The majority of breast cancers are hormone positive. These breast cancers are generally considered lower risk compared to aggressive subtypes like triple negative and HER2+ breast cancers. But the risk of recurrence never goes away with hormone positive cancers, which can recur many years (even decades) later. While just 5% of women with breast cancer are under age 40, these women tend to have more aggressive disease.
The question for women and their doctors remains how much treatment is enough for ER+ breast cancer? What is the role of chemotherapy, ovarian suppression, Aromotase Inhibitors (AI’s) (in this case exemestane ), and tamoxifen for women with hormone driven breast cancers? And are there particular groups of women, such as young women, who may benefit more from a specific treatment than others?
We’ve known for some time that women who develop chemotherapy-induced ovarian suppression (amenorrhea) have better outcomes. However, is adding deliberate ovarian function suppression in women with hormone driven breast cancers beneficial? In the U.S., the standard of care is tamoxifen for ER+ breast cancers. In Europe, they suppress the ovaries and give tamoxifen.
The SOFT trial (session citation below) is the only study to date to strictly evaluate ovarian function suppression. This large multinational study involves 426 centers in 25 countries and hypothesized that ovarian suppression in women who did not have chemo-induced menopause might improve outcomes.
The analysis included women who had been previously treated with chemotherapy as well as those who had no chemo. The no-chemo group was slightly older (47 years) compared to those who received prior chemo (40 years), which is not surprising given that cancers in younger women are considered higher risk and treatment often includes chemotherapy. Again, it is not surprising that most of the recurrences and death occurred in the higher risk group that had previously received chemo.
The study found that ovarian suppression was of benefit only to women under 40 and the greatest benefit of ovarian suppression occurred in women 35 and younger. The outcomes (measured as disease-free survival) for the study arms one and two are relatively equal, but the real benefit for ovarian suppression was in those women who were treated with chemotherapy. Additionally, this same group of higher risk women received more benefit from the addition of exemestane rather than tamoxifen to the ovarian suppression.
The outcomes for the group of women with no chemo were very good. After five years of taking tamoxifen alone, 95% were free from disease and there was no meaningful benefit from the addition of ovarian suppression.
Those with prior chemo with higher risk breast cancers did see improved outcomes with ovarian function suppression. After five years, 78% of women taking tamoxifen alone had no evidence of disease, which was increased to 82.5% with the addition of ovarian suppression. For the third arm, using exemestane instead of tamoxifen with ovarian suppression, there was an additional increase in the number of women free from breast cancer after five years.
Looking deeper at breakdowns in the groups, 94% of women under age 35 received chemotherapy. This high risk group saw the most striking advantage from ovarian suppression. Within the first five years, one-third of women on tamoxifen alone had a recurrence compared to only one-sixth of women on exemestane and ovarian suppression. Furthermore, there was 16% absolute improvement in women under 35 who received exemestane + ovarian suppression over the women of the same age who were treated with tamoxifen + ovarian suppression.
It is important to note there is no overall survival data from this trial, as it is too early to tell which treatment saves more women’s lives.
This reduction in recurrence (which hopefully will translate to improved overall survival) comes at a cost. Between a quarter and a third of women (depending on the treatment arm) experienced significant (grade 4 & 5) adverse events: primarily vasomotor, sexual, depression, insomnia but also osteoporosis, diabetes, and other harmful events.
Because of these side effects, 15% of patients stopped ovarian suppression by 2 years and a little over 20% of patients stopped by 4 years. Half of the women reported depression, with 4% of those taking tamoxifen and 5% of the ovarian suppression group experiencing severe depression.
A second study looked at quality of life (QOL) issues associated for women in the SOFT trial. For the most part, differences in quality of life were associated with ovarian suppression (rather than tamoxifen alone) and occurred during the first two years of the study. The gap between the groups narrowed as time progressed so that by five years there was no significant difference in the quality of life measures. However, there was no data collected on individual adherence to the treatment regime so it is possible that the patients with the worst side effects stopped treatment to manage their symptoms that would mean a potential underestimation of QOL issues.
Interestingly, patients who received prior chemo reported worse baseline quality of life scores and so global side effects appeared not to be much worse for the group who had chemo. (Patients with prior chemo had already experienced toxicity so for those people, maybe the addition of ovarian suppression was not identified as an issue). However, Hope Rugo from UCSF suggests this might really indicate that global side effect measures don’t reflect important endocrine effects!
Francis PA, Regan MM, Fleming GF, Lang I, Ciruelos EM, Bellet M, Bonnefoi H, Climent MA, Pavesi L, Burstein HJ, Martino S, Davidson NE, Geyer, Jr CE, Walley BA, Coleman RE, Kerbrat P, Rabaglio-Poretti M, Coates AS, Goldhirsch A, Gelber RD. SOFT Investigators, International Breast Cancer Study Group, Breast International Group, and North American Breast Cancer Group, Bern, Switzerland.