Keynote: How Has the Management of Young ER-Positive Breast Cancer Patients Changed Over the Years?

Prudence Francis, MD

Adjuvant treatment options for premenopausal women with hormone receptor–positive breast cancer now include endocrine therapy and ovarian function suppression (OFS) based on clinicopathologic characteristics that determine composite risk of recurrence.¹ A landmark study published nearly 50 years ago demonstrated the first evidence for the potential benefit of ovarian ablation in patients with estrogen receptor (ER)-positive breast cancer. In this study, adjuvant treatment with a regimen of cyclophosphamide, methotrexate, and fluorouracil resulted in high rates of amenorrhea; however, most patients responded to treatment.² At 27 months, treatment failure had occurred in 24% of 179 control patients compared with 5.3% of 207 patients who received combination therapy (P<10^-6).² Subsequently, the benefit of ovarian ablation was confirmed by a meta-analysis that included women aged <50 years.³

Based on those results, breast cancer studies continued to progress and methods of treatment other than surgical ovarian ablation, such as tamoxifen, endocrine therapy, and OFS, were developed and evaluated in clinical trials. These trials showed that adjuvant tamoxifen therapy in women with ER-positive breast cancer reduced disease recurrence and decreased 15-year mortality by approximately one-third relative to patients who did not receive adjuvant tamoxifen.⁴ The risk of new contralateral breast cancer in women aged <45 years over 15 years was also reduced by approximately 50%. There were 9 deaths in the tamoxifen group versus 1 in the control group from uterine cancer and 6 deaths in the tamoxifen group versus none in the control group from pulmonary embolism.⁴ International Breast Cancer Study Group Trial 13-93 confirmed these findings. In the ER-positive subgroup, treatment with chemotherapy followed by tamoxifen improved disease-free survival (DFS) compared with chemotherapy alone.⁵ Furthermore, results from the ATLAS trial showed that extending treatment with tamoxifen for up to 10 years further reduced the risk of recurrence compared with 5-year treatment. In patients treated for ≥10 years, the relative risk of recurrence was 0.75 (0.62-0.90) compared with 0.90 (0.79-1.02) in patients treated for 5 to 9 years.⁶

Advances in molecular testing techniques led to the evolution of how ER positivity is defined. For instance, ER-low positive patients, defined as those with ER positivity only 1% to 10% of cells, may also derive benefit from adjuvant endocrine therapy; however, their tumor may behave more like an ER-negative tumor.⁷

The SOFT trial randomized premenopausal women with ER-positive breast cancer to 5-year adjuvant tamoxifen, tamoxifen plus OFS, or exemestane plus OFS.⁸ The primary objective was to compare DFS between tamoxifen plus OFS and tamoxifen alone. The secondary objective was to compare exemestane plus OFS versus tamoxifen. After a median follow-up of 12 years, DFS remained significantly improved with tamoxifen plus OFS compared with tamoxifen only (hazard ratio [HR], 0.82; 95% confidence interval [CI], 0.69-0.98). The 12-year DFS was 71.9% with tamoxifen, 76.1% with tamoxifen plus OFS, and 79.0% with exemestane plus OFS. The 12-year overall survival (OS) was improved with tamoxifen plus OFS versus tamoxifen alone (HR, 0.78; 95% CI, 0.60-1.01) and was 86.8% with tamoxifen, 89.0% with tamoxifen plus OFS, and 89.4% with exemestane plus OFS. In the no-chemotherapy cohort, the 12-year OS exceeded 95% in all 3 treatment groups. Among the predominant subgroup of patients with HER2-negative tumors—and in the prior chemotherapy cohort—the 12-year OS was 78.8% with tamoxifen, 81.1% with tamoxifen plus OFS, and 84.4% with exemestane plus OFS. Furthermore, meaningful OS was observed at 12 years in women aged <35 years with OFS. Quality-of-life analysis showed that vasomotor symptoms improved over time. However, noncompliance is a real issue, especially in the younger patient population.⁹

The recently reported results of the ASTRRA trial further supported the findings of the SOFT trial.¹⁰ The 8-year DFS rate was 85.4% in the tamoxifen-plus-OFS group and 80.2% in the tamoxifen-only group (HR, 0.67; 95% CI, 0.51-0.87). There was no significant difference in OS between the 2 groups, with OS rates of 96.5% and 95.3% in the tamoxifen-plus-OFS and tamoxifen-only groups, respectively (HR, 0.78; 95% CI, 0.49-1.25).

Currently, there is a wide range of endocrine therapy and OFS options for the adjuvant treatment of premenopausal women with hormone receptor–positive breast cancer based on composite risk of recurrence and a combination of clinicopathologic characteristics. An online tool is available (https://rconnect.dfci.harvard.edu/CompositeRiskSTEPP) to assist in selecting treatment regimens based on patients’ clinicopathologic features.

References

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