One of the most reported studies emanating from the 2014 ASCO Annual Meeting involves the use of the luteinizing hormone–releasing hormone (LHRH) agonist goserelin (Zoladex) to reduce the risk of ovarian failure among women being treated with chemotherapy for early-stage breast cancer, and to increase the likelihood of a successful pregnancy afterward (see page 22).¹ Network and cable television, national and regional newspapers, and international news services covered the study and what it might mean to women concerned about preserving fertility after being treated for cancer.

In an interview with The ASCO Post, the study’s lead author, Halle Moore, MD, said that she welcomed the media coverage because “the more the public is aware of fertility preservation options for patients receiving chemotherapy, the more likely it is that those patients will ask their doctors about [such measures].” Dr. Moore is a Staff Physician and Chair of the Survivorship Program at the Cleveland Clinic. The study was funded by the National Institutes of Health, and Dr. Moore was hopeful that the extensive media coverage might also help the public see “where our dollars are going” and understand the importance of federally funded research.

What the Study Showed

The phase III Prevention of Early Menopause Study (POEMS)/Southwest Oncology Group (SWOG) S0230 recruited 257 premenopausal women, aged 18 to 49, with stage I to IIIA estrogen receptor–negative and progesterone receptor–negative breast cancer, and 218 patients were evaluable. The primary endpoint of the study was the rate of ovarian failure at 2 years, defined as having no menstrual periods for the prior 6 months and postmenopausal levels of follicle-stimulating hormone (FSH).

“By this definition, the ovarian failure rate was 22% in the standard chemotherapy arm and 8% in the goserelin arm,” Dr. Moore reported at an ASCO press briefing on patient care and quality of life. “In the stratified analysis, this represented a 70% reduction in ovarian failure with a P value of .04. Using a less stringent ovarian failure definition of either postmenopausal FSH or absent menstrual periods for the prior 6 months, 45% of patients in the standard arm vs 20% in the goserelin arm experienced ovarian failure. This difference was highly significant with an adjusted P value of .006,” she added.

Among women receiving chemotherapy alone, 11% reported becoming pregnant, with 7% actually delivering a total of 12 babies, and two other women still pregnant at the time of data submission. Among women who also received goserelin, 21% became pregnant, with 15% actually delivering a total of 18 babies, and three other women still pregnant at the time of data submission. “The greater-than-twofold differencea in becoming pregnant and having a successful outcome was associated with P values between .03 and .05,” Dr. Moore noted.

The pregnancy results applied only to the 5-year study period, and “not all patients on study were actually interested in becoming pregnant,” Dr. Moore pointed out in the interview with The ASCO Post. “The rates might be higher in a highly motivated group or in a younger patient population.”

Goserelin Injections

Goserelin injections were started at least 1 week before chemotherapy and continued once a month for the duration of the chemotherapy. The monthly goserelin dose was 3.6 mg.

“It takes about 10 days to fully suppress ovarian function with this medication,” Dr. Moore noted. “But we also didn’t want to limit patients’ interest in the study by making them wait too long before starting their chemotherapy. We didn’t want to do anything that would delay their chemotherapy in any significant way. So we compromised at starting at least 1 week prior to the first chemotherapy dose. One week actually appeared to work very well.”

The chemotherapy regimens used for early-stage breast cancer typically extend over a period of 3 to 6 months, Dr. Moore explained, “and the most common regimen that we use in the United States in this population is about a 4-month regimen, which would be about four injections of goserelin for the average patient.”

Goserelin is currently approved by the U.S. Food and Drug Administration for advanced breast cancer, but not for early-stage disease.

Not Mutually Exclusive

Goserelin injections and cryopreservation of embryos, the most established fertility-preservation methods for women undergoing chemotherapy, are not mutually exclusive options. While goserelin must be started at least 1 week before chemotherapy, the entire process of cryopreservation takes between 2 and 6 weeks.² The process includes stimulating the ovaries to mature multiple eggs, removing the mature eggs, and then fertilizing them in the lab with sperm from a partner or donor to create embryos through in vitro fertilization, before freezing them for future use.

“With some other cancers, you may not have the luxury of time to pursue those treatments,” Dr. Moore said. “We were looking at operable breast cancer. So even though assisted reproduction might delay treatment by a month or two or even more, if somebody has had their surgery and the cancer is out, that might be okay in breast cancer, whereas if you have an aggressive lymphoma, you really may not have the opportunity to take the time to do this.”

Interrupting Endocrine Therapy

The International Breast Cancer Study Group, one of the key participants in the POEMS/SWOG S0230 trial, “is planning a study addressing a somewhat different question. It is called the Positive Study, and it is going to look at women with hormone receptor–positive breast cancer and whether it is safe to interrupt endocrine therapy to have a pregnancy,” Dr. Moore noted. “It would be contraindicated to attempt a pregnancy while on tamoxifen, so the study is looking at stopping the tamoxifen in women with hopes of becoming pregnant, and then resuming after the pregnancy, with a plan to be off of the endocrine therapy for no more than 2 years.”

Recommendations to continue tamoxifen for 5 to 10 years present particular challenges for a woman who is diagnosed with breast cancer in her late 20s and hasn’t had children yet. After chemotherapy and 5 years of tamoxifen, the woman would be in her early 30s, and “she still may have an opportunity to have children. It might be difficult, but it is still an option,” Dr. Moore said. “If you add another 5 years of hormonal therapy, that makes it even more difficult. So I think it is a very important question to address for these patients.”

Currently, “if someone really wants to have a child, we recommend that the tamoxifen be stopped first. You could conceive on it, but it should be stopped immediately if that were to happen. So we recommend using barrier contraceptives while on tamoxifen.”

Surprising Survival Improvement

After adjusting for disease stage, women who received goserelin in the POEMS/S0230 study had a 50% reduction in mortality 4 years after starting chemotherapy compared with  those who received chemotherapy alone, a result considered somewhat surprising. One possible explanation, Dr. Moore said, is the observation that many breast cancers, including triple-negative breast cancers, have LHRH receptors, and preclinical studies suggest that LHRH agonists and antagonists increase cell death.

Another possible explanation was offered by a study presented during the ASCO Annual Meeting Breast Cancer–HER2/ER poster session. In that study, Recchia et al found that administering an LHRH agonist to premenopausal women with high-risk early breast cancer after surgery but before chemotherapy resulted in a reduction in vascular endothelial growth factor (VEGF) and regulatory T cells, which are considered fundamental for the development of breast cancer. ■

Disclosure: Dr. Moore reported no potential conflicts of interest.

References

1. Moore HCF, Unger JM, Phillips K-A, et al: Phase III trial (Prevention of Early Menopause Study [POEMS]-SWOG S0230) of LHRH analog during chemotherapy to reduce ovarian failure in early-stage, hormone receptor-negative breast cancer: An international Intergroup trial of SWOG, IBCSG, ECOG, and CALGB (Alliance) ASCO Annual Meeting. Abstract LBA505. Presented May 31, 2014.

2. LIVESTRONG Foundation: Fertility preservation options for women. Available at www.livestrong.org. Accessed June 11, 2014.

3. Recchia F, Candeloro G, Cesta A: Total estrogen blockade and chemotherapy in high-risk premenopausal early breast cancer: Long-term follow-up of a phase II study. ASCO Annual Meeting. Abstract 537. Presented June 2, 2014.