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Women with HR+ breast cancer who remained premenopausal after receiving chemotherapy had a lower risk of disease recurrence when adding ovarian suppression to adjuvant exemestane or-to a lesser extent-tamoxifen, compared with standard tamoxifen alone, according to results from the phase III SOFT trial.
Prudence Francis, MD
Women with HR+ breast cancer who remained premenopausal after receiving chemotherapy had a lower risk of disease recurrence when adding ovarian suppression to adjuvant exemestane or—to a lesser extent—tamoxifen, compared with standard tamoxifen alone, according to results from the phase III SOFT trial. The data were presented at the 2014 San Antonio Breast Cancer Symposium (SABCS) and were simultaneously published online in the New England Journal of Medicine.
The more robust exemestane data showed a 35% reduction in the risk of disease recurrence in the premenopausal women treated with the aromatase inhibitor combined with ovarian suppression compared with tamoxifen alone.
“This treatment as compared to standard treatment…resulted in 7 or 8 fewer women out of 100 experiencing further breast cancer within the next 5 years,” said Prudence Francis, MD, lead author of the SOFT study, who presented the results at SABCS.
Francis, who is head of Breast Medical Oncology at the Peter MacCallum Cancer Centre in Australia, believes the results will change clinical practice.
“Going forward, I think this is a practice-changing result because what you’ll find is that now, for women who are in this younger, premenopausal age group…increasingly doctors will be talking to them about these results and discussing with them the option of undergoing ovarian function suppression treatment with an aromatase inhibitor as an alternative to tamoxifen.”
Francis also noted that the SOFT data were particularly encouraging for “very young” women (aged <35 years), who have a higher risk of recurrence with hormone sensitive breast cancers. The benefit of adding ovarian suppression to exemestane was most pronounced in this population.
“One in three women receiving tamoxifen alone experienced further breast cancer within 5 years as compared with one in six of the women assigned to exemestane plus ovarian suppression.”
Not all women in the SOFT trial benefitted from ovarian suppression, however. Patients were stratified by receipt of chemotherapy and women in the chemotherapy-naïve cohort did well whether they received tamoxifen alone or ovarian suppression combined with either tamoxifen or exemestane. “These women have had excellent outcomes with all three treatments and we see no advantage for adding ovarian suppression in this group.”
The SOFT trial data presented at SABCS included 3047 premenopausal women with early HR+ breast cancer randomized to 5 years of tamoxifen (n = 1018) or ovarian function suppression (OFS) added to either tamoxifen (n = 1015) or exemestane (n = 1014).
Ovarian suppression was achieved by choice of monthly triptorelin injections, bilateral oophorectomy, or bilateral ovarian irradiation. Patients initially administered triptorelin were allowed to subsequently undergo surgery or receive radiation.
Fifty-three percent of patients (n = 1628) had received prior adjuvant or neoadjuvant chemotherapy and remained premenopausal. These women were younger (average age, 40 years) and had higher-risk tumors. Patients in this cohort were allowed to enter the study up to 8 months after completing chemotherapy. During those 8-months, patients could receive tamoxifen. To enter the trial, women had to have a blood test measuring their estrogen levels to demonstrate that their ovaries were still functioning.
The remaining 47% of women (n = 1419) were chemotherapy-naïve. These patients tended to have lower-risk breast cancers and were older (average age, 46 years). They entered the study within 12 weeks of surgery and tamoxifen was their only systemic therapy.
The primary SOFT analysis compared tamoxifen with tamoxifen plus OFS across both chemotherapy cohorts. According to Francis, “At a median follow-up of 5.6 years, we saw that adding ovarian suppression to tamoxifen resulted in a small but not significant improvement in disease-free survival [DFS]” (86.6% vs 84.7%; HR = .83; 95% CI, 0.66-1.04; P = .10).
In the chemotherapy cohort, adding tamoxifen to OFS reduced the risk of disease recurrence by 22% versus tamoxifen alone (HR = .78; 95% CI, 0.60-1.02). Further benefit was observed with exemestane, which had an HR for DFS of 0.65 when combined with OFS versus treatment with standard tamoxifen (95% CI, 0.49-0.87).
In the lower-risk, chemotherapy-naïve cohort, the 5-year DFS was 95.8% with tamoxifen alone, compared with 95.1% with tamoxifen plus OFS (HR = 0.95; 95% CI, 0.54-1.69) and 97.1% with exemestane plus OFS (HR = 0.59; 95% CI, 0.31-1.14).
“One of the important things we’ve also learned from this study is that this lower risk group can actually do very well with tamoxifen alone, ” said Francis.
Among the 350 women aged <35 in the overall study population, 94% of whom had received chemotherapy, the 5 year-DFS rates were 83.4% (95% CI, 74.9-89.3), 78.9% (95% CI, 69.8-85.5), and 67.7% (95% CI, 57.3-76.0), respectively, for patients treated with exemestane plus OFS, tamoxifen plus OFS, and tamoxifen alone.
Francis said the benefit with OFS observed in these younger patients is critical because they are unlikely to be able to wait for the benefit that has been established with long-term hormonal therapy.
“This youngest group is having the breast cancer events early [within the first 5 years] and it’s too long to wait to see if the extended hormonal therapy might benefit them because they may have already had a distant relapse by that time.”
The toxicity profile in the study was acceptable, according to Francis. “Overall quality of life and general health were not reduced,” she said. “However, ovarian suppression did result in increased menopausal symptoms, which were particularly troublesome for the women in the first couple of years.” Additionally, women receiving exemestane plus OFS had side effects related to sexual functioning.
Francis noted that strictly ensuring the HR sensitivity and premenopausal status of patients enrolled in SOFT was critical to obtaining the observed benefit of ovarian suppression in the trial. “In previous trials, the effect of ovarian suppression has really been diluted because some women went into those trials with uncertain hormone-receptor status of their breast cancer, so there were a mix of hormone receptor positive and negative. Also, women went into those trials straight after chemotherapy and many of them were probably permanently postmenopausal from the treatment, so any effect from ovarian suppression was diluted.”
The next step for the SOFT trial, said Francis, will be to determine how these different treatments will affect overall survival.
In her summary, Francis reiterated her belief that the results are practice changing.
“For me, if I go back to my practice on Monday, and I see a woman under 35 with a hormone sensitive breast cancer, I will now know what to advise that woman. Also, when I see the woman who is 48 and has a small, nonaggressive breast cancer, I will feel more comfortable that she can do very well with tamoxifen alone.
Francis PA , Regan MM, Fleming GF, et al. Randomized comparison of adjuvant tamoxifen (T) plus ovarian function suppression (OFS) versus tamoxifen in premenopausal women with hormone receptor-positive (HR+) early breast cancer (BC): analysis of the SOFT trial. Presented at: 2014 SABCS; December 9-12, 2014; San Antonio, TX. Abstract S3-08.