A0269 Development and validation of a multimodal predictive recurrence score (MPRS) integrating clinical, radiological, and histopathological information for multicenter patients with clear cell renal cell carcinoma (ccRCC)

Abstract Background: In early-stage estrogen receptor-positive (ER+), HER2-negative (HER2−) breast cancer, the Oncotype DX® Recurrence Score (RS) is a clinically validated 21-gene assay that informs prognosis and predicts the benefit of adding chemotherapy to endocrine therapy. While germline pathogenic variants (PVs) in cancer susceptibility genes may influence tumor biology, treatment response and surgical management, their relationship with RS remains insufficiently explored and has been primarily limited to BRCA1/2 genes. This study investigates the association between Oncotype DX RS and the presence of germline PVs across a broader spectrum of breast cancer predisposition genes. Methods: We retrospectively analyzed data from a Greek cohort of early-stage ER+, HER2- breast cancer pts who underwent both germline testing using a 52-gene panel and Oncotype DX testing between 2015 and 2025. Pts were stratified by Oncotype DX Recurrence Score (RS) into low (RS 0-10), intermediate (RS 11-25), and high-risk (RS >25) genomic groups. Germline testing results were categorized into three groups: (a) pathogenic/likely pathogenic (P/LP) variants identified, (b) variants of uncertain significance (VUS), and (c) no variants detected. The P/LP group was further subdivided based on the presence of variants in (a) BRCA1/2, (b) other high-risk genes, (c) moderate-risk genes, and (d) incidental findings in additional genes. Results: A total of 1,465 pts were analyzed. The distribution of Oncotype DX RS across the various germline testing groups is detailed in the table below. Conclusion: The distribution of RS varied notably across genetic variant groups. Pts with BRCA1/2 and other high-risk gene variants exhibited statistically significant higher median RS values (p<0.0001) and higher percentage of pts with RS>25 (p<0.0001) compared to all other subgroups (moderate risk variants, incidental findings, VUS and cases without detected variants). These patterns suggest that pts with germline mutations in high-risk susceptibility genes are more likely to have an unfavorable prognosis for distant recurrence and a greater likelihood of receiving chemotherapy, as indicated by their elevated RS values Citation Format: V. Venizelos, K. Papazisis, C. Markopoulos, G. Xepapadakis, R. Iosifidou, G. Kapetsis, S. Giannoulakis, N. Tsoulos, A. Meintani, D. Bouzarelou, G. Tsaousis, D. Grosomanidis, N. Bredakis, F. Zagouri, C. Christodoulou, K. Anastasakou, M. Paraskeva, D. Mavroudis, N. Michalopoulos, D. Tryfonopoulos, S. Papadopoulos, A. Adamidis, D. Dimas, E. Angelidou, E. Papadopoulou, G. Nasioulas. Association of Oncotype DX Recurrence Score with Germline Mutations in Cancer Susceptibility Genes Including BRCA1/2 in HR+/HER2− Early Breast Cancer [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 PS3-08-24.

Abstract Background The Oncotype Dx Recurrence Score (RS) has been validated in TAILORx and RxPONDER as both prognostic and predictive of chemotherapy benefit in women with hormone receptor positive (HR+) breast cancer with tumor size 1-5cm and 0-3 lymph nodes involved. It is unclear whether the ability of RS to predict breast cancer outcomes varies by histologic type because a large proportion of women in these studies had invasive ductal cancer (IDC). The goal of this analysis is to compare the clinical utility of RS by histologic type at diagnosis among women treated at an NCI designated comprehensive cancer center in Detroit, with particular attention to invasive lobular histology. Methods The study population included women diagnosed between 2013 and 2022, age 18 to 79 years, with invasive, HR+, HER2 negative, AJCC stage I or II breast cancer. All women with invasive lobular carcinoma (ILC) and mixed IDC/ILC were included, with a random sample of women with IDC selected. A medical record review was conducted to supplement cancer registry data obtained from the Metropolitan Detroit Cancer Surveillance System (MDCSS). Two abstractors performed the review, with a third reviewing a random sample of charts to assess accuracy. We compared the proportion of women with low risk (RS≤25) vs high risk (RS>25) stratified by histologic group using chi-square tests. Time to distant recurrence was the primary end point, with patients censored at death or last clinic visit. Results Of the 787 women identified, we included 366 for medical record review; 140 with IDC, 92 ILC, 48 mixed IDC & ILC, and 86 other histologies. Of these, 208 (57%) had documentation of quantitative RS in the medical record and were included in the analysis. There was a significant difference in high RS by histologic group, with 25.0% of IDC, 3.6% of ILC, and 4.4% of mixed IDC/ILC having RS >25 (p=0.001). There were a total of 14 distant recurrences after a mean 6.7 years of follow-up: five recurrences among women with IDC, four ILC, and five mixed IDC/ILC. Further analyses compared women with ILC or mixed vs. IDC. For women with low RS who did not receive chemotherapy, 4% (n=2/55) of women with IDC had distant recurrence compared with 9% (n=6/69) of women with ILC or mixed. Of the women with high RS who received chemotherapy, 13% (n=2/15) of women with IDC recurred compared to 100% (n=2/2) of women with ILC or mixed. Of the women with high RS who did not receive chemotherapy, 22% (n=2/9) of women with IDC recurred compared to 100% (n=1/1) of women with ILC or mixed. Conclusion High RS was significantly more common among women with IDC compared to tumors with lobular histology in this cohort of women with early-stage invasive breast cancer. There was a suggested higher rate of distant recurrence among women with lobular histology compared to those with IDC or mixed. All women with invasive lobular histology and RS > 25 developed a distant recurrence, regardless of whether they received chemotherapy, however the total number was small. Longer follow-up is needed for additional evaluation of differences in the predictability of RS by histologic type among women with early-stage breast cancer. We have received a grant from the Dynami Foundation to continue this work. Citation Format: M. Mayo, H. Assad, J. J. Ruterbusch, J. Boerner, S. Karne, M. S. Simon. Distribution and prognostic significance of recurrence score by histologic sub-type among women with early-stage hormone receptor-positive invasive breast cancer [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 PS2-12-30.

Abstract Background: The 21-gene Oncotype DX® assay is a validated prognostic and predictive tool for assessing chemotherapy (CT) benefit in patients with estrogen receptor–positive (ER+), HER2-negative (HER2–) early-stage breast cancer. It has demonstrated clinical utility in node-negative (N0) patients and postmenopausal patients with N1 disease. However, financial cost associated with the test may significantly limit its accessibility to patients. The present study evaluates whether machine learning models based on routinely available clinicopathologic and immunohistochemical data could accurately predict high likelihood of a Recurrence Scores greater than 25, possibly providing support for clinical decision-making. Methods: We retrospectively assembled a cohort of 897 patients diagnosed with ER+ breast cancer (BC) diagnosed between 2005–2024 at seven cancer centers. All patients had Oncotype DX® results and a complete pathology report. Of these, 158 (18%) had RS > 25. Statistical analysis identified Ki-67 (%), progesterone receptor (PR) status, and histologic grade as the most predictive variables. These were included in a ridge regression model to estimate continuous RS values (Table 1). Discriminative performance for RS > 25 was measured by AUC. To test robustness, we performed leave-one-center-out cross-validation: training on six centers and testing on the seventh. Performance was averaged across folds. Results: Among the 897 patients included, 708 (78.9%) had N0 disease, 62 (6.9%) N1mic, and 118 (13.2%) N1 disease. Of note, nodal information was unavailable for 9 patients (1.0%). The median age was 54 years (range, 24–83). Oncotype DX® testing indicated low (<11), intermediate (11–25), and high (>25) genomic risk in 165 (18.4%), 574 (64.0%), and 158 (17.6%) of patients, respectively. The model achieved a mean Pearson correlation of 0.50 ± 0.03 between predicted and actual RS, and an AUC of 0.78 ± 0.03 for detecting high-risk (RS ≥ 25) tumors. AUC stratified by menopausal status showed no significant difference (p = 0.858), indicating similar performance across groups. After min–max scaling, Ki-67 was the strongest positive predictor, followed by histologic grade conversely, PR status was inversely correlated with RS. These findings are consistent with established tumor biology and previous studies, in which a high proliferative index, poor histologic differentiation, and low immunohistochemistry PR expression are features associated with more aggressive tumor characteristics. Conclusion: A simple machine learning model using only Ki-67, histologic grade, and PR status moderately predicts the Oncotype DX® score and accurately identifies high-risk cases. In resource-limited settings, this approach could support clinical decision-making. Prospective validations are needed to confirm its clinical utility.Table 1: Significant variables according to Recurrence Score (RS) categories (RS ≤ 25 and RS > 25). Values are expressed as mean ± standard deviation for the continuous variable (Ki-67) and as number (percentage) for all categorical variables. Citation Format: J araujo, D araujo, L. Oliveira, P. de Souza, D. Rosa, A. Katz, D. Suzuki, D. Argolo, S. Sanches, L. Testa, J. Bines, R. Kaliks, R. Sousa, T. Corrêa, A. Shimada, C. dos Anjos, R. Linck, T. Megid, D. Batista, D. Gomes, M. Cesca, D. Gaudêncio, L. Moura, R. Bonadio, Z. Souza, J. Beal, M. Lopes, L. Sales, J. Marlière, M. Mano, D. Gagliato. Machine Learning Prediction of High Oncotype DX® RS based on Clinicopathologic features: Results from the GBECAM 0520 Multicenter Retrospective Study [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 PS3-08-12.

Abstract Background: Invasive lobular carcinoma (ILC) accounts for 10-15% of breast cancer (BC) cases and is predominantly hormone receptor-positive (HR+) and HER2-negative (HER2-). Although existing data indicates that ILC is less responsive to chemotherapy (CT) than invasive ductal carcinomas, the benefit of adjuvant CT in early-stage (ES) ILC is incompletely characterized. Further, the utility of the Oncotype DX Recurrence Score (RS), which has been used to predict response to CT in HR+/HER2- BC, has been debated for ILC. To address these issues, we studied the role of adjuvant CT on overall survival (OS) and by RS categories in ES ILC. Methodology: We queried the National Cancer Database for patients (pts) with ES HR+ HER2- ILC who underwent upfront surgical resection between 2010-2021. Pts were categorized to two cohorts based on receipt of adjuvant CT (CT+ and CT-). Subgroup analyses were performed based on RS score categories: low (L) 0-15, intermediate (I) 16-25, high (H) ≥26). Kaplan-Meier curves and log-rank tests determined OS between cohorts. Multivariate Cox proportional hazards models assessed OS, adjusting for potential confounders including age, race, stage, grade, and treatment variables. Results: Of the 162,430 ILC pts identified, 79.6% received adjuvant CT. The CT+ cohort were more likely to be younger pts (median age, IQR: 65 (55, 75) vs 66 (56, 72) years), have fewer comorbidities (Charlson-Deyo score (CDS) 0: 82.5 vs 82.3%, CDS 1: 13.1 vs 12.6%), intermediate grade disease (64.1 vs 62.2%), tumors <2 cm (67.1 vs 50.7%), clinically node negative disease (92.0 vs 77.7%), and receive radiation (63.5 vs 52.3%), and hormonal therapy (98.4 vs 51.4%), (all p<0.001). In the CT+ cohort, more pts had RS L (20.2 vs 8.9%), I (17.1 vs 7.5%), H (3.1 vs 1.7%) compared to CT-cohort (p<0.001). CT receipt conferred higher 5-year and 10-year OS. This survival benefit with adjuvant CT was observed among all RS groups with the highest benefit observed in H RS group (10Y OS: 84.5 vs 63.9%, p<0.001) ( Table 1). In multivariate analysis adjusting for relevant confounders, receipt of adjuvant CT was associated with decreased morality in the overall ILC cohort (Hazard ratio (HR), 95% CI: 0.79, 0.76-0.83, p<0.001) and the RS subgroups, though not statistically significant in L RS group (HR, 95% CI: L - 0.77, 0.59 - 1.01, p= 0.06; I - 0.78, 0.62 - 0.98, p= 0.04; H - 0.67, 0.50 - 0.89, p= 0.006). Conclusion: In this study, adjuvant CT was associated with improved OS in ILC pts with RS> 15. These data support use of RS for CT decision-making in appropriate candidates. Further investigations are needed to identify ILC pts who would benefit the most from adjuvant CT. Citation Format: A. Roy, Y. Gokun, B. Slover, N. Lopetegui-Lia, D. Quiroga, G. Bader, M. Cherian, A. Davenport, K. Johnson, S. Sardesai, R. Wesolowski, S. Myers, E. Burke, M. Gatti-Mays, N. Williams, D. Stover. Benefit of adjuvant chemotherapy for early-stage hormone receptor positive and HER2 negative lobular breast cancer patients: Analysis based on genomic risk scores [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 PS2-02-06.

Abstract Background: In early-stage estrogen receptor-positive (ER+), HER2-negative breast cancer, adjuvant chemotherapy decisions are increasingly guided by the Oncotype DX (ODX) Recurrence Score (RS). However, the high cost of ODX limits its use in resource-constrained settings. NHS PREDICT, a validated clinical prognostic tool, is often used to estimate survival benefit from adjuvant therapy. This study aimed to assess the correlation between NHS PREDICT estimates and ODX RS, to evaluate whether NHS PREDICT can help identify patients who would benefit most from ODX testing. Methodology: This multicentric retrospective study included 320 patients with early-stage ER+/HER2− breast cancer who underwent ODX testing between January 2012 and May 2025 across 3 tertiary cancer centers in India. The study was approved by the Institutional Ethics Committee (Waiver No. 2025/TMC/350/IRB7). NHS PREDICT scores were calculated using the online PREDICT tool. Chemotherapy recommendations based on NHS PREDICT were derived via multidisciplinary team (MDT) discussions, while final decisions were based on ODX RS. Clinical data were retrieved from REDCap databases and institutional electronic records. Statistical analysis was performed using SPSS version 25. Results: The mean age was 57.5 ± 10.2 years, mean tumor size 2.57 ± 1.15 cm, Ki-67 24.0 ± 17.6%, ODX RS 17.9 ± 10.8, and NHS PREDICT chemotherapy benefit score 3.29 ± 2.35%. A weak, non-significant correlation was observed between ODX RS and NHS PREDICT benefit score (Pearson r = 0.060, p = 0.285). Clinical risk and Recurrence Score (RS) were concordant in 55.9%. Concordance was highest in postmenopausal node-negative patients (72.5%) and lowest in postmenopausal node-positive patients (43.8%). RS upgraded 23.8% of clinically low-risk patients, highest in premenopausal node-negative cases (36.7%) and lowest in postmenopausal node-positive cases (2.8%). RS downgraded 79.8% of clinically high-risk patients, most notably in postmenopausal node-positive cases (84.1%). On a median follow-up of 29 months (IQR 24-33), there were 8 recurrences (4 local, 4 distant) and 6 deaths (2 cancer-related). The 5-year estimated distant disease-free survival was 96.5%, and cancer-specific survival was 98.9%. Conclusion: In this large multicentric Indian cohort, concordance between NHS PREDICT and RS for adjuvant chemotherapy decision-making was poor. NHS PREDICT frequently overestimated chemotherapy benefit, especially in postmenopausal node-positive patients, where 84% were downgraded by RS. Notably, in postmenopausal node-positive patients with low predicted benefit on NHS PREDICT, only 2.8% were upgraded by RS, suggesting that Oncotype DX testing may be safely omitted in this subgroup. These findings support a selective, cost-effective testing strategy in resource-limited settings Citation Format: S. K. Agrawal, M. Nadkarni, R. Ahmed, R. Sarin. Can NHS PREDICT Guide Oncotype DX Use in ER+/HER2− Early Breast Cancer: A Multicentre Analysis [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 PS2-02-16.

Abstract As shown by the TAILORx and RxPONDER trials, recurrence score (RS) identifies many postmenopausal pts who do not benefit from addition of ACT to endocrine therapy (ET); however, it also identifies certain subsets of premenopausal pts who do benefit (node-neg/high clinical risk/RS 16-20, node-neg/RS 21-25, and node-pos/RS ≤25). Most premenopausal pts in these trials did not receive ovarian function suppression (OFS) as part of their ET regimen. Given the observed benefit from OFS in high-risk premenopausal pts with HR+/HER2- BC in the SOFT/TEXT trials, we question whether the noted ACT benefit in TAILORx/RxPONDER may have been the result of chemotherapy-induced OFS. To address this, we developed OFSET, a phase III clinical trial comparing OFS+ET v ACT+OFS+ET. We hypothesize that addition of ACT to OFS+ET is superior to OFS+ET in improving invasive breast cancer-free survival (IBCFS) among premenopausal, early-stage BC pts with HR+/HER2- tumors and a 21-gene RS between 16-25 (for pN0 pts) and 0-25 (for pN1 pts). Secondary objectives include invasive disease-free survival, overall survival, distant recurrence-free interval, breast cancer-free interval, and health-related quality of life (HRQOL). Pts must be node-neg with RS 16-20 (plus high clinical risk), or RS 21-25, or have 1-3 positive nodes with RS ≤25. Stratification is by nodal status/RS status (pN0 RS 16-25 v pN1 RS 0-15 and pN1 RS 16-25), intent to receive CDK4/6 inhibitor (yes; no), and age (18-39 v ≥40). Pts are randomized after surgery to either OFS+ET or ACT+OFS+ET. ET is an aromatase inhibitor (AI) per physician discretion; or tamoxifen if AI is not tolerated or if OFS is incomplete. Radiotherapy will be administered per protocol guidelines. The HRQOL substudy will assess differences between arms in severe menopausal symptoms (measured by FACT ESS-19) and pain severity (PROMIS). Blood and tumor specimens will be collected for future research. We anticipate accrual of 3,960 pts in 7 yrs, 7 mos. Per NSABP B-28/RxPONDER data, 5-yr IBCFS of pN1 pts on the ACT+OFS+ET arm is estimated at 92.3%. Based on TAILORx data, 5-yr IBCFS of pN0 pts on the ACT arm is ∼95%. Assuming 56% of pts to be pN0 and 44% pN1, and a 0.5% annual loss-to-follow-up rate, the definitive analyses to detect a hazard ratio: 0.75 with ACT+OFS+ET v OFS+ET, with 1-sided α of 0.025 and 80% power, will require 380 IBCFS events, expected to occur ∼11 yrs after study initiation. Accrual is 292/3,960 (from 8/2023 to 5/2025). Among 148 pts with OFS data available, 79 (53.4%) were prescribed goserelin and 69 (46.6%) leuprolide. A monthly dosing schedule was prescribed for 86.1% of pts receiving goserelin and 73.5% of those receiving leuprolide; the remaining received a 3-monthly schedule. NCT05879926 Support: U10 CA180868, -80822, UG1 CA189867, U24 CA196067 Citation Format: S. Swain, G. Tang, S. L. Puhalla, P. A. Ganz, N. L. Henry, R. S. Cecchini, S. A. Reid, P. Rastogi, C. E. Geyer, Jr., J. R. White, A. S. Clark, T. C. Haddad, G. A. Vidal, N. Wolmark, E. P. Mamounas. NRG-BR009: A phase III trial evaluating addition of adjuvant chemotherapy to Ovarian Function Suppression + Endocrine Therapy in premenopausal women with pN0-1, HR+/HER2- breast cancer and recurrence score ≤25 (OFSET) [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 PS5-07-04.

Abstract Background: Invasive lobular carcinoma (ILC) represents 10-15% of all breast cancers (BC) and differs biologically and clinically from invasive ductal carcinoma (IDC). Conflicting data exist with regard to variation in prognosis and benefit of chemotherapy (CT) between these histologic subtypes. Here, we compare the impact of adjuvant CT on survival outcomes in patients (pts) with early-stage (ES) HR+/HER2- ILC and IDC. Methods: We queried the National Cancer Database for pts who received upfront surgical resection for ES HR+ HER2- invasive BC between 2010 and 2021, classifying cohorts into ILC or IDC subtypes. Cox proportional hazards models assessed the relationship between overall survival (OS) and histology type adjusting for potential confounders including age, race, stage, grade, and treatment variables. Subgroup analyses were performed based on CT receipt and Oncotype DX recurrence score (RS), a genomic assay used to predict response to CT, categorized as (low (L) 0-15, intermediate (I) 16-25, high (H) >=26). Results: Of the 1,101,920 pts included, 14.7% (n= 162,430) had ILC. Compared to pts with IDC, the ILC cohort was comprised of a greater proportion of Whites (87.7 vs 85.4%), intermediate-grade (63.7 vs 48.8%), clinical T2 (26.5 vs 22.1%) and N0 disease (89.1 vs 88.3%) (all p<0.001). RS scores varied by histologic subtype with a greater proportion of ILC having L (17.9 vs 17.2%) and I RS (15.2 vs 11.9%) compared to IDC, in which H RS was more common (2.8 % ILC vs 5.8% IDC). Use of adjuvant CT (79.6 vs 77.3%) and hormonal therapy (89.3 vs 86.4%) was higher in ILC, while radiation use was lower (61.3 vs 64.5%) (all p<0.001). The 5-year (Y) OS of ILC was similar to IDC (89.5 (89.3-89.7) vs 90.4 (90.3-90.5) %), however 10Y OS was worse for ILC cohort (73.6 (73.3-74.0) vs 76.7 (76.6-76.9) %, p <0.001). Among pts who received adjuvant CT, at 5 Y, OS was nearly identical between ILC and IDC across all RS groups. However, at 10 Y, OS was consistently lower in ILC compared to IDC, with a more pronounced difference in the I and H RS groups (Table 1). While OS was lower in ILC pts who received CT compared to IDC pts that received CT in univariate analyses of the overall cohorts (HR: 1.16, p<0.001) and when stratified by RS (L - 1.07, p= 0.01; I - 1.18, p<0.001; H - 1.12, p = 0.02), these associations did not retain significance when adjusting for clinically relevant confounders (HRs: Overall - 1.01, p= 0.16; L - 0.98, p= 0.52; I - 0.95, p= 0.11; H - 0.97, p= 0.51). An interaction was observed between histology type and stage (p = 0.0026). Conclusion: Our study suggests that while 5-year survival may be comparable, ES ILC pts receiving adjuvant CT may experience worse long-term outcomes compared to IDC, particularly among those with higher genomic risk. Further research is needed to personalize treatment strategies for ILC by identifying underlying molecular differences that drive this disparity. Citation Format: A. Roy, Y. Gokun, B. Slover, N. Lopetegui-Lia, D. Quiroga, G. Bader, M. Cherian, A. Davenport, K. Johnson, S. Sardesai, R. Wesolowski, S. Myers, E. Burke, M. Gatti-Mays, D. Stover, N. Williams. Impact of adjuvant chemotherapy in the survival outcomes of early-stage hormone receptor (HR)-positive HER2-negative lobular versus ductal carcinoma patients [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 PS4-08-04.

Abstract Background The Oncotype DX® assay is a validated genomic test that aids in assessing the risk of distant recurrence and in predicting the potential benefit of adjuvant chemotherapy in patients with early-stage HR+, HER2- breast cancer. In premenopausal women with 1-3 positive lymph nodes (N1) and a Recurrence Score (RS) of 0-25, the RxPONDER trial demonstrated a 2.4% improvement in distant recurrence-free interval (DRFI) and a 4.9% improvement in invasive disease-free survival (IDFS) in pts receiving chemo-endocrine therapy compared to endocrine therapy alone. Pts who received only endocrine therapy had a DRFI of 93,9% and an IDFS of 89%. The aim of this observational study is to establish a registry and present data on DRFI and IDFS in premenopausal women with node-positive breast cancer and a low RS who, either by choice or due to comorbidities, did not receive chemotherapy and were treated with endocrine therapy alone (with/without ovarian function suppression - OFS). Methods We conducted a retrospective multicenter analysis across 9 institutions in Greece, focusing on pre- & peri-menopausal women diagnosed with ER+/HER2-, node-positive (pN1 or pN1mic) early breast cancer, who underwent Oncotype DX® testing between 01/2012-01/2025, had a low RS (0-25), and did not receive chemotherapy. Three additional pts with N0(i+) disease were not included in the cohort analysis. Results A total of 74 pts were included in the analysis. The median age of diagnosis was 47 (range 26-54) and the median RS was 12 (range 0-22). Cohort clinical data are summarized below. With a median follow-up of 4.8 years (range: 1-150 months), one patient developed a distant recurrence in the lung (T1, N1mic, G3, no OFS, RS 17), while another was diagnosed with contralateral breast cancer (T1, N1, G2, with OFS, RS 15). The estimated 5-year DRFI and IDFS were 98.6% (95% CI, 92.5%-99.9%) and 97.3% (95% CI, 90.7%-99.5%), respectively. Among the three N0(i+)pts, no recurrences were observed during a mean follow-up of 3.4 years. Conclusion While the RxPONDER trial demonstrated a modest benefit from the addition of chemotherapy in premenopausal node positive pts independently of the RS, these real-world data suggest that selected pts may achieve favorable outcomes with endocrine therapy alone. A substantial proportion of pts received OFS (52.7%), with nearly half having N1mic disease (44.6%) and most presenting with T1 tumors (81.1%), suggesting a biologically distinct subgroup with potentially different treatment needs. This highlights the potential of individualized treatment planning using Oncotype DX in pre-/peri-menopausal pts with limited axillary tumor burden. Further studies with larger patient cohorts and longer follow-up are warranted to better define outcomes and optimize treatment strategies in this subgroup. Citation Format: L. Papadopoulos, C. Markopoulos, K. Papazisis, F. Zagouri, S. Triantafyllidou, A. Tsiftsoglou, A. Zavos, A. Koumarianou, M. Kontos, A. Fokianou, P. Ntasiou, P. Kalogerakos, S. D. Eleftheriadis, F. Fostira, C. Iosifidou, C. Stefanou, D. Maniatis, S. Filippidou, R. Alevizou, A. Papadopoulou, G. Kapetsis, S. Giannoulakis, D. Grigoriadis, G. Xepapadakis. Retrospective observational study of premenopausal ER+/HER2- patients in Greece with axillary tumor burden but low Oncotype DX® Recurrence Score who did not receive chemotherapy [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 PS3-09-02.

Abstract Background Nearly 70% of breast cancer patients are diagnosed with estrogen receptor (ER) positive, human epidermal growth factor-2 (HER2) negative breast cancer—a subtype with generally more favorable survival. Precision medicine for this subtype has been informed by gene expression assays, such as the Oncotype DX (ODX) recurrence score, that assess the 10-year risk of distant recurrence (Low, Medium, or High) and guide treatment decisions. Air pollution is recognized has been linked to more aggressive breast cancer subtypes, suggesting that exposure to air pollution may contribute to more aggressive tumors. However, no study has examined air pollution in relation to ODX, which can be used as a marker of tumor aggressiveness. We evaluated the associations of two air pollutants (PM2.5 and NO2) with ODX recurrence score among Black and White breast cancer patients. Methods We identified all women aged ≥18 years, diagnosed with a stage I-III first primary breast cancer between 2010 and 2015 in the Georgia Cancer Registry. Breast cancer patients were included if they were non-Hispanic Black (NHB) or non-Hispanic White (NHW) and had an ODX recurrence score. Daily ambient PM2.5 and NO2 concentrations were predicted at a 1-km resolution for the years 2005-2010 using an ensemble of three machine learning models available from the Environmental Protection Agency. For each patient, we assigned PM2.5 and NO2 exposures based on the average value in the 5-years prior to their diagnosis. We used multinomial regression to estimate the associations between a 5-unit increase in PM2.5 and NO2 and higher ODX scores (Intermediate vs Low and High vs Low), overall and by race. Models were adjusted for age at diagnosis (years), race (overall model only), and rurality. Results In the Georgia cohort (77% NHW, 23% NHB), 6985 women received ODX testing—4090 (56%) were classified as Low, 2394 (34%) as Intermediate, and 501 (7.2%) as High risk. A larger proportion of those with a High ODX recurrence score were NHB (30%) compared with a Low recurrence score (21%). In the overall study population, a 5-unit increase in PM2.5 was associated with higher odds of both an Intermediate (odds ratio [OR]=1.20, 95%CI: 1.02, 1.41) and High (OR=1.31, 95%CI: 0.97, 1.76) recurrence score compared with those in the Low-risk group (Table 1). Among NHW patients, these associations were attenuated (Intermediate vs Low: OR=1.14, 95%CI: 0.95, 1.36; High vs Low: OR=1.23, 95%CI: 0.87, 1.75). However, among NHB women, the associations were more pronounced (Intermediate vs Low: OR=1.48, 95%CI: 1.05, 2.09; High vs Low: OR=1.56, 95%CI: 0.88, 2.76). We did not observe associations between NO2 and ODX groups. Conclusions Our preliminary results suggest that air pollution, particularly PM2.5, may influence tumor aggressiveness. Moreover, this association may differentially impact NHB breast cancer patients, who are also more likely to live in areas with higher air pollution. Citation Format: L. J. Collin, T. Armide, L. E. Barber, K. Bishop, C. M. Destin, M. L. Maliniak, J. M. Switchenko, L. E. McCullough. Air Pollution and Oncotype DX recurrence socre: implications for racial disparities in breast cancer [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 PS4-09-28.

Abstract Background: TheTAILORx trial established that adjuvant endocrine therapy (ET) is non-inferiorto chemotherapy plus ET (CET) in T1-2N0 HR+/HER2-negative early breast cancer(EBC) with an Oncotype DX (ODX) 21-gene recurrence score (RS) of 11-25, RS 0-10is associated with low distant recurrence (DR) rates with ET alone, and RS26-100 is associated with higher DR rates despite CET. Although ODX isprognostic for 10-year DR, it has limited value for late DR >5 years. Inorder to develop improved DR risk prognostication, we developed multimodal AImodels integrating clinical, molecular, and histopathology features to provideprognostic information for early (<5years), late (>5 years), and overall DR at 15 years using primary tumorsamples and clinical data from volunteers who participated in TAILORx. Methods: DigitizedH&E slides were generated and nucleic acids extracted and sequenced from∼5000 primary tumor samples using Caris MI Tumor Seek-Hybrid, of which 2,808(56%) were used for model training and 5-fold nested cross validation (60/20/20split). Models included single-modality (clinical [C], image [I], molecular [M:ODX genes]), dual-modality (CM, IC), and multimodal (ICM). An expandedmolecular model (M+) model was also derived from expanded molecular inputsderived from whole transcriptome sequencing (WTS) data, including 5 commercialgene signatures (ODX, MammaPrint, Prosigna, EndoPredict, BCI) and 57 high-variancegenes; only EndoPredict, BCI, and ODX gene signatures were retained for model M+.Model-CM+ combined clinical plus expanded molecular features, while ICM/ICM+integrated image, clinical, and (expanded) molecular inputs. Risk scores were dichotomized into high vs. low risk groups usingthresholds chosen to yield risk group proportions closely matching thosedefined by the ODX RS cutoff of 25 for distinguishing high vs. low genomicrisk. Theprimary endpoint was distant recurrence (DR). Prognostic performance wasassessed using truncated concordance index (C-index, 90th percentile of eventtimes), hazard ratios (HRs), and log-rank tests. DNA-level whole exomesequencing (WES) features were also tested but did not provide additionalprognostic information and thus excluded from final models. Results: Theactual ODX continuous RS achieved a C-index of 0.625 for overall DR and 0.743early DR, but no prognostic value for late DR (0.52). Similar results for theC-index were observed for ODX+C for overall DR (0.619), early DR (0.724), andlate DR (0.514). Of all modelsevaluated, model-ICM+ gave the best overall prognostic accuracy for overall DR (C-index0.713; hazard ratio [HR] 3.56 for comparison of high vs. low risk, p<0.001)and late DR (C-index 0.655; HR 2.36, p<0.001), and ranked second for earlyDR (C-index 0.772; HR 6.59, p<0.001) behind the CM+ model (C-index 0.782). Amongsingle-modality models, Model-M+ improved early DR prognostication comparedwith a molecular model including only ODX genes(C-index 0.767 vs 0.744 for M),whereas Model-I was strongest for late DR prognostication (C-index 0.635). Conclusions: Molecularfeatures primarily drove prognostic accuracy for early DR within 5 years,whereas histopathology features strengthened the prognostic accuracy for lateDR after 5 years. Multimodal models captured these complementary signals, withICM+ giving the best overall accuracy for individualized prognostic assessment.Additional validation of the optimized ICM+ model and other models is beingperformed in an intendent validation sample of 2000 TAILORx volunteers, withresults to be presented at the meeting.Supported by the Breast CancerResearch Foundation and the U.S. NIH/NCI U10CA180820 and 5U24CA196172, and theU.S. Postal Service Breast Cancer Stamp Fund. Citation Format: J. A. Sparano, V. Wang, R. J. Gray, D. F. Makower, K. S. Albain, D. F. Hayes, C. E. Geyer, E. C. Dees, M. P. Goetz, J. A. Olson, S. S. Badve, T. J. Saphner, T. J. Whelan, M. Radovich, V. G. Kaklamani, G. W. Sledge. Multimodal artificial intelligence (AI) models integrating image, clinical, and molecular data for predicting early and late breast cancer recurrence in TAILORx [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 GS1-08.

Abstract Background: The optimal use of adjuvant chemotherapy in premenopausal women with early-stage hormone receptor-positive (HR+), HER2-negative (HER2−), node-negative breast cancer and intermediate Oncotype DX recurrence scores remains an area of clinical uncertainty. While prospective trials have provided clearer guidance for postmenopausal women, real-world treatment patterns and decision-making processes among premenopausal patients remain less well defined. Methods:We performed a retrospective analysis using the National Cancer Database (NCDB) to identify premenopausal women (<50 years) diagnosed from 2010-2021 with stage I-II, HR+/HER2−, node-negative breast cancer and recurrence scores of 11-25. We examined trends in chemotherapy omission, identified sociodemographic and clinical predictors of omission using multivariate logistic regression, and evaluated survival outcomes using Kaplan-Meier analysis and Cox regression. Results: Among 27,459 patients, 77.9% had stage I disease (n=21,408) and 22.1% had stage II (n=6,051). Chemotherapy was administered to 28.3% (n=7,773), while 71.7% (n=19,686) omitted it. Median age was 42 years among those who received chemotherapy and 44 years among those who did not. Among stage I patients, 24.2% received chemotherapy; in stage II, 42.6% received it. Chemotherapy use declined significantly from 35.4% in 2010 to 23.6% in 2021 (p < 0.001).Factors associated with chemotherapy omission included age 40-50 (OR 1.82, p < 0.001), diagnosis in 2014-2017 (OR 1.45, p < 0.001) or 2018-2021 (OR 1.58, p < 0.001) compared to 2010-2013, treatment at comprehensive (OR 1.09, p = 0.023), academic (OR 1.13, p = 0.002), or network centers (OR 1.11, p = 0.006) versus community centers, Medicare insurance (OR 1.81, p < 0.001), higher median income ≥$46,000 (OR 1.14, p = 0.002), and higher Charlson-Deyo scores (score 2: OR 1.23, p = 0.001; score ≥3: OR 1.32, p = 0.012).Conversely, chemotherapy omission was less likely among Black (OR 0.85, p < 0.001), South Asian (OR 0.68, p < 0.001), Hispanic (OR 0.83, p < 0.001), and rural patients (OR 0.88, p = 0.005) compared to non-Hispanic White and metropolitan patients, respectively.Five-year overall survival was similar between chemotherapy and no chemotherapy groups (98.1% vs. 97.6%, p = 0.244), with no significant survival benefit in Cox regression (HR 0.98, 95% CI 0.89-1.07, p = 0.51). Conclusions: Chemotherapy omission has increased over time among node negative premenopausal women with intermediate recurrence scores, yet practice variability remains. In this real-world population where treatment decisions were made by patients and physicians, there did not appear to be a survival benefit associated with chemotherapy.Ongoing prospective studies are further evaluating the safety of chemotherapy omission in premenopausal women with low genomic and higher anatomic risk, including the OFSET Trial (NRG-BR009, NCT05879926). Citation Format: I. Ajjawi, M. Wong, W. Wei, T. Park, J. Du, M. Rozenblit, S. Schellhorn, A. Kahn, N. Casasanta, E. Winer, M. Lustberg. Real-world patterns of chemotherapy use in premenopausal women with node-negative early-stage HR+/HER2− breast cancer and intermediate genomic risk [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 PS3-08-16.

Abstract Background: The Oncotype DX ® test (21-gene Recurrence Score (RS) test) is widely used to guide adjuvant chemotherapy (CT) decisions in hormone receptor-positive (HR+), HER2-negative early breast cancer. However, variability in clinical interpretation persists in real-world settings. This study prospectively assessed how the Oncotype DX test influences CT decision-making among Swiss breast cancer experts. Methods: From a cohort of 325 patients with HR+/HER2− early breast cancer and available Recurrence Score ® results, 50 anonymized randomly selected cases were chosen. Ten board-certified Swiss medical oncologists, all specialized in breast cancer, independently evaluated each case and made CT recommendations before and after disclosure of the Recurrence Score results. Changes in treatment decisions were assessed using McNemar’s test and ANOVA. Results: The Oncotype DX test led to changes in treatment recommendations in 19.8% of cases. CT was recommended in 35.4% of pre-testing decisions, compared to 21% post-testing, representing a 14.4% net reduction. Changes in CDK4/6 inhibitor and osteoprotection recommendations were minimal (0.4% and 0.2%, respectively). The most pronounced impact was observed in cases with intermediate clinical risk, particularly tumors 2-4.5 cm and N0 status. Notably, 23 (46%) patients had tumors with node-positive disease. One-way ANOVA showed no significant difference in mean treatment recommendations before and after Oncotype DX testing (F(1,58)=0.29, p=0.59). However, McNemar’s test revealed a highly significant directional shift (p<0.0001), primarily reflecting de-escalation of CT. Only one oncologist escalated treatment in a single case. Inter-observer variability decreased following Recurrence Score result disclosure. Conclusions: The Oncotype DX test significantly influenced adjuvant treatment decisions, primarily leading to chemotherapy de-escalation. It also increased decision consistency among Swiss breast cancer specialists, underscoring its value not only in guiding individual care but also in harmonizing expert judgment in routine practice. Citation Format: M. Vetter, S. Ebner, E. Kralidis, C. Kurzeder, A. Oseledchyk, E. Chiru, J. Landin, K. Schmutz-Kober. Decision-making on adjuvant chemotherapy in early hr+ breast cancer: a prospective evaluation of oncotype dx® utility among swiss breast cancer experts [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 PS3-10-10.

Abstract BACKGROUND Genomics platform (GP) has transformed the management of patients with early stage, HR+, HER2 negative (HER2-) BC by guiding personalised treatment decisions regarding adjuvant CT. However, real world patterns of CT used base of recurrence score (RS) remain a topic interest. Using our hospital-based database we evaluated testing patterns, factors associated with GP testing and examined predictor of CT use among patients by RS. METHODS This retrospective observational study included patients ≥ 18 years with early-stage, HR+/HER2- BC diagnosed from 2021-2024 who underwent surgery with pT1-T3, pN0-N1 staging and meet clinical guideline criteria for requesting a genomic study were included. Descriptive analyses were used, including demographic and clinical characteristics of patients. Multivariable logistic regression was used to examine factors associated with receipt of GP testing and predictors of CT use, stratified by Low risk, intermediate risk and high risk RESULTS A total of 196 patients were included, with a median age of 60 years. The majority had stage IA (54%), grade 2 (79%) tumors, and infiltrating ductal histology (84.7%), with 36% presenting Ki67 ≥20%. Twenty-six percent were premenopausal, and 27% had axillary involvement. Oncotype DX was the most commonly used genomic platform (81%) followed by MammaPrint (17.1%) and Prosigna (1.7%). Risk stratification showed 72% low risk, 12% intermediate risk, and 15% high risk. All high-risk patients, except one, received adjuvant chemotherapy, while no intermediate-risk patients received chemotherapy. With a median follow-up of 34 months, only two local recurrences were observed, both in low-risk patients. Low progesterone levels, Ki67 >20%, and premenopausal status were significantly associated with high risk (p<0,0001). Lymph node involvement and tumor grade were not significantly associated with high risk, although grade 3 showed a trend toward statistical significance (p=0.057). Regarding HER2 status, only 4% of HER2 0 patients were high risk, whereas 20% of HER2 1+/2+ patients were high risk; this association was not statistically significant (p=0.1). CONCLUSIONS Our study confirms the utility of genomic platforms, particularly Oncotype DX, in guiding adjuvant chemotherapy decisions for early-stage, HR+/HER2- breast cancer, with 81% of patients tested using this platform. The high proportion of low-risk patients (72%) and the absence of chemotherapy in intermediate-risk patients align with clinical guidelines, reflecting risk-stratified treatment de-escalation. The significant association of low progesterone levels, Ki67 >20%, and premenopausal status with high risk underscores their role as prognostic factors, consistent with prior literature. The trend toward significance for grade 3 tumors (p=0.057) and the higher proportion of high-risk patients among HER2 1+/2+ cases (20% vs. 4% in HER2 0, p=0.1) warrant further investigation, as these may indicate subgroups with distinct biological behavior. Limitations include the single-center design and relatively short follow-up, which may limit generalizability and detection of late recurrences. Larger, multicenter studies with longer follow-up are needed to validate these findings and refine the role of HER2 status in risk stratification. Citation Format: R. Urbano, R. García, A. Beltran, M. Martin-Salvago, A. Cano, A. Jaén, P. Sánchez-Rovira. Genomic Platform (GP) Testing and Adjuvant Chemotherapy (CT) Use in Early-Stage hormone receptor-positive (HR+) /HER2 negative (HER2-) Breast Cancer (BC): Real-World Insights and Prognostic Factors [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 PS3-10-03.

Abstract Introduction Abemaciclib is a selective CDK4/6 inhibitor approved for adjuvant treatment in patients with high-risk hormone receptor-positive, HER2-negative (HR+/HER2-) early breast cancer (eBC). The MONARCH-E trial demonstrated significant increase in invasive disease-free survival (iDFS) when combined abemaciclib with endocrine therapy. Nonetheless, real-world data regarding safety, treatment adherence, and drug-drug interactions (DDIs), particularly among elderly and comorbid populations often excluded from clinical trials, remain limited. Evaluating these real-world factors is critical to optimizing treatment and patient outcomes in clinical practice. Methods This retrospective study analyzed consecutive patients with HR+/HER2- eBC treated at 21 Italian oncology centers who received adjuvant abemaciclib combined with an aromatase inhibitor (AI). Comprehensive clinical data, medication usage, and adverse events (AEs) were collected. Drug-PIN®, a platform integrating clinical (age, sex, race, smoking and alcohol habits), laboratory (renal and hepatic function), and pharmacological parameters (chronic concomitant treatments), was utilized to assess DDIs, providing a numeric interaction score (Drug-PIN score) and qualitative risk tiers (green: none; yellow/dark yellow: intermediate; red: high risk). Statistical analyses, including univariate and multivariate approaches, identified predictors of AEs. Results We enrolled 714 patients with a median age of 56 years (range 30-86); 44% were premenopausal, and 51% had at least one comorbidity, while 13% had multiple comorbidities. Notably, 60 patients (8.4%) were aged ≥75 years. Genetic testing performed in 350 patients identified 29 mutated. Disease characteristics included node-positive (c/pN2) status in 389 (54%), carcinoma of no special type in 73%, lobular carcinoma in 14%, and high-grade tumors (G3) in 57%. Chemotherapy was omitted in 10% of cases. Oncotype DX testing was conducted in 42 patients (6%), with a mean recurrence score (RS) of 26 (range 8-50); 20 had an RS ≤25. With a median follow-up of 13.2 months (range 1-33), 85% of patients experienced any-grade AEs, primarily diarrhea (76%), asthenia (41%), and neutropenia (27%). Grade ≥3 AEs occurred in 30%, with severe diarrhea reported in 11%, mostly during the first two cycles. Dose reductions were required in 47% and discontinuation due to toxicity occurred in 9.5%. Patients aged ≥75 showed comparable diarrhea rates (p = 0.20) but a trend toward increased dose reductions (p = 0.09). Concomitant medications were reported in 50% of patients, and 8% had polypharmacy. The median Drug-PIN interaction score was 12.0 (range 3-100), with at least one DDI identified in 17.3% of the patients, with 10.5% categorized in the intermediate-high or high-risk tiers. Notably, high-risk DDIs occurred more frequently among patients who discontinued treatment due to toxicity (25% vs 10%, p = 0.04). Conclusions Adjuvant abemaciclib is safe and manageable in real-world settings, even among elderly and comorbid patients, showing slightly higher but comparable AE rates and dose adjustments relative to clinical trials. Overall, abemaciclib treatment presents a low incidence of drug-drug interactions. However, the significant association observed between DDIs and dose reductions emphasizes the necessity for further prospective investigations to better define these interactions and inform clinical practice. Citation Format: S. Scagnoli, M. Verrico, S. Pisegna, R. Caputo, F. Pantano, P. Falbo, G. D'Auria, A. Orlandi, D. Alesini, I. Portarena, P. Vici, M. Fabbri, L. Rossi, T. Di Palma, G. Gentile, M. Bonomo, L. Sisca, C. Bonadonna, L. Strigari, G. Ricciardi, M. Pizzoli, E. Giordani, A. Irelli, M. Sanò, M. Palleschi, R. Preissner, A. Daneri, O. Garrone, G. Bianchini, C. Martinelli, C. Criscitiello, M. Lambertini, A. Fabi, M. De Laurentiis, L. Del Mastro, G. Curigliano, P. Marchetti, A. Botticelli. Early AB-ITALY: Evaluating Real-World Use of Adjuvant Abemaciclib and Drug Interaction Risk in HR+/HER2- early Breast Cancer [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 PS3-09-18.

Abstract Background: The SWOG S1007 (RxPONDER) trial demonstrated that premenopausal women with hormone receptor-positive, Her2-negative breast cancer, 1–3 positive nodes, and Recurrence Score (RS) < 26 benefit from adjuvant chemotherapy, but postmenopausal women do not. Most patients in RxPONDER underwent axillary lymph node dissection (ALND) to stage the axilla; however, axillary management has evolved. It is unclear whether the RxPONDER trial results were similar in patients who had sentinel lymph node biopsy (SLNB) only versus ALND. Methods: We performed a secondary analysis from RxPONDER to evaluate whether clinical outcomes differed between patients undergoing SLNB alone versus ALND. Endpoints included invasive disease-free survival (IDFS), distant relapse-free survival (DRFS), and locoregional recurrence (LRR). Results: Of 4980 women with available surgical data, 1847 (37%) had SLNB only, 707 (14%) ALND only, and 2426 (48.7%) both SLNB and ALND. Compared to the SLNB + ALND group, the SLNB-only group was older, postmenopausal, obese, and more likely to undergo partial mastectomy. Tumors were lower-grade, smaller, more often ductal, and less likely to be multicentric or have lymphovascular invasion (LVI). RS was similar across groups. SLNB-only patients had fewer nodes removed, less internal mammary node involvement, fewer positive nodes, and smaller SLN metastases. Those with a single positive node had a similar profile. On multivariate analysis, postmenopausal status and obesity increased the likelihood of SLNB alone; larger tumors and LVI decreased it. Among 1774 mastectomy patients, 352 had SLNB only; they were more often postmenopausal and obese, with otherwise similar features. IDFS, DRFS, and LRR were comparable across axillary surgery types after adjustment for clinical variables. In premenopausal SLNB-only patients (N=550), the chemotherapy arm had numerically improved IDFS (HR 0.68; 95% CI 0.43–1.07; p=0.09) and LRR (HR 0.45; 95% CI 0.14–1.42; p=0.17), though not statistically significant. This result is consistent with the main trial effect. Among SLNB-only patients who underwent partial mastectomy, 96% received adjuvant radiation. Conclusions: In this secondary analysis of RxPONDER, over one-third of patients underwent SLNB alone. These patients were older, more likely postmenopausal, and had more favorable tumors. Despite having less nodal surgery with fewer nodes removed, outcomes including IDFS, DRFS, and LRR were similar to those who underwent more extensive surgery. Among premenopausal patients, chemotherapy was associated with numerically better outcomes in the SLNB-only group, though not statistically significant. These findings support the safety of SLNB alone in selected patients and suggest further study in key subgroups.Funding: NIH/NCI/NCTN grants U10CA180888, U10CA180819 Citation Format: R. F. Hwang, W. E. Barlow, K. Kalinsky, R. Jagsi, L. Pusztai, A. Thompson, G. N. Hortobagyi, P. Sharma, F. Meric-Bernstam. Sentinel Lymph Node Biopsy and Clinical Outcome of Patients with Node-Positive Breast Cancer in the RxPONDER Trial (S1007) [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 PD12-05.

Abstract Background: The Oncotype DX® test, 21-gene recurrence score assay, is a commercially available genomic assay that calculates a Recurrence Score® (RS) result ranging from 0 to 100 based on the expression of 21-genes. The RS result provides prognostic information independent of clinicopathological factors and predicts the benefit of chemotherapy (CT) to guide adjuvant treatment decisions in patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2-) early breast cancer (BC). In Japan, the Oncotype DX test has been reimbursed under public health insurance since September 1, 2023, and is expected to help optimize CT decision-making. However, real-world evidence (RWE) on its clinical use remains limited. This study presents the first large-scale, real-world analysis in Japan using a nationwide claims database to describe clinical and demographic characteristics, as well as treatment patterns associated with the use of Oncotype DX testing. Methods: We conducted a retrospective cohort study of pts with BC who underwent Oncotype DX testing between the start of reimbursement (September 2023) and December 2024 using a nationwide claims database provided by Medical Data Vision Co., Ltd. (Tokyo, Japan), which includes data from approximately 230 acute care hospitals. All Oncotype DX-tested pts were included in the analysis of clinical and demographic characteristics. For treatment pattern analysis, the cohort was limited to those with at least 6 months of follow-up after testing. CT and endocrine therapy (ET) were classified as either neoadjuvant or adjuvant. Results: A total of 3,837 pts with BC who underwent ODX testing following reimbursement were identified. The median age was 57.0 [IQR: 49.0-67.0], including 17 male pts (0.4%), and the median BMI was 22.6 [IQR: 20.3-25.7].The majority of pts had T1 (55.1%) or T2 (40.4%) tumors and were node-negative(N0: 87.4%). Distant metastasis was rare (M1: 0.1%). Whereas 49.9%, 38.7% and 7.0% of pts had Stage IA, Stage IIA or Stage IIB disease, Stage III or IV disease was rare (<1%).Most pts (87.8%) were treated at designated cancer care hospitals. Over half received care at large hospitals with ≥500 beds (53.3%), and 45.8% were treated at mid-sized hospitals with 200-499 beds. Among pts with at least 6 months of follow-up after Oncotype DX testing, 23.2% received adjuvant CT. The most common regimen was ACT (anthracycline, cyclophosphamide, and taxane) (48.4%) followed by TC (taxane, cyclophosphamide) (43.4%). ET was administered to 9.1% of pts as neoadjuvant treatment and to 95.1% as adjuvant treatment. Among pts who received adjuvant ET, aromatase inhibitors were most frequently used (58.0%), followed by selective estrogen receptor modulators (SERMs) alone (21.8%), and a combination of luteinizing hormone-releasing hormone agonists and SERMs (15.9%). Additionally, 36.9% pts received radiation therapy. Conclusion: This study presents the first nationwide RWE on the clinical use of the Oncotype DX test in Japan. The findings indicate that the large majority of pts with BC who undergo Oncotype DX testing receive care at cancer-specialized or large medical centers. Cancer staging and treatment patterns suggest that the Oncotype DX test is being appropriately applied in pts with HR+/HER2- early BC, consistent with current guidelines for personalized treatment. Citation Format: M. Hihara, H. Bando, A. Shimomura, N. Sugiyama, N. Yoshii, R. Kawai, A. Shintani, S. Saji. Real-world evidence on the use of a 21-gene recurrence score assay in patients with HR+/HER2− early breast cancer in japan: a nationwide claims database analysis [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 PS3-08-28.

Abstract Background: The OncotypeDX Recurrence Score® (RS) is a validated multigene assay yielding prognostic and predictive information in patients with hormone receptor (HR) positive HER2neu negative early breast cancer and is part of guideline recommendations in national and international guidelines. The clinical utility of the RS has been prospectively investigated using risk levels of low risk (0-10), intermediate risk (11-25) and high risk (26-100). In patients older than 50 years the risk groups low and intermediate are indicating a low risk of recurrence (justifying omission of adjuvant chemotherapy), whereas an RS of 26-100 indicates high risk. In patients age 50 and younger the granularity is higher with risk levels of low (0-15), low to medium (16-20), intermediate (21-25) and high risk (26-100). However, a continuous interpretation of the score would be helpful in risk assessment and counseling given the fact that recurrence risk is a biological continuum. Here we are presenting an analysis of RS values as a continuous parameter from a real-world population. Methods: Patients included in this analysis had HR positive HER2neu negative early breast cancer with 0-3 involved lymph nodes assessed as intermediate risk by institutional guidelines including Ki67 and a complete follow-up. An RS was performed in all tumors with material from the core cut biopsy. Patients with a RS of 26 and higher received neoadjuvant chemotherapy. Disease free survival (DFS) events were defined as local or distant recurrence or death from any cause. Overall survival (OS) events were defined as death from any cause. Associations of Recurrence Score® and DFS or OS events were calculated by Cox Regression. Results: 79 female patients were included in this analysis. Median follow-up was 6.9 (0.9-11.0) years. Patient characteristics were as follows: median tumor size 1.4 (0.3-4.5) cm, median age at diagnosis 60.7 (34.7-82.5) years, median Ki67 20 (2-35) %, median RS 16 (0-46). Sixty-two patients (78.5%) were postmenopausal. 2 (2.5%), 74 (93.7%) and 3 (3.8%) patients had grade 1, 2 and 3 disease, respectively. 79 (100%) patients had ER positive, 73 (92.4%) patients had PR positive tumors. 20 patients (25.3%) had node positive (1-3 positive lymph nodes) disease. 9 (11.4%) patients received anthracycline- and taxane-containing neoadjuvant chemotherapy. During follow-up 5 (6.3%) patients experienced a locoregional recurrence and 8 (10.1%) patients a distant recurrence. 5 (6.3%) patients died, in 4 cases (5.1%) from breast cancer. The risk for a DFS event increased by 8.1% by every one-unit (integer) in RS (p=0.022). For OS events, every one-unit increase in RS increased the risk of death by 9.3% (p=0.027). Conclusion: In our population of patients with intermediate risk by traditional risk parameters including Ki67 survival was excellent with 93.7% of patients alive after a median follow-up of 6.9 years. However, within this selected risk group the continuous assessment of the RS performed using material from core cut biopsies indicated an increased risk for a DFS or OS event by every one-unit increase in RS. Our analysis is hypothesis-generating and justifies an approach in a multicenter registry population with greater statistical power allowing multivariate analysis and the assessment of confounding parameters. If our results can be reproduced in a large-scale analysis they could help calculating the risk of an individual patient with more granularity than by use of risk groups alone. Citation Format: H. Kolberg, S. Hildebrandt, L. Akpolat-Basci, A. Farag, A. Maguz, M. Stephanou, C. Kolberg-Liedtke. Use of the OncotypeDX Recurrence Score® (RS) as a continuous prognostic biomarker in hormone receptor (HR) positive HER2neu negative early breast cancer with intermediate risk of recurrence may asses risk of recurrence or death more appropriately [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 PS3-09-01.

Abstract Background: There is growing evidence supporting the benefits of the Mediterranean diet in breast cancer (BC) prevention, but their contribution to prognosis remains unclear. Our objective is to investigate whether adherence to the Mediterranean dietary patterns before diagnosis is associated with the risk of BC recurrence and tumor proliferation in an exploratory cohort of the multicenter case-control EpiGEICAM study. Methods: Transcriptome-wide gene expression was assessed using the nCounter Breast Cancer 360 panel (NanoString). Formalin-fixed paraffin-embedded tumor tissues from an exploratory cohort of 89 pre- or perimenopausal BC patients from the EpiGEICAM study were used. The PAM50 gene expression signature was employed to classify tumors into the gold-standard BC intrinsic molecular subtypes, and to compute both the PAM50 risk of recurrence (ROR) and PAM50 proliferation scores. Dietary patterns over the five years prior to diagnosis were identified in the control population of the EpiGEICAM study, applying principal components analysis without rotation of the variance-covariance matrix over 26 inter-correlated food groups. The association between adherence to Mediterranean dietary patterns and both ROR and proliferation scores was analyzed using linear regression models with continuous outcomes. All models were adjusted for age and adherence to a Western dietary pattern, with additional adjustment for PAM50 molecular subtype in the proliferation score analysis. Results: The mean age was 44 years and 28% had a family history of BC. Regarding molecular subtypes, 49.4% corresponded to Luminal A, 22.5% to Luminal B, 13.5% to HER2-enriched and 14.6% to Basal-like subtype. High adherence to the Mediterranean dietary pattern was observed in 56% of participants, with higher prevalence among women with Luminal A and Luminal B subtypes. The mean ROR score was 51 (95%CI=46-57) in women with low adherence to the Mediterranean diet, and 46 (95%CI=40-51) in those with high adherence. Mean proliferation scores were 4.8 (95%CI=4.6-5.1) and 4.5 (95%CI=4.3-4.8), respectively. Although no statistically significant associations were observed, women with high adherence to the Mediterranean dietary pattern showed lower mean ROR score (β=-5.8; 95%CI=-14.0-2.5) and a reduced proliferation score (β=-0.14; 95%CI=-0.40-0.12) compared to those with low adherence. Conclusion: The present EpiGEICAM exploratory analysis showed that adherence to a Mediterranean dietary pattern prior to diagnosis may be associated with lower breast cancer PAM50 proliferation and risk of recurrence scores. Studies with larger sample sizes are needed to confirm these results and to clarify the effect of the Mediterranean diet on the biology and prognosis of this tumor. Citation Format: V. Lope, P. Fernández, Á. Guerrero-Zotano, P. Sánchez-Rovira, A. Antón-Torres, M. Benavent-Viñuales, J. Baena-Cañada, S. Antolín, M. Muñoz, L. Paris, J. Chacón, C. Olier, S. González, J. García-Sáenz, Á. Jimenez-Arranz, A. Oltra, J. Brunet, M. Marin-Alcala, A. De Juan, B. Pérez-Gómez, R. Rincón, R. Caballero, B. Bermejo, M. Martín, M. Pollan. Association between adherence to the mediterranean dietary pattern and PAM50-derived breast cancer proliferation and recurrence risk scores. Exploratory analysis from the Epigeicam study [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 PS3-01-27.

Abstract Background: Breast cancer is the most common cancer and leading cause of cancer-related death in women. Invasive lobular carcinoma (ILC) is the second most common histological type of breast cancer after Invasive breast carcinoma of no special type (invasive ductal carcinoma [IDC]). ILC accounts for 10-15% of all breast cancer cases. Prior studies have suggested different patterns of short-term (<5 years) and long-term (>5 years) survival between ILC and IDC. However, comprehensive data on both outcomes is limited. The objective of our study was to identify the factors associated with early and late mortality in patients with ILC. Methods: We conducted a retrospective analysis using the National Cancer Database (NCDB) from 2006-2020. Inclusion criteria were female gender, age ≥ 18 years, lobular histology, breast cancer stage I-III and removal of breast cancer tumor and axillary lymph nodes. Our primary endpoint, overall survival (OS), was defined as time in months from the date of diagnosis until death. The short-term OS analysis evaluated survival from diagnosis until 5 years from diagnosis (censored data at 5 years). The long-term OS analysis evaluated those patients who were alive after 5 years from diagnosis. We used the Pearson X2 test to evaluate the relationship between categorical variables and the t test for continuous variables. Cox hazard regression models were used to identify factors associated with short-term (< 5 years) and long-term OS (> 5 years). Results: The analysis of short-term OS included 115,159 patients, most of them were Non-Hispanic White (81%) with a median age of 63 years. Most tumors were T1 (57%), N0 (71%), Hormone Receptor positive (ER+ 100%, PR+ 87%), HER2 negative (81%). 52,503 (46%) patients underwent mastectomy. The 5-year OS rate was 93%. Old age (Hazard Ratio [HR] 2.16; p <0.001), large tumor size (HR 1.97 p <0.001), axillary node involvement (HR 5.15; p <0.001), high grade (HR 1.59; p <0.001), and lymphovascular invasion (LVI) (HR 1.19; p <0.001) were associated with worse short-term OS; whereas mastectomy (HR 0.84, p <0.001), chemotherapy (HR 0.77; p <0.001), radiation (HR 0.6; p <0.001), PR positivity (HR 0.74; p <0.001) and endocrine therapy (ET) (HR 0.5; p <0.001) were associated with improved short-term OS. Among patients who had OncotypeDx testing (N= 3,800), compared to low-OncotypeDx recurrence score, those with high OncotypeDx recurrence score had worse short-term OS (HR 1.68; p <0.001), whereas the short-term OS was similar for those with intermediate OncotypeDx recurrence score (HR 0.67; p = 0.3). The analysis of long-term OS included 67,927 patients with a median age of 62 years. The 10-year OS rate for this cohort was 86%. Old age (HR 1.89; p <0.001), large tumor size (1.58; p <0.001), axillary nodal involvement (HR 4.38; p <0.001), high tumor grade (HR 1.37; p <0.001), and LVI (HR 1.12; p = 0.01) were associated with worse long-term OS; whereas mastectomy (HR 0.94; p = 0.04), chemotherapy (HR 0.81; p <0.001), radiation (HR 0.84; p <0.001), PR positivity and ET (HR 0.78; p <0.001) were associated with improved long-term OS. Among patients who had OncotypeDx testing (N= 18,339), compared to low OncotypeDx recurrence score, those with high OncotypeDx recurrence score had worse long-term OS (HR 1.8; p <0.001); whereas the long-term OS was similar for those with intermediate OncotypeDx recurrence score (HR 1.17; p = 0.08) Conclusion: Pathological characteristics such as size and nodal status are prognostic for short-term and long-term survival outcomes in ILC. Adjuvant chemotherapy and endocrine therapy improve short-term and long-term OS in ILC. High OncotypeDx recurrence score can identify patients with worse short-term and long-term OS. Our results highlight the prognostic value of pathological characteristics, genomic profiling, and adjuvant therapies in ILC beyond 5 years. Citation Format: J. Avila, X. Xue, A. Gyamfi, J. D. Anampa. Factors Associated with Early and Late Mortality in Invasive Lobular Carcinoma [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 PD9-10.