Adjuvant Endocrine Therapy in Premenopausal Breast Cancer: 12-Year Results From SOFT.

Adjuvant ovarian function suppression (OFS) with oral endocrine therapy improves outcomes for premenopausal patients with hormone receptor-positive (HR+) breast cancer but adds adverse effects. A genomic biomarker for selecting patients most likely to benefit from OFS-based treatment is lacking. To assess the predictive and prognostic performance of the Breast Cancer Index (BCI) for OFS benefit in premenopausal women with HR+ breast cancer. This prospective-retrospective translational study used all available tumor tissue samples from female patients from the Suppression of Ovarian Function Trial (SOFT). These individuals were randomized to receive 5 years of adjuvant tamoxifen alone, tamoxifen plus OFS, or exemestane plus OFS. BCI testing was performed blinded to clinical data and outcome. The a priori hypothesis was that BCI HOXB13/IL17BR ratio (BCI[H/I])-high tumors would benefit more from OFS and high BCI portended poorer prognosis in this population. Settings spanned multiple centers internationally. Participants included premenopausal female patients with HR+ early breast cancer with specimens in the International Breast Cancer Study Group tumor repository available for RNA extraction. Data were collected from December 2003 to April 2021 and were analyzed from May 2022 to October 2022. Primary end points were breast cancer-free interval (BCFI) for the predictive analysis and distant recurrence-free interval (DRFI) for the prognostic analyses. Tumor specimens were available for 1718 of the 3047 female patients in the SOFT intention-to-treat population. The 1687 patients (98.2%) who had specimens that yielded sufficient RNA for BCI testing represented the parent trial population. The median (IQR) follow-up time was 12 (10.5-13.4) years, and 512 patients (30.3%) were younger than 40 years. Tumors were BCI(H/I)-low for 972 patients (57.6%) and BCI(H/I)-high for 715 patients (42.4%). Patients with tumors classified as BCI(H/I)-low exhibited a 12-year absolute benefit in BCFI of 11.6% from exemestane plus OFS (hazard ratio [HR], 0.48 [95% CI, 0.33-0.71]) and an absolute benefit of 7.3% from tamoxifen plus OFS (HR, 0.69 [95% CI, 0.48-0.97]) relative to tamoxifen alone. In contrast, patients with BCI(H/I)-high tumors did not benefit from either exemestane plus OFS (absolute benefit, -0.4%; HR, 1.03 [95% CI, 0.70-1.53]; P for interaction = .006) or tamoxifen plus OFS (absolute benefit, -1.2%; HR, 1.05 [95% CI, 0.72-1.54]; P for interaction = .11) compared with tamoxifen alone. BCI continuous index was significantly prognostic in the N0 subgroup for DRFI (n = 1110; P = .004), with 12-year DRFI of 95.9%, 90.8%, and 86.3% in BCI low-risk, intermediate-risk, and high-risk N0 cancers, respectively. In this prospective-retrospective translational study of patients enrolled in SOFT, BCI was confirmed as prognostic in premenopausal women with HR+ breast cancer. The benefit from OFS-containing adjuvant endocrine therapy was greater for patients with BCI(H/I)-low tumors than BCI(H/I)-high tumors. BCI(H/I)-low status may identify premenopausal patients who are likely to benefit from this more intensive endocrine therapy.

The quest to define optimal endocrine therapy for premenopausal women with early-stage breast cancer began more than 50 years ago but is still unfulfilled. Multiple strategies have emerged, including tamoxifen, ovarian function suppression (OFS) by surgery, luteinizing hormone–releasing hormone agonist or radiation, and combination strategies such as tamoxifen plus OFS or aromatase inhibitor plus OFS. An added confounder is that these strategies have frequently been assessed in the context of adjuvant chemotherapy, which is commonly used in premenopausal women and may have indirect endocrine effects because of chemotherapy-induced menopause. This complex landscape was reviewed in a 2011 American Society of Clinical Oncology (ASCO) endorsement of the 2010 Cancer Care Ontario guideline recommending against the routine use of OFS in addition to tamoxifen or chemotherapy and a 2014 ASCO guideline endorsing consideration of 10 years of tamoxifen for these young women with hormone-responsive disease. Against this backdrop, in the article that accompanies this editorial, Tevaarwerk et al report the final results of a phase III Eastern Cooperative Oncology Group trial (E-3193, INT-0142) in which 345 premenopausal women with lymph node–negative, hormone receptor–positive breast cancer measuring 3 cm were randomly assigned from 1994-1997 to receive 5 years of tamoxifen alone or 5 years of tamoxifen plus OFS; no chemotherapy was permitted. With a median follow-up of almost 10 years, there were no significant differences in the primary end points of disease-free survival (DFS; 87.9% v 89.7% P .62) or overall survival (95.2% v 97.6%; P .67). Secondary end points included toxicity and several patient-reported outcomes (PROs) including menopausal symptoms, sexual function, and health-related quality of life. These results suggest that tamoxifen plus OFS leads to increased toxicity, more menopausal symptoms, and reduced sexual function, peaking around year 3 and then diminishing over time. The strengths of this study include the importance of the question, the clean design that enabled the testing of hormone therapies in the absence of chemotherapy, the focus on hormone-responsive tumors, the balance between the arms, the long follow-up, and the assessment of PROs. The major limitation is, of course, that the study’s early closure as a result of poor accrual left it vastly underpowered for its primary end points; this trial fell victim to the 1997 report of National Surgical Adjuvant Breast and Bowel Project (NSABP) B20, which recommended the use of chemotherapy in addition to tamoxifen for women with axillary lymph node–negative, hormoneresponsive breast cancer, especially women younger than 50 years of age. However, E-3193 was a success in its collection of detailed PROs, and it is noteworthy that it met the prespecified target accrual for these secondary end points. Given the exceptional outcomes for patients enrolled onto this trial, which had greater than 95% overall survival in the absence of chemotherapy, such patient-reported data are valuable contributions to the discussion between physicians and patients about the risks and benefits of individual therapies. Several crucial questions remain. Given the statistical limitations of this trial, might the combination of OFS plus tamoxifen actually be better than tamoxifen? What about the combination of OFS plus an aromatase inhibitor, given the efficacy of aromatase inhibitors in postmenopausal hormone receptor–positive breast cancer? Three large trials are helping to address these two questions: ABCSG-12 (Austrian Breast and Colorectal Cancer Study Group trial 12), SOFT (Suppression of Ovarian Function Trial), and TEXT (Tamoxifen and Exemestane Trial). A lingering concern is how we can integrate the results of all of these trials that use 3 to 5 years of adjuvant endocrine therapy with the findings of the ATLAS (Adjuvant Tamoxifen: Longer Against Shorter) and aTTom (Adjuvant Tamoxifen—To Offer More?) trials, which support the use of 10 years of tamoxifen. In the SOFT trial, 3,066 premenopausal women with hormoneresponsive breast cancer were randomly assigned to 5 years of tamoxifen, tamoxifen plus OFS, or exemestane plus OFS; (neo)adjuvant chemotherapy was permitted as long as patients remained premenopausal at its completion. In the TEXT trial, 2,672 premenopausal patients with hormone-responsive breast cancer were randomly assigned to receive 5 years of tamoxifen plus OFS or exemestane plus OFS; endocrine therapy was started concurrently with chemotherapy if chemotherapy was planned. Because of lower than expected event rates, the statistical plans for these two trials were revised some years ago to enable a joint analysis of 4,690 women receiving tamoxifen plus OFS versus exemestane plus OFS. In contrast to E-3193, 42% of these women were lymph node positive, and 57% received some type of chemotherapy. At a median follow-up of 68 months, a significantly improved DFS was seen with exemestane plus OFS (91.1% v 87.3%; HR, 0.72; 95% CI, JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 32 NUMBER 35 DECEMBER 1

Tamoxifen (T) is a pro-drug that undergoes CYP2D6-mediated metabolic activation to metabolites that more potently inhibit estrogen stimulated growth compared to the parent drug. While many studies have examined the role of CYP2D6 genotype in T-treated postmenopausal women, the role of CYP2D6 metabolism in premenopausal women (pre-MW) receiving T, with or without ovarian function suppression (OFS) or exemestane (E) and OFS is unknown. Methods: SOFT randomized 3066 (pre-MW) from 2003-2011 in 27 countries, stratified according to prior receipt or nonreceipt of chemotherapy and nodal status, to receive 5 years of T, T+OFS, or E+OFS. We designed a pharmacogenetics substudy (activated October 2010) to collect blood DNA from North American (NA) patients (pts) or to extract non-tumor DNA from available formalin fixed paraffin embedded (FFPE) tissue blocks. For pts with a blood sample, CYP2D6 was genotyped beginning with the Luminex Tag-It Mutation Detection Kit and when needed, with a copy number variation assay and/or sequencing assays. For pts with FFPE-derived DNA, CYP2D6 genotyping for *3, *4, *6, *9, *10, *17 and *41 was performed using a Taqman Allelic Discrimination Assay. CYP2D6 phenotypes were called by classifying pts on the basis of a combination of poor (PM: *3, *4, *5, *6, *7, *8), slow (SM: *10), intermediate (IM: *9, *17, *29, *41) and extensive metabolizer alleles (EM; all others). Activity scores (AS) from phenotypes assigned for each allele: 0 if PM, 0.25 if SM, 0.5 if IM and 1 if EM allele, and multiplied x2 or x3 if duplicate or triplicate. With concomitant use of potent CYP2D6 inhibitor, AS=0; use of weak inhibitor subtracted 0.5. Metabolizer status was defined by CYP2D6 genotype alone or in combination with CYP2D6 inhibitor use at randomization from the AS: extensive (AS 1.25 to 3), intermediate (AS >0.5 to <1.25), slow/poor (AS 0 to 0.5) metabolizer status. The laboratory was blinded to all clinical data. The substudy primary objective was to assess the association between disease-free survival (DFS) and CYP2D6 metabolizer status in the T arm, and secondarily in the T + OFS, and E + OFS arms. A Cox model estimated hazard ratios comparing status according to treatment assignment, with prespecified prognostic factors. Results: 1200/3047 (39%) randomized pts in the intention-to-treat (ITT) population had successful CYP2D6 genotyping and 50% received prior chemotherapy. Following randomization, 435/1023 (42%) NA pts provided a blood sample and CYP2D6 genotypes were derived in 435/435. Non-tumor tissue was macrodissected from 1277 available FFPE blocks, resulting in DNA concentrations of > 0.3 ng/ml in 1053, and successfully derived CYP2D6 genotypes for 765/3047 pts (25%). 182 (15%) pts had DFS events after 8 yrs median follow-up. Metabolizer status from genotype was 57% extensive, 29% intermediate, 15% slow/poor. Metabolizer status was not associated with DFS in pts assigned T alone (P=0.60; Table), nor in pts assigned T+OFS (P=0.41) or E+OFS (P=0.30). 11% of pts used CYP2D6 inhibitors concomitantly at randomization; for 8% it changed the metabolizer status. The results using this definition were consistent. Conclusion: This retrospective-prospective SOFT pharmacogenetics substudy found no relation of CYP2D6 metabolizer status with DFS in premenopausal pts receiving T, T + OFS, or E + OFS. Given that 50% were pretreated with chemotherapy, further study is needed regarding the role of CYP2D6 metabolism in patients treated with T monotherapy. TableTreatment GroupN pts (N events)Comparison (N pts)Hazard Ratio95% CITamoxifen324 (56)Intermediate (114) vs Extensive (210)0.780.43-1.39Tamoxifen265 (52)Slow/Poor (55) vs Extensive (210)1.110.58-2.13Tamoxifen + OFS357 (46)Intermediate (122) vs Extensive (235)0.730.38-1.40Tamoxifen + OFS299 (45)Slow/Poor (64) vs Extensive (235)1.250.64-2.43Exemestane + OFS344 (46)Intermediate (107) vs Extensive (237)0.590.28-1.22Exemestane + OFS293 (47)Slow/Poor (56) vs Extensive (237)1.130.56-2.27 Citation Format: Matthew P. Goetz, Gini F. Fleming, Mary Kuffel, John R. Hawse, John L. Black, Richard Weinshilboum, James N. Ingle, Patrizia dell’Orto, Olivia Biasi, Roswitha Kammler, Sherene Loi, Marco Colleoni, Giuseppe Viale, Prudence A Francis, Meredith M Regan. The role of CYP2D6 mediated tamoxifen metabolism in the suppression of ovarian function trial (SOFT) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD2-09.

507 Background: In young women with hormone receptor-positive (HR+) breast cancer (BC), ovarian function suppression (OFS) has been shown to improve outcomes when combined with adjuvant endocrine therapy (ET). However, limited evidence exists on its efficacy in germline BRCA (gBRCA) carriers. Here we investigated the association between OFS plus ET and outcomes in the largest global cohort of young g BRCA carriers with BC. Methods: The BRCA BCY Collaboration (NCT03673306) is an international, multicenter, hospital-based, retrospective cohort study of women harboring germline BRCA1/2 pathogenic/likely pathogenic variants, diagnosed between 2000 and 2020 with stage I-III invasive BC at age of ≤ 40 years. The analysis included patients with HR+ BC and available data on ET and OFS. The OFS group included patients treated with luteinizing hormone-releasing hormone agonists (LHRHa) and/or bilateral risk-reducing salpingo-oophorectomy (RRSO) within 1 year of BC diagnosis. Outcome analyses included disease-free survival (DFS), BC-free interval (BCFI) and overall survival (OS). Cox proportional hazard models, stratified for country, year of diagnosis, nodal status, and surgery type and adjusted for RRSO and bilateral risk-reducing mastectomy (time-dependent), were used to explore the association between OFS use (vs non-use) and outcomes. Sensitivity analysis explored OFS as time-dependent covariate. To address immortal time bias, an additional Cox model accounted for left truncation, considering differences in time to BRCA testing. Results: Among 5,660 patients from 109 centers, 1,865 patients with HR+ BC were included, of whom 1,071 (57%) received OFS plus ET ( 35% with an aromatase inhibitor [AI], 65% with tamoxifen [tam])and 794 (43%) received tam alone. Patients receiving OFS were more likely to have node-positive disease (56% vs 47%), receive treatment in recent years (36% vs 17%), undergo mastectomy (70% vs 57%) and be tested for g BRCA at diagnosis (46% vs 30%). With a median follow-up of 7.8 years (IQR 4.6-12.1), OFS combined with ET was associated with significantly improved DFS (adjusted HR [aHR] 0.79, 95% CI 0.66-0.94), BCFI (aHR 0.74, 95% CI 0.61-0.89) and OS (aHR 0.66, 95% CI 0.50-0.88) over tam alone. Sensitivity analysis using OFS as a time-dependent factor yielded consistent results. No significant interactions were observed between OFS use and specific g BRCA mutations or HER2 status. Sub-analyses by type of ET (OFS + AI vs. OFS + tam vs. tam alone) will be presented at the conference. Conclusions: In this global cohort of young BRCA mutation carriers, OFS combined with ET was associated with improved DFS, BCFI and OS versus tam without OFS. These findings support the consideration of OFS as a key component of adjuvant therapy in this population.

506 Background: Addition of Ovarian Suppression to Tamoxifen in Young Women With Hormone-Sensitive Breast Cancer Who Remain Premenopausal or Regain Vaginal Bleeding After Chemotherapy (ASTRRA) trial, at 63 months median follow-up, showed that the addition of 2 years of ovarian function suppression (OFS) to Tamoxifen (TAM) significantly improved disease-free survival (DFS) compared with TAM alone in patients with hormone receptor–positive breast cancer who remain in a premenopausal state or resume ovarian function after chemotherapy. We report updated long-term outcomes from ASTRRA trial with 106.4 months median follow-up. Methods: This study is a post-trial follow-up of the ASTRRA trial, which randomly assigned 1,298 patients with breast cancer in a 1:1 ratio to receive TAM only (n = 647) or TAM + OFS (n = 635). The primary endpoint was DFS and secondary endpoint was overall survival (OS). We used Kaplan-Meier estimates for time to event endpoints and hazard ratios (HR) with 95% confidence interval (CI) from Cox-regression model. Results: At 106.4 months of median follow-up, there continues to be a statistically significant reduction in DFS event rate in favor of the TAM+OFS group. The estimated 8-year DFS rate was 85.4% in the TAM + OFS group and 80.2% in the TAM-only group (HR 0.67; 95% CI, 0.51 to 0.87). There were no significant differences in OS between two groups. The estimated 8-year OS rate was 96.5% in the TAM + OFS group and 95.3% in the TAM-only group (HR, 0.78; 95% CI, 0.49 to 1.25). The results of DFS and OS between the two groups defined from the time of random assignment to the time of events were also similar. Conclusions: These data demonstrate consistent survival advantages of adding OFS 2 years to TAM treatment over time, with the long-term follow-up reported to date. This study finding suggest that adding OFS to TAM should be considered for those who remain in a premenopausal state or resume ovarian function after chemotherapy. Longer follow-up is needed to fully evaluate the OS benefit.

Background: The SOFT and TEXT trials have shown substantial survival benefit from adding ovarian function suppression (OFS) with gonadotropin-releasing hormone agonists (GnRHa) to aromatase inhibitors (AI), compared with tamoxifen alone in premenopausal patients with hormone receptor (HR)-positive breast cancer. This benefit was particularly pronounced among women with a higher risk of recurrence, such as younger patients and those who received adjuvant chemotherapy, with an absolute improvement of 15% in disease-free survival. Although most pivotal trials used monthly GnRHa, many clinicians prescribe 3-monthly depot injections for convenience, despite limited prospective data supporting their efficacy. Retrospective data from a Brazilian cohort presented at the 2023 ASCO Annual Meeting [JCO 41, no. 16_suppl (June 1, 2023) 527-527] suggested fewer estradiol (E2) increases with 3-monthly compared to monthly GnRHa, prompting the need for a prospective randomized trial. Methods: This single-institution, randomized, investigator-initiated phase II trial will enroll 50 premenopausal breast cancer patients (age ≤40) who are candidates for adjuvant OFS plus AI at Memorial Sloan Kettering. Eligible participants are women diagnosed with stage I, II, or III HER2-negative or HER2-positive, HR-positive breast cancer (ER >1% and/or PR >1%, according to American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines). Patients will be stratified by prior chemotherapy (yes vs. no) and randomly assigned in a 1:1 ratio to receive either leuprolide at a dose of 22.5 mg every 12 weeks (Cohort A) or leuprolide at a dose of 7.5 mg every 4 weeks (Cohort B), both administered as a single intramuscular injection, in combination with an AI. Leuprolide was selected due to its widespread use in the United States. E2 levels will be measured using high-sensitivity gas chromatography-tandem mass spectrometry (GC/MS/MS) at baseline and at 3, 6, 9, and 12 months. Patients with at least one E2 level above the pre-established threshold of 2.72 pg/mL during the 12-month follow-up will be considered to have suboptimal OFS. Patients in the 3-monthly group will undergo testing at the same frequency as those in the monthly group. The primary endpoint is the difference in the proportion of patients in each treatment arm who experience at least one E2 level > 2.72 pg/mL during the 12-month follow-up. Additionally, E2 levels will be described at each time point, and associations between baseline characteristics and E2 increases will be explored. Conclusions: OFS management remains a major challenge for oncologists worldwide, with limited evidence to guide optimal GnRHa dosing schedules. This study will generate prospective data comparing OFS using monthly versus 3-monthly GnRHa in combination with adjuvant endocrine therapy, addressing an important gap in clinical practice. The findings may contribute to future clinical guidelines for OFS, while also improving convenience, supporting treatment adherence, and enhancing quality of life for premenopausal breast cancer patients globally. Current Status: This investigator-initiated study is supported by the Long-term International Fellowship (LIFe) Award from Conquer Cancer, the ASCO Foundation. IRB approval was obtained in July 2025, and the study is currently in the activation phase. Patient enrollment is expected to begin shortly thereafter. Citation Format: D. Audi Blotta, Y. Chen, A. Buzaid, M. Robson. A randomized phase II study comparing monthly versus 3-monthly GnRH agonist for ovarian function suppression in premenopausal patients with HR-positive breast cancer: study design and rationale [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS5-09-10.

Adjuvant endocrine therapy for premenopausal ER+breast cancer had a relatively challenging initial pathway. The earliest trials testing adjuvant ovarian ablation in premenopausal breast cancer were hampered by the lack of ability to test for the relevant target, namely the estrogen receptor (ER). Therefore, trials testing adjuvant ovarian ablation and subsequently ovarian suppression with gonadotropin releasing hormone agonists (GnRHa) were diluted by the inclusion of women with estrogen receptor negative tumors. The subsequent demonstration of the effectiveness of adjuvant chemotherapy, initially with the CMF regimen, diverted some attention away from adjuvant endocrine therapy in premenopausal women, notwithstanding the fact that CMF, initially given for 12 months, resulted in permanent ovarian function suppression in many premenopausal women. Use of adjuvant CMF made it even more challenging to discern the added value of ovarian ablation or suppression. Oral adjuvant endocrine therapy with the selective estrogen receptor modulator tamoxifen became recommended for postmenopausal women, subsequently refined to only those with ER+ breast cancer, but the value of tamoxifen in premenopausal women was initially considered uncertain. Eventually, 5 years of adjuvant tamoxifen became a standard recommendation for premenopausal ER+ early breast cancer, although it took some time for evidence to emerge on the value of adding tamoxifen in women who received chemotherapy. The value of extending adjuvant endocrine therapy beyond 5 years was subsequently studied. More recent randomized premenopausal adjuvant endocrine therapy trials have focused of delineating the value of ovarian function suppression (OFS) added to tamoxifen or to an aromatase inhibitor. There are now a range of options for adjuvant endocrine therapy for premenopausal ER+ breast cancer, and identifying the clinical-pathologic features most appropriate for intensification of adjuvant endocrine therapy can assist with optimizing recommendations for an individual patient. Citation Format: Carlos Arteaga, Prudence Francis. Plenary Lecture 2: Premenopausal ER+ Breast Cancer: Past, Present, and Future [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PL2.

Current standard of care for patients with HR+/HER2- early breast cancer (EBC) includes adjuvant endocrine therapy with an aromatase inhibitor (AI) or tamoxifen (TAM). We present a trial-level meta-analysis on efficacy of AI vs TAM in patients with HR+/HER2- EBC. A systematic literature review was conducted using key medical literature databases (eg, PubMed; inception to October 2023) and data from conferences (to December 2023). Phase 3 randomized controlled trials (RCTs) that had ≥80% of patients with HR+/HER2- EBC (or available subgroup data) and reported a disease-free survival (DFS) hazard ratio for AI vs TAM were included in the meta-analysis, regardless of menopausal status and ovarian function suppression (OFS) use. The generic invariance method was used to calculate a pooled effect estimate of DFS hazard ratios and 95% CIs. A base-case analysis (all RCTs) and scenario analyses for NSAI-only, premenopausal, and postmenopausal RCTs were conducted. Five RCTs were identified for inclusion in the meta-analysis. In the base-case analysis, DFS significantly favored AI±OFS vs TAM±OFS (pooled hazard ratio, 0.68; 95% CI, 0.61-0.76; P<.0001). Results from scenario analyses were consistent with the base case; NSAI-only (pooled hazard ratio, 0.68; 95% CI, 0.59-0.78; P<.0001), premenopausal (pooled hazard ratio, 0.65; 95% CI, 0.56-0.76; P<.0001), and postmenopausal (pooled hazard ratio, 0.72; 95% CI, 0.61-0.86; P=.001) RCTs favored AI±OFS over TAM±OFS. This trial-level meta-analysis demonstrated a significant DFS benefit with AI vs TAM for patients with HR+/HER2- EBC, which was more pronounced in premenopausal women.

9004 Background. The RAMES Study (EudraCT Number 2016-001132-36) is a multicenter, double-blind, randomized phase II trial exploring the efficacy and the safety of the addition of ramucirumab to gemcitabine as the second-line treatment in MPM patients (pts) after platinum/pemetrexed regimens. Methods. The pts were assigned (1:1) to receive Gemcitabine 1000 mg/m2 i v on days 1 and 8 every 21 days with Placebo (Arm A) or Ramucirumab 10 mg/kg i v on day 1, of a 21-day cycle (Arm B), until tolerability or progressive disease. Pts was stratified by ECOG/PS (0-1 vs 2), age (≤ 70 vs &gt; 70 yrs), histology (epithelioid vs non-epithelioid) and time to progression (TTP) after first-line therapy. The primary endpoint was overall survival (OS). Assuming a proportion of OS equal to 40% at 1 year in arm A, a 12% absolute improvement in OS at 1 yrs was expected in Arm B (hazard ratio = 0.70).114 events (156 subjects) are required for a one-sided log-rank test with α = 0.15 to have 80% power. Results. From December 2016 to July 2018, 164 pts were randomized, 81 pts in Arm A and 80 Arm B; 3 pts were randomized but not treated. Characteristics of pts were: median age 69 yrs (44-81), males 119 (73.9%), females 42 (26.1%); ECOG/PS0 96 (59.6%) ECOG/PS1-2 65 (40.4%); histotype epithelioid 132 (81.9%), non-epithelioid 29 (18.1%); stage III 98 (60.7%), stage IV 60 (37.3%), 3 (2.0%) missing; asbestos exposure assessed 80 (49.7%). Median of courses was 3.50 in Arm A and 7.50 in Arm B. OS was significantly longer in Arm B with median 13.8 mths (70% CI 12.7-14.4) vs Arm A with 7.5 mths (70% CI 6.9-8.9), HR 0.71 (70% CI 0.59-0.85, p = 0.057). OS at 6 and 12 mths was in Arm A 63.9% and 33.9%, and in Arm B 74.7% and 56.5%, respectively. In Arm B OS was not correlated to TTP at first-line therapy (13.6 mths in TTP ≤6 mths and 13.9 mths in TTP &gt; 6 mths) and histotypes (13.8 months in the epithelioid and 13.0 months in non-epithelioid). No significant differences in thromboembolism G3-4 events were observed in Arm A vs Arm B (p= 0.64). None hypertension G3-4 was reported in Arm A vs 5 pts (6.3%) in Arm B (p= 0.022). No significant differences in G3-4 haematological toxicities between the two arms were reported. Conclusion: In the RAMES Study the addition of Ramucirumab to Gemcitabine significantly improved OS regardless of age of pts, tumor histotype and TTP at the first-line treatment. Gemcitabine plus Ramucirumab can be considered a manageable regimen in second-line treatment of advanced MPM pts. Clinical trial information: NTC03560973.

PurposeBased on SOFT and TEXT trials data, a composite recurrence risk score (CR-score) model was developed for early premenopausal women with hormone receptor -positive (HR+), human epidermal growth factor receptor 2-negative (HER2-) breast cancer using the subgroup treatment effect map (STEPP) method to guide ovarian function suppression (OFS) application. However, the CR-score model has yet to be validate in real-world settings.MethodsOur study included patients diagnosed between January 1, 2013, and December 31, 2021, from 42 breast centers in China. We utilized restricted cubic splines (RCS) to visualize continuous CR-score and hazard ratios for breast cancer recurrence. After adjusting for confounding factors via propensity score matching (PSM), Kaplan-Meier curves were used to compare disease-free survival (DFS) among premenopausal patients between the OFS and non-OFS groups.ResultsThe hazard ratio of recurrence consistently increased with higher CR-scores. Notably, 87.68% of patients who received OFS had a CR-score above 1.42. Following PSM, adjuvant OFS significantly improved DFS in the high CR-score group (CR-score above 1.42)(HR 0.571; 95% CI 0.403–0.809; p = 0.001). Among patients younger than 35 years old, those receiving OFS had significantly better DFS compared to those without OFS. After matching for age, grade, ER, PR, and lymph node status, OFS can significantly improve the DFS of those chemotherapy-treated patients with CR-score above 1.42 (p = 0.006). Furthermore, the group with high CR-score but ER expression below 50% did not benefit from OFS.ConclusionThe CR-score model can effectively guide clinicians in making decisions regarding OFS for premenopausal patients with HR+/HER2- breast cancer.

The use of tamoxifen is conventional adjuvant hormone therapy in premenopausal patients with receptor-positive breast cancer. Clinical trials demonstrating the benefits of ovarian function suppression as adjuvant treatment had an ambiguous interpretation. There is no scientific evidence favoring the empiric use of ovarian suppression for these patients. The members of the American Society of Clinical Oncology consider that ovarian ablation or suppression should be used during adjuvant hormone therapy only in certain cases. Irreversible ovarian function ablation may improve time to relapse, by simultaneously deteriorating the quality of life in patients. Irreversible fertility loss in the patients who have experienced breast cancer may become a leading stressful factor for these patients. Many investigators believe that chemotherapy-induced amenorrhea reduces the risk of recurrence. The paper discusses the usage of gonadotropin-releasing hormone agonists in combination with tamoxifen and aromatase inhibitors during adjuvant hormone therapy for early breast cancer. Whether ovarian suppression is needed during hormone therapy is considered, it is the reversible ovarian function suppression that must be standard treatment in premenopausal patients.

Objective To study the clinical effect of Longniu Bubi Granule on prevention and treatment of bone loss caused by premenopausal ovarian function suppression (OFS) combined with breast cancer aromatase inhibitor (AIs) . Methods Forty patients with postmenopausal and high risk of breast cancer treated with OFS combined with aromatase inhibitors were divided into treatment group (n=23) and control group (n=17) . The two groups were treated with calcium VitD3125IU, 1 tablet per day. The treatment group received the additional of Longniu Bugu Decoction, 2 doses daily, with continuous medication for 6 months. The bone mineral density (BMD) level, bone mineral density (T) and serum bone alkaline phosphatase (BALP) were measured before and 6 months after treatment. Results There were significant differences in lumbar (L2-4) and femoral neck bone mineral density, bone mineral density (T) and serum bone alkaline phosphatase (P<0.05) between the two groups after treatment, and the treatment group was superior to the control group. Conclusion Longniu Bugu Decoction can reduce bone loss in patients with premenopausal breast cancer caused by OFS combined with AIs therapy and improve patients’ life quality. Key words: Longniu Bugu Decoction; Premenopausal young high-risk breast cancer; Ovarian function inhibition combined with aromatase inhibitors; Bone loss

Background First results of the TEXT and SOFT international phase III trials were practice-changing, indicating that: i) 5y adjuvant exemestane+ovarian function suppression (E+OFS) reduces recurrence risk relative to tamoxifen(T)+OFS or to T alone, ii) T+OFS reduces recurrence risk vs T in women who are at sufficient risk to warrant chemotherapy (CT) and remain premenopausal afterwards, and iii) T alone remains appropriate for some premenopausal women. However, median follow-up (FU) was only 5.5y and &amp;lt;5% pts had died. FU is immature given the long natural history of HR+ disease and EBCTCG overviews showing overall survival (OS) improvements for T vs no-T emerged during 5-15y. It is crucial to establish if changing standard adjuvant endocrine therapy from T improves survival and if there are associated late toxicities. Trial Design and Aims Premenopausal women had invasive early breast cancer (BC) assessed as ≥10% ER and/or PgR. SOFT was designed to determine the value of adding OFS to T, and the role of E+OFS in two cohorts: women who remained premenopausal after completion of neo/adjuvant CT, and women for whom adjuvant T alone was considered suitable treatment. SOFT compares 5y of T to T+OFS or E+OFS. OFS was GnRH analog triptorelin x5y, oophorectomy or ovarian irradiation. Median age was 43y; 35% had N+ disease. 53% enrolled after prior neo/adjuvant CT. TEXT was designed to determine the role of adjuvant E in premenopausal women receiving OFS from the start of adjuvant therapy, comparing 5y of E+OFS vs T+OFS. Patients enrolled at start of all adjuvant therapy; 60% had CT concurrent with triptorelin after entry. Median age was 43y; 48% had N+ disease. Secondary objectives include effects on OS, late side effects of early menopause and late toxicities. Accruals TEXT: 2672 women, Nov03-Mar11 SOFT: 3066 women, Dec03-Jan11 Statistical Methods The primary endpoint, invasive disease-free survival, is time from randomization to invasive local, regional, or distant relapse, contralateral BC, second non-BC malignancy, or death. Secondary endpoints are BC-free interval, distant recurrence-free interval and OS. Primary results were reported in 2014, after ∼5.5y median FU; 30% pts were still on 5y treatment and &amp;gt;90% continued in FU. Long-term FU Updated results are planned for FU through Dec16, with ∼8y median FU. Pts finished 5y treatment by Apr16. Yearly visits continue; data collection includes weight, performance status, menstrual status, pregnancy attempts, GYN procedures, late AEs (cardiovascular, bone fracture), extended adjuvant therapy, invasive recurrence at first and subsequent sites, second non-BC malignancy, in situ cancers, OS. FU through 2020 is planned, for min and median FU of 10 and 12y, roughly doubling the numbers of endpoints events since the first report. This will be critical to determine whether short-term treatment benefits persist for late recurrence, improve power to detect treatment effects on distant recurrence and OS endpoints with lower event rates occurring later in FU, and define associated late toxicities and side effects of early menopause. A consortium to fund long-term FU is being pursued. Citation Format: Francis PA, Fleming GF, Regan MM, Pagani O, Walley BA, Price KN, Coates AS, Goldhirsch A, Gelber R. Long-term follow-up of TEXT and SOFT trials of adjuvant endocrine therapies for premenopausal women with HR+ early breast cancer [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OT3-02-03.

Background: The landmark Suppression of Ovarian Function Trial (SOFT) in premenopausal breast cancer patients revealed that the addition of ovarian function suppression (OFS) to adjuvant endocrine therapy with either tamoxifen (T+OFS) or exemestane (E+OFS) reduces the risk of recurrence compared with adjuvant tamoxifen alone. The benefit from the addition of OFS was most clinically meaningful for patients at higher clinico-pathologic risk of recurrence. There are no biomarkers to aid decision-making about intensification of endocrine therapy with OFS and its resultant toxicities. The Breast Cancer Index (BCI) is a gene expression–based signature that stratifies patients based on the risk of overall (0-10 years) and late (post-5 years) distant recurrence (DR) and predicts the likelihood of benefit from extended endocrine therapy in early stage HR+ breast cancer. The purpose of this study is to assess BCI’s prognostic and predictive ability in premenopausal women randomly assigned to 5-years treatment with E+OFS or T+OFS vs T alone in the SOFT trial. Methods: All available FFPE tumor samples from the SOFT trial (n=1718 of 3047) were included in the study. BCI testing was performed blinded to clinical characteristics, treatment and outcome. Median follow-up was 13 years. Primary endpoint was breast cancer-free interval (BCFI). Secondary endpoints were distant recurrence-free interval (DRFI) and disease-free survival (DFS). Kaplan-Meier analysis and Cox proportional hazards regression models, stratified by prior chemotherapy and lymph node status, were used to evaluate the predictive performance of BCI (H/I) status (High vs Low), and secondarily H/I as a continuous score. Hypothesis testing for interaction was performed by stratified log-rank tests. Results: Tumor samples from 1687 (98%) patients (30.4% &amp;lt; 40 years, 64.1% T1, 50.1% G2, 65.8% N0, 85.5%% HER2-, 53.3% received prior chemotherapy) were successful in BCI testing and included in the final analysis. Patient characteristics in the translational cohort are representative of the parent SOFT trial. 42.4% of patients’ tumors had H/I-High status. Prognostic and predictive analyses are ongoing and will be presented at the meeting. Citation Format: Ruth O’Regan, Yi Zhang, Gini F. Fleming, Prudence Francis, Roswitha Kammler, Giuseppe Viale, István Láng, Meritxell Bellet Ezquerra, Hervé R. Bonnefoi, Sherene Loi, Marco Colleoni, Catherine A. Schnabel, Kai Treuner, Meredith Regan. Evaluation of the Breast Cancer Index in premenopausal women with early-stage HR+ breast cancer in the SOFT trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS1-06.

To provide decision-focused estimates of the benefit of perioperative durvalumab in cisplatin-eligible muscle-invasive bladder cancer using Bayesian modeling of reconstructed individual patient data (rIPD) from the phase 3 NIAGARA trial. Individual patient data were reconstructed from published Kaplan-Meier curves and event counts (durvalumab, n=533; control, n=530). Bayesian piecewise-exponential models with prespecified intervals (0-12, 12-24, 24-36, and 36-60months) were used to estimate interval-specific hazards, posterior probabilities of benefit, absolute survival differences, number needed to treat (NNT), and restricted mean survival time (RMST). For event-free survival (EFS), the overall hazard ratio (HR) was 0.68 (95% credible interval [CrI], 0.56-0.82). The absolute improvement in EFS with durvalumab was 6.3%, 8.5%, and 10.8% at 12, 24, and 36months, respectively, corresponding to median NNT values of 15.8, 11.7, and 9.2. The gain in RMST for EFS was 2.48months over 36months and 5.98months over 60months. For overall survival (OS), the overall HR was 0.74 (95% CrI, 0.59-0.93). The absolute improvement in OS was 2.7%, 7.3%, and 7.5% at 12, 24, and 36months, respectively, with a median NNT of 13.8 at 24months. The gain in RMST for OS was 1.66months over 36months and 3.31months over 60months. This Bayesian rIPD reanalysis complements the primary NIAGARA report by translating relative effects into clinically meaningful absolute benefits over prespecified perioperative time points, supporting perioperative counseling and institutional decision-making.