The breast cancer treatment landscape is changing, and the optimal adjuvant endocrine therapy for premenopausal women with hormone receptor (HR)-positive breast cancer is uncertain. Added to this, ovarian function suppression (OFS) is now used in combination with endocrine therapy. The Tamoxifen and Exemestane Trial (TEXT) and the Suppression of Ovarian Function Trial (SOFT) were designed to determine the optimal endocrine therapy in premenopausal women with HR-positive breast cancer. Specifically, a joint analysis of these trials, presented by Olivia Pagani, MD, at the ASCO Annual Meeting, attempts to answer the question of whether adjuvant therapy with exemestane plus OFS improves disease-free survival (DFS) relative to tamoxifen plus OFS in this patient population.
In the TEXT trial, 2,672 patients were randomized to tamoxifen plus OFS for 5 years vs exemestane plus OFS for 5 years. OFS was achieved with triptorelin, a gonadotropin-releasing hormone agonist. Bilateral oophorectomy or irradiation were allowed as alternatives to triptorelin after 6 months. In the SOFT trial, 3,066 patients were randomized to tamoxifen for 5 years vs tamoxifen plus OFS for 5 years vs exemestane plus OFS for 5 years. The OFS method was investigators’ choice. Oral endocrine therapy was exemestane (25 mg daily) or tamoxifen (20 mg daily). The patient population included premenopausal women with HR-positive invasive breast cancer confirmed to the breast and/or axillary lymph nodes. All patients had to receive prior proper local-regional treatment, with no residual disease. All patients in TEXT and SOFT who did not receive chemotherapy were randomized within 12 weeks of surgery, and those in SOFT who did receive chemotherapy were randomized within 8 months. Adjuvant trastuzumab was allowed, if indicated. Annual mammography and dual-energy X-ray absorptiometry were recommended.
The primary endpoint was DFS, which included invasive recurrence, invasive contralateral breast cancer, second (non-breast) malignancy, and death without primary cancer event. However, the DFS event rate was much lower than anticipated, and as such, the protocols were amended and a planned secondary joint analysis of TEXT and SOFT was promoted to become the primary efficacy analysis. The joint analysis consisted of 4,690 women (does not include the tamoxifen-only arm in the SOFT trial). The median age of patients was 43 years old. Forty-two percent of the patients had lymph node–positive disease, 36% had a tumor size ≥ 2 cm, and 12% were HER2-positive.
The median follow-up was 5.7 years. Exemestane plus OFS improved DFS compared with tamoxifen plus OFS. The 5-year DFS for exemestane plus OFS was 91.1% vs 87.3% for tamoxifen plus OFS, with an absolute benefit of 3.8% (hazard ratio = 0.72; P = .0002). Results were similar for breast cancer–free interval (BCFI) and distant recurrence–free interval (DRFI). Exemestane plus OFS had a BCFI of 92.8% and a DRFI of 93.8% compared with a BCFI of 88.8% and a DRFI of 92% in the tamoxifen plus OFS group. The increases in BCFI and DRFI were statistically significant. Exemestane plus OFS had an overall survival (OS) of 96.9% vs 95.9% in the tamoxifen plus OFS group. This was not statistically significant (P = .37), but survival data are not yet mature.
In terms of safety, adverse event profiles were comparable with postmenopausal women. Depression, hypertension, and hot flashes were the most common. Musculoskeletal pain, vaginal dryness, libido decrease, dyspareunia, osteoporosis, and fracture were more common in the exemestane plus OFS group. Venous thromboembolism and hot flashes were more common in the tamoxifen plus OFS group. Quality of life assessment did not favor either treatment. Early cessation of all assigned treatments was more frequent in the exemestane group compared with the tamoxifen group (16% vs 11%, respectively).
In conclusion, a joint analysis of TEXT and SOFT showed that exemestane plus OFS significantly improves DFS, BCFI, and DRFI compared with tamoxifen plus OFS, and is a new treatment option for premenopausal women with HR-positive early breast cancer. At this time, there is no significant difference in OS, but conclusions are still premature.
This now raises the question, where do we go from here? What are the options for adjuvant endocrine therapy in premenopausal women, and how long are the treatments? Current options are 10 years of tamoxifen (ATLAS and aTTom trials) or 5 years of tamoxifen followed by 5 years of an aromatase inhibitor (MA. 17 trial); we can now add 5 years of an aromatase inhibitor plus OFS to this list. The results of SOFT are expected at the end of 2014 and will help answer the question of the role of OFS for women receiving tamoxifen. Long-term follow-up for benefit and toxicity is vital and will help shape the answers to these questions in the future.