Ovarian function suppression (OFS) coupled with exemestane provided better long-term freedom from distant recurrences than tamoxifen plus OFS or sole tamoxifen in premenopausal women with hormone receptor (HR)-positive, HER2-negative breast cancer and high risk of recurrence, according to findings presented at the 2018 American Society of Clinical Oncology (ASCO) Annual Meeting, held 1 to 5 June in Chicago, USA1. The results from a prespecified updated analysis of SOFT and the combined analysis of data from SOFT and TEXT after a median follow-up of 8 and 9 years are simultaneously published in The New England Journal of Medicine2.
Meredith M. Regan of the Dana-Farber Cancer Institute in Boston, USA presented at ASCO 2018 Annual Meeting freedom from distant recurrence findings from the TEXT (NCT00066690) and SOFT (NCT00066703) studies after 8.5 years of follow-up on behalf of the International Breast Cancer Study Group. In the two trials, premenopausal women with HR-positive breast cancer at high recurrence risk were randomly assigned to receive 5 years of treatment with exemestane plus OFS, tamoxifen plus OFS, or tamoxifen alone. Recurrence risk was defined by clinicopathological characteristics.
The endpoint of distant recurrence-free interval (DRFI) was evaluated in the HR-positive, HER2-negative population of both trials, consisting of 4891 patients, who were stratified by receipt of prior chemotherapy. The DRFI was defined as the time from randomisation to first appearance of a distant recurrence (DR). A continuous, composite recurrence risk index (CRI) was also calculated for each patient using a Cox model that comprised age, nodal status, tumour size and grade, and the expression levels of the ER, PgR, and Ki-67. Subpopulation Treatment Effect Pattern Plot (STEPP) methodology was used to estimate the 8-year absolute treatment effects for the subgroups, as defined by CRI values.
Disease free survival rate was highest in women receiving exemestane plus OFS
After a median follow-up of 9 years of the 4690 patients in the combined TEXT and SOFT populations who received ovarian suppression, the 8-year disease-free survival (DFS) rate was 86.8% among patients assigned to receive exemestane plus OFS compared to 82.8% in patients receiving tamoxifen plus OFS, a difference of 4.0 percentage points (hazard ratio [HR] for recurrence, a second invasive cancer, or death, 0.77; 95% confidence interval [CI] 0.67, 0.90; p < 0.001).
In the combined population, more than 96% of the patients who did not receive chemotherapy were free from distant recurrence at 8 years in each treatment group. The 8-year DRFI was 91%, based upon 433 (9.25) patients reporting a DR in the overall population studied. The DFRIs ranged from approximately 100% to 63% across a range of CRIs from the lowest of 0.2 to the highest of 3.4.
Evaluation of data from the 2267 patients in the TEXT trial revealed a median [interquartile range; IQR] CRI of 1.7 [1.2 to 2.3]. In the TEXT population, the 8-year DRFI was 92%, with 194 DRs reported. The absolute benefit of exemestane plus OFS versus tamoxifen plus OFS was 3%, with benefit ranging from 0% at the lowest CRI (both therapies showed 100% 8-year DRFI) to 15% at the highest CRI. Women with HER2-negative cancers who received chemotherapy demonstrated an 8-year rate of distant recurrence with exemestane plus ovarian suppression that was lower than the rate with tamoxifen plus ovarian suppression by 5.0 percentage points.
In the SOFT trial, data from 1271 patients remaining premenopausal after chemotherapy were assessed. SOFT also included a tamoxifen only arm. The 8-year DRFI in patients overall was 99%, which included 23 DRs, and all three therapies exceeded 97% across the range of CRI. The 8-year DFS rate was 85.9% with exemestane plus OFS. This rate was 78.9% with tamoxifen alone compared to 83.2% with tamoxifen plus OFS (p = 0.009 for tamoxifen alone versus tamoxifen plus OFS).
In SOFT, the median [IQR] CRI was 2.1 [1.5 to 2.7]. The 8-year DRFI was 82%, which included 216 DRs. The absolute benefit of exemestane plus OFS versus tamoxifen was 5% and this benefit ranged from 2% to 10% across CRI. For the comparison of tamoxifen plus OFS versus tamoxifen, the absolute benefit ranged from 0% to 5%.
The 8-year overall survival (OS) rates were 92.1% with exemestane plus OFS, 91.5% with tamoxifen alone, and 93.3% with tamoxifen plus OFS, and (p = 0.01 for tamoxifen alone versus tamoxifen plus OFS).
The majority (87.8%) of distant recurrences occurred in patients who had received chemotherapy. Among the women with HER2-negative cancers who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression by 7.0 percentage points.
SOFT also included a no-chemotherapy cohort of 1353 patients who demonstrated a median CRI [IQR] of 1.1 [0.3 to 1.4].
In the combined analysis, 320 patients (6.8%) had died after a median follow-up of 9 years. Eight-year overall survival rates were 93.4% in patients receiving exemestane plus OFS and 93.3% in the tamoxifen plus OFS arm, HR for death, 0.98; 95% CI 0.79, 1.22 (p = 0.84).
Adverse event rates were slightly higher with exemestane plus OFS
The rate of early discontinuation of ovarian suppression by triptorelin without substitution of ovarian ablation was 19.0% in the combined population and was similar between treatment groups.
Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen-alone group (SOFT), 31.0% of the combined tamoxifen–OFS arm, and in 32.3% of the combined exemestane–OFS group.
Early discontinuation of assigned oral endocrine therapy, with or without alternative therapy, occurred in 22.5% of the tamoxifen group in SOFT, and in the combined trials, 19.3% of the combined tamoxifen–OFS, and 23.7% of the combined exemestane–OFS discontinued treatment.
Marc E. Lippman commented in associated editorial article published in The New England Jounral of Medicine that it is very difficult to predict which patients who receive endocrine treatment will have few side effects and who will be seriously harmed in terms of sexual functioning, depression, and osteoporosis. He continued that it is unfortunate that the use of bone-strengthening agents or RANKL inhibitors was not permitted unless such use was medically indicated, since it is now clear that such agents reduce skeletal events associated with aromatase inhibitors, reduce fracture recurrences, and increase overall survival.3
Based on findings from the two trials, the authors concluded that premenopausal patients with HR-positive, HER2-negative breast cancer at high risk of recurrence may experience a 10% to 15% absolute improvement in 8-year DRFI with exemestane plus OFS over tamoxifen plus OFS or tamoxifen alone.
However, the potential benefit of escalating endocrine therapy versus tamoxifen alone is minimal for patients at low risk, and may be 4% to 5% for patients at intermediate risk.
The authors advised that, given the side effects of ovarian suppression, the overall results of SOFT do not imply that this treatment should be prescribed for all premenopausal women with HR-positive early breast cancer.
Sponsorship was disclosed by Pfizer, the International Breast Cancer Study Group, and the US National Cancer Institute for the conduct of SOFT and TEXT.
Pfizer and Ipsen provided the trial drugs. Support for the International Breast Cancer Study Group was provided by the Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research, Cancer Research Switzerland, Oncosuisse, Cancer League Switzerland, Foundation for Clinical Cancer Research of Eastern Switzerland, a grant (CA075362) from the US National Institutes of Health, and a grant (16-185) from the Breast Cancer Research Foundation.
- Regan MM, Francis PA, Pagani O, et al. Absolute improvements in freedom from distant recurrence with adjuvant endocrine therapies for premenopausal women with hormone receptor-positive (HR+) HER2-negative breast cancer (BC): Results from TEXT and SOFT. J Clin Oncol 36, 2018 (suppl; abstr 503).
- Francis PA, Pagani O, Fleming GF, et al.Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer. NEJM. Published online 4 June, 2018. DOI: 10.1056/NEJMoa1803164.
- Lippman ME.Endocrine Adjuvant Therapy for Localized Breast Cancer. NEJM. Published online 4 June, 2018. DOI: 10.1056/NEJMe1806130.