Temporary ovarian suppression during chemotherapy as a means of preserving ovarian function and fertility in young women with early breast cancer is controversial. An eagerly awaited meta-analysis including individual patient data from five randomized controlled trials found that the use of gonadotropin-releasing hormone (GnRH) analogs during chemotherapy was associated with a reduced risk of premature ovarian insufficiency and a higher number of patients with a posttreatment pregnancy,1 suggesting this is a valid option for preserving ovarian function and potential fertility in premenopausal patients undergoing neoadjuvant or adjuvant chemotherapy. The meta-analysis was presented at the 2017 San Antonio Breast Cancer Symposium.
Our meta-analysis showed that [use of GnRH analogs] during chemotherapy was associated with a significant reduction in the risk of chemotherapy-induced premature ovarian insufficiency.— Matteo Lambertini, MD
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Two other studies were presented that lend support to ovarian function suppression as an adjuvant endocrine therapy strategy to reduce breast cancer recurrence. Taken together, the evidence suggests ovarian function suppression with GnRH analogs should be used in higher-risk patients, and the decision should be based on patient preference after weighing risks vs benefits.
“Oocyte and embryo cryopreservation has been the standard of care, but this does not prevent the risk of chemotherapy-induced premature ovarian insufficiency,” explained lead author of the meta-analysis, Matteo Lambertini, MD, and ESMO Fellow, Institut Jules Bordet, Brussels.
“Our meta-analysis showed that [use of GnRH analogs] during chemotherapy was associated with a significant reduction in the risk of chemotherapy-induced premature ovarian insufficiency. More women in the GnRH analog group had posttreatment pregnancies, and disease-free survival and overall survival were similar between the treated and control groups,” he stated.
The meta-analysis included individual patient data from five randomized controlled trials: PROMISE-GIM6, POEMS/SWOG S0230, Anglo-Celtic Group OPTION, GBG-37 ZORO, and a Moffitt Cancer Center–led study. Eight other randomized controlled trials of this strategy were excluded from the analysis because they did not provide individual patient data.
The five included trials enrolled a total of 873 patients. The primary endpoints were premature ovarian insufficiency rate (according to the definition used in each trial) and posttreatment pregnancy rate. A secondary endpoint was the rate of amenorrhea at 1 and 2 years after the end of chemotherapy, as well as disease-free survival and overall survival.
The five trials used slightly different definitions of premature ovarian insufficiency, Dr. Lambertini said. Two used amenorrhea as the only marker, whereas the other three used a composite endpoint (ie, amenorrhea and postmenopausal hormone levels). The time point for premature ovarian insufficiency ranged from 6 to 24 months after the end of chemotherapy. Eligibility criteria also differed among the five trials; two enrolled only patients with estrogen receptor–negative disease, and three included patients with both estrogen receptor–negative and –positive disease. Also, age eligibility differed slightly.
Looking at all five trials at baseline, the median age was around 38 years; about two-thirds of patients were younger than 40; 40% had estrogen receptor–positive disease; and about 50% received an anthracycline/taxane regimen. There were no differences in the cumulative dose of cyclophosphamide.
The use of temporary ovarian suppression during chemotherapy reduced the likelihood of developing premature ovarian insufficiency by 62%, with an absolute difference of approximately 17% between the two groups—30.9% in controls vs 14.1% for the GnRH analog recipients (P < .001).
“The effectiveness of GnRH [analog] use was homogeneous across all the different subgroups analyzed, regardless of age at diagnosis, estrogen receptor status, and type and duration of chemotherapy,” Dr. Lambertini told listeners.
No significant difference in amenorrhea rate was observed between the GnRH analog–treated group and controls at 1 year, but at 2 years, the GnRH analog group had lower rates of amenorrhea: 18.2% vs 30.2%, respectively (P = .009).
In the three largest randomized controlled trials, pregnancies were reported in 37 (10.3%) patients in the ovarian suppression arms vs 20 (5.5%) in controls (P = .03). All pregnancies were observed in patients diagnosed before the age of 40, and the majority (86%) occurred in women with estrogen receptor–negative tumors. No differences in pregnancy rate were observed across subgroups.
At a median follow-up of 5 years, no significant difference was observed between groups in disease-free survival (79.5% in the GnRH analog arm vs 80% among controls). Similarly, no significant difference in overall survival was observed, although survival was numerically higher in the GnRH analog arm (90.2% vs 86.3%).
No significant interaction was found between estrogen receptor status and treatment arm, suggesting the safety of administering GnRH analog during chemotherapy in both patients with estrogen receptor–positive and negative tumors. More than 95% of patients with estrogen receptor–positive status were alive at 5 years, compared with 87% of those with estrogen receptor–negative tumors.
Update of TEXT and SOFT Trials
Speaking after Dr. Lambertini, Prudence Francis, MD, Associate Professor and Head of Medical Oncology in the Breast Service at the Peter MacCallum Cancer Centre, Melbourne, presented a planned update of a pooled analysis of the ovarian suppression groups from the TEXT and SOFT trials, with 8 years of follow-up.2 Both trials compared exemestane plus ovarian function suppression vs ovarian function suppression plus tamoxifen in premenopausal women with hormone receptor–positive early breast cancer. Primary findings from the combined analysis with 5.7 years of follow-up were previously published in The New England Journal of Medicine.3
Longer term follow-up of a combined analysis of [the TEXT and SOFT] trials confirms the benefit in disease outcomes with exemestane plus ovarian function suppression over tamoxifen plus ovarian function suppression.— Prudence Francis, MD
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“Longer term follow-up of a combined analysis of these two trials confirms the benefit in disease outcomes with exemestane plus ovarian function suppression over tamoxifen plus ovarian function suppression. With exemestane plus ovarian suppression, there is a sustained absolute improvement in disease-free survival of 4% and an absolute benefit of 2.1% for freedom from distant recurrence vs tamoxifen plus ovarian function suppression. In patients with HER2-negative disease, exemestane plus ovarian function suppression improved all disease outcomes in all treatment cohorts. Clinically meaningful benefits were observed with exemestane plus ovarian suppression in HER2-negative patients who received chemotherapy,” Dr. Francis said.
At 8 years of follow-up, no difference in overall survival was observed between treatment arms. Follow-up is continuing, because of the risk of late relapse in hormone receptor–positive patients, she noted.
TEXT enrolled 2,672 women with planned ovarian function suppression using triptorelin (Trelstar, Triptodur) every 4 weeks. SOFT enrolled 3,066 women who retained or regained premenopausal status after treatment. Chemotherapy was optional in both trials.
In addition to the overall results of the updated analysis, the effect of exemestane plus ovarian function suppression was greater in those with HER2-negative tumors, with an absolute benefit of 5.4% in disease-free survival and an absolute benefit in freedom from distant recurrence of 3.4%.
“Clinically meaningful benefits were seen in HER2-negative patients deemed at sufficient risk to receive chemotherapy. Across both trials, a 7% to 9% improvement was seen in disease-free survival and 5% to 7% benefit in distant recurrence–free interval in these patients. These results in HER2-positive patients require further investigation. A significant percentage of patients with HER2-positive disease did not get adjuvant HER2-targeted therapy,” she said.
About one-third of patients in each group had grade 3 adverse events. More grade 3/4 musculoskeletal events and fractures were observed in the exemestane group, whereas more thrombosis was reported in the tamoxifen group.
By 4 years, 25% of patients had stopped exemestane and 19% had stopped tamoxifen. Almost 20% of patients in both groups stopped taking triptorelin at 4 years.
“Oncologists need to discuss and weigh benefits and toxicity in each patient with hormone receptor–positive, premenopausal breast cancer,” Dr. Francis said.
Disease-free survival was further improved by use of exemestane plus ovarian function suppression, with an almost 9% absolute benefit overall.— Gini Fleming, MD
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A separate updated analysis of the SOFT trial found that at 8 years, SOFT findings were positive for the primary endpoint of disease-free survival; tamoxifen plus ovarian function suppression significantly improved disease-free survival vs tamoxifen alone, with an absolute benefit of 4%, -representing a 24% relative improvement.4
Outcomes at 8 years were further improved by the use of exemestane plus ovarian function suppression, with an absolute disease-free survival benefit of 7% vs tamoxifen only. In women younger than 35 years, the absolute disease-free survival benefit of tamoxifen plus ovarian suppression vs tamoxifen alone was 8.7%.
“Disease-free survival in women under 35 was further improved by use of exemestane plus ovarian function suppression, with a 13% absolute benefit,” said Gini Fleming, MD, Professor of Medicine and Director of the Gynecologic Oncology and Medical Oncology Breast Program at the University of Chicago Medical Center, who presented the results.
SOFT was designed to compare 5 years of treatment with tamoxifen alone vs tamoxifen plus ovarian function suppression vs exemestane plus ovarian function suppression. The primary analysis was the comparison of tamoxifen alone vs tamoxifen plus ovarian function suppression. A secondary analysis compared exemestane plus ovarian function suppression vs tamoxifen alone, whereas the comparison of the two ovarian function suppression groups was handled by joint analysis with the TEXT trial.
Tamoxifen plus ovarian function suppression achieved a small benefit in distant recurrence–free survival vs tamoxifen alone at 8 years in women treated with prior chemotherapy (absolute difference, 2.1%) as well as a small benefit in overall survival (absolute benefit, 4.3%). Longer follow-up for overall survival is required, Dr. Fleming said.
“Patients who didn’t get chemotherapy have a very low risk of metastasis at 8 years on tamoxifen alone,” Dr. Fleming noted.
There were no new toxicity signals for tamoxifen or exemestane. Ovarian function suppression plus tamoxifen was associated with more hot flashes and decreased libido than tamoxifen alone. ■
DISCLOSURE: Dr. Francis has received honoraria from AstraZeneca and lectured for Pfizer. Drs. Lambertini and Fleming reported no conflicts of interest.
1. Lambertini M, Moore HCF, Leonard RCF, et al: Pooled analysis of five randomized trials investigating temporary ovarian suppression with gonadotropin-releasing hormone analogs during chemotherapy as a strategy to preserve ovarian function and fertility in premenopausal breast cancer patients. 2017 San Antonio Breast Cancer Symposium. Abstract GS4-01. Presented December 7, 2017.
2. Pagani O, Regan MM, Fleming GF, et al: Randomized comparison of adjuvant aromatase inhibitor plus ovarian function suppression versus tamoxifen plus ovarian function suppression in premenopausal women with hormone receptor-positive early breast cancer: Update of the combined TEXT and SOFT trials. 2017 San Antonio Breast Cancer Symposium. Abstract GS4-02. Presented December 7, 2017.
3. Francis PA, Regan MM, Fleming GF, et al: Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 372:436-446, 2015.
4. Fleming G, Francis PA, Lang I, et al: Randomized comparison of adjuvant tamoxifen plus ovarian function suppression versus tamoxifen in premenopausal women with hormone receptor-positive early breast cancer: Update of the SOFT trial. 2017 San Antonio Breast Cancer Symposium. Abstract GS4-03. Presented December 7, 2017.
Ann H. Partridge, MD, MPH, FASCO
“The simple questions are whether ovarian function suppression adds clinical benefit in premenopausal women, and is ovarian function suppression better with an aromatase inhibitor or tamoxifen,” said formal discussant of these trials, Ann H. Partridge, MD,...!-->!-->