Ovarian Function Suppression in Premenopausal Women with Breast Cancer

Ovarian Function Suppression in Premenopausal Women with Breast Cancer

Ovarian function suppression (OFS) has been proposed as a mechanism to improve outcomes among premenopausal women with breast cancer, although emerging data suggest that careful patient selection helps maximize benefits.

Providers should be aware of the potential for OFS to affect fertility and the role of adjuvant therapy and other interventions in helping patients maintain bone density and reduce fracture risk, according to a panel of experts speaking during the Education Session “Controversies in the Management of Premenopausal Breast Cancer: The Role for Ovarian Suppression, Fertility Preservation, Bisphosphonates, and Local Therapy,” held on Friday, May 29.

Dr. Hope S. Rugo

Rationale for Ovarian Function Suppression

A study published in 2011 showed that 5 years of tamoxifen use among patients younger than age 45 with ER-positive breast cancer reduced breast cancer mortality and all-cause mortality.1 However, whether OFS is truly additive in an era with improved options for treating these patients remains a topic of debate, according to Hope S. Rugo, MD, of the UCSF Helen Diller Family Comprehensive Cancer Center.

In part, questions about the role of OFS arise because of a 2007 meta-analysis that suggested that the addition of OFS to chemotherapy with or without tamoxifen provided only modest benefit in reducing risk of recurrence and reduction in risk of death after recurrence.2 Yet these data should be viewed with some caution, Dr. Rugo said, as they represent only 6.8 years of median follow-up; furthermore, they may have been influenced by suboptimal use of tamoxifen.

A deeper look at subgroups in the meta-analysis showed a significant interaction of age for the addition of OFS. Among women aged 35 or younger, the addition of OFS yielded an almost 40% reduction in recurrence risk (hazard ratio [HR] 0.66), and among women aged  35-39, OFS reduced recurrence by more than 20% (HR 0.77).

“This makes sense, because these are women less likely to have ovarian suppression effect from the chemotherapy regimens that were used at that time,” Dr. Rugo said. “What this suggests is that if you pick the right patient, and maybe if you treat the patient without chemotherapy, you would see a benefit of ovarian suppression in modern-day use of oral hormone therapies.”

Benefit among subgroups was also demonstrated in the National Surgical Adjuvant Breast and Bowel Project (NSABP) B30 study, wherein amenorrhea for 6 months or longer predicted improved overall survival (HR 0.52; p = 0.002) and disease-free survival (HR 0.51; p < 0.001).3,4

The ABCSG-12 trial compared different oral OFS agents in a population of women who were “largely young and with smaller tumors, but there was still a group of patients with moderate risk: 30% node-positive and 20% with grade 3 histology,” Dr. Rugo said. As well, 97% of these women had received no chemotherapy.

Without the confounding factor of chemotherapy, Dr. Rugo said, the data showed worse survival with anastrazole.5 During subsequent subgroup analysis, researchers found that OFS may be less effective among overweight and obese patients (defined as a body mass index [BMI] of 25 or higher).6

However, a substantial downside to OFS is associated toxicity. In the TEXT and SOFT trials, approximately 50% of patients reported depression to their provider, and increases in menopausal symptoms, osteoporosis, and insomnia were noted. Among patient-reported symptoms, sexual dysfunction and bone/joint pain were noted frequently in patients in the exemestane groups, whereas hot flashes and sweats were noted in the tamoxifen groups.7 Overall, Dr. Rugo said, OFS was associated with an increased risk for osteoporosis.

Preserving Fertility Options

Premenopausal women undergoing treatment for breast cancer may wish to preserve their ability to one day start or extend their family. The best way to do so, however, remains controversial.

Ovarian failure is a common long-term side effect of chemotherapy treatment in premenopausal women, according to Halle C. F. Moore, MD, of the Cleveland Clinic Taussig Cancer Institute. The risk of ovarian failure depends on the chemotherapy regimen, its duration, and the patient’s age at the time of treatment. Published studies have reported chemotherapy-related amenorrhea incidences ranging from 9%-76% of cases.

There is no evidence that pregnancy after treatment for breast cancer increases the recurrence risk, nor is there evidence that chemotherapy contributes to birth defects and congenital abnormalities, Dr. Moore said. However, the need for long-term endocrine therapy complicates the timing of pregnancy for premenopausal women with hormone-sensitive breast cancer.

One potential option for preserving fertility is to use gonadotropin-releasing hormone (GnRH) analogs (GnRHa) during adjuvant chemotherapy for breast cancer. Although considered an off-label use, case series and phase II studies of GnRHa with chemotherapy have demonstrated high rates of menses recovery and successful pregnancies, Dr. Moore said.

As well, it is plausible that GnRHa cause a reduction in ovarian blood flow and perfusion while activating GnRH receptors on oocytes or granulosa cells. In turn, these biochemical pathways may lead to an upregulation of anti-apoptotic pathways and prevention of accelerated follicular atresia through interruption of follicle-stimulating hormone (FSH) secretion.8

A number of clinical trials have evaluated GnRHa for preservation of ovarian function with varying degrees of success. Overall, Dr. Moore said, there appears to be a rationale for GnRHa use to preserve menses among premenopausal women being treated for breast cancer.

Dr. Kutluk Oktay

However, preservation of menses is an inappropriate marker to gauge whether therapy preserves fertility after cancer treatment, according to Kutluk Oktay, MD, FACOG, of New York Medical College and the Innovation Institute for Fertility Preservation.

In fact, Dr. Oktay said, there is no biologic plausibility that GnRHa should be effective, because primordial follicle oocytes, which account for the ovarian reserve, do not express FSH or GnRHa receptors. Additionally, he said, investigators have known since the late 1980s that it is not possible to completely suppress gonadotropin levels with initiation of treatment 1-2 weeks before starting chemotherapy.

“Menstruation should not be used as an outcome in clinical studies,” Dr. Oktay said.

Premenopausal women being treated for breast cancer who express interest in or ambivalence regarding fertility should instead be referred as early as possible in the disease course to a fertility specialist to discuss whether embryo and oocyte freezing is appropriate, Dr. Oktay said. There is now emerging evidence that letrozole used as an alternative to tamoxifen during breast cancer treatment may help stimulate ovulation induction effectively and safely (i.e., without causing an uptick in estradiol, which would raise estrogen levels, which, in turn, stimulates malignant cells).

Contrary to popular belief, Dr. Oktay said, oocyte yield is not low among patients with breast cancer, although women with a BRCA mutation may experience premature aging of the ovaries, and, thus, loss of oocyte viability.

Dr. Oktay said he is working on a protocol to freeze ovarian tissue for later transplantation. In a pilot study in which women with a mean age of 23.7 had ovarian tissue cryogenically frozen and implanted approximately 7 years later, there was a 33% clinical pregnancy rate (70% of which were spontaneous pregnancies) and a 25% live birth rate.

Bisphosphonates in Premenopausal Women

Dr. Barbara L. Smith
 One of the known side effects of breast cancer treatment is the potential to accelerate bone mineral density loss and, therefore, increase the risk of fracture. However, it is unknown if adjunctive bisphosphonate therapy slows bone loss or reduces fracture risk, said Robert E. Coleman, MBBS, MD, FRCP, of the Mellanby Centre for Bone Research at the University of Sheffield, United Kingdom.

Whereas women lose approximately 2% of bone mass following menopause, multiple case series show that, on average, premenopausal women being treated for breast cancer lose up to 7.7% of bone mass after the induction of therapy, Prof. Coleman said. Although that rate may slow down, there is little doubt that bone loss is accelerated in the subset of patients with induced menopause, he added.

“When we introduce therapies that induce menopause, we are essentially accelerating bone loss. In the same way that the ovaries age about 10 years in response to treatment, so too do the bones,” Prof. Coleman said.

There is also an increased risk of fracture among patients treated for breast cancer, although that risk is likely influenced by other known risk factors (e.g., age, bone mineral density, corticosteroid use for longer than 3 months, family history of osteoporotic hip fracture, prior fragility fracture, low BMI, alcohol use higher than 3 units/day, smoking, and secondary causes of osteoporosis).

In published studies, bisphosphonate use during cancer treatment has been shown to have a benefit for preserving bone density (Fig. 1). However, there are no data demonstrating that bisphosphonate use during cancer treatment has any effect on reducing fracture risk, Prof. Coleman said.

Instead, he said, it appears that patient counseling and education about proper diet, the need for exercise, fall prevention, alcohol use, and smoking cessation may have a larger effect on reducing fracture risk than pharmacologic intervention.

According to Barbara L. Smith, MD, PhD, of Massachusetts General Hospital and Harvard Medical School, younger patients with breast cancer may be more prone to recurrence following surgery because this age group does not routinely get mammograms, has denser breast tissue, and may be concurrently lactating or pregnant. Thus, younger patients may present with larger tumors with a higher risk of nodal involvement.

Modern techniques, such as using MRI to plan the surgical intervention and delivering a radiation boost to the tumor bed at the time of surgery, may help lower recurrence risk, Dr. Smith said.  

Watch the session, visit the ASCO Virtual Meeting website.