VOLUME 35 • NUMBER 27 • SEPTEMBER 20, 2017 JOURNAL OF CLINICAL ONCOLOGY O R I G I N A L R E P O R T Treatment Efficacy, Adherence, and Quality of Life Among Women Younger Than 35 Years in the International Breast Cancer Study Group TEXT and SOFT Adjuvant Endocrine Therapy Trials Poornima Saha, Meredith M. Regan, Olivia Pagani, Prudence A. Francis, Barbara A. Walley, Karin Ribi, Jürg Bernhard, Weixiu Luo, Henry L. Gómez, Harold J. Burstein, Vani Parmar, Roberto Torres, Josephine Stewart, Meritxell Bellet, Antonia Perelló, Faysal Dane, Antonio Moreira, Daniel Vorobiof, Michelle Nottage, Karen N. Price, Alan S. Coates, Aron Goldhirsch, Richard D. Gelber, Marco Colleoni, and Gini F. Fleming; for the SOFT and TEXT Investigators and the International Breast Cancer Study Group Author affiliations and support information (if applicable) appear at the end of this article. Published at jco.org on June 27, 2017. Clinical trial information: SOFT, NCT00066690; TEXT, NCT00066703. Corresponding author: Gini F. Fleming, MD, The University of Chicago Medical Center, Knapp Center for Biological Discovery, 900 E 57th St, Room 8118, Chicago, IL 60637; e-mail: gfleming@ medicine.bsd.uchicago.edu. © 2017 by American Society of Clinical Oncology 0732-183X/17/3527w-3113w/$20.00 A B S T R A C T Purpose To describe benefits and toxicities of adjuvant endocrine therapies in women younger than 35 years with breast cancer (n = 582) enrolled in the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT). Methods In SOFT, women still premenopausal after surgery with or without chemotherapy were randomly assigned to tamoxifen alone, tamoxifen plus ovarian function suppression (OFS), or exemestane plus OFS. In TEXT, all received OFS with or without concomitant chemotherapy and were randomly assigned to exemestane plus OFS or tamoxifen plus OFS. We summarize treatment efficacy, quality of life, and adherence of the cohort of women younger than 35 years in SOFT and TEXT, alongside data from the cohort of older premenopausal women. Results For 240 human epidermal growth factor receptor 2–negative patients younger than 35 years enrolled in SOFT after receiving chemotherapy, the 5-year breast cancer–free interval (BCFI) was 67.1% (95% CI, 54.6% to 76.9%) with tamoxifen alone, 75.9% with tamoxifen plus OFS (95% CI, 64.0% to 84.4%), and 83.2% with exemestane plus OFS (95% CI, 72.7% to 90.0%). For 145 human epidermal growth factor receptor 2–negative patients younger than 35 years in TEXT, 5-year BCFI was 79.2% (95% CI, 66.2% to 87.7%) with tamoxifen plus OFS and 81.6% (95% CI, 69.8% to 89.2%) with exemestane plus OFS. The most prominent quality of life symptom for patients younger than 35 years receiving OFS was vasomotor symptoms, with the greatest worsening from baseline at 6 months (on the order of 30 to 40 points), but loss of sexual interest and difficulties in becoming aroused were also clinically meaningful ($ 8-point change). The level of symptom burden was similar in older premenopausal women. A total of 19.8% of women younger than 35 years stopped all protocol-assigned endocrine therapy early. ASSOCIATED CONTENT See accompanying Editorial on page 3092 Appendix DOI: https://doi.org/10.1200/JCO. 2016.72.0946 Data Supplement DOI: https://doi.org/10.1200/JCO. 2016.72.0946 DOI: https://doi.org/10.1200/JCO.2016. 72.0946 Conclusion In women younger than 35 years with hormone receptor–positive breast cancer, adjuvant OFS combined with tamoxifen or exemestane produces large improvements in BCFI compared with tamoxifen alone. Menopausal symptoms are significant but are not worse than those seen in older premenopausal women. J Clin Oncol 35:3113-3122. © 2017 by American Society of Clinical Oncology INTRODUCTION Women younger than 35 years with breast cancer have historically had poor outcomes, with increased rates of both local and distant recurrence.1-5 Although women younger than 35 years have higher rates of triple-negative breast cancer, it is paradoxically in the hormone receptor (HR)–positive subgroup that the most significantly worse outcomes have been observed. Some data6 come from earlier trials, © 2017 by American Society of Clinical Oncology 3113 Saha et al in which premenopausal women with HR-positive tumors received chemotherapy but no endocrine therapy, and the authors suggested that differences in outcomes were related to differential likelihood of undergoing chemotherapy-induced ovarian function suppression (OFS). However, age-related differences in outcomes persist in the face of endocrine therapy. In the US Intergroup INT0101 trial for node-positive HR-positive disease, women younger than 40 years treated with chemotherapy plus OFS (goserelin) with or without tamoxifen had 9-year diseasefree survivals of 64% and 55%, versus 69% and 62% for premenopausal women age 40 years or older.7 It has also been hypothesized that the difference in outcomes is related to a greater ratio of luminal B to luminal A cancers in women younger than 35 years.8 Yet, a recent large analysis of US National Comprehensive Cancer Network data on women presenting with breast cancer between January 2000 and December 2007, when endocrine therapy was standard for all women with HR-positive disease, found significantly worse outcomes among women # 40 years old specifically for the group with luminal A tumors.9 The Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT) have recently demonstrated that for premenopausal women with HR-positive breast cancer and high-risk clinicopathologic factors, treatment with OFS plus exemestane can produce an absolute improvement of 10% to 15% in 5-year breast cancer–free interval (BCFI).10 In SOFT and TEXT, HR-positive/human epidermal growth factor receptor 2 (HER2)–negative women younger than age 35 years had a 5-year BCFI of 79%, versus 95% for women age 45 to 49 years. 10 Symptom-specific quality of life (QoL; focusing on symptoms related to endocrine therapy) was worse with the addition of OFS.11,12 We hypothesized that women younger than 35 years would report more endocrine-related symptoms. We present a summary of benefits and risks of endocrine therapy that includes OFS specific to women younger than 35 years to help facilitate joint decision making. METHODS The designs and conduct of the TEXT and SOFT phase III trials have been described.13-15 Ethics committees at participating centers approved the protocols, and all patients provided written informed consent. In both trials, eligible premenopausal women with surgically resected, invasive early-stage breast cancer with $ 10% estrogen receptor (ER)– and/or progesterone receptor (PR)-expressing cells were randomly assigned between November 2003 and March 2011. TEXT enrolled 2,660 women in the intention-to-treat (ITT) population within 12 weeks after definitive surgery and randomly assigned them to 5 years of exemestane plus OFS or 5 years of tamoxifen plus OFS. OFS was achieved by gonadotropin-releasing hormone (GnRH) agonist triptorelin, bilateral oophorectomy, or ovarian irradiation. Chemotherapy was optional and, when administered, was started concurrently with triptorelin. SOFT randomly assigned 3,047 women in the ITT population to 5 years of exemestane plus OFS or tamoxifen plus OFS or tamoxifen alone. Patients who did not receive chemotherapy were enrolled within 12 weeks after definitive surgery; those patients who received (neo)adjuvant chemotherapy were enrolled within 8 months after the final dose of chemotherapy, after a premenopausal estradiol level was confirmed. The trial end points were: disease-free survival (DFS), defined as the time from random assignment to the first appearance of: invasive recurrence of breast cancer (local, regional, or distant), invasive contralateral breast cancer, second nonbreast invasive cancer, or death; BCFI, from random assignment to the recurrence of invasive breast cancer or invasive contralateral breast cancer; distant recurrence-free interval (DRFI), from random assignment to recurrence at a distant site; overall survival, from random assignment to death from any cause. Overall survival is not yet mature after a median follow-up of 6 years in TEXT and 5.6 years in SOFT. Study Population SOFT, TEXT ITT Populations (N = 5,707) SOFT, TEXT QoL* Populations (N = 4,957) Analysis of: Characteristics Prognostic value of age Nonadherence with protocolassigned endocrine therapy Analysis of: Treatmentspecific outcomes Age < 35 years at enrollment No chemotherapy SOFT No chemotherapy TEXT Prior chemotherapy SOFT Chemotherapy TEXT (n = 582) (n = 21) (n = 41) (n = 329) (n = 191) Age < 35 years, HER2-negative (n = 442) No chemotherapy SOFT (n = 20) No chemotherapy TEXT (n = 37) Prior chemotherapy SOFT (n = 240) Chemotherapy TEXT (n = 145) Analysis of: Quality of life Age < 35 years, QoL* (Chemotherapy-treated patients only): Prior chemotherapy SOFT (n = 291) (n = 170) Chemotherapy TEXT Age ≥ 35 years at enrollment No chemotherapy SOFT (n = 1,398) No chemotherapy TEXT (n = 1,012) Prior chemotherapy SOFT (n = 1,299) Chemotherapy TEXT (n = 1,416) Age ≥ 35 years, HER2-negative No chemotherapy SOFT (n = 1,338) Chemotherapy TEXT (n = 954) Prior chemotherapy SOFT (n = 1,056) Chemotherapy TEXT (n = 1,147) Age ≥ 35 years, QoL* (Chemotherapy-treated patients only): Prior chemotherapy SOFT (n = 1,136) (n = 1,230) Chemotherapy TEXT Fig 1. Flow diagram of analysis populations. (*) Quality-of-life (QoL) populations were 87% of the intention-to-treat (ITT) populations, after exclusion of patients having eligibility exemption and of patients at centers not compliant with QoL submission.11,12 HER2, human epidermal growth factor receptor 2; SOFT, Suppression of Ovarian Function Trial; TEXT, Tamoxifen and Exemestane Trial. 3114 © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Women Younger Than 35 Years in TEXT and SOFT Table 1. Patient, Tumor, and Treatment Characteristics According to Age at Random Assignment in the SOFT and TEXT Randomized Trials Age at Random Assignment , 35 Years Characteristic No. patients Trial/chemotherapy cohort No chemotherapy TEXT No chemotherapy SOFT Chemotherapy TEXT Prior chemotherapy SOFT Age at random assignment, years , 25 25-29 30-34 35-39 40-44 45-49 $ 50 Race/ethnicity Other Asian Black/African American Hispanic/Latino/South American native White BMI, kg/m2 Unknown Normal (, 25) Overweight (25 to , 30) Obese ($ 30) Ever pregnant Unknown No Yes Pregnant at diagnosis Unknown No Yes Menstruation status at random assignment Unknown Normal Irregular (cycles continuing) Persistent amenorrhea* Hormone receptor status ER-positive/PR-positive ER-positive/PR-negative ER-negative/PR-positive Other† HER2 status Negative Positive Ki-67 expression by CPR Unknown (no tissue for CPR) , 20% $ 20% No. nodes positive Unknown N0 N-positive 1-3 N-positive 4-9 N-positive $ 10 Tumor size, cm #2 . 2-5 .5 Unknown jco.org $ 35 Years No. % No. % 582 100.0 5,125 100.0 41 21 191 329 7.0 3.6 32.8 56.5 1,012 1,398 1,416 1,299 19.7 27.3 27.6 25.3 13 128 441 — — — — 2.2 22.0 75.8 — — — — — — — 995 1,830 1,803 497 — — — 19.4 35.7 35.2 9.7 14 29 16 71 452 2.4 5.0 2.7 12.2 77.7 117 144 143 250 4,471 2.3 2.8 2.8 4.9 87.2 17 341 124 100 2.9 58.6 21.3 17.2 119 2,699 1,293 1,014 2.3 52.7 25.2 19.8 5 221 356 0.9 38.0 61.2 33 789 4,303 0.6 15.4 84.0 5 563 14 0.9 96.7 2.4 31 5,073 21 0.6 99.0 0.4 8 381 128 65 1.4 65.5 22.0 11.2 90 3,643 729 663 1.8 71.1 14.2 12.9 455 101 18 8 78.2 17.4 3.1 1.4 4,574 396 86 69 89.2 7.7 1.7 1.3 442 140 75.9 24.1 4,495 630 87.7 12.3 120 166 296 20.6 28.5 50.9 980 2,440 1,705 19.1 47.6 33.3 — 259 203 86 34 — 44.5 34.9 14.8 5.8 29 3,096 1,443 405 152 0.6 60.4 28.2 7.9 3.0 49.7 40.7 6.4 3.3 3,306 1,561 176 82 64.5 30.5 3.4 1.6 289 237 37 19 (continued on following page) © 2017 by American Society of Clinical Oncology 3115 Saha et al Table 1. Patient, Tumor, and Treatment Characteristics According to Age at Random Assignment in the SOFT and TEXT Randomized Trials (continued) Age at Random Assignment , 35 Years Characteristic Tumor grade 1 2 3 Unknown Vessel invasion (lymphatics and/or blood vessels) No Yes Not assessed/unknown Primary invasive histology Ductal Lobular Other Locoregional treatment Mastectomy, no radiotherapy Mastectomy with radiotherapy Other‡ BCS with radiotherapy Axillary lymph node dissection Unknown No (sentinel lymph node biopsy only) Yes $ 35 Years No. % No. % 63 266 243 10 10.8 45.7 41.8 1.7 1,181 2,756 1,107 81 23.0 53.8 21.6 1.6 300 253 29 51.5 43.5 4.9 3,409 1,423 293 66.5 27.8 5.8 537 15 30 92.3 2.6 5.2 4,259 598 268 83.1 11.7 5.2 124 174 16 268 21.3 29.9 2.7 46.0 1,262 793 64 3,006 24.6 15.5 1.2 58.7 1 158 423 0.2 27.1 72.7 3 2,134 2,988 0.1 41.6 58.3 NOTE. The distributions of all factors were significantly different according to age at random assignment (P , .001 by Fisher’s exact tests). Abbreviations: BCS, breast-conserving surgery; BMI, body mass index; CPR, central pathology review; ER, estrogen receptor; HER2, human epidermal growth factor receptor 2; PR, progesterone receptor; SOFT, Suppression of Ovarian Function Trial; TEXT, Tamoxifen and Exemestane Trial. *Persistent amenorrhea was primarily among patients in SOFT who had received prior chemotherapy: 59 of 65 (91%) younger than 35 years and 564 of 663 (85%) age $ 35 years. †Other includes ER-unknown and PR-unknown, or ER-negative and PR-negative (who were ineligible). ‡Other includes BCS without radiotherapy, or radiotherapy unknown; radiotherapy was required after BCS and optional after mastectomy. The trials used the International Breast Cancer Study Group QoL core form and a symptom-specific module focusing on symptoms related to endocrine therapy at baseline, 6, 12, 18, and 24 months, and annually during years 3 to 6. All indicators were in the linear analog self-assessment format and ranged from 0 to 100, with higher numbers indicating a better QoL. A clinically significant change was conservatively defined as $ 8-point difference.11,12 Statistical Considerations Comparisons of characteristics between age groups used Fisher’s exact tests. The association of age younger than 35 years at random assignment with end points used Cox proportional hazard modeling, stratified by trial, chemotherapy receipt, and lymph node status and adjusted for other prognostic and treatment characteristics (number of positive lymph nodes, tumor size, grade, receptor status, HER2 status/therapy, local therapy) and treatment assignment. The distributions of time-to-event end points among patients with HER2-negative tumors were estimated using the Kaplan-Meier method. Adherence to protocol-assigned therapy was estimated from cumulative incidence of cessation, with competing risk of a DFS event, and compared between age groups using Gray’s test. Changes in QoL indicators from baseline were summarized as mean and 95% CI, estimated using mixed-effects models (of all time points) adjusting for treatment assignment, with focus on estimates at the 6-, 24-, and 60-month time points among the chemotherapy cohorts.11,12 RESULTS Study Population A total of 5,707 women were enrolled in the SOFT and TEXT ITT populations (Fig 1). Of these, 582 (10.2%) were younger than 3116 © 2017 by American Society of Clinical Oncology 35 years at random assignment and form the basis of this analysis. This includes 11.5% and 8.7% of the SOFT and TEXT ITT populations, respectively. Characteristics of the Cohort of Women Younger Than Age 35 Years Although ER and/or PR positivity was only required to be $ 10% for enrollment, the vast majority of patients had strongly ERpositive/PR-positive tumors.16 However, in the population younger than 35 years there was a higher percentage of women with ERpositive/PR-negative tumors (17.4% v 7.7% in premenopausal women $ 35 years old by local assessment). Overall, the women younger than 35 years enrolled had higher-risk tumor characteristics than the older premenopausal women (Table 1): 47.1% had a tumor . 2 cm versus 33.9% of women age $ 35 years, 55.5% (v 39.3%) had node-positive disease, 41.8% (v 21.6%) had grade 3 histology, 43.5% (v 27.8%) had lymphovascular invasion, and 50.9% (v 33.3%) had Ki-67 levels $ 20% on central pathology review. The majority of women younger than 35 years were treated with chemotherapy: 329 (94%) of 350 in SOFT and 191 (82%) of 232 in TEXT. Independent Prognostic Value of Age In the study population, age younger than 35 years at random assignment was associated with higher risk of a breast cancer event (hazard ratio [HR], 1.53; 95% CI, 1.24 to 1.88 v age $ 35 years), distant recurrence (HR, 1.52; 95% CI, 1.21 to 1.91), and DFS event JOURNAL OF CLINICAL ONCOLOGY Women Younger Than 35 Years in TEXT and SOFT (HR, 1.43; 95% CI, 1.18 to 1.74) even after controlling for treatment and disease characteristics (which included HER2 status). this cohort, eight patients (14%) had invasive breast cancer events, including three distant recurrences and one death. In the cohort of women younger than age 35 years who had received chemotherapy before SOFTenrollment, 5-year BCFI was 67.1% (95% CI, 54.6% to 76.9%) for tamoxifen alone, 75.9% (95% CI, 64.0% to 84.4%) for tamoxifen plus OFS, and 83.2% (95% CI, 72.7% to 90.0%) for exemestane plus OFS (Fig 2; Appendix, online only). Their 5-year DRFI was 74.6% (95% CI, 62.7% to 83.2%) for tamoxifen alone, 77.3% (95% CI, 65.5% to 85.5%) for tamoxifen plus OFS, and 84.4% (95% CI, 74.0% to 90.9%) for exemestane plus OFS (Appendix Fig A1, online only). For women younger than 35 years enrolled in TEXTwho received chemotherapy, the 5-year BCFI was 79.2% (95% CI, 66.2% to 87.7%) with tamoxifen plus OFS and 81.6% (95% CI, 69.8% to 89.2%) with exemestane plus OFS. Their 5-year DRFI was 80.9% (95% CI, 68.1% to 89.0%) for tamoxifen plus OFS and 81.0% (95% CI, 68.8% to 88.8%) with exemestane plus OFS (Appendix Fig A1, online only). Treatment-Specific Outcomes of Women Younger Than 35 Years With HER2-Negative Disease TEXT and SOFT began enrollment before the widespread use of adjuvant trastuzumab for patients with HER2-positive breast cancer. Because women enrolled in these trials with HER2-positive disease did not all receive anti-HER2 therapy according to current standards, we chose to exclude HER2-positive disease from the efficacy analysis for this report. Four hundred forty-two women younger than 35 years had HER2-negative disease. After a median follow-up of 6.0 and 5.6 years in TEXT and SOFT, respectively, 102 (23%) had invasive breast cancer events (v 384 [8.5%] of 4,495 for $ 35 years of age). Recurrence at a distant site was reported in 81 patients (18.3%). Death was reported in 50 patients (11.3%); 49 of these deaths occurred in women who had received chemotherapy. The number of women younger than 35 years with HER2negative disease who did not receive chemotherapy was small (n = 57; SOFT = 20, TEXT = 37); these women seem to have low-risk tumors (94% node-negative, 84% # 2 cm, and 23% grade 1). In B SOFT prior chemotherapy cohort age < 35 years Free From Breast Cancer (%) Free From Breast Cancer (%) A 100 80 60 40 Prior chemotherapy T Prior chemotherapy T+OFS 20 Prior chemotherapy E+OFS 0 1 2 3 4 5 SOFT prior chemotherapy cohort age ≥ 35 years 100 80 60 40 Prior chemotherapy T Prior chemotherapy T+OFS 20 Prior chemotherapy E+OFS 0 6 Time Since Randomization (years) 1 2 3 4 5 6 Time Since Randomization (years) No. at risk No. at risk T 79 70 58 56 45 34 21 T 363 331 312 291 245 180 104 T+OFS 77 70 65 62 51 39 21 T+OFS 356 340 317 294 243 182 113 E+OFS 84 78 75 68 59 41 29 E+OFS 337 322 307 287 240 163 100 D TEXT chemotherapy cohort age < 35 years Free From Breast Cancer (%) Free From Breast Cancer (%) C 100 80 60 40 20 Chemotherapy T+OFS Chemotherapy E+OFS 0 1 2 3 4 5 TEXT chemotherapy cohort age ≥ 35 years 100 80 Fig 2. Kaplan-Meier estimates of breast cancer–free interval (BCFI) among patients with human epidermal growth factor receptor 2–negative disease in the chemotherapy cohorts of the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT), according to age at random assignment and treatment assignment. Median follow-up was 5.6 years in SOFT and 6.0 years in TEXT. (A, B) SOFT prior chemotherapy, age younger than 35 years and $ 35 years. (C, D) TEXT chemotherapy, age younger than 35 years and $ 35 years. E, exemestane; OFS, ovarian function suppression; T, tamoxifen. 60 40 20 Chemotherapy T+OFS Chemotherapy E+OFS 1 0 6 Time Since Randomization (years) No. at risk jco.org QoL Most patients younger than 35 years are likely to receive chemotherapy as part of adjuvant treatment, and 94% and 82% of women younger than 35 years enrolled in SOFT and TEXT did receive chemotherapy and are the focus of QoL analysis. In TEXT, the 2 3 4 5 6 Time Since Randomization (years) No. at risk T+OFS 66 62 58 48 41 40 27 T+OFS 576 558 526 440 372 350 252 E+OFS 79 73 66 55 44 41 31 E+OFS 571 541 529 453 394 375 272 © 2017 by American Society of Clinical Oncology 3117 Saha et al baseline QoL assessment occurred before adjuvant chemotherapy. In SOFT, the baseline QoL assessment occurred after chemotherapy (median, 3.5 months from last dose of chemotherapy); approximately 40% had also received tamoxifen before enrollment. Women enrolled in the prior-chemotherapy SOFT cohort generally had worse baseline QoL symptoms but reported better coping than those enrolled in TEXT (Table 2). Other global indicators were similar between these cohorts. This is expected, because patients in SOFT had already received chemotherapy (and possibly tamoxifen). For patients in SOFT with prior chemotherapy, only a few baseline symptom-specific QoL indicators differed by $ 8 points between women younger and older than 35 years (hot flushes [mean difference, 10; 95% CI, 6 to 14], sweats [mean difference, 10; 95% CI, 6 to 13], bone or joint pain [mean difference, 9; 95% CI, 5 to 12]), with women younger than 35 years being less affected for all. The greatest difference in baseline global QoL indicators between women younger and older than 35 years in the SOFT prior-chemotherapy cohort was only 5 points (95% CI, 2 to 8 points) for coping effort, and the women younger than 35 years were more affected. Because of the baseline QoL differences between patients in SOFTand TEXT, and to isolate the added toxicity of OFS combined with oral endocrine therapy from that of chemotherapy, we have focused on the 291 women younger than age 35 years who had received chemotherapy before enrollment in SOFT (Fig 3). The most prominent change in symptom-specific QoL in the women younger than age 35 years in SOFT who had prior chemotherapy was an increase in symptoms seen between baseline and the 6-month time point; in general, symptoms improved over time thereafter. Vasomotor symptoms (hot flushes, sweats) showed the greatest worsening from baseline to 6 months (on the order of 30to 40-point change with OFS). Thereafter, vasomotor symptoms improved in women younger than 35 years receiving OFS but without reaching baseline, whereas scores worsened over time in patients younger than 35 years receiving tamoxifen alone. Changes in gynecologic symptoms were smaller than for vasomotor symptoms but were clinically meaningful for loss of sexual interest and difficulties in becoming aroused among patients younger than 35 years assigned to OFS and also for vaginal dryness among those receiving exemestane plus OFS; loss of sexual interest and vaginal dryness showed little improvement over time. Women treated with exemestane plus OFS noted increase in bone/joint pain at the 6-month time point that stabilized thereafter. Women younger than 35 years old treated with tamoxifen alone or tamoxifen plus OFS were also found to have an increase in bone/joint pain over time, which was slower in onset but reached a level similar to that of the exemestane plus OFS group by 24 months. Changes in global QoL indicators Table 2. Quality-of-Life Symptom and Global Indicator Scores at Baseline According to Cohort and Age at Random Assignment Cohort and Age at Random Assignment Chemotherapy TEXT Indicator No. of patients† Symptom indicators Vasomotor Hot flushes Sweats (including night sweats) Gynecologic or sexual Vaginal discharge Vaginal dryness Vaginal itching/irritation Loss of sexual interest‡ Difficulty in becoming aroused Musculoskeletal or neurologic pain Bone or joint pain Headaches Constitutional or psychological Sleep disturbance Tiredness Troubled by weight gain Being irritable Global indicators Physical well-being Mood Coping effort Treatment burden Health perception Prior Chemotherapy SOFT , 35 Years $ 35 Years Mean Score 6 SD Mean Score 6 SD 170 1,230 91 6 19 86 6 22 92 6 17 88 6 19 20 (23 to 3) 22 (26 to 1) 85 93 91 81 87 90 94 93 78 84 26 21 23 3 3 6 6 6 6 6 21 15 16 25 19 6 6 6 6 6 16 12 14 27 20 Mean Difference* (95% CI) (28 (23 (25 (22 (21 to to to to to 23) 1) 20) 7) 6) , 35 Years $ 35 Years Mean Score 6 SD Mean Score 6 SD 291 1,316 80 6 27 83 6 23 69 6 32 73 6 29 10 (6 to 14) 10 (6 to 13) 76 81 87 73 74 80 80 86 66 72 24 1 1 7 2 6 6 6 6 6 25 25 21 29 27 6 6 6 6 6 23 26 22 31 27 Mean Difference* (95% CI) (27 to 21) (23 to 4) (22 to 4) (3 to 11) (22 to 6) 89 6 15 82 6 23 88 6 20 85 6 21 2 (22 to 5) 23 (26 to 0) 83 6 24 82 6 23 74 6 28 82 6 23 9 (5 to 12) 21 (24 to 2) 76 64 90 73 6 6 6 6 25 27 17 23 71 65 88 74 6 6 6 6 27 26 20 24 5 21 1 21 (1 to 9) (25 to 3) (22 to 5) (25 to 3) 72 56 72 70 6 6 6 6 29 28 32 25 66 56 69 73 6 6 6 6 29 26 31 24 6 0 3 23 (2 to 10) (23 to 4) (21 to 7) (26 to 0) 78 69 58 74 70 6 6 6 6 6 20 24 28 25 21 77 70 60 76 70 6 6 6 6 6 22 24 28 24 22 0 21 22 22 20 (23 (25 (26 (26 (24 78 74 65 71 72 6 6 6 6 6 22 22 27 25 21 77 75 70 72 73 6 6 6 6 6 21 22 25 24 21 1 21 25 22 21 (22 (24 (28 (25 (24 to to to to to 4) 3) 3) 2) 3) to to to to to 4) 2) 22) 2) 2) NOTE. Quality-of-life scores for all indicators range from 0 to 100, with higher scores indicating a better state. Abbreviations: SD, standard deviation; SOFT, Suppression of Ovarian Function Trial; TEXT, Tamoxifen and Exemestane Trial. *Because of rounding, the mean difference between age groups may be different from the differences between the mean scores. †The quality-of-life population was 87% of the intention-to-treat populations. The number of patients who answered each question differs slightly from the overall number of patients in the respective group. ‡Loss of sexual interest was to be answered only by patients who reported that they had been sexually active in the past 6 months (n = 127, 941, 229, 812 in the four groups, respectively). 3118 © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Women Younger Than 35 Years in TEXT and SOFT Tamoxifen SYMPTOM INDICATOR 6 months Tamoxifen plus OFS Exemestane plus OFS 24 months 60 months Vasomotor Hot flushes Sweats (including night sweats) Gynecological/sexual Vaginal discharge Vaginal dryness Vaginal itching/irritation Loss of sexual interest Difficulties in becoming aroused Musculoskeletal/neurology pain Bone or joint pain Headaches Constitutional/psychological Sleep disturbance Tiredness Troubled by weight gain Being irritable GLOBAL INDICATOR Physical well-being Mood Coping effort Treatment burden Health perception –60 –50 –40 30 –20 Worsening –8 0 8 20 –60 –50 –40 30 –20 Improving Worsening –8 0 8 20 –60 –50 –40 30 –20 Improving Worsening –8 0 8 20 Improving Fig 3. Change in quality-of-life symptom and global indicator scores from baseline (mean with 95% CI), for 291 patients in the Suppression of Ovarian Function Trial who were younger than 35 years at random assignment and had received prior chemotherapy. Plus or minus 8 is the minimal clinical meaningful change of quality-of-life scores, indicated by dashed vertical lines. OFS, ovarian function suppression. (physical well-being, mood, coping effort, and health perception) were minimal and similar among treatment groups. Treatment burden was greater than baseline at the 6-month time point in women younger than 35 years treated with exemestane plus OFS but improved over time to baseline levels in all treatment groups. These data are similar to those previously published for all age groups combined.11,12 The only clinically meaningful difference (defined as $ 8-point difference) between the younger than 35 years and $ 35 years age groups when adjusted for assigned endocrine therapy was a greater worsening in sweats for women younger than 35 years (eg, 28; 95% CI, 212 to 23 at 6 months), with similar trend in hot flushes (data shown only for younger than 35 years old). This should be viewed in the context of the worse hot flushes and sweats present at baseline for participants in SOFT $ 35 years of age than those younger than 35 years (Table 2). In both SOFTand TEXT cohorts treated with chemotherapy, the changes in global QoL indicators were similar for the younger than 35 years and the $ 35 years age groups. Nonadherence to Protocol-Assigned Endocrine Therapy All women enrolled in SOFT and TEXT, regardless of chemotherapy use and HER2 status, were included in the adherence jco.org analysis. Adherence was defined as continuing assigned endocrine therapy for 5 years or until DFS event; women who were switched to an alternate endocrine therapy were considered nonadherent. Women who initially achieved OFS with a GnRH agonist but subsequently decided on a permanent method of ovarian ablation, such as surgery, were considered adherent; whether a woman received every triptorelin dose on the 28-day (63 days) schedule per protocol was not taken into account. Of the women younger than 35 years enrolled in SOFT and TEXT, 19.8% (115 of 582) stopped all protocol-assigned therapy early (19.2% continued receiving protocol-assigned therapy at time of analysis). Nonadherence with assigned oral endocrine therapy was higher in women younger than 35 years (P = .01) than in women $ 35 years. The cumulative incidence of nonadherence with oral endocrine therapy in women younger than 35 years at 1 year was 11%, increasing to approximately 17%, 23%, and 25% at 2, 3, and 4 years after random assignment (Fig 4). For those $ 35 years old, it was 9%, 14%, 18%, and 21%, respectively. Of 470 women younger than 35 years assigned to OFS, six never started OFS, 45 (9.6%) chose oophorectomy after receiving some GnRH agonist, and five had oophorectomy as the only means of OFS. Nonadherence with © 2017 by American Society of Clinical Oncology 3119 Saha et al medical OFS, which required monthly injections for 5 years, was significantly higher among patients younger than 35 years (P = .009). The cumulative incidence of nonadherence to medical OFS in women younger than 35 years at 1 year was 10%, increasing to approximately 15%, 20%, and 23% at 2, 3, and 4 years after random assignment (Fig 4); for the $ 35 years age group it was 8%, 12%, 15%, and 17%, respectively. More women older than 35 years opted for permanent OFS via surgery or radiotherapy. DISCUSSION Women younger than 35 years in SOFT and TEXT had worse outcomes overall than older premenopausal women, with 5-year BCFI of only 79% for those younger than 35 years with HER2-negative disease.8 It may be that recurrence rates will increase by 10 years of follow-up. For women in SOFT with HER2-negative disease who received chemotherapy, outcomes at 5 years were substantially improved by the use of OFS, increasing to a BCFI of 81.6% with the use of exemestane plus OFS from 67.1% for the use of tamoxifen alone. As noted in other studies,1 there was a higher incidence of HER2 positivity in women younger than 35 years, and the HER2-positive subgroups of SOFT and TEXT will be explored in future analyses. The number of women younger than 35 years who did not receive adjuvant chemotherapy was small, and the majority of them received OFS. Only six women younger than 35 years were treated with tamoxifen and no chemotherapy in SOFT. Although most guidelines would not suggest the use of OFS in women younger than 35 years with low-risk tumor characteristics, the 5- to 6-year median follow-up is too short for definite conclusions about the value of OFS in this lower-risk group; 50% of recurrences in HR-positive tumors will occur after 5 years.8,17 A limitation of our study is that genomic testing, which is now widely used to identify women of low risk, was not used in this study. Benefit from the addition of OFS must be weighed against toxicity. The primary QoL analyses for patients enrolled in TEXT and SOFT have been previously published.11,12 We had hypothesized that women younger than 35 years might report more severe endocrine symptoms than their older premenopausal B Age < 35 years Age ≥ 35 years 80 60 40 20 0 1 2 3 4 Time Since Randomization (years) C 100 100 Age < 35 years Use of Permanent Ovarian Ablation (%) 100 Cessation of Medical OFS, GnRH Agonist (%) Cessation of Protocol-Assigned Oral Endocrine Therapy (%) A counterparts, but that did not seem to be the case. However, all age groups suffered bothersome symptoms. Symptoms overall improved after the 6-month time point, with the exception of bone and joint pain in the tamoxifen-treated groups and vaginal dryness and loss of sexual interest in the OFS groups. Some symptom indicators remained at a level indicating substantial treatment burden necessitating persistent attention to symptom alleviation and supportive care. No data are yet available on patient-reported symptoms at . 5 years from enrollment, when protocol-assigned treatment would have stopped, and future analyses will address the reversibility of treatment-induced menopausal symptoms. Future analyses could also consider protocol-assigned and nonprotocol endocrine therapy actually received to assess whether some of the improvement in symptoms over time resulted from cessation of therapy by patients reporting the worst symptoms. Women younger than 35 years in SOFT and TEXT had a higher rate of nonadherence than those $ 35 years of age. Several observational studies have reported that younger age is associated with lower rates of treatment compliance with endocrine therapy, possibly suggesting the level of toxicity (eg, sexual toxicity) is less acceptable to women younger than 35 years.18-20 In a large medical and pharmacy insurance claims database, Neugut et al21 found that patients with breast cancer who were younger than 45 years had an odds ratio of 2.0 of nonadherence to oral endocrine therapy compared with women 55 to 64 years of age. The need to come to a physician’s office for injectable hormone therapy might further increase the difficulties of endocrine therapy for women younger than 35 years who have competing responsibilities, such as career and childcare.22 Finally, a desire for pregnancy may also be relevant; only 10% of women younger than 35 years of age opted for oophorectomy. The POSITIVE (Pregnancy Outcome and Safety of Interrupting Therapy for women with endocrine responsive breast cancer) trial (ClinicalTrials.gov identifier: NCT02308085) is currently enrolling young women who wish to interrupt endocrine therapy to become pregnant. In summary, in two international randomized trials of endocrine therapy among premenopausal women with HR-positive early breast cancer, women younger than 35 years had higherrisk disease characteristics than their older premenopausal counterparts and were also at increased risk for recurrence Age ≥ 35 years 80 60 40 20 0 1 2 3 4 Time Since Randomization (years) Age < 35 years Age ≥ 35 years 80 60 40 20 0 1 2 3 4 Time Since Randomization (years) Fig 4. Adherence with protocol-assigned endocrine therapy according to age at random assignment. (A) Cumulative incidence of cessation of assigned oral endocrine therapy (exemestane or tamoxifen). (B) Cumulative incidence of cessation of medical ovarian function suppression (OFS) by gonadotropin-releasing hormone (GnRH) agonist; patients switching to permanent OFS are not considered as having ceased medical OFS. (C) Cumulative incidence of permanent ovarian ablation by bilateral oophorectomy or ovarian irradiation. 3120 © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Women Younger Than 35 Years in TEXT and SOFT independent of assessed baseline tumor characteristics and treatment. There was a meaningful clinical benefit in breast cancer outcomes with the addition of OFS to tamoxifen and some additional benefit from use of an aromatase inhibitor with OFS. Longer follow-up is critical to clarify potential survival benefits. There were substantial adverse effects from these combined endocrine treatments, but they were not different in the younger and older than 35 years populations. Despite this, rates of nonadherence were slightly higher in women younger than 35 years. Availability of these age-specific data regarding risks and benefits of combined endocrine therapy will support shared decision making regarding OFS among young women at high risk for recurrence and death from breast cancer and, it is hoped, improve adherence among those who select OFS. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Disclosures provided by the authors are available with this article at jco.org. REFERENCES 1. Azim HA Jr, Partridge AH: Biology of breast cancer in young women. Breast Cancer Res 16:427, 2014 2. Chung M, Chang HR, Bland KI, et al: Younger women with breast carcinoma have a poorer prognosis than older women. Cancer 77:97-103, 1996 3. Gnerlich JL, Deshpande AD, Jeffe DB, et al: Elevated breast cancer mortality in women younger than age 40 years compared with older women is attributed to poorer survival in early-stage disease. J Am Coll Surg 208:341-347, 2009 4. Aebi S, Castiglione M: The enigma of young age. Ann Oncol 17:1475-1477, 2006 5. Colleoni M, Rotmensz N, Robertson C, et al: Very young women (,35 years) with operable breast cancer: features of disease at presentation. Ann Oncol 13:273-279, 2002 6. Goldhirsch A, Gelber RD, Yothers G, et al: Adjuvant therapy for very young women with breast cancer: need for tailored treatments. J Natl Cancer Inst Monogr 30:44-51, 2001 7. Davidson NE, O’Neill AM, Vukov AM, et al: Chemoendocrine therapy for premenopausal women with axillary lymph node-positive, steroid hormone receptor-positive breast cancer: Results from INT 0101 (E5188). J Clin Oncol 23:5973-5982, 2005 8. Sheridan W, Scott T, Caroline S, et al: Breast cancer in young women: Have the prognostic implications of breast cancer subtypes changed over time? Breast Cancer Res Treat 147:617-629, 2014 AUTHOR CONTRIBUTIONS Conception and design: Poornima Saha, Meredith M. Regan, Olivia Pagani, Prudence A. Francis, Barbara A. Walley, Aron Goldhirsch, Gini F. Fleming Provision of study materials or patients: Poornima Saha, Olivia Pagani, Prudence A. Francis, Barbara A. Walley, Karin Ribi, Jürg Bernhard, Henry L. Gómez, Harold J. Burstein, Vani Parmar, Roberto Torres, Josephine Stewart, Meritxell Bellet, Antonia Perelló, Faysal Dane, Antonio Moreira, Daniel Vorobiof, Michelle Nottage, Alan S. Coates, Richard D. Gelber, Marco Colleoni, Gini F. Fleming Collection and assembly of data: Meredith M. Regan, Olivia Pagani, Prudence A. Francis, Barbara A. Walley, Karin Ribi, Jürg Bernhard, Weixiu Luo, Henry L. Gómez, Harold J. Burstein, Vani Parmar, Roberto Torres, Josephine Stewart, Meritxell Bellet, Antonia Perelló, Faysal Dane, Antonio Moreira, Daniel Vorobiof, Michelle Nottage, Karen N. Price, Aron Goldhirsch, Marco Colleoni, Gini F. Fleming Data analysis and interpretation: Poornima Saha, Meredith M. Regan, Prudence A. Francis, Karin Ribi, Jürg Bernhard, Weixiu Luo, Karen N. Price, Alan S. Coates, Aron Goldhirsch, Richard D. Gelber, Gini F. Fleming Manuscript writing: All authors Final approval of manuscript: All authors Accountable for all aspects of the work: All authors 9. Partridge AH, Hughes ME, Warner ET, et al: Subtype-dependent relationship between young age at diagnosis and breast cancer survival. J Clin Oncol 34:3308-3314, 2016 10. Regan MM, Francis PA, Pagani O, et al: Absolute benefit of adjuvant endocrine therapies for premenopausal women with hormone receptorpositive, human epidermal growth factor receptor 2-negative early breast cancer: TEXT and SOFT trials. J Clin Oncol 34:2221-2231, 2016 11. Ribi K, Luo W, Bernhard J, et al: Adjuvant tamoxifen plus ovarian function suppression versus tamoxifen alone in premenopausal women with early breast cancer: Patient-reported outcomes in the suppression of ovarian function trial. J Clin Oncol 34: 1601-1610, 2016 12. Bernhard J, Luo W, Ribi K, et al: Patientreported outcomes with adjuvant exemestane versus tamoxifen in premenopausal women with early breast cancer undergoing ovarian suppression (TEXT and SOFT): A combined analysis of two phase 3 randomised trials. Lancet Oncol 16:848-858, 2015 13. Regan MM, Pagani O, Fleming GF, et al: Adjuvant treatment of premenopausal women with endocrine-responsive early breast cancer: Design of the TEXT and SOFT trials. Breast 22:1094-1100, 2013 14. Pagani O, Regan MM, Walley BA, et al: Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med 371: 107-118, 2014 15. Francis PA, Regan MM, Fleming GF, et al: Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med 372:436-446, 2015 16. Regan MM, Pagani O, Francis PA, et al: Predictive value and clinical utility of centrally assessed ER, PgR, and Ki-67 to select adjuvant endocrine therapy for premenopausal women with hormone receptor-positive, HER2-negative early breast cancer: TEXT and SOFT trials. Breast Cancer Res Treat 154:275-286, 2015 17. Colleoni M, Sun Z, Price KN, et al: Annual hazard rates of recurrence for breast cancer during 24 years of follow-up: Results from the International Breast Cancer Study Group trials I to V. J Clin Oncol 34:927-935, 2016 18. Hershman DL, Kushi LH, Shao T, et al: Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol 28:4120-4128, 2010 19. Partridge AH, Wang PS, Winer EP, et al: Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol 21: 602-606, 2003 20. Huiart L, Ferdynus C, Giorgi R: A metaregression analysis of the available data on adherence to adjuvant hormonal therapy in breast cancer: Summarizing the data for clinicians. Breast Cancer Res Treat 138:325-328, 2013 21. Neugut AI, Zhong X, Wright JD, et al: Nonadherence to medications for chronic conditions and nonadherence to adjuvant hormonal therapy in women with breast cancer. JAMA Oncol 2:1326-1332, 2016 22. Smits-Seemann RR, Kaul S, Zamora ER, et al: Barriers to follow-up care among survivors of adolescent and young adult cancer. J Cancer Surviv 11: 126-132, 2017 Affiliations Poornima Saha and Gini F. Fleming, The University of Chicago Medical Center, Chicago, IL; Meredith M. Regan, Weixiu Luo, Harold J. Burstein, and Richard D. Gelber, Dana-Farber Cancer Institute; Meredith M. Regan, Harold J. Burstein, and Richard D. Gelber, Harvard Medical School; Karen N. Price and Richard D. Gelber, Frontier Science and Technology Research Foundation; Richard D. Gelber, Harvard T.H. Chan School of Public Health, Boston, MA; Olivia Pagani, Institute of Oncology of Southern Switzerland, Lugano Viganello; Karin Ribi and Jürg Bernhard, International Breast Cancer Study Group Coordinating Center; Jürg Bernhard, Bern University Hospital, Inselspital, Bern, Switzerland; Prudence A. Francis, Peter MacCallum Cancer Center; St Vincent’s Hospital; University of Melbourne, Melbourne; Josephine Stewart, Austin and Heidelberg Repatriation Medical Center, Heidelberg, Victoria; Prudence A. jco.org © 2017 by American Society of Clinical Oncology 3121 Saha et al Francis, Josephine Stewart, and Michelle Nottage, University of Newcastle, Newcastle; Alan S. Coates, University of Sydney, Sydney, New South Wales; Michelle Nottage, Royal Brisbane Hospital, Brisbane, Queensland, Australia; Barbara A. Walley, University of Calgary; National Cancer Institute of Canada, Calgary, Alberta, Canada; Henry L. Gómez, Instituto Nacional de Enfermedades Neoplásicas, Lima, Peru; Vani Parmar, Tata Memorial Centre, Mumbai, India; Roberto Torres, Instituto Nacional del Cancer, Santiago de Chile, Chile; Meritxell Bellet, Vall d’Hebron Institute of Oncology; Vall d’Hebron University Hospital; Universitat Autònoma de Barcelona, Barcelona; Antonia Perelló, Hospital Universitari Son Espases, Palma de Mallorca, Spain; Faysal Dane, Marmara University Hospital, Istanbul, Turkey; Antonio Moreira, Instituto Português de Oncologia Francisco Gentil - Centro de Lisboa, Lisbon, Portugal; Daniel Vorobiof, Sandton Oncology Centre, Johannesburg, South Africa; and Aron Goldhirsch and Marco Colleoni, European Institute of Oncology, Milan, Italy. nnn 3122 © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Women Younger Than 35 Years in TEXT and SOFT AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Treatment Efficacy, Adherence, and Quality of Life Among Women Younger Than 35 Years in the International Breast Cancer Study Group TEXT and SOFT Adjuvant Endocrine Therapy Trials The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO’s conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/site/ifc. Poornima Saha No relationship to disclose Meritxell Bellet No relationship to disclose Meredith M. Regan Consulting or Advisory Role: Merck, Ipsen (Inst) Research Funding: Veridex (Inst), OncoGeneX (Inst), Pfizer (Inst), Ipsen (Inst), Novartis (Inst), Merck (Inst), Ferring Pharmaceuticals (Inst), Celgene (Inst), AstraZeneca (Inst), Pierre Fabre (Inst) Antonia Perelló No relationship to disclose Olivia Pagani Consulting or Advisory Role: Roche Pharma AG, Pfizer, Celgene Research Funding: Roche (Inst), MSD Oncology (Inst), Bayer AG (Inst), Novartis (Inst) Antonio Moreira Consulting or Advisory Role: Roche Travel, Accommodations, Expenses: Roche Prudence A. Francis Honoraria: AstraZeneca Travel, Accommodations, Expenses: Pfizer Barbara A. Walley No relationship to disclose Karin Ribi No relationship to disclose Jürg Bernhard No relationship to disclose Weixiu Luo No relationship to disclose Henry L. Gómez No relationship to disclose Harold J. Burstein No relationship to disclose Vani Parmar No relationship to disclose Roberto Torres No relationship to disclose Josephine Stewart No relationship to disclose jco.org Faysal Dane Honoraria: Roche, Pfizer, Novartis Daniel Vorobiof Consulting or Advisory Role: Bristol-Myers Squibb, MSD Oncology Speakers’ Bureau: MSD Oncology, Bristol-Myers Squibb Travel, Accommodations, Expenses: Bristol-Myers Squibb, Pfizer Michelle Nottage Consulting or Advisory Role: Roche Australia, Amgen Australia Travel, Accommodations, Expenses: Amgen Australia Karen N. Price No relationship to disclose Alan S. Coates No relationship to disclose Aron Goldhirsch No relationship to disclose Richard D. Gelber Research Funding: AstraZeneca (Inst), GlaxoSmithKline (Inst), Novartis (Inst), Roche (Inst), Celgene (Inst), Merck (Inst), Pfizer (Inst), Ipsen (Inst), Ferring Pharmaceuticals (Inst) Marco Colleoni Honoraria: Novartis Consulting or Advisory Role: AstraZeneca, Pierre Fabre, Pfizer, Celldex Therapeutics, OBI Pharma, Puma Biotechnology Gini F. Fleming Research Funding: Corcept Therapeutics (Inst) Other Relationship: Aeterna Zentaris © 2017 by American Society of Clinical Oncology Saha et al Acknowledgment TEXT and SOFT received financial support for trial conduct from Pfizer, the International Breast Cancer Study Group (IBCSG), and the US National Cancer Institute (NCI). Pfizer and Ipsen provided drug supply. The pharmaceutical companies have no role in the reporting or interpretation of the trials, other than a minority representation on the Steering Committee. Support for the coordinating group, IBCSG: Frontier Science and Technology Research Foundation, Swiss Group for Clinical Cancer Research, Cancer Research Switzerland/Oncosuisse, the Foundation for Clinical Cancer Research of Eastern Switzerland, and the US NCI Grant No. CA75362. Grant support of cooperative groups: Australia and New Zealand Breast Cancer Trials Group supported by National Health and Medical Research Council Grants No. 351161, 510788, and 1105058; Southwest Oncology Group supported by National Institutes of Health (NIH) Grant No. CA32102; Alliance for Clinical Trials in Oncology supported by NIH Grant No. CA180821; Eastern Cooperative Oncology Group–American College of Radiology Imaging Network supported by NIH Grants No. CA21115 and CA16116; National Surgical Adjuvant Breast and Bowel Project/NRG Oncology supported by NIH Grants No. U10-CA-12027, U10-CA-69651, U10-CA37377, and U10-CA-69974; National Cancer Institute of Canada Clinical Trials Group supported by NIH Grant No. CA077202 and Canadian Cancer Society Research Institute Grants No. 015469 and 021039; Institute of Cancer Research Clinical Trials and Statistics Unit on behalf of the National Cancer Research Institute Breast Clinical Studies Group United Kingdom supported by Cancer Research UK Grants No. CRUKE/03/022, CRUKE/03/023, and A15955; National Institute for Health Research Royal Marsden/Institute of Cancer Research Biomedical Research Centre; and National Institute for Health Research Cambridge Biomedical Research Centre. We thank the patients, physicians, nurses, and trial coordinators who participated in the TEXTand SOFT clinical trials. The trials were coordinated by the IBCSG, in collaboration with Breast International Group, Breast International Group Cooperative Groups, and US NCI–supported cooperative groups. Appendix Supplemental Results Among 442 women younger than 35 years with human epidermal growth factor receptor 2–negative disease, 111 had luminal A-like tumors, 221 had luminal B-like tumors, and 110 could not be classified because centrally assessed Ki-67 values were not available. Luminal A-like tumors were defined by progesterone receptor $ 20% and Ki-67 , 20%; luminal B-like tumors were defined by either progesterone receptor , 20% or Ki-67 $ 20% (or both). The 5-year breast cancer–free interval of women younger than 35 years assigned to ovarian function suppression was 83.6% in those who had luminal A-like tumors (v 96.2% for $ 35 years) and 79.2% in luminal B-like tumors (v 86.4% for $ 35 years). © 2017 by American Society of Clinical Oncology JOURNAL OF CLINICAL ONCOLOGY Women Younger Than 35 Years in TEXT and SOFT A B SOFT prior chemotherapy cohort age < 35 years SOFT prior chemotherapy cohort age ≥ 35 years 100 Free From Distant Recurrence (%) Free From Distant Recurrence (%) 100 80 60 40 Prior chemotherapy T Prior chemotherapy T+OFS 20 Prior chemotherapy E+OFS 1 0 2 3 4 5 80 60 40 Prior chemotherapy T Prior chemotherapy T+OFS 20 Prior chemotherapy E+OFS 6 1 0 Time Since Random Assignment (years) 2 3 4 5 6 Time Since Random Assignment (years) No. at risk No. at risk T 79 70 60 58 47 37 23 T 363 337 320 301 256 192 112 T+OFS 77 71 66 63 52 40 21 T+OFS 356 342 321 300 249 186 115 E+OFS 84 78 75 69 59 41 29 E+OFS 337 324 309 292 247 168 104 C D TEXT chemotherapy cohort age ≥ 35 years TEXT chemotherapy cohort age < 35 years 100 Free From Distant Recurrence (%) Free From Distant Recurrence (%) 100 80 60 40 20 Chemotherapy T+OFS Chemotherapy E+OFS 0 1 2 3 4 5 80 60 40 20 Chemotherapy E+OFS No. at risk 1 0 6 Time Since Random Assignment (years) Chemotherapy T+OFS 2 3 4 5 6 Time Since Random Assignment (years) No. at risk T+OFS 66 62 58 49 42 41 27 T+OFS 576 559 528 447 379 359 260 E+OFS 79 73 67 56 45 41 32 E+OFS 571 542 531 455 394 376 276 Fig A1. Kaplan-Meier estimates of distant recurrence-free interval among patients with human epidermal growth factor receptor 2–negative disease in the chemotherapy cohorts of the Suppression of Ovarian Function Trial (SOFT) and Tamoxifen and Exemestane Trial (TEXT), according to age at random assignment and treatment assignment. Median follow-up was 5.6 years in SOFT and 6.0 years in TEXT. (A, B) SOFT prior chemotherapy, age younger than 35 years and $ 35 years. (C, D) TEXT chemotherapy, age younger than 35 years and $ 35 years. E, exemestane; OFS, ovarian function suppression; T, tamoxifen. jco.org © 2017 by American Society of Clinical Oncology