Absolute Improvements in Freedom From Distant Recurrence to Tailor Adjuvant Endocrine Therapies for Premenopausal Women: Results From TEXT and SOFT

Olivia Pagani, Prudence A Francis, Gini F Fleming, Barbara A Walley, Giuseppe Viale, Marco Colleoni, István Láng, Henry L Gómez, Carlo Tondini, Graziella Pinotti, Angelo Di Leo, Alan S Coates, Aron Goldhirsch, Richard D Gelber, Meredith M Regan, SOFT and TEXT Investigators and International Breast Cancer Study Group, Olivia Pagani, Prudence A Francis, Gini F Fleming, Barbara A Walley, Giuseppe Viale, Marco Colleoni, István Láng, Henry L Gómez, Carlo Tondini, Graziella Pinotti, Angelo Di Leo, Alan S Coates, Aron Goldhirsch, Richard D Gelber, Meredith M Regan, SOFT and TEXT Investigators and International Breast Cancer Study Group

Abstract

Purpose: The Tamoxifen and Exemestane Trial (TEXT)/Suppression of Ovarian Function Trial (SOFT) showed superior outcomes for premenopausal women with hormone receptor (HR)-positive breast cancer treated with adjuvant exemestane plus ovarian function suppression (OFS) or tamoxifen plus OFS versus tamoxifen alone. We previously reported the magnitude of absolute improvements in freedom from any recurrence across a continuous, composite measure of recurrence risk to tailor decision making. With longer follow-up, we now focus on distant recurrence.

Methods: The TEXT/SOFT HR-positive/human epidermal growth factor receptor 2 (HER2)-negative analysis population included 4,891 women stratified by predetermined chemotherapy use. Kaplan-Meier estimates of 8-year freedom from distant recurrence were analyzed using subpopulation treatment effect pattern plot (STEPP) methodology across subpopulations defined by the continuous composite measure of recurrence risk. For each patient, the composite risk value was obtained from a Cox model that incorporated age; nodal status; tumor size; grade; and estrogen receptor, progesterone receptor, and Ki-67 labeling index expression levels.

Results: The overall rate of 8-year freedom from distant recurrence was 91.1% and ranged from approximately 100% to 63% across lowest to highest composite risks. TEXT patients who received chemotherapy had an average absolute improvement with exemestane plus OFS versus tamoxifen plus OFS of 5.1%, and STEPP analysis showed improvements from less than 1% to more than 15% from lowest to highest composite risks. SOFT patients who remained premenopausal after chemotherapy had an average 5.2% absolute improvement with exemestane plus OFS versus tamoxifen and reached 10% across composite risks; for tamoxifen plus OFS versus tamoxifen, the maximum improvement was approximately 3.5%. Women who did not receive chemotherapy had a more than 97% rate of 8-year freedom from distant recurrence, and improvements with exemestane plus OFS ranged from 1% to 4%.

Conclusion: Premenopausal women with HR-positive/HER2-negative breast cancer and high recurrence risk, as defined by clinicopathologic characteristics, may experience a 10% to 15% absolute improvement in 8-year freedom from distant recurrence with exemestane plus OFS versus tamoxifen plus OFS or tamoxifen alone. The potential benefit of escalating endocrine therapy versus tamoxifen alone is minimal for those at low recurrence risk.

Trial registration: ClinicalTrials.gov NCT00066690 NCT00066703.

Figures

FIG 1.
FIG 1.
Kaplan-Meier estimates of distant recurrence (DR)–free interval in the overall hormone receptor–positive/human epidermal growth factor receptor 2–negative analysis population according to seven clinicopathologic characteristics. (A) Age at random assignment, (B) number of positive lymph nodes, (C) tumor size, (D) estrogen receptor (ER) expression, (E) progesterone receptor (PgR) expression, (F) tumor grade, and (G) labeling index Ki-67 (Ki67) expression. Unknown values are omitted.
FIG 2.
FIG 2.
Kaplan-Meier estimates of 8-year freedom from distant recurrence in seven clinicopathologic subgroups in the four patient cohorts defined by trial and chemotherapy use according to treatment assignment. The values are listed in Appendix Tables A3 and A6. Unknown values are omitted. ER, estrogen receptor; EXEM, exemestane; Ki-67, Ki-67 labeling index; OFS, ovarian function suppression; PgR, progesterone receptor; SOFT, Suppression of Ovarian Function Trial; TAM, tamoxifen; TEXT, Tamoxifen and Exemestane Trial.
FIG 3.
FIG 3.
(A) Subpopulation treatment effect pattern plot of 8-year freedom from distant recurrence according to median composite risk in subpopulations and (B) histogram of the composite risk distribution in the overall hormone receptor (HR)–positive/human epidermal growth factor receptor 2 (HER2)–negative analysis population. The horizontal lines above the histogram indicate the ranges of composite risks in subpopulations that are plotted at the subpopulation median value. The overall 8-year freedom from distant recurrence rate of 91.1% also is indicated on the y-axis. The overall median composite risk of 1.42 is indicated by the vertical dashed lines.
FIG 4.
FIG 4.
Kaplan-Meier estimates of distant recurrence (DR)–free interval in the four patient cohorts defined by trial and chemotherapy use according to treatment assignment. (A) Tamoxifen and Exemestane Trial (TEXT) chemotherapy, (B) Suppression of Ovarian Function Trial (SOFT) prior chemotherapy, (C) TEXT no chemotherapy, and (D) SOFT no chemotherapy. EXEM, exemestane; OFS, ovarian function suppression; TAM, tamoxifen.
FIG 5.
FIG 5.
Subpopulation treatment effect pattern plots of 8-year freedom from distant recurrence according to median composite risk in subpopulations and histograms of the composite risk distributions for each of the four cohorts in the hormone receptor (HR)–positive/human epidermal growth factor receptor 2 (HER2)–negative analysis population according to treatment assignment. (A) Tamoxifen and Exemestane Trial (TEXT) chemotherapy, (B) Suppression of Ovarian Function Trial (SOFT) prior chemotherapy, (C) TEXT no chemotherapy, and (D) SOFT no chemotherapy. The horizontal lines above each histogram indicate the ranges of composite risks in subpopulations that are plotted at the subpopulation median composite risk value. The vertical dashed lines indicate the median composite risk of 1.42 in the overall HR-positive/HER2-negative analysis population. EXEM, exemestane; OFS, ovarian function suppression; TAM, tamoxifen.
FIG A1.
FIG A1.
Flow diagram of the 4,891 patients included in the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT) hormone receptor (HR)–positive/human epidermal growth factor receptor 2 (HER2)–negative analysis population. EXEM, exemastane; ITT, intent to treat; OFS, ovarian function suppression; TAM, tamoxifen.
FIG A2.
FIG A2.
Kaplan-Meier estimates of 8-year freedom from distant recurrence in seven clinicopathologic subgroups, according to treatment assignment, separately by trial. The plotted values are provided in Tables A2 and A5. Unknown values are omitted. ER, estrogen receptor; EXEM, exemestane; Ki-67, Ki-67 labeling index; PgR, progesterone receptor; OFS, ovarian function suppression; SOFT, Suppression of Ovarian Function Trial; TAM, tamoxifen; TEXT, Tamoxifen and Exemestane Trial.
FIG A3.
FIG A3.
Estimated relative treatment effects on distance recurrence–free interval (DRFI) overall and according to seven clinicopathologic subgroups for the hormone receptor (HR)–positive/human epidermal growth factor receptor (HER2)–negative analysis population. The hazard ratios were estimated from Cox proportional hazards models stratified by cohort. Estimates not provided for unknown groups of

FIG A4.

Subpopulation treatment effect pattern plots…

FIG A4.

Subpopulation treatment effect pattern plots (STEPP) of 8-year freedom from distant recurrence (…

FIG A4.
Subpopulation treatment effect pattern plots (STEPP) of 8-year freedom from distant recurrence (y-axis) according to median composite risk in subpopulations (x-axis) and histograms of the composite risk distributions for each of the four cohorts in the hormone receptor (HR)–positive/human epidermal growth factor receptor 2 (HER2)–negative analysis population according to treatment assignment. The horizontal lines above each histogram indicate the ranges of composite risks in subpopulations that are plotted at the subpopulation median composite risk value in each corresponding STEPP. The red vertical line on the histograms indicates the selected composite risk, and intersects one or more subpopulations in which the composite risk value is represented. The dark orange circles on the STEPPs indicate the corresponding subpopulations in which the selected composite risk is represented. The black vertical dashed lines indicate the median composite risk of 1.42 in the overall HR-positive/HER2-negative analysis population. Three scenarios are presented: (A) A high-risk scenario (composite risk = 3.00; 35-39 years of age, pT2pN1a, grade 3, estrogen receptor [ER] ≥ 50%, progesterone receptor [PgR] ≥ 50% and Ki-67 labeling index [Ki-67] ≥ 26%). In this scenario, there are no circles on the Tamoxifen and Exemestane Trial (TEXT) no chemotherapy and Suppression of Ovarian Function Trial (SOFT) no chemotherapy STEPPs because there were too few patients with the same or similar composite risk values.
All figures (9)
FIG A4.
FIG A4.
Subpopulation treatment effect pattern plots (STEPP) of 8-year freedom from distant recurrence (y-axis) according to median composite risk in subpopulations (x-axis) and histograms of the composite risk distributions for each of the four cohorts in the hormone receptor (HR)–positive/human epidermal growth factor receptor 2 (HER2)–negative analysis population according to treatment assignment. The horizontal lines above each histogram indicate the ranges of composite risks in subpopulations that are plotted at the subpopulation median composite risk value in each corresponding STEPP. The red vertical line on the histograms indicates the selected composite risk, and intersects one or more subpopulations in which the composite risk value is represented. The dark orange circles on the STEPPs indicate the corresponding subpopulations in which the selected composite risk is represented. The black vertical dashed lines indicate the median composite risk of 1.42 in the overall HR-positive/HER2-negative analysis population. Three scenarios are presented: (A) A high-risk scenario (composite risk = 3.00; 35-39 years of age, pT2pN1a, grade 3, estrogen receptor [ER] ≥ 50%, progesterone receptor [PgR] ≥ 50% and Ki-67 labeling index [Ki-67] ≥ 26%). In this scenario, there are no circles on the Tamoxifen and Exemestane Trial (TEXT) no chemotherapy and Suppression of Ovarian Function Trial (SOFT) no chemotherapy STEPPs because there were too few patients with the same or similar composite risk values.

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Source: PubMed

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