Early Breast Cancer Trialists Research Articles

Abstract PO1-17-07: Invasive disease-free survival as a surrogate for overall survival in patients with hormone receptor−positive/human epidermal growth factor receptor 2−negative early breast cancer: a real-world analysis

Abstract Background: Although the goal of treatment is to improve overall survival (OS), in the adjuvant setting, disease-free survival (DFS) is an important endpoint because DFS risk reduction may reduce mortality risk. After introduction of the STEEP criteria, invasive DFS (iDFS) was adopted as an objective, well accepted primary endpoint in early breast cancer (EBC) trials. This analysis evaluated iDFS as a surrogate for OS in the HR+/HER2− EBC adjuvant treatment setting using real-world data. Methods: This retrospective analysis of the ConcertAI Patient360 database contains deidentified electronic medical records of patients (pts) treated at US academic and community oncology clinics from Jan 1, 1995 to Apr 30, 2021. The cohort included pts with AJCC (8th ed.) stage II-III (if IIIB or IIIC, confirmation was required on residual tumor status; pathological and/or clinical staging [pathological stage was prioritized if both existed in the record]) HR+/HER2− EBC who had surgery and initiated adjuvant endocrine therapy (ET); ovarian function suppression was permitted. iDFS (disease recurrence, metastasis, second primary tumor, or death) and OS (death due to any cause) were defined as time between ET start and first qualifying event. Pts not experiencing an event were censored at data cutoff or maximum follow-up (whichever was first) for iDFS and maximum follow-up for OS. Correlation analyses between individual iDFS and OS times were performed using Pearson and Spearman correlations and an iterative multiple imputation (IMI) algorithm. Subgroup analyses were conducted by first ET, menopausal status (imputed as 50 years if missing), stage, nodal status, prior (neo)adjuvant chemotherapy, and prior radiation. Results: In total, 3133 pts were analyzed. Mean (SD) age (index or ET initiation date) was 58.4 (12.4) years; 98.8% of pts were female, 29.9% were premenopausal, 80.9% had stage II disease, 57.1% had nodal involvement, and 41.6% and 48.8% had received (neo)adjuvant chemotherapy and radiation therapy. Overall, 1854 and 653 pts received nonsteroidal aromatase inhibitors and tamoxifen only. The median follow-up time was 55.1 months for iDFS and 68.2 months for OS. The iDFS (1103 events [35.2%]) rates were 88.9% and 73.9% at 2 and 5 years. The OS (554 events [17.7%]) rates were 97.4% and 90.5% at 2 and 5 years. There was a significant and high correlation ( >0.85 based on IQWiG 2011 guidelines) between iDFS and OS in the overall cohort (Pearson 0.91, P< .001; Spearman 0.88, P< .001) with 82% of OS variation explained by iDFS (least square R2=0.82; Table). Results were confirmed by IMI rho (0.83, P< .001), which is interpreted as very strong ( >0.8). Results were consistent among all reported subgroups; Pearson and Spearman correlations exceeded 0.85 and IMI exceeded 0.8, except for pts with stage III disease where correlation remained high (Pearson 0.88, P< .001) or medium/strong (Spearman 0.84, P< .001; IMI 0.79, P< .001) and where most censoring was observed (38.2% of pts). Conclusions: This retrospective cohort analysis demonstrates a very strong pt-level surrogacy between iDFS and OS among pts with HR+/HER2− EBC treated in a real-world, US-based, academic and community setting. The findings complement the trial-level surrogacy from prior analyses using data from randomized controlled trials and support iDFS as a surrogate endpoint for OS in HR+/HER2− EBC trials. Citation Format: Stephanie Graff, Sara Tolaney, Lowell Hart, Pedram Razavi, Wolfgang Janni, Lee Schwartzberg, Andrii Danyliv, Juan Carlos Mora Payan, Ilia Ferrusi, Rishi Rajat Adhikary, Joyce O'Shaughnessy. Invasive disease-free survival as a surrogate for overall survival in patients with hormone receptor−positive/human epidermal growth factor receptor 2−negative early breast cancer: a real-world analysis [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-17-07.

Abstract PO5-02-11: Is There A Survival Benefit With Adjuvant Chemotherapy Use In Elderly Breast Cancer Patients? A Retrospective Study Using The National Cancer Database

Abstract Background Geriatric patients (Age >=65 years) with Breast Cancer (BC) face a unique challenge due to the relatively lower functional status, as well as co-existing comorbidities. Studies like the recently published meta-analysis by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) group provide irrefutable evidence for the recurrence free survival benefit of anthracycline and taxane based adjuvant chemotherapy (ACT) regimes in early-stage BC patients. However, the age range of the trials analyzed ranged between 46-55 years, with underrepresentation of the geriatric group. The question on whether ACT results in an overall survival (OS) benefit for the elderly remains at large, which we hope to answer through our study. Methods The 2019 National Cancer Database (NCDB) was used to extract patients aged >= 65 years with breast cancer. We included stage 1-3 patients and stratified them into those who received ACT (ACT+) and those who did not (ACT-). Patients who received ACT were identified from the columns that specified the times of events from diagnosis or from the column for systemic therapy-surgery sequence. Patients should have had definitive surgery for their BC management to be included. Odds Ratio (OR) from logistic regression was used to analyze the utility of ACT based on various factors. Kaplan Meier (KM) survival curves and Hazard Ratio (HR) estimates from multivariate cox model was used to compare OS outcomes. Results Our cohort had 866,071 (ACT+: 642721, ACT-:223350) patients. The age distribution showed that ACT+ had 86.45% in the 65-80 years group and 13.55% in the >80 years group. ACT- had 68.32% aged 65-80 and 31.68% >80 years. The distribution of various demographic, pathologic and clinical factors by ACT use are shown in Table 1. Factors associated with ACT use based on OR estimates are shown in Table 2. ACT use is more likely in younger age group (65-80), lower comorbidity score, poorly differentiated and undifferentiated tumors, ER/PR negativity, T2 and lymph node positivity, those who underwent partial mastectomy and regional lymph node surgery, and HER2 positivity. Both 5-year (86.3 vs 74.2%) and 10-year (66 vs 50.8) OS were better with ACT+ (Table 2). The HR using propensity score (PS) weighted cox model revealed a higher hazard rate on omitting ACT [1.436, 95% Confidence Interval (CI) 1.417,1.456, p< .0001] (Table 2). HR estimates between ACT- vs ACT+, stratified by subgroups [Age (65-80, >80), T stage, grade (G), HER2] favored ACT use in all groups except G1 tumors (Table 3). Discussion Our study using a large national database, supports the use of ACT in the geriatric BC population by showing a clear OS advantage of 15.2% at 10 years. This benefit was observed even in BC patients aged more than 80 years with a HR of 1.683 when compared to ACT-, as represented in Table 3. While the existing literature provides robust evidence for ACT use in situations such as a high oncotype recurrence score, our study provides real-world evidence from a population-based dataset to supports its use in the elderly, including those above 80 years. The geriatric assessment recommended by the American Society of Clinical Oncology guideline for geriatric oncology should be followed in this setting. Utilization of geriatric assessment tools among oncologists has been poor with a survey revealing that 60% of providers did not utilize these tools in making treatment decisions. Limitations of our study include the potential for missing confounding factors and the retrospective nature of the study using a large database. Table 1 Demographic, pathological, and clinical characteristics of the study population and their distribution based on ACT use. Table 2 Odds Ratio for ACT use, KM survival curves and HR estimates of ACT use Table 3 HR estimates of mortality for ACT- vs ACT+ stratified by various subgroups Citation Format: Prashanth Ashok Kumar, Metlapalli Venkata Sravanthi, Dongliang Wang, Danning Huang, Abirami Sivapiragasam. Is There A Survival Benefit With Adjuvant Chemotherapy Use In Elderly Breast Cancer Patients? A Retrospective Study Using The National Cancer Database [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-02-11.

Abstract PO1-03-03: STEEP criteria v2.0 validation: A multi-trial analysis using GEICAM and TRIO adjuvant trials to evaluate surrogate endpoints for overall survival

Abstract Background: Standardized definitions of efficacy endpoints are needed to improve clinical trial designs, data reporting and interpretation of results, and to allow cross-trial comparisons. STEEP (Standardized Definitions for Efficacy Endpoints) criteria were proposed in 2007 by an expert panel from the National Cancer Institute (NCI) to provide common definitions for clinical trials in early breast cancer (BC). Invasive disease-free survival (IDFS) was selected as a candidate surrogate endpoint for overall survival (OS) in adjuvant trials and has been widely used in the last 15 years. Advances in BC systemic treatment led to review these criteria (STEEP v2.0), with the definition of a new modified endpoint: invasive BC-free survival (IBCFS). IBCFS excludes second primary non-breast invasive cancers from IDFS which may better detect efficacy effects when the toxicity profile of the intervention is well-known and the risk of second primary cancer is small. Methods: We proposed a multi-trial analysis of 8 adjuvant chemotherapy (CT) trials from GEICAM and TRIO to evaluate the different surrogate endpoints defined in the STEEP v2.0. Trial-level surrogacy was assessed through correlation between the ln hazard ratio (HR) of OS and the ln HR of the different studied endpoints across trials. The correlation was estimated by the weighted, by trial size, least squares regression (WLS) line and evaluated comparing the R2 values between OS and the corresponding endpoint tested. Primary analyses evaluated the correlation of OS with IDFS/IBCFS. Secondary analyses evaluated the correlation of OS with other STEEP v2.0 endpoints (distant disease-free survival [DDFS], distant relapse-free survival [DRFS], recurrence-free survival [RFS], recurrence-free interval [RFI] and distant recurrence-free interval [DRFI]) and explored the surrogacy between OS and all endpoints in specific groups of patients (pts) according to their risk of relapse: hormone receptors positive (HR+)/HER2-negative (HER2-) pts with intermediate/high and high-risk and triple negative (TN) pts. Results: A total of 14,473 pts were included. Median age was 50 years (range, 20–82). All were female, and 51.8% were postmenopausal. With a median follow-up of 115 months (range, 0.0–188) we found 2,504 OS events, 4,146 IDFS events (60.9% being distant recurrences) and 3,810 IBCFS events (62.4% being distant recurrences). For each trial, HR of OS, IDFS and IBCFS indicated same conclusions. If HR< 1 for OS, it was also for IDFS and IBCFS and the same was true when HR >1. R2 results of the weighted linear correlations between the ln HR of OS versus (vs) IDFS and OS vs IBCFS were 0.86 and 0.89, respectively. Confidence intervals (CI) at 95% were both overlapping. All other efficacy endpoints showed strong correlation with OS in the overall analysis. R2 values for HR+/HER2- intermediate/high and high-risk pts were 0.89 (OS vs IDFS) and 0.84 (OS vs IBCFS). For TN pts the correlations were weaker, being 0.63 (OS vs IDFS) and 0.73 (OS vs IBCFS). All WLS R2 values are described in the table. Conclusions: All tested STEEP v2.0 endpoints were strongly correlated with OS (R2 close to 1), meaning that their use as surrogate endpoints for adjuvant CT trials is appropriate. Notably, no differences were found between them in this multi-trial analysis. Therefore, none of them is more appropriate than other to discriminate the value of a new intervention vs comparator in adjuvant CT studies with mature data and long-term follow-up. Table: Citation Format: Sara López-Tarruella, Marina Pollan, Ander Urriticoechea, Eva Carrasco, Gonzalo Spera, Miguel Martín, Begoña Bermejo, Linnea Chap, Manuel Ruíz - Borrego, John Crown, Jose Angel García-Sáenz, Arlene Chan, Angel Guerrero, Valerie Bee, Lourdes Calvo, Rodrigo Fresco, Andrea Blasco, Andrés Hernando, Dennis Slamon. STEEP criteria v2.0 validation: A multi-trial analysis using GEICAM and TRIO adjuvant trials to evaluate surrogate endpoints for overall survival [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-03-03.

Disease-free survival as a surrogate for overall survival in HR+/HER2– early breast cancer: A correlation analysis

BackgroundOverall survival (OS) is a universally accepted measure of clinical benefit; however, prolonged follow-up is needed to observe sufficient events. Disease-free survival (DFS) has been widely adopted as a primary endpoint for early breast cancer (EBC) trials, as follow-up is comparatively shorter. Here, we present an analysis evaluating DFS as a surrogate for OS for adjuvant treatment of hormone receptor–positive/human epidermal growth factor receptor 2–negative (HR+/HER2–) EBC. MethodsA systematic literature review which included randomized controlled trials (RCTs) with ≥80% of adult patients with HR+/HER2– EBC was conducted. The RCTs evaluated various systemic therapeutic categories; key inclusion criteria included reporting of DFS and OS hazard ratios (HRs) and mature OS data. Spearman rank correlation and weighted linear regression analyses evaluated DFS and OS HR correlation. A scenario analysis tested base-case analysis robustness, and a parallel analysis using patient-level data was conducted. ResultsThe base case (N = 14 RCTs) showed an unweighted Spearman coefficient of 0.81 between OS and DFS (weighted: 0.81), with 84% of the variability in OS explained by DFS differences (R2 from weighted regression). The surrogate threshold effect (Burzykowski T, Buyse M. Pharm Stat. 2006;5:173–186) was 0.82 for DFS/OS HR. Scenario analysis (n = 9 RCTs), which excluded chemotherapy trials, and patient-level analysis using FACE trial data were consistent with the base-case analysis. ConclusionsThese analyses support DFS as a reliable surrogate endpoint for OS in adjuvant HR+/HER2− EBC trials. Using DFS as a surrogate measure will permit timelier access to novel treatments for patients with HR+/HER2− EBC.

Long-Term Follow-Up of the Anthracyclines in Early Breast Cancer Trials (USOR 06-090, NSABP B-46-I/USOR 07132, and NSABP B-49 [NRG Oncology]).

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.The primary joint efficacy analysis of the Anthracyclines in Early Breast Cancer (ABC) trials reported in 2017 failed to demonstrate nonanthracycline adjuvant therapy was noninferior to anthracycline-based regimens in high-risk, early breast cancer. Full analyses of the studies had proceeded when the prespecified futility boundary was crossed at a planned futility analysis for the ability to demonstrate noninferiority of a nonanthracycline regimen with continued follow-up. These results were presented with 3.3 years of median follow-up. This manuscript reports results of the final analyses of the study efficacy end points conducted with 6.9 years of median follow-up. Long-term analysis of invasive disease-free survival (IDFS), the primary end point of the ABC trials, remains consistent with the original results, as noninferiority of the nonanthracycline regimens could not be declared on the basis of the original criteria. The secondary end point of recurrence-free interval, which excluded deaths not due to breast cancer as events, favored anthracycline-based regimens, and tests for heterogeneity were significant for hormone receptor status (P = .02) favoring anthracycline regimens for the hormone receptor-negative cohorts. There was no difference in overall survival, and review of the type of IDFS events in the groups suggested reductions in cancer recurrences achieved with anthracycline regimens were offset by late leukemias and deaths unrelated to breast cancer.

Impact of oncoplasty in increasing breast conservation rates Post neo-adjuvant chemotherapy.

The essential goal of neoadjuvant chemotherapy (NACT) is to downstage the primary tumor making it amenable for breast conservation surgery (BCS). However, since the safety of this surgery is paramount, post-NACT breast conservation rates remain low. As per the recommendation of the 2018 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) overview of long-term post-NACT follow-up, we have devised a protocol for imaging, localization, rad-path analysis, and documentation of radiotherapy techniques to ensure the safety of post-NACT breast conservation. This is a retrospective cohort of 180 breast cancer patients who received NACT and were operated on by a single surgical oncologist from 2015 to 2020. After selection based on published guidelines, patients were treated with neoadjuvant systemic (chemo or hormone) therapy. In cases where primary tumors responded and reduced to 1-2 cm in size mid-NACT, the residual tumors were localized by clips under ultrasound guidance and calcification was wire localized. All patients were treated using appropriate surgical and oncoplastic techniques where indicated. Negative margins were ensured by intra-operative rad-path analysis. Adjuvant chemotherapy and radiotherapy were given as per protocol. In 81 cases that required mastectomy at presentation, we were able to achieve a 72.8% post-NACT BCS rate with the help of oncoplasty. Overall, 142 of 180 (80%) patients were treated with breast conserving surgery of which 80% (121 of 142) were oncoplasty. Margins were assessed on intra-operative frozen and re-excised in the same setting. No positive margins were reported in final histopath of 142 breast conservation procedures. Post-operative complication rates after breast conservation in the first year were at 17% (24 of 142 including two major complications). Patient reported outcomes were satisfactory with increased satisfaction for breast conservation compared with immediate breast reconstruction. Employing oncoplastic breast surgery (OBS) techniques following stringent protocols for accurate localization of the residual tumor, intra-operative rad-path analysis, and adjuvant treatments, we show successful breast conservation in 72.8% of our mastectomy-qualified patients after downstaging by NACT. We also report satisfactory outcomes for post-NACT surgery, patient-reported satisfaction, and survival.

Whole Breast Irradiation in Comparison to Endocrine Therapy in Early Stage Breast Cancer-A Direct and Network Meta-Analysis of Published Randomized Trials.

Multiple randomized trials have established adjuvant endocrine therapy (ET) and whole breast irradiation (WBI) as the standard approach after breast-conserving surgery (BCS) in early-stage breast cancer. The omission of WBI has been studied in multiple trials and resulted in reduced local control with maintained survival rates and has therefore been adapted as a treatment option in selected patients in several guidelines. Omitting ET instead of WBI might also be a valuable option as both treatments have distinctly different side effect profiles. However, the clinical outcomes of BCS + ET vs. BCS + WBI have not been formally analyzed. We performed a systematic literature review searching for randomized trials comparing BCS + ET vs. BCS + WBI in low-risk breast cancer patients with publication dates after 2000. We excluded trials using any form of chemotherapy, regional nodal radiation and mastectomy. The meta-analysis was performed using a two-step process. First, we extracted all available published event rates and the effect sizes for overall and breast-cancer-specific survival (OS, BCSS), local (LR) and regional recurrence, disease-free survival, distant metastases-free interval, contralateral breast cancer, second cancer other than breast cancer and mastectomy-free interval as investigated endpoints and compared them in a network meta-analysis. Second, the published individual patient data from the Early Breast Cancer Trialists' Collaborative Group (EBCTCG) publications were used to allow a comparison of OS and BCSS. We identified three studies, including a direct comparison of BCS + ET vs. BCS + WBI (n = 1059) and nine studies randomizing overall 7207 patients additionally to BCS only and BCS + WBI + ET resulting in a four-arm comparison. In the network analysis, LR was significantly lower in the BCS + WBI group in comparison with the BCS + ET group (HR = 0.62; CI-95%: 0.42-0.92; p = 0.019). We did not find any differences in OS (HR = 0.93; CI-95%: 0.53-1.62; p = 0.785) and BCSS (OR = 1.04; CI-95%: 0.45-2.41; p = 0.928). Further, we found a lower distant metastasis-free interval, a higher rate of contralateral breast cancer and a reduced mastectomy-free interval in the BCS + WBI-arm. Using the EBCTCG data, OS and BCSS were not significantly different between BCS + ET and BCS + WBI after 10 years (OS: OR = 0.85; CI-95%: 0.59-1.22; p = 0.369) (BCSS: OR = 0.72; CI-95%: 0.38-1.36; p = 0.305). Evidence from direct and indirect comparison suggests that BCS + WBI might be an equivalent de-escalation strategy to BCS + ET in low-risk breast cancer. Adverse events and quality of life measures have to be further compared between these approaches.

Do tumor infiltrating lymphocytes (TILs) predict benefits from trastuzumab therapy for HER2 positive breast cancer? Meta-analysis of individual patient data from 4097 women in 5 trials.

508 Background: High TIL counts are associated with a lower risk of breast cancer recurrence, especially in women with ER negative, HER2 negative tumors and, possibly, greater benefit from trastuzumab in women with HER2 positive cancer: the FinHER trial reported a differential effect of trastuzumab based upon TIL status. We performed a meta-analysis of randomized trials of trastuzumab in early breast cancer to attempt to validate this finding. Methods: TILs were quantified in 4097 women in 5 randomized controlled trials (NSABP B-31, FinHER, HERA, Intergroup N9831, PACS-04). All trials contributed to the Early Breast Cancer Trialists' Collaborative Group individual patient data meta-analysis of trastuzumab for women with HER2 positive tumors which found a significant benefit for trastuzumab therapy. TILs were assessed using established International Guidelines, with HERA using digital TIL-scores. The primary outcome was time to first recurrence. Cox regression analyses, adjusted for trial, treatment allocation, and nodal status, were used to quantify the prognostic value of TILs; and standard stratified logrank tests were used to assess the differential effect of trastuzumab therapy. Results: The median percentage TILs was 13% (Interquartile Range 5-30), with fewer than 10% of patients exhibiting TILs >50%. The prognostic value of TILs was confirmed, with patients with higher TILs being at lower risk for recurrence (adjusted hazard ratio per 10% increase in TILs 0.87 (95% CI 0.84-0.90), p<.0001) with similar effects in both treatment groups. Outcomes improved steadily with increasing TILs, and unadjusted 10-year recurrence rates fell from 30% in women with TILs <10% to 15% in those with TILs 70% or greater. Consequently, analyses of the predictive effect of TILs were stratified into 5 groups (0-9, 10-19, 20-39, 40-59, 60+). Overall, there was a highly significant benefit of trastuzumab on recurrence (HR 0.62 (0.54-0.70) p<.0001), but there was no evidence of any interaction between TILs and the proportional reduction in recurrence (p=0.8 for heterogeneity and trend). Conclusions: While higher TILs are associated with lower recurrence rates, there was no indication that the proportional reduction in recurrence with trastuzumab varied by TILs, although the number of patients with high levels was limited. Owing to a lower underlying recurrence rate, absolute benefits from trastuzumab were lower, but still substantial, in women with high TIL tumors. Clinical trial information: NCT00045032 , ISRCTN76560285 , NCT00005970 , NCT00004067 , NCT00054587 . [Table: see text]

Abstract P1-02-01: Comparing the efficacy of aromatase inhibitors vs tamoxifen in hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: a systematic review and trial-level meta-analysis

Abstract Background: Five years of adjuvant endocrine therapy (ET) including aromatase inhibitors (AIs) and tamoxifen (TAM) is considered the standard of care in hormone receptor–positive, human epidermal growth factor–negative (HR+/HER2−) early breast cancer (eBC). Clinical practice guidelines recommend the use of an AI or TAM depending on menopausal status and clinical risk stratification. Although TAM is generally recommended and more commonly used in premenopausal women, there is mixed evidence for different clinical outcomes. Patient-level meta-analyses conducted by the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) showed significantly lower rates of BC recurrence with AIs vs TAM. However, this was not specific to patients with HR+/HER2− eBC. This trial-level meta-analysis was conducted to compare AIs ± ovarian function suppression (OFS) vs TAM ± OFS in HR+/HER2−, pre- and postmenopausal patients with eBC. Methods: A systematic literature review (SLR) was conducted using key literature databases, ie, Embase, PubMed, and MEDLINE In-Process (from database inception to March 2022) and key conferences (2019-2021). Studies selected for the SLR were those that included either ≥80% of patients with HR+/HER2− eBC in the mixed patient population or subgroup data provided specifically for patients with HR+/HER2− eBC. Of these, randomized controlled trials (RCTs) investigating AI ± OFS vs TAM ± OFS and assessing disease-free survival (DFS) were included in the trial-level meta-analysis. This meta-analysis was conducted using the generic invariance method to obtain a pooled effect estimate (hazard ratio [HR]) together with its CI for DFS. This pooled estimate was calculated as a weighted average of the intervention effects estimated in the individual trials. Both fixed- and random-effect models (FEM, REM) were used to estimate the effect size. A base-case analysis was performed including all eligible trials. Three other scenario analyses were conducted: trials investigating only nonsteroidal AIs (NSAIs), assessing only premenopausal women, and assessing only postmenopausal women. Heterogeneity across the trials was assessed using I2 statistic. Results: A total of 5 RCTs comparing AI ± OFS vs TAM ± OFS were eligible for the meta-analysis (SOFT, HOBOE, BIG 1-98, N-SAS BC 03, Li 2019; additional information on rationale for exclusion of specific trials will be reported). Two studies assessing NSAI vs TAM included postmenopausal women, while 3 studies assessing AIs + OFS vs TAM ± OFS included premenopausal women. A total of 6623 patients were followed up for 34-97.2 months across these five trials. Heterogeneity was found to be low (I2 < 40%) across all scenarios. The base-case results (including all studies) using FEM significantly favored AIs ± OFS over TAM ± OFS, with a 29% reduction in risk of recurrence or death (pooled HR, 0.71 [95%CI, 0.64-0.80]). Similar results were observed with NSAIs ± OFS vs TAM ± OFS (HR, 0.73 [95% CI, 0.64-0.83]). Among premenopausal patients, the pooled HR for AIs + OFS vs TAM ± OFS was 0.66 (95% CI, 0.54-0.79). For postmenopausal women, the HR was 0.75 (95% CI, 0.65-0.87), favoring AIs over TAM. The findings for the base-case and different scenarios remained consistent when REM was used. Conclusions: This trial-level meta-analysis suggests significantly greater benefit with AIs than with TAM for HR+/HER2− eBC. Notably, AIs in combination with OFS are associated with a 34% reduction in risk of recurrence or death vs TAM ± OFS in premenopausal women; these results are aligned with the patient-level data findings of the EBCTCG. The findings indicate that AIs ± OFS are associated with a better DFS in the HR+/HER2− population, especially premenopausal women, than TAM ± OFS. Citation Format: Wolfgang Janni, Michael Untch, Nadia Harbeck, Joseph Gilgorov, William Jacot, Stephen K. Chia, Jean-Francois Boileau, Sina Haftchenary, Rhea Gupta, Namita Mishra, Purnima Pathak, Giuseppe Curigliano. Comparing the efficacy of aromatase inhibitors vs tamoxifen in hormone receptor-positive, human epidermal growth factor receptor 2-negative early breast cancer: a systematic review and trial-level meta-analysis [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 P1-02-01.

Abstract P2-02-01: Benefit of adjuvant bisphosphonates in early breast cancer treated with contemporary systemic therapy: A meta-analysis of randomized control trials

Abstract Introduction: Based on trials performed over a 25-year period, the Early Breast Cancer Trialists Collaborative Group (EBCTCG) identified a small but significant benefit of adjuvant bisphosphonates (BP) in reducing bone recurrence with a subsequent modest improvement in breast cancer-specific survival in post-menopausal women. Multiple studies show that contemporary event rates in early-stage breast cancer are much lower than those observed over a decade ago. This observation likely reflects the impact of modern adjuvant systemic therapy such as anthracycline and taxane chemotherapy and aromatase inhibitors. Therefore, re-evaluating the benefit of adjuvant bisphosphonate in the modern era is warranted. Methods: We reviewed reports of randomized trials of adjuvant BP that accrued patients exclusively beyond 2000 and extracted 5-year disease free survival (DFS) and overall survival (OS) in BP and control group arm along with hazard ratios (HR) when reported. The mean 5-year DFS and OS weighted by study sample size was calculated for each group. HR for DFS and OS were pooled in a meta-analysis using generic inverse variance and random effects modelling. Trial level absolute differences in DFS and OS between BP and control arms were calculated. Meta-regression comprising linear regression weighted by sample size (mixed effects) was then performed to explore association between disease and treatment related factors and absolute differences in benefit from BP. Quantitative significance was explored using methods described by Burnand et al. Analyses were performed using SPSS version 28 (IBM Corp, Armonk NY) and Review manager v5.4. Results: Twelve trials comprising 24109 patients were included in the analysis. Weighted mean DFS and OS in patients receiving BP were 85.8% and 91.7% respectively. For control group patients, these estimates respectively were 83.4% and 91.0%. For DFS, pooled HR across trials was 0.89 (0.81-0.97) with a 2.9% weighted mean difference favoring BP over control. Among patients receiving anthracycline and taxane based chemotherapy (n=3007), relative benefits were smaller; (HR DFS 0.94, 0.85-1.05). There was no significant OS benefit with BP (HR 0.92, 0.82-1.03) and this finding was observed irrespective of type of chemotherapy. The impact of BP on OS was smaller in both relative and absolute terms in studies with recruitment occurring more recently. Meta-regression results are shown in Table. There was lesser benefit in higher risk patients (node+, larger tumor size, ER-, grade 3 or those receiving chemotherapy). Overall, 1.13% patients experienced osteonecrosis related to BP therapy. Conclusions: Compared to EBCTCG data, relative and absolute benefit from BP is similar or modestly lower among more recent trials. Benefit from adjuvant BP appears smaller in patients treated with more contemporary adjuvant systemic therapy especially anthracycline and taxane containing chemotherapy. It is uncertain if the impact of BP on OS (rather than breast-cancer specific survival) is of a clinically meaningful magnitude. Despite de-escalated dosing compared to metastatic disease, osteonecrosis was observed in >1% of patients. It is possible that the benefits of BP are driven by patients with clinically low-risk disease rather than those with at high-risk. The balance between benefits and risks of adjuvant BP should be considered in individual patients. Table 1: Metaregression Results Citation Format: Abhenil Mittal, Faris Tamimi, Consolacion Molto Valiente, Massimo Di Iorio, Eitan Amir. Benefit of adjuvant bisphosphonates in early breast cancer treated with contemporary systemic therapy: A meta-analysis of randomized control trials [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 P2-02-01.

Abstract P2-02-04: De-escalation of bone-targeted treatment: Does the number of 6-monthly adjuvant zoledronate infusions received affect treatment efficacy for early breast cancer? A sub-study of ABCSG-12

Abstract Background: The results of the Early Breast Cancer Trialist Group (EBCTCG) meta-analysis (Lancet 2015) led to the widespread adoption of bisphosphonates as adjuvant therapy for postmenopausal early-stage breast cancer (EBC). Despite evaluating multiple bisphosphonate agents and regimens, there was no signal of varying efficacy with different agents, routes of administration or dose/dose intensity. We evaluated the question of treatment de-escalation using long-term outcome data from the prospective randomized ABCSG-12 trial. Patients and methods: Between 1999 and 2006, ABCSG-12 accrued 1803 patients with hormone-receptor positive EBC on ovarian function suppression for three years that were randomized to receive 4 mg zoledronic acid 6-monthly or not (and tamoxifen or anastrozole, in a 2:2 factorial design). In the current retrospective study, we evaluated whether the number of zoledronate infusions actually received had an impact on breast cancer-specific and fragility fracture outcomes. Based on the results of the EBCTCG meta-analysis, we hypothesized that amongst patients who receive less infusions than the planned seven zoledronate infusion in this trial, the number of infusions has no differential effect on these outcomes. Time to event endpoints were analyzed with Cox models and Kaplan Meier curves starting from a 3-year landmark. BMD subset analyses were restricted to patients who participated in the BMD sub-study with available BMD data. Results: 725 patients who received at least one zoledronate infusion were included in the time-to-event-analysis. There was no statistically significant difference in disease-free survival (adjusted HR 0.83, 95% CI 0.48–1.44, p=0.51) or overall survival (HR 0.97, 95% 0.30-3.11, p=0.96) in patients who received ≤6 zoledronate infusions (n=170) compared to those who received ≥7 zoledronate infusions (n=555) (adjusted HR 0.83, 95% CI 0.48 – 1.44, p=0.51). Both subgroups show stable lumbar spine and total hip BMD measurements across the five years. Conclusions: Comparable to the metastatic bone disease and fragility fracture settings, there was no evidence observed to indicate that a reduced number of zoledronate infusions is associated with reduced adjuvant efficacy. Further studies to define optimal regimens of adjuvant bone-targeted therapies (prospective evaluation of “how-low-can-you-go”) are required. Table 1: Multivariate Cox Regression: DFS and OS Table 2: BMD and percent change from baseline at the total hip and lumbar spine (L1-L4) over 60 months Citation Format: Ana-Alicia Beltran-Bless, Mark Clemons, Christian Fesl, Dominik Hlauschek, Lidija Soelkner, Gregory R. Pond, Lisa Vandermeer, Richard Greil, Marija Balic, Vesna Bjelic-Radisic, Christian F. Singer, Guenther Steger, Ruth Helfgott, Daniel Egle, Simon P. Gampenrieder, Stephanie Kacerovsky-Strobl, Christoph Suppan, Magdalena Ritter, Gabriel Rinnerthaler, Georg Pfeiler, Hannes Fohler, John Hilton, Michael Gnant. De-escalation of bone-targeted treatment: Does the number of 6-monthly adjuvant zoledronate infusions received affect treatment efficacy for early breast cancer? A sub-study of ABCSG-12 [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 P2-02-04.

Does the number of 6-monthly adjuvant zoledronate infusions received affect treatment efficacy for early breast cancer? A sub-study of ABCSG-12

BackgroundThe widespread adoption of adjuvant bisphosphonate therapy for postmenopausal early breast cancer (EBC) patients was based on results of the Early Breast Cancer Trialist Group (EBCTCG) meta-analysis. Despite multiple regimens evaluated, there was no signal of varying efficacy with type, dose/dose intensity of bisphosphonate administration. We evaluated the effect of early treatment cessation using long-term outcome data from the ABCSG-12 trial. Patients and methodsABCSG-12 randomized 1803 hormone-receptor positive EBC patients on ovarian suppression between 1999 and 2006 to receive 4 mg zoledronic acid 6-monthly or not (and tamoxifen or anastrozole, 2:2 factorial design). In the current study, we evaluated whether the number of zoledronate infusions had an impact on breast cancer-specific outcomes. We hypothesized that amongst patients who received at least one zoledronate infusion, the number of infusions had no effect on outcomes. Time-to-event endpoints were analysed with Cox models and Kaplan Meier curves starting from a 3-year landmark. BMD analysis was restricted to patients who participated in the BMD sub-study. Results725 patients who received at least one zoledronate infusion were included in the time-to-event analysis. There was no statistically significant difference in disease-free or overall survival in the patients who received ≤6 zoledronate infusions (n = 170) compared to those who received ≥7 zoledronate infusions (n = 555). ConclusionsComparable to efforts to de-escalate treatment duration in metastatic bone disease, there was no evidence to indicate that a reduced number of zoledronate infusions is associated with reduced adjuvant efficacy. Further studies to define optimal regimens of adjuvant bone-targeted therapies are required.

Accelerated Partial Breast Irradiation (APBI) Using Five Daily Fractions: A Prospective, Phase II, Multi-Center Trial of Cosmetic Outcomes and Toxicity: Final Results

<h3>Purpose/Objective(s)</h3> To report final results of a clinical trial of APBI using intensity modulated radiotherapy (IMRT) to deliver 27 Gy in 5 daily fractions following breast conserving surgery (BCS) prospectively designed to assess the efficacy and cosmetic outcomes of a 1-week, APBI regimen among women with early breast cancer. <h3>Materials/Methods</h3> Women ≥ 50 years, with lymph node-negative, ER positive, HER-2 negative breast cancer or ductal carcinoma in situ (DCIS), ≤ 3cm diameter, following BCS with margins ≥ 2mm, and excellent or good baseline cosmesis received 27 Gy in 5 daily fractions to the seroma plus 1 cm CTV and 0.7 cm PTV margins. Clinical photographs, patient and provider cosmetic scores, breast fibrosis, telangiectasia and pain were collected prospectively, prior to RT and at 6 weeks, 1 and 2 years after RT. The primary endpoint was the proportion of women who retained Excellent or Good cosmesis at 2 years using the EORTC Cosmetic Rating System. Cosmetic failure was deterioration from Excellent or Good to Fair or Poor. A panel of 5 radiation oncologists independently assessed the cosmetic photographs. Secondary endpoints were rates and grades of breast fibrosis, telangiectasia, breast pain, ipsilateral breast tumor recurrence (IBRT), overall (OS), breast cancer-specific survival (BCSS) and subsequent mastectomy. Efficacy outcomes were assessed at clinic visits and by review of charts. ClinicalTrials.gov registration: NCT02681107. <h3>Results</h3> A total of 298 patients were treated between April 25, 2016, and October 31, 2019. At a median follow up of 48 months, the 4-year OS was 98.5% (95% CI 96.1% - 99.5%) and BCSS was 99.7% (95% CI 97.6% - 99.9%). The 4-year IBRT rate was 3.3% (95% CI 1.1% - 6.4%). There were 10 contralateral breast events for a 4-year rate of 3.9% (95% CI 2.2% - 6.9%). There were 10 ipsilateral and 6 contralateral mastectomies. Two patients died of unrelated causes prior to 2 years; 79 patients declined in-clinic attendance due to COVID or competing comorbidities and 217 women had 2-year cosmetic photographs and clinical assessments performed. Consensus of the photo-panel cosmesis at baseline was: Excellent: n=116 (53%), Good: n=102 (47%), Fair: n=1 (0.5%) and Poor: n=0. Consensus overall cosmesis at 2 years was: Excellent: n=141 (65%), Good: n=78 (35%), Fair: n=0 and Poor: n=0. Most patients had either improved (n=168; 77%) or no change (n=43; 20%) in cosmesis at 2-years. No patient had cosmetic failure but 6 (3%) had a change from Excellent to Good at 2 years. Most patients reported either no (79%) or mild (21%) pain, with no moderate or severe pain. Two patients (0.9%) had grade 2 fibrosis and 5 patients (2%) had visible telangiectasia that did not detract from overall cosmesis. <h3>Conclusion</h3> APBI using 27 Gy in 5 fractions using a conformal IMRT technique, achieved excellent 2-year cosmesis with minimal toxicity. The IBRT risk was comparable to the contralateral new breast cancer risk and to local recurrence rates of recently published early breast cancer trials.

Bone-Targeted Agents and Metastasis Prevention

Simple SummaryBone metastases are common in cancer patients and the role of bone-targeted agents in prevention of metastasis have been evaluated in multiple clinical trials over the past 20 years. Results show that in breast cancer the use of adjuvant bisphosphonates (and possibly denosumab) reduce bone metastases and breast cancer deaths in postmenopausal women. These effects are in addition to the benefits associated with the use of standard adjuvant endocrine, cytotoxic and targeted treatments with prevention of one in six breast cancer deaths at 10 years. Similar benefits have not been observed in other cancers that typically spread to bone, such as prostate or lung cancers. Biomarkers that can predict patient benefit from the use of bone targeted treatments in the adjuvant setting are being evaluated. Currently, tumour expression of the transcription factor, MAF, seems to be the most promising biomarker; benefits from adjuvant bisphosphonates are seen in the 80% of patients with normal levels of expression irrespective of menopausal status, while over-expression is associated with a poor prognosis and a higher rate of visceral metastases.The use of bone-targeted treatments has transformed the clinical care of many patients with metastatic breast cancer. In addition, due to the profound effects of bisphosphonates and denosumab on bone physiology and the bone microenvironment, the potential of bone-targeted agents to modify the process of metastasis has been studied extensively. Many adjuvant trials with bisphosphonates in early breast cancer have been performed. Variable outcomes in terms of disease recurrence have been reported, with any treatment benefits apparently influenced by the age and menopausal status of the patients. The Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) conducted a meta-analysis of individual patient data from all available randomised trials to investigate this observation further. This meta-analysis failed to show any benefits of adjuvant bisphosphonates in premenopausal women, but highly significant improvements in bone recurrence (RR = 0.72; 95% CI 0.60–0.86, 2p = 0.0002) and breast cancer mortality (RR = 0.82; 95% CI 0.73–0.93, 2p = 0.002) were seen in the 11,767 postmenopausal women included in the meta-analysis. As a result, clinical guidelines recommend the incorporation of adjuvant bisphosphonates that inhibit osteoclast activity into routine clinical care. Denosumab, which has similar effects on bone cell physiology, appears not to consistently influence disease outcomes, perhaps suggesting that it is the “off target” effects of bisphosphonates on immune function and the biological processes involved in metastasis that are important. Predictive biomarkers beyond menopause are being sought and assessment of the transcription factor MAF (mesenchymal aponeurotic fibrosarcoma gene) appears to identify patients able to benefit from the addition of a bisphosphonate to standard adjuvant anticancer therapies.

Locoregional Management of Breast Cancer: A Chronological Review.

Locoregional management of breast cancer is founded on evidence generated over a vast time period, much longer than the career span of many practicing physicians. Oncologists rely on specific patient and tumour characteristics to recommend modern-day treatments. However, some of this information may not have been available during prior periods in which the evidence was generated. For example, the comprehensive Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analyses published in the 2000s typically included older trials accruing patients between the 1960s and 1980s. This raises some uncertainty about whether conclusions from studies conducted in prior eras are as relevant or applicable to modern-day patients and treatments. Reviewing the chronological order and details of the evidence can be beneficial to understanding these nuances. This review discusses the evolution of locoregional management through some key clinical trials. We aim to highlight the time period in which the evidence was generated and emphasize the 10-year outcomes for the comparability of results. Evidence supporting surgical management of the breast and axilla, as well as details of radiotherapy are discussed briefly for all stages of breast cancer.

Effect of neoadjuvant versus adjuvant chemotherapy on ipsilateral breast tumor recurrence after breast-conserving surgery and whole-breast irradiation.

604 Background: Early Breast Cancer Trialists’ Collaborative Group conducted a large meta-analysis and reported that patients who underwent neoadjuvant chemotherapy (NAC) had higher ipsilateral breast tumor recurrence (IBTR) rate than those with adjuvant chemotherapy. However, since the study was conducted with patients treated two decades ago, the results could not reflect the advance in treatments and IBTR rate was much higher than in recent studies, Thus, we investigated the association between chemotherapy settings and IBTR rates in breast cancer patients. Methods: We retrospectively reviewed the data of 5,307 patients who underwent breast conserving surgery followed by whole breast irradiation between January 2004 and December 2018 in a single institution. Patients who underwent mastectomy or omitted chemotherapy were excluded. Results: The 1,473 patients who underwent NAC showed significantly higher IBTR rate than the 3,564 patients who underwent adjuvant chemotherapy (10-year risk: 4.5% vs. 4.0%; log-rank p=0.045, hazard ratio 1.42 [95%CI,1.01-1.99]). The difference was more evident for patients with hormone receptor (HR) positive and human epidermal growth factor receptor-2 (HER2) negative tumor (unadjusted p=0.001, hazard ratio 2.27 [95%CI,1.37-3.74; adjusted p=0.002, hazard ratio 2.80 [95%CI,1.45-5.42]], and the statistical significance was still remained after 1:1 propensity score matching (p=0.026). In contrast, patients with other subtypes did not show significant differences between two groups. Conclusions: Patients who underwent NAC for HR+/HER2- tumors carry increased risk of IBTR than those who underwent adjuvant chemotherapy. Our observation supports the need for considering tumor subtypes in initial treatment. In addition, more intensive surveillance would be needed for patients with HR+/HER2- tumors after NAC.

Historical early treatment effects of adjuvant endocrine therapy for breast cancer in high-risk subgroups: Reanalysis of BIG 1-98, SOFT and TEXT.

508 Background: Clinical trials testing adjuvant endocrine therapy (ET) have not historically limited enrollment to patients with clinically high-risk breast cancer (BC), nor estimated treatment (trt) effects prior to 5 yrs. In light of recent trial results for adjuvant CDK4/6 inhibitors, we estimated early relative and absolute trt effects of aromatase inhibitor (AI) vs tamoxifen (T), with ovarian suppression (OFS) if premenopausal, in high risk subgroups. Methods: From pts enrolled in adjuvant phase 3 randomized clinical trials BIG 1-98 (postmenopausal, 5yr AI v T), TEXT (5yr AI+OFS v T+OFS) and SOFT (5yr AI+OFS v T+OFS v T), we identified subgroups with HR+/HER2- BC and high risk features (≥4 pLN; or 1-3 pLN with grade 3, pT≥5 cm and/or Ki-67≥20% [retrospectively centrally assessed]). TEXT randomized at start of adjuvant trt; BIG 1-98 and SOFT after chemotherapy. Disease-free survival (DFS) was defined from randomization to invasive recurrence at local, regional, distant or contralateral breast, second non-breast malignancy or death. We estimated trt effects as differences in 2, 3 and 5yr DFS Kaplan-Meier estimates (KM diffs at t yrs) and hazard ratios over time intervals of 0-2, 0-3 and 0-5 yrs (HRs over 0 to t yrs) to approximate the maturity of trial results with increasing follow-up. Results: The high-risk HR+/HER2- subgroups were 695/4922, 707/2660 and 526/3047 pts in BIG 1-98, TEXT and SOFT with 202, 122, 142 DFS events observed by 5 yrs since randomization. 60%, 46% and 44% of pts had ≥4 pLNs; 42%, 90% and 92% had chemotherapy. The table summarizes results. Conclusions: In re-analysis of clinical high risk HR+/HER2- subgroups of 3 trials each ̃700 pts, 5 yrs AI vs T had similar magnitude of early trt effects after 2-3 yrs follow-up of all pts vs trt effects observed after 27 mos median follow-up in monarchE trial (HR=0.70; KM diffs 2.7% at 2 yrs, 5.4% at 3 yrs; n=5637). Relative and absolute trt effects sometimes diminished when estimated over 5 yrs rather than over 2 yrs, but meaningful absolute differences remained at 5 yrs in contrast to Penelope-B trial results. Design and interpretation of high risk HR+/HER2- early BC trials may depend on timing of randomization and selection of backbone adjuvant trts; follow-up &gt;5 yrs must remain standard. [Table: see text]

Primary results of ANZ 1002: Post-operative radiotherapy omission in selected patients with early breast cancer trial (PROSPECT) following pre-operative breast MRI.

572 Background: Selective use of radiotherapy (RT) after surgery for early breast cancer (EBC) has been an elusive goal. The role of breast MRI in localised EBC is controversial. We aimed to determine if preoperative MRI could identify patients with EBC in whom the ipsilateral invasive recurrence (IIR) rate was sufficiently low without RT, such that RT might be safely omitted. Here we report primary and secondary outcomes, and imaging/biopsy findings for occult lesions. Methods: PROSPECT is a prospective single-arm study. Criteria for omission of RT included age at least 50, nil/minimal or mild Background Parenchymal Enhancement (BPE) on MRI, unifocal pT1N0 cancer, not Triple Negative (TNBC), no LVI. All patients who underwent PROSPECT MRI were included in the analysis. Imaging findings on MMG, US and MRI were documented and all biopsies were recorded. Pathology of lesions identified by MRI was described. The primary outcome was the IIR at 5 years of those treated without RT. An IIR rate of 5% or less was considered acceptable. The protocol specified primary analysis occurred after the 100th patient reached 5 years follow up in May 2021. Results: Between 9/2011 and 5/2019, 443 patients had MRI after diagnosis. BPE was nil/minimal or mild in 344 patients. MRI detected 194 occult lesions in 144 (33%) patients; 139 (72%) were ipsilateral. 61 MMG/US occult malignant lesions - 36 invasive and 25 DCIS - were identified in 48 patients (11% of total cohort). Of 38 ipsilateral lesions in 32 patients (7% of total cohort), 23 were DCIS, 4 were T1a, 7 T1b and 4 T1c. 201 patients were treated on trial without RT. The median age was 63 years (range: 50 to 84), median tumour size 11 mm (range: 2 to 20), grade 1 (104), grade 2 (86) or grade 3 (11). The rate of IIR at 5 years was 1% (1/101). There were 2 IIRs at 4.6 and 7.7 years follow up, 1 regional recurrence, and 1 patient with both a regional and distant recurrence with 1 breast cancer death. There was 1 contralateral (CL) breast cancer, 1 CL DCIS, 2 other cancer diagnoses and 1 death from other causes. Of 242 patients undergoing MRI but not in the main study, median age was 63 range: 50-80, median tumour size, 13mm (range: 4-145). 9 underwent mastectomy (2% of total cohort). Followup is complete for 235. There was 3 IIR, 3 CL primary and no distant metastases or breast cancer deaths. Conclusions: Breast MRI in selected, low risk patients identified occult malignancy in 11% of patients. At a median of 5 years follow up the IIR and other breast cancer events was very low. This suggests that local recurrences may be due to occult breast cancers, and MRI may allow the identification of truly localised cancers for which radiation may be safely omitted. The event rate for the entire cohort was very low, suggesting that identification of occult malignancy in apparently unifocal EBC is beneficial. Confirmatory trials are needed. Clinical trial information: 12610000810011.

Abstract PD14-08: Effectiveness of aromatase inhibitors versus tamoxifen in lobular compared to ductal carcinoma: Individual patient data meta-analysis of 9328 women with central histopathology, and 7654 women with e-Cadherin status

Abstract Background: In post-menopausal women with hormone receptor (HR) positive early breast cancer, aromatase inhibitors (AIs) are more effective than tamoxifen as endocrine therapy. However, some trial reports indicate greater benefit from AIs in lobular than ductal cancers. Invasive lobular cancer can be identified using conventional microscopy and/or immunohistochemistry for e-Cadherin status. We performed an individual patient data meta-analysis to explore possible differential treatment benefits for AI vs tamoxifen in women with lobular vs ductal hormone receptor positive breast cancer. Methods: Individual patient data were collected from three randomised controlled trials (BIG 01-98, TEAM and ATAC) of AI vs tamoxifen for postmenopausal women with estrogen receptor positive breast cancer, as well as results of central pathology review and e-Cadherin expression. Central pathology and e-Cadherin data were available on 9328 and 7654 women. Local pathology data was available for TEAM, BIG 01-98. Data were analysed using the same methodology as the previous EBCTCG meta-analysis of AI vs tamoxifen: results of different methods of diagnosing ductal vs lobular cancer were cross tabulated, and outcomes analysed using log-rank methods, yielding event rate ratios (RR) and confidence intervals. Interactions were evaluated using standard tests for heterogeneity; the primary outcomes were time to any invasive breast cancer recurrence, and time to distant recurrence. Results: Rates of lobular cancer were higher when assessed by central pathology (BIG 01-98 16%; ATAC 16%; TEAM 12%) than e-Cadherin (15% vs 14% vs 9%). Methods agreed in over 80% of cases classified as ductal using either pathology or e-Cadherin, while the agreement rate for lobular cancers was only about 50%. A similar pattern was seen comparing local pathology with either central pathology or e-Cadherin. Consequently, analyses were stratified by pathology and e-Cadherin both separately and together. Consistent with the previous meta-analysis there was a significant reduction in recurrence for AI compared to tamoxifen (RR 0.73 (0.61-0.87) p=0.0004). Exploration of interaction found no evidence of heterogeneity of treatment effect on recurrence by pathology (ductal HR 0.76 (0.64-0.89); lobular HR 0.76 (0.50-1.15) interaction p&amp;gt0.99; nor by e-Cadherin status (interaction p=0.9). No significant interactions were seen on other endpoints. Conclusion: Analyses of three large trials of adjuvant AI vs tamoxifen found discordance in identifying patients with lobular carcinoma by local or central pathology or e-Cadherin status, indicating variability in the consistency of diagnosis. The trials included showed a benefit for AI over tamoxifen in line with the previous meta-analysis, but with no evidence of differential efficacy in lobular compared to ductal carcinomas, however measured. These data cannot rule out smaller quantitative interactions or differences in site of recurrence: however, in contrast to earlier reports, this meta-analysis of the totality of the data does not identify ductal/lobular cancer as a predictive marker for differential endocrine treatment benefit. Citation Format: Robert K Hills, Steffi Oesterreich, Otto Metzger, David Dabbs, Hongchao Pan, Jeremy Braybrooke, Richard Gray, Richard Peto, Rosie Bradley, Ewan Straiton, Richard Berry, Daniel Rea, David Cameron, Jack Cuzick, Meredith Regan, Mitch Dowsett, Ivana Sestak, Jonas Bergh, Sandra M Swain, John Bartlett, Early Breast Cancer Trialists' Collaborative Group. Effectiveness of aromatase inhibitors versus tamoxifen in lobular compared to ductal carcinoma: Individual patient data meta-analysis of 9328 women with central histopathology, and 7654 women with e-Cadherin status [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD14-08.

Abstract GS2-06: Taxane with anthracycline versus taxane without anthracycline: An individual patient-level meta-analysis of 16,500 women with early-stage breast cancer in 13 randomised trials

Abstract Background: Anthracycline and taxane-containing chemotherapy regimens reduce the rate of breast cancer recurrence by about one third compared to no chemotherapy. However, concerns about the increased risks of cardiac toxicity and leukaemia with anthracyclines have resulted in wider use of taxane chemotherapy schedules without anthracycline, in particular docetaxel-cyclophosphamide (DC). The benefits and risks of this approach have been assessed in several randomised trials but with conflicting results. Methods: We did an individual patient-level meta-analysis of data on 16,500 participants from 13 randomised controlled trials starting before 2010. Four compared 6 courses of DC with and without concurrent anthracycline (Anth), six compared sequential Anth then taxane (3 or 4 courses of Anth then 3 or 4 D, or vice versa) versus 6 courses of DC (resulting in a higher cumulative dose of taxane in the DC group), and 3 compared sequential Anth + D versus other taxane schedules. Primary outcomes were time to invasive breast cancer recurrence (distant, loco-regional, or new contralateral breast primary) and breast cancer mortality (by log-rank subtraction). Log-rank analyses were used to assess the first-event-rate ratio (RR) and confidence intervals. Pre-specified subgroup investigations included site of recurrence, age, ER/PR status, nodal status, tumor diameter, grade and HER2 status. Results: Overall, patients treated with an anthracycline and taxane combination averaged 18% lower rates of breast cancer recurrence (RR 0.82, 95%CI 0.75-0.90; p&amp;lt;0.0001) than those receiving a taxane schedule without anthracycline, equating to an absolute reduction of 3.1% (95%CI 1.4-4.8) in 10-year recurrence. The 10-year risk of death from breast cancer was reduced by 1.8% (RR 0.85, 95%CI 0.75-0.95; p=0.006) with no increase in deaths without recurrence. The proportional reduction in recurrence was greatest in trials of concurrent Anth + DC versus DC (RR 0.66, 95%CI 0.55-0.79; p&amp;lt;0.0001), where the only difference between arms was the addition of anthracycline (cumulative dose of doxorubicin≈300mg/m2). By contrast, in trials of sequential Anth + D versus the higher cumulative taxane dose DC regimen there was no significant benefit from Anth (cumulative dose of epirubicin≈300mg/m2): RR 0.93, 95%CI 0.80-1.07; p&amp;gt;0.1. In sub-group analyses of all trials, the benefit of anthracycline and taxane chemotherapy persisted throughout years 0-1, 2-4 and 5-9 with little data beyond year 10. There was a similar and highly significant proportional reduction in recurrence in ER-positive and in ER-negative disease and the RRs for recurrence did not differ significantly by any other pre-specified group including age, nodal status, tumor diameter, grade and HER2 status. There were no significant increases in deaths from cardiovascular disease or leukaemia, though longer follow-up is needed to fully assess risks. Conclusion: The addition of anthracycline to taxane chemotherapy, compared to taxane alone reduced the risk of breast cancer recurrence by 18% with larger proportional reductions in trials of DC ± concurrent Anth, in which the taxane dose was the same in both groups and the cumulative anthracycline dose was higher. Citation Format: Jeremy Braybrooke, Rosie Bradley, Richard Gray, Robert Hills, Zulian Liu, Hongchao Pan, Richard Peto, Joanne Blum, Xiaosong Chen, Bent Ejlertsen, Wolfgang Janni, Ulrike Nitz, Dennis Slamon, Masakazu Toi, Toru Watanabe, Sandra Swain, Jonas Bergh, on behalf of the Early Breast Cancer Trialists Collaborative Group. Taxane with anthracycline versus taxane without anthracycline: An individual patient-level meta-analysis of 16,500 women with early-stage breast cancer in 13 randomised trials [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr GS2-06.