There have long been data suggesting that the addition of ovarian suppression to therapy improved clinical outcomes among premenopausal women with breast cancer. However, it has been difficult to interpret these results, as they were not done in a way that is compatible with the evolution of treatment in the modern era. Then, the very large, randomized, phase 3 SOFT trial really got at the question of whether ovarian suppression adds to modern endocrine therapy. SOFT was designed to evaluate the addition of ovarian suppression to tamoxifen and to determine the role of the aromatase inhibitor exemestane plus ovarian suppression. This study showed that adding ovarian suppression to tamoxifen improved disease-free and overall survival in premenopausal women with early hormone receptor–positive (HR+)/human epidermal growth factor receptor 2–negative (HER2-) breast cancer compared with tamoxifen alone. Still, it was unclear exactly which specific groups of women benefited.

At the 2023 ASCO Annual Meeting, Gray and colleagues presented a meta-analysis of data from 25 trials and confirmed that ovarian ablation or suppression was associated with a 12.1% decrease in 15-year recurrence risk and an 8% improvement in 15-year breast cancer and all-cause mortality among premenopausal women with estrogen receptor–positive (ER+) or unknown tumors (abstract 503). Further, women who were under 45 years of age achieved significantly greater benefits compared with those who were 45 to 54 years of age. Receipt of prior chemotherapy did not appear to affect outcomes, as long as the women were clearly premenopausal when they started the ovarian suppression.

There have been multiple studies indicating that, stage for stage, and despite having seemingly similar breast cancer, very young women may have poorer outcomes than others; in these studies, very young has been defined in different ways (eg, <35 years, <40 years). It has been difficult to tease out the reasons for these observations, including whether poorer outcomes occur because of biologic differences in the tumors or because younger women are underdiagnosed and often present with a later stage of disease.

In an effort to further understand intrinsic subtypes and recurrence risk scores in very young and young premenopausal women, Brown et al analyzed tumor samples from patients with HR+/HER2- breast cancer in the SOFT trial using PAM50 gene expression testing (abstract 504). The results showed the enrichment of aggressive biology in very young women (ie, aged <40 years). A total of 38% of these very young women had luminal B tumors compared with only 22% of those aged 40 years and older. Additionally, even when very young women had the less proliferative luminal A subtype, they had higher rates of distant recurrence at 10 years than the women aged 40 years and older. Interestingly, women under 40 years who had node-negative disease also had a significantly higher risk of recurrence than those aged 40 years and older (36% vs 14%, respectively).

Another study that was presented at ASCO 2023 provides evidence that there are immunological differences in the tumors of younger (aged ≤35 years) and older (aged 36-40 years) premenopausal women (abstract 505). Tesch and colleagues presented data showing that the distribution of tumor-infiltrating lymphocytes (TILs) is different in women with HR+/HER2- breast cancer who are under 40 years of age vs those who are over 40 years of age. Older women had a higher expression of stromal CD8+ and CD8+PD-1+ (exhausted) cytotoxic TILs, and CD3+CD8- helper TILs within the tumor. A high stromal expression of CD3+CD8- TILs was linked to improved invasive breast cancer–free and distant disease-free survival. Further, researchers reported that a high stromal expression of CD3+CD8- TILs was also associated with improved overall survival and that a high stromal expression of FoxP3+CD3+ TILs was associated with improved invasive breast cancer–free survival, but only on adjusted analyses in both cases. Exactly how this works is still open to question, and we are going to have to go back to the laboratory to try to tease out exactly how these differences in lymphocytes affect tumor biology.