416 patients, but they lost their drug-funding source. In the end, there were 218 eligible patients, 135 of whom had primary end point data.
In that group, 5 of the 66 women treated with chemotherapy plus goserelin experienced premature ovarian failure 2 years after cancer treatments, as did 15 of the 69 women treated with chemotherapy alone (8% vs 22%; odds ratio [OR], 0.30; P = .04).
Goserelin was given as monthly injections starting 1 week before the first dose of chemotherapy. It costs about $500 to $600 per injection, and each patient received four injections.
Pregnancies were a secondary end point. Roughly the same number of women in the two groups reported attempting to conceive. However, more women treated with chemotherapy plus goserelin than with chemotherapy alone became pregnant (21% vs 11%; OR, 2.45; P = .03).
More babies were born to women treated with chemotherapy plus goserelin than with chemotherapy alone (18 vs 12). In addition, at the time of data submission, there were five ongoing pregnancies in women treated with chemotherapy plus goserelin and three in women treated with chemotherapy alone.
Median follow-up in the study was 4.1 years.
These findings "confirm and extend" those from similar studies, according to the authors.
In fact, a recent meta-analysis of randomized trials on the use of GnRH analogs for the protection of ovarian function during chemotherapy showed a 57% reduction in the risk for ovarian failure (Cancer Treat Rev. 2014;40:675-683), which is consistent with the POEM results.
At ASCO, a number of experts not involved with the study hailed the results as pivotal.
"This is really a practice-changing presentation," said Patricia Ganz, MD, from the Jonsson Comprehensive Cancer Center at the University of California, Los Angeles. She moderated the ASCO press conference during which the study was highlighted.
"This is something I would seriously consider with appropriate patients. There's relatively little downside," Claudine Isaacs, MD, from the breast cancer program at the Georgetown Lombardi Comprehensive Cancer Center in Washington, DC, told Medscape Medical News at the time.
Sharon Giordano, MD, from the University of Texas M.D. Anderson Cancer Center in Houston, said she "would be comfortable offering this option to my patients with estrogen receptor (ER)-negative breast cancer who desire future fertility or prevention of premature menopause."
However, Dr Giordano said she is concerned about the less-than-targeted patient accrual and resulting smaller study population. "Some uncertainty" exists about the study and the strategy, she noted. "I don't think we can consider these results definitive."
In their study, Dr Moore and her coauthors address this issue.
"Interpretation of the main findings is complicated by incomplete enrollment and missing data," they write.
But they reviewed their patient group data and found that the groups were balanced.
Furthermore, they performed sensitivity analyses that incorporated "partial information from patients with missing data" and found consistency with the main findings.
At the ASCO meeting, Dr Giordano said that she would relay these "caveats" about the smaller study population to patients when she was offering goserelin in conjunction with chemotherapy. In short, even an outspoken doubter of the trial planned on introducing the treatment strategy to patients.
Endocrine-Positive Breast Cancer Excluded
Notably, women with hormone-receptor-positive disease were not eligible for the study.
The authors explain why: "The use of adjuvant endocrine therapy after chemotherapy complicates the assessment of longer-term ovarian function after administration of a GnRH agonist with chemotherapy."
In other words, treatments such as tamoxifen, which also suppresses ovarian function, but through a different mechanism, would muddy the waters of cause and effect.
The recent randomized phase 3 Tamoxifen and Exemestane Trial (TEXT) showed that GnRH agonists actually have a therapeutic role in ER-positive breast cancer.
The POEM investigators also found such a therapeutic effect, which they called "unexpected" because rates of disease-free and overall survival improved in the goserelin group.
The 4-year Kaplan–Meier estimate of the rate of disease-free survival was 89% with chemotherapy plus goserelin and 78% with chemotherapy alone (adjusted hazard ratio, 0.49; P = .04).
Eight patients treated with chemotherapy plus goserelin and 17 treated with chemotherapy alone died.
The 4-year Kaplan–Meier estimate of the rate of overall survival was 92% with chemotherapy plus goserelin and 82% with chemotherapy alone (adjusted hazard ratio, 0.43; P = .05).
But at ASCO, Dr Isaacs said she does not put much stock in the survival data.
"The numbers are too small to make conclusions about the impact of goserelin on breast cancer survival. I would be very cautious about that," she said.
The POEM investigators also did not emphasize these findings. "Disease risk factors were not stratified in the study, making it difficult to draw conclusions about any therapeutic effect of the GnRH agonist," they write.
The study was funded by the National Institutes of Health. Some of the study authors report financial ties to AstraZeneca.
N Engl J Med. 2015;372:923-932. Abstract
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