HER2-negative Early Breast Cancer Research Articles

The emerging predictive and prognostic role of HER2 in HER2-negative early breast cancer: a retrospective study.

Many patients with early breast cancer (eBC) undergoing neoadjuvant chemotherapy do not achieve pathological complete response (pCR), which is a prognostic factor. We examined the role of HER2-low expression in predicting pCR and prognosis in HER2-negative eBC. We evaluated patients with stage I-III HER2-negative BC, treated between 2013 and 2023 at The Royal Marsden NHS Foundation Trust, London. Tumors were classified based on estrogen receptor (ER) status and into HER2-low and HER2-zero subgroups. We analyzed pCR rates, relapse-free survival (RFS) and overall survival (OS). 754 patients were included in the analysis. pCR rate was 8.9% in the ER+ /HER2-low, 16.5% in the ER+ /HER2-zero, 38.9% in the ER- ER-/HER2-low and 35.9% in the ER-/HER2-zero eBC (p < 0.001). Multivariable analysis showed a significantly lower pCR rate in HER2-low compared to HER2-zero BC in the ER+ subgroup. At a median follow-up of 63.8months (59.9-67.4), we observed longer OS in HER2-low compared to HER2-zero patients in the overall and in the ER+ population. There was no predictive or prognostic impact of HER2-low status in the ER- population. This study supports the interpretation of HER2 status as a possible prognostic and predictive biomarker for HER2-negative eBC, especially among patients with ER+ disease.

Long-term prospective outcome data using EndoPredict as risk stratification and chemotherapy decision biomarker in hormone receptor-positive, HER2-negative early breast cancer

Abstract Purpose To report the prospective long-term outcome data of patients whose chemotherapy decision was guided by the EndoPredict test. Methods Patients with hormone receptor-positive HER2-negative early breast cancer with 0–3 positive lymph nodes were enrolled. The EndoPredict test was carried out on all tumor samples. Treatment compliance, local recurrence, distant metastases, and survival were evaluated. Associations of EPclin risk stratification with 5-year disease-free survival and distant metastasis-free survival were evaluated by time-to-event analysis. Results 368 consecutive patients were included in the analysis. Median follow-up was 8.2 years. EndoPredict allocated 238 (65%) in the low-risk and 130 (35%) patients in the high-risk group. Risk for disease recurrence or death in EPclin high-risk patients was twofold higher than in EPclin low-risk patients (hazard ratio [HR] 2.08; 95% CI 1.26–3.44; p = 0.004). EPclin low-risk patients had a 5-year disease-free survival of 95.3% (95% CI 92.6–98.0%). EPclin high-risk patients were at higher risk of developing distant metastases or death (HR 2.21; 95% CI 1.27–3.88; p = 0.005). EPclin high-risk patients who underwent chemotherapy had a 5-year DFS of 89.1% (95% CI 82.7–96.1%) in contrast to high-risk patients without chemotherapy (68.9%; 95% CI 56.2–84.5%; HR 0.46; 95% CI 0.23–0.95; p = 0.036). EPclin high-risk patients were at higher risk of experiencing distant metastases or death than EPclin low-risk patients regardless of menopausal status (premenopausal: HR 3.55; 95% CI 1.17–12.32; p = 0.025; postmenopausal: HR 1.92; 95% CI 0.99–3.7; p = 0.054). Conclusion EndoPredict can guide decisions on adjuvant chemotherapy in early luminal breast cancer. EndoPredict risk stratification is also applicable in premenopausal women.

Abstract PO2-02-03: Clinical and pathological factors associated with Oncotype DX® 21-Gene recurrence score in patients diagnosed with early stage breast cancer in a low-middle income country

Abstract INTRODUCTION: Oncotype DX® recurrence score (ODX RS) is a 21-gene assay warranted to determine the the prognosis in patients with hormone receptor positive, HER-2 negative early stage breast cancer. In this context, the test is also predictive of benefit of adjuvant chemotherapy.1,2,3 OBJECTIVES: We aimed to correlate the clinical and pathological factors associated with Oncotype DX® 21-Gene in patients diagnosed with early stage Breast Cancer. Additionally, description of adjuvant treatment patterns and survival outcomes were described according to the Oncotype DX® 21-Gene result. METHODS: Data from medical records from a single center in Brazil were collected retrospectively from women over 18 years diagnosed with early breast cancer between 2012 and 2022. Included patients were diagnosed with stage T1-T2 breast cancer, hormone receptor positive, HER-2 negative, with up to three positive lymph nodes. All included patients had an Oncotype DX® test performed after definitive breast surgery. The ODX RS has been categorized into two levels according to menopausal status. Correlation between breast cancer recurrence and clinicopathological characteristics was done. The software SPSS was used for statistical analyzes with the significance of 0.05. RESULTS: From 197 patients, 20 have had breast cancer recurrence (10.15%) whom 10 were premenopausal and 10 were postmenopausal. The median ODX RS in these 20 patients was 15 (ranged from 9 to 31). The most common site of recurrence was breast and regional recurrence in 18 patients (90%). Adjuvant chemotherapy was omitted in 16 patients (80%) who have had breast cancer recurrence. Among premenopausal patients whose ODX RS was &amp;gt;20, 33 patients (91.66%) received adjuvant chemotherapy. Among postmenopausal patients whose ODX RS was &amp;gt;25, 19 (86.36%) received adjuvant chemotherapy. The probability of recurrence free survival was worse in premenopausal patients &amp;gt; 44-years-old compared to those with &amp;lt; =44 years-old (p = 0.036) and also worse in histological grade 3 tumors compared to grade 1 (p=0.0048). Tumor size &amp;gt;14 millimeters (mm) was correlated to worse recurrence free survival in premenopausal patients (p=0.017). Low estrogen and progesterone receptor was associated with a higher ODX RS (p=0.0035 and p&amp;lt; 0.0001, respectively) in premenopausal patients, but not associated with recurrence free survival. Clinicopathological characteristics and recurrence free survival correlation in postmenopausal patients were not significant. CONCLUSION: This retrospective analysis suggests that factors other than the Oncotype DX® score, such as age and grade contributed to worse survival outcomes among our patients population. Of note, age older than 44 years-old, histological grade 3 and tumor size &amp;gt;14 mm were associated with a higher probability of recurrence in premenopausal patients, despite the Oncotype DX® score. REFERENCES: 1. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M, et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med [Internet]. 2004;351(27):2817–26. Available from: http://dx.doi.org/10.1056/NEJMoa041588. 2. Sparano JA, Gray RJ, Makower DF, Pritchard KI, Albain KS, Hayes DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med [Internet]. 2018;379(2):111–21. Available from: http://dx.doi.org/10.1056/NEJMoa1804710. 3. Kalinsky K, Barlow WE, Gralow JR, Meric-Bernstam F, Albain KS, Hayes DF, et al. 21-gene assay to inform chemotherapy benefit in node-positive breast cancer. N Engl J Med [Internet]. 2021;385(25):2336–47. Available from: http://dx.doi.org/10.1056/NEJMoa2108873. Table 1 – Clinical and pathological characteristics of 197 hormone receptor positive, HER-2 negative early breast cancer patients who did the Oncotype DX® 21-Gene Recurrence Score assay. Data from medical records collected retrospectively of women diagnosed with early breast cancer between 2012 and 2022 from a single center in Brazil. Figure 1 – Probability of recurrence free survival in premenopausal patients according to age &amp;lt;=44 (blue line) or &amp;gt; 44-years-old (pink line). Data from medical records collected retrospectively of women with hormone receptor positive, HER-2 negative early breast cancer who did the Oncotype DX® 21-gene assay diagnosed between 2012 and 2022 from a single center in Brazil. Figure 2 – Probability of recurrence free survival in premenopausal patients according to histological grade. Tumor with histological grade 1 (blue line) or histological grade 3 (pink line). Data from medical records collected retrospectively of women with hormone receptor positive, HER-2 negative early breast cancer who did the Oncotype DX® 21-gene assay diagnosed between 2012 and 2022 from a single center in Brazil. Citation Format: Carolina Cavalcanti Gonçalves Ferreira, Julio Araujo, Shermann Brandão Rodrigues Moreira, Antônio Buzaid, Débora Gagliato. Clinical and pathological factors associated with Oncotype DX® 21-Gene recurrence score in patients diagnosed with early stage breast cancer in a low-middle income country [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 PO2-02-03.

Abstract PO3-16-08: Real-World Treatment Patterns in Elderly Patients with HER2-Negative Early Breast Cancer

Abstract Background: As the treatment landscape of human epidermal growth factor receptor 2-negative (HER2–) early breast cancer (BC) evolves, an understanding of treatments given in real-world settings to elderly patients with HER2– early BC is needed to gain insight into the potential unmet needs of this population for whom clinical data are limited. This study described demographics, clinical characteristics, and neoadjuvant and adjuvant treatment patterns in elderly patients with HER2– early BC in the United States. Methods: This retrospective study used SEER-Medicare data (2010–2019) to identify patients aged ≥66 years with HER2– early (Stage I–III) BC receiving primary surgery. Patient characteristics were evaluated at primary surgery or at BC diagnosis. Neoadjuvant and adjuvant therapies were defined as any National Comprehensive Cancer Network-recommended regimens received between BC diagnosis and primary surgery, and during the 180-day period following primary surgery, respectively. Patient characteristics were described using means and standard deviations (SDs) for continuous characteristics, and frequencies and proportions for categorical characteristics. Neoadjuvant and adjuvant therapies were summarized using frequencies and proportions. All analyses were conducted for the overall population and stratified by breast cancer subtype (hormone receptor-positive [HR+]/HER2– vs. triple negative BC [TNBC]) and stage at diagnosis (Stage I vs. Stage II/III). Results: Of 28,655 eligible patients, 25,899 (90.4%) had HR+/HER2– BC and 2,756 (9.6%) had TNBC; 17,961 (62.7%) had Stage I BC and 10,694 (37.3%) had Stage II/III BC. Mean (SD) age at diagnosis was 75.8 (6.4) years, mean (SD) National Cancer Institute comorbidity index was 1.9 (2.1), and 23.7% received single or multi-gene testing for a breast cancer gene 1 and/or 2 (BRCA1/2) mutation (HR+/HER2– BC: 24.6%; TNBC: 15.5%), with most (86.3%) testing occurring after primary surgery. Relative to HR+/HER2– BC patients, TNBC patients were less likely to present with Stage I disease (46.7% vs. 64.4%), had a larger mean tumor size at diagnosis (2.6 cm vs. 1.9 cm), and higher-grade tumors (Grade III or IV: 70.6% vs. 14.6%). TNBC patients were also more likely to receive neoadjuvant chemotherapy (90.9% vs. 35.3%) and adjuvant radiation therapy (81.2% vs. 66.4%) than HR+/HER2– BC patients (Table 1). By BC stage, neoadjuvant therapy was more common among Stage II/III patients relative to Stage I patients (12.3% vs. 2.7%), with most (90.4%) neoadjuvant chemotherapy use observed among Stage II/III patients. Adjuvant therapy use was similar between Stage I and Stage II/III patients (87.4% vs. 88.1%) and the most common adjuvant therapies across both subgroups were endocrine therapy (85.2% vs. 82.2%) and radiation therapy (68.5% vs. 66.1%). Conclusion: In elderly patients with HER2– early BC, treatment with adjuvant therapy was common, while neoadjuvant therapy was limited. Moreover, one in four HER2– early BC patients were tested for a BRCA1/2 mutation in real-world clinical practice. Our findings highlight the need for a better understanding of the role of increased and timely BRCA1/2 testing to inform optimal treatment strategies across neoadjuvant and adjuvant settings in this population. Table 1. Treatment Patterns Among Patients with TNBC and HR+/HER2– Early Breast Cancer Citation Format: Jagadeswara Earla, Allison Kurian, Kalé Kponee-Shovein, Ambika Satija, Yan Song, Nathaniel Downes, Malena Mahendran, Qi Hua, Arun Kumar, Jaime Mejia. Real-World Treatment Patterns in Elderly Patients with HER2-Negative Early Breast Cancer [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 PO3-16-08.

Abstract PO2-17-06: Real world treatment patterns and clinical outcomes by germline BRCA (gBRCA) mutation status in patients with HER2-negative early breast cancer in the US community oncology setting: a retrospective observational chart-review study

Abstract Background: Women with early-stage breast cancer (eBC) who have inherited BRCA1 or BRCA2 mutations (gBRCAm) are typically diagnosed at a younger age and often require more intensive treatment. In the randomized, double-blind OlympiA trial of HER2-negative (HER2–) gBRCAm patients, olaparib, a targeted poly (ADP-ribose) polymerase inhibitor (PARPi), significantly improved invasive disease free survival (IDFS), distant disease free survival (DDFS) and overall survival (OS) and was subsequently approved for adjuvant treatment of gBRCAm HER2– high-risk eBC patients. This study examined the real-world patient characteristics, treatment patterns and clinical outcomes by gBRCA status among patients with HER2– eBC in a US community oncology setting prior to olaparib US approval for treatment of eBC. Methods: This retrospective observational study used chart review data from The US Oncology Network's iKnowMed database to examine adult patients diagnosed with HER2– eBC (stage I-III) initiating systemic neoadjuvant or adjuvant therapy with chemotherapy and/or endocrine therapy between January 1, 2012 and December 31, 2018. Patients with valid gBRCAm test results (all gBRCAm and randomly selected BRCAwt patients) were included and followed through December 31, 2021. Patients were excluded if they had HER2+ tumors and progressed to stage IV within 6 months after initiation of neoadjuvant therapy or were diagnosed with another primary cancer. Descriptive analyses assessed patient characteristics. Kaplan Meier methods and multivariate Cox proportional hazard models (CPHM) were used to evaluate IDFS, DDFS and OS by gBRCA status and by HR+/HER2– or TNBC eBC subsets. Results: Among 298 BC patients meeting initial criteria, 42% had gBRCAm (n=124, 43% hormone receptor positive [HR+], 56% triple-negative BC [TNBC], 1% unknown), and 58% had gBRCAwt (n=174, 74% HR+, 22% TNBC). Median (interquartile) age at surgery was numerically lower in gBRCAm (45 [36,55] years) than gBRCAwt (48 [41,55] years) patients. A numerically higher proportion of gBRCAm patients received neoadjuvant therapy compared with gBRCAwt (Neoadj: gBRCAm 37.1% vs gBRCAwt 12.6%) but the reverse was true for adjuvant (Adj: gBRCAm 42.7% vs gBRCAwt 65.5%) and neoadjuvant + adjuvant use was numerically similar (Neoadj+Adj: gBRCAm 20.1% vs gBRCAwt 21.8%). The majority of TNBC patients received neoadjuvant therapy while the majority of HR+ patients received adjuvant therapy (Neoadj: TNBC 51.4% vs HR+ 6.6%, Adj: TNBC 29.0% vs HR+ 71.4%, Neoadj+Adj: TNBC 19.6% vs HR+ 22.0%). Median IDFS, DDFS, and OS in both study cohorts were not reached. Median follow-up from surgery was &amp;lt; 5 years (overall 59.0 months; gBRCAm 50.6 months; gBRCAwt 61.3 months). At 60 months, in gBRCAm and gBRCAwt respectively, estimated IDFS were 85.5% and 90.9%, estimated DDFS 88.1% and 92.2%, and estimated survival 91.9% and 95.2%. At 60 months, in HR+/HER2– and TNBC respectively, estimated IDFS were 92.4% and 81.2%, estimated DDFS 93.9% and 85.7%, and estimated survival 96.3% and 90.9%. CPHM results showed that risks of invasive disease (HR 1.74; 95% CI 0.83-3.64; p=0.15), distant disease (HR 1.24; 95% CI 0.50-3.07; p=0.65) and death (HR 1.79; 95% CI 0.52-6.13; p=0.353) were similar between gBRCAm and gBRCAwt patients. Between HR+/HER2– and TNBC patients, risks of invasive disease (HR=0.63; 95% CI 0.21-1.89; p=0.41), distant disease (HR=0.42; 95% CI 0.11-1.67; p=0.22) and death (HR 0.48; 95% CI 0.09-2.70; p=0.41) were similar. Conclusions: This real-world chart review study of data through 2021 (before PARPi approval for eBC) with limited follow up of 5 years found that gBRCAm patients had a numerically shorter survival (IDFS, DDFS and OS) than gBRCAwt, but this difference was not statistically significantly different. Given that the follow-up period was too short to draw conclusions, further studies examining clinical outcomes over a longer follow-up period after approval of PARPi may be of interest. Citation Format: Jay Andersen, Jagadeswara Earla, Nicole Fulcher, Juliet Ndukum, Nicholas J Robert, Mark Robson, Weiyan Li, Jaime Mejia. Real world treatment patterns and clinical outcomes by germline BRCA (gBRCA) mutation status in patients with HER2-negative early breast cancer in the US community oncology setting: a retrospective observational chart-review study [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 PO2-17-06.

Abstract PO2-02-13: A Mechanical Conditioning gene expression (MeCo) score detects the patients that benefit from neoadjuvant anti-fibrotic therapy in early HER2-negative breast cancer (HER2negBC)

Abstract Background: Extracellular matrix (ECM) stiffness in the tumor microenvironment is associated with aggressive features that lead to adverse clinical outcomes, including metastasis. Mechanical conditioning (MC) is the phenomenon whereby cancer cells that have grown in a fibrotic-like stiff ECM acquire aggressive features which can be maintained after metastasis in distant sites (Cell Rep.; 35:109293). MeCo Score is a gene expression signature that measures the response to ECM stiffness in early tumors which is associated with subsequent metastasis. We sought to study whether MeCo Score is associated with pathologic complete response (pCR) in early HER2negBC, and whether anti-fibrotic treatment with nintedanib (a multikinase VEGFR1-3, FGFR1-3 and PDGFRA/B inhibitor approved for idiopathic lung fibrosis) is able to mitigate the impact of MC. Methods: Baseline tumor samples from patients (N=130) from a randomized phase II clinical trial (Clin Cancer Res 23: 1432-42) in early HER2negBC trial comparing weekly paclitaxel monotherapy (85 mg/m2 x 12 courses; N=65; Arm A) versus the same treatment plus nintedanib (150 mg p.o. bid, continuous schedule; Arm B) were analyzed by RNAseq. MeCo Score was computed as previous described (Cell Rep.; 35:109293), and intrinsic PAM50 subtypes were determined using the R package genefu. Clinical, demographic and pathologic variables were gathered for all patients; pCR was graded according to the Residual Cancer Burden (RCB) score, RCB=0. Regression models were built using the variables RCB, T, N, G, age, intrinsic subtype, Ki67, MeCo Score and treatment arm. Bi-variate correlations were analyzed with the Pearson coefficient. All statistic tests were two-sided. Results: MeCo Score was successfully determined in 76 women (50% from each arm); the average score was 0.34 (range: 0.052 – 0.617). Of them, 48.6% were Luminal A, 34.2% Luminal B, 14.5% Basal-like, and 2.7% Normal according to PAM50. Median age was 49 y.o. (range: 30.6 – 79.2); tumor size distribution was T1:3.0%; T2:68.2%; T3:24.3%; T4: 4.5%; 47% of the patients were N0, 47% were N1 and 6% were N2. Most patients (85%) were ER and/or PR positive; 15% were “triple-negative”. Histological grade distribution was G1/G2/G3: 15%/62%/23%. The average Ki67 was 28.7% (range: 1%-98%). pCR was 10.8% and 4.5% in arms A and B. The average MeCo Score by intrinsic subtype was 0.26 (LumA); 0.43 (LumB) and 0.38 (Basal), LumB vs LumA P&amp;lt; 0.001; LumB vs Basal: P=0.037. We did not find correlation between MeCo Score and G, T, N, age or Ki67, neither in the Luminal subgroup or the whole cohort. In Arm A, patients with high MeCo Score (i.e., above median) had a 0% pCR rate compared to 10.5% pCR rate for those with low MeCo Score (P=0.035); however, in the nintedanib arm (Arm B) no differences were found: 10.5% versus 11.1% pCR rate in high versus low MeCo Score (P=0.4). Conclusions: Among early HER2negBC, Luminal B cases display the highest MeCo Scores. MeCo Score was independent of all classic prognostic variables. High MeCo Score is associated with lack of pCR to neoadjuvant paclitaxel monotherapy, but concurrent administration of the anti-fibrotic agent nintedanib rescues this association. Citation Format: Miguel Quintela-Fandino, Adam Watson, Adam Grant, Gus Mouneimne, Maria J. Bueno, Silvana Mouron. A Mechanical Conditioning gene expression (MeCo) score detects the patients that benefit from neoadjuvant anti-fibrotic therapy in early HER2-negative breast cancer (HER2negBC) [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 PO2-02-13.

Abstract PO2-01-14: Development of Artificial Intelligence-based Machine Learning Models for Predicting Survival In Hormone-Receptor-Positive/HER2-Negative Early Breast Cancer undergoing Neoadjuvant Chemotherapy

Abstract Background. In hormone-receptor positive (HoR)/HER2 negative early breast cancer (BC) multiple efforts have been made to predict disease recurrence and survival. Machine learning techniques have been used but few studies have looked into their applicability in predicting survival on the basis of clinico-pathological characteristics. The aim of this study was to evaluate a random survival forest model to predict the prognosis of this specific BC subtype. Methods. In this multicenter, retrospective study, patients who fulfilled the following inclusion criteria were included: (1) diagnosis of pathologically confirmed HoR-positive/HER2-negative invasive BC; (2) early or locally advanced, stage I-II-III (3) patients receiving neoadjuvant anthracycline and/or taxane-based chemotherapy, concurrently or sequentially; (4) patients undergoing surgery for primary BC. Survival endpoints were disease-free survival (DFS) and overall survival (OS). A random survival forest algorithm was used to develop the predictive model. Ten-fold cross-validation was performed. The C-index and the continuous rank probability score (CRPS) were used to evaluate the discrimination of the predictive model, and a ROC curve was used to evaluate model precision. A cut point analysis based on maximally selected rank statistics was conducted to evaluate the best cut-off in the out-of-bag (OOB) mortality that could maximize DFS and OS prediction. Variable importance was assessed using Breiman-Cutler permutation importance. Results. Overall, 572 patients with HoR-positive/HER2-negative early BC were included. At univariate analysis age, T stage, N stage, grading, ER, PR and Ki67 were found to be significantly associated with DFS and ER, PgR, HER2, pCR ypT and ypN retained statistical significance at multivariate analysis. ER, pCR, pathological T and N stage were found to be significantly associated with OS at univariate and multivariate analysis. The following variables were included in the final model: menopausal status, age, histology, grade, clinical T/N, ER/PgR, Ki67 and HER2, pathological complete response (pCR), ypT and ypN. For DFS, the cross-validated C-index was 0.68 (95% CI 0.63-0.73) and the OOB CRPS was 0.15, with a OOB performance error of 0.31. The AUC calculated at 60 months was 0.91 (95% CI 0.88-0.94). Out-of bag RSF-based risk scores for individual patients were calculated and an optimal cut-off of 22.58 was identified. The HR between high risk and low risk group was 3.08 (95% CI 2.16-4.39, p&amp;lt; 0.001). For OS, the cross-validated C-index was 0.66 (95% CI 0.60-0.71) and the OOB CRPS was 0.17, with a OOB performance error of 0.35. The AUC calculated at 60 months 0.91 (95% CI 0.88-0.95). An optimal cut-off of 21.54 was identified and the HR between low risk and high risk group was 2.50 (95% CI 1.73-3.61, p&amp;lt; 0.001). For DFS, the most important variables were cN (9.00), ypN (7.35), ER (7.21), ypT (5.38), PgR (4.11), pCR (4.01) and age (2.82) while for OS the most important variables were cN (7.88), ER (5.37), PgR (3.61), age (3.37), pCR (2.80), ypT (2.64) and ypN (2.60). Discussion. We analyzed the performance of RSF in the prediction of DFS and OS based on the contribution of clinico-pathological features commonly available at the baseline of the NCT and post-surgery. By selecting patients with HoR-positive HER2-negative disease, we were able to show which clinico-pathological features within a ML model have greater predictive importance. The model could be integrated with image-based tumor and radiology features to improve its predictive accuracy. This retrospective multicenter study suggests that the combination of easily accessible clinico-pathological features within a ML model may reliably predict DFS and OS in the context of HoR-positive/HER2-negative BCs. Citation Format: Luca Mastrantoni, Giovanna Garufi, Noemi Maliziola, Elena Di Monte, Giorgia Arcuri, Valentina Frescura, Angelachiara Rotondi, Giulia Giordano, Luisa Carbognin, Alessandra Fabi, Ida Paris, Gianluca Franceschini, Armando Orlandi, Antonella Palazzo, Giovanni Scambia, Giampaolo Tortora, Emilio Bria. Development of Artificial Intelligence-based Machine Learning Models for Predicting Survival In Hormone-Receptor-Positive/HER2-Negative Early Breast Cancer undergoing Neoadjuvant Chemotherapy [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 PO2-01-14.

Abstract PS16-04: Denosumab as an enhancer of the immune infiltrate in hormone receptor-positive early breast cancer. Subgroup analysis from the D-Biomark window-of-opportunity clinical trial (NCT03691311)

Abstract Background: The receptor activator of nuclear factor κB (RANK) signaling pathway has emerged as a therapeutic target in breast cancer (BC). Recent studies indicate that inhibition of the RANK pathway induces tumor cell differentiation and may enhance the anti-tumor immune response. The D-Biomark clinical trial aims to evaluate the antitumor (antiproliferative and proapoptotic) and immunomodulatory effects of denosumab in HER2-negative early BC. Methods: Patients with early HER2-negative BC scheduled for primary surgery were randomized in a 2:1 ratio to receive two doses of 120 mg denosumab on days 1 and 8 vs no treatment before surgery. Immunohistochemistry (IHC) was used to assess Ki67 (proliferation), cleaved caspase-3 (cell survival), RANK and RANKL. Stromal tumor infiltrating lymphocytes (TILs) and serum markers including free RANKL (sRANKL), tartrate-resistant acid phosphatase 5b (TRACP5b), and osteoprotegerin (OPG) were also analyzed. Paired t-test was used to compare values between core biopsy (biopsy A) and surgical samples (biopsy B). Subgroup analysis by intrinsic subtype was performed on 47 matched cases using PAM50. Results: Between July 2019 and May 2021, we enrolled 60 patients, 58 evaluable, including 10 triple-negative breast cancer (TNBC). The clinicopathologic characteristics of the population at the time of enrollment were well balanced, but the TNBC recruited included 5 out of 10 tumors with a more indolent behavior than the typical tumors of this lineage (apocrine tumors, low cell proliferation). Due to this and the small number of cases, no conclusions can be drawn in this subgroup. RANK expression was detected in 19 tumor cases, while 17 cases expressed RANKL. The treated group showed a decrease in sRANKL (p &amp;lt; 0.000), indicating denosumab activity, while the control group showed no change (p1.0). OPG levels in the experimental group showed a non-significant increase (p0.07), while TRACP5b remained unchanged. Both groups showed a non-clinically relevant increase in cell proliferation (5 percentage points), control p0.04, experimental p0.01. Subgroup analysis of tumors with RANK+ or RANKL+ tumor cells also showed no reduction in Ki67. Cell survival did not decrease in the overall cohort (control p0.05, experimental p0.24), nor in subgroups or in tumors with RANK+ or RANKL+ tumor cells. Denosumab treatment increased TILs in the overall population (control p0.06, experimental p0.0006) and in the subgroups: RANK+ tumors, RANKL+ tumors, premenopausal and postmenopausal, less so in the TNBC group. The subgroup analysis is shown in Table 1. Analysis by intrinsic subtype showed that in the experimental group there was an increase in cases with a change to luminal A lineage (17%) compared to the control group (6%), suggesting a possible cellular differentiation towards less aggressive tumors. Although the number of patients is small, these changes warrant further investigation and highlight the role of denosumab as an immune activator in these luminal tumors known for their low inflammatory infiltrate. Conclusion: Two doses of denosumab prior to surgery did not reduce proliferation or increase apoptosis. However, this short course of denosumab increased TILs in early BC, particularly in luminal tumors, and may induce tumor cell differentiation into luminal A-like tumors. Table. Citation Format: Andrea Vethencourt, Eva Trinidad, Eduard Dorca, Anna Petit, Teresa Soler-Monsó, Agostina Stradella, Cristina Capo, Ander Urriticoechea, Marta Matas, Gema Pérez-Chacon, María Jimenez, Marina Ciscar, Emilia Brizzi, Gonzalo Soria Alcaide, Gonzalo Gomez, Elena Piñeiro, Elvira Purqueras, Amparo Garcia, Ariadna Iserte, M Jesus Pla, Miriam Campos, Miguel Gil-Gil, Sonia Pernas, Eva Gonzalez-Suarez, Catalina Falo. Denosumab as an enhancer of the immune infiltrate in hormone receptor-positive early breast cancer. Subgroup analysis from the D-Biomark window-of-opportunity clinical trial (NCT03691311) [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 PS16-04.

Abstract PO5-17-12: Impact of HER2-low status on axillary response and surgical management after neoadjuvant chemotherapy in early breast cancer

Abstract Background: Breast cancer (BC) with low expression of HER2 (HER2-low) might constitute a group of tumors with unique clinical and biological characteristics. Little is known about axillary downstaging and nodal surgical outcomes in HER2-low BC after neoadjuvant chemotherapy (NACT). The aim of this study was to evaluate axillary response and surgical management of the axilla in HER2-low BC patients submitted to NACT. Methods: In this cross-sectional single center study, we consecutively included all patients diagnosed with early HER2-negative BC between 2017 to 2021 that were treated with NACT. Patients must have biopsy-confirmed stage II-III BC, submitted to breast surgery after NACT. Clinical and pathological response in the axilla, type of axillary surgery, and surgical outcomes data were collected. HER2-low was defined by IHC score 1+, or 2+ ISH non-amplified; HER2-zero was defined by IHC score 0. Pathological response was determined locally. Results: At diagnosis, 291 patients had clinically involved axillary nodes (cN1: 69.4%; cN2: 25.1%; cN3: 5.5%). Among 136 patients eligible for SLN biopsy after NACT, 77 (26.5%) had pathologically negative SLN. Of those submitted to upfront axillary dissection (n=154), 52 (33.7%) had pN0 disease. In total, 129 (44.3%) patients with clinically involved axillary lymph nodes at diagnosis were converted to cN0 after NACT. There was no difference in the rate of axillary downstaging between HER2-low and HER2-zero tumors, 17.8% vs 26.5%, respectively (p=0.0026). 236 patients were submitted to sentinel lymph node biopsy (SLN), of whom 214 (81.4%) with blue dye-only, 40 (15.2%) with radioactive isotope, and 7 (2.7%) with dual tracer. SLN detection failure were reported for 12 patients (0.046%). Mean number of lymph nodes retrieved were 2.7. Most patients had a negative SLN biopsy (180/263; 68.4%), of whom 91 (50.6%) were HER2-low and 89 (49.4%) were HER2-zero. Positive SLN biopsy were reported in 83 patients (isolated tumor cells: 20,5%; micrometastasis: 24.1%; macrometastasis: 55.4%), with capsular extravasation in 25.3%. A positive SLN biopsy occurred in 61.4% of patients with HER2-low tumors, and in 38.5% of patients with HER2-zero tumors. Among patients with a positive SLN biopsy (n=83), 67 were submitted to axillary dissection, of whom 39 (58.2%) had no additional nodes involved (HER2-low: 61.5%; HER2-zero: 38.4%). Considering N0 tumors at diagnosis, 127 patients were submitted to SNL, and only 18.9% had a positive result (HER2-low: 66.6%; HER2-zero: 33.3%). In the subgroup of initially cN+ disease, 136 (46.7%) underwent SLN biopsy, with 59 (43.4%) with a positive result (HER2-low: 59.3%; HER2-zero: 40.7%). Conclusions: Our results showed that HER2-low BC patients had a statistically significant lower frequency of axillary downstaging after NACT. More than 40% of patients with cN+ at diagnosis were downstaged to cN0 and were submitted to SNL biopsy. Axillary dissection were avoided in roughly 25% of patients with cN+ BC at initial staging. Citation Format: Leonardo Roberto da Silva, Guilherme Sartori, Susana Ramalho, Tomás Reinert, Mahira Lopes Da Rosa, Grazielle Morais Tavares, Higor Mantovani, Vivian Vasconcelos, Ana Elisa Ribeiro Da Silva Cabello, Guilherme Coelho, Jovana Mandelli, Facundo Zaffaroni, Carlos Barrios, Marcia Silveira Graudenz, César Cabello. Impact of HER2-low status on axillary response and surgical management after neoadjuvant chemotherapy in early breast cancer [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 PO5-17-12.

Abstract PO1-27-07: Is HER2-low a biologically distinct breast cancer (BC) subtype? Prognosis and pathological complete response rate after neoadjuvant treatment (NAT) in early breast cancer (BC) HER2 negative

Abstract Background: Overexpression of HER2 is a significant prognostic and predictive factor in early breast cancer. HER2 positive tumors are those scored by immunohistochemistry (IHC) 3+ or 2+ with amplification by in situ hybridization (ISH). These tumors may benefit from HER2-targeted treatment and additionally, in early HER2-positive BC, achieving a complete pathological response after neoadjuvant treatment improves patient survival. In recent years, new anti-HER2 antibody-drug conjugates have proven effective for HER2 low BC (defined as IHC score 1+ or 2+ not amplified) in the metastatic disease setting; however, in HER2-low early BC, studies testing novel anti-HER2 antibody-drug conjugates as neoadjuvant therapy (NAT) are ongoing. Currently, we don´t know exactly whether HER2 expression can influence the pathological response rate after NAT or disease-free survival (DFS) in these patients compared to HER2-zero (IHC 0). The aim of our study is to determine the impact on response rate to NAT and survival outcomes in early HER2-negative BC. Methods: We conducted a retrospective study in two hospitals in Andalucia, Spain. Patients with early HER2 negative BC treated with NAT from January 2015 to June 2022 were included. Patients were divided into HER2 low patients (IHC 1+ or 2+ not amplified) and HER2 0 (IHC 0). We collected clinical and pathological characteristics, pathological response rate using the Residual Cancer Burden (RCB) system where a complete pathological response (pCR) was defined as ypT0/ypTis and ypN0, and survival outcomes. The primary objective of the study was to analyze the pCR rate after NAT according to HER2 score, and secondary objectives were to assess disease-free survival and overall survival (DFS and OS rates). Results: 574 patients were included (100% women). 397 patients had hormone receptors (luminal BC) on these tumors, and 177 did not have them, i.e., triple-negative BC (TNBC). 225 patients were HER2-zero, and 312 patients were HER2-low (253/312 patients had luminal BC and 59/312 patients were TNBC). The pCR in HER2-low patients was 17.3% and 23.1% in HER2-zero patients (p=0.047). For luminal BC patients, the pCR was 16.7% in HER2-low tumors and 13.7% in HER2-zero tumors (p=0.29). Similarly, there was no difference in pCR rates in TNBC patients (45.8% in HER2-low and 53.8% in HER2-zero tumors, respectively, (p=0.958). The overall survival (OS) at 96 months was 88.7% (95% CI 85.6%-92%). Regarding survival outcomes, neither HER2 expression level was associated with higher 8-year DFS: 81.1% in HER2-low patients (95% CI 75.7%-86.8%) and 74.9% in HER2-zero patients (95% CI 62.3%-90.1%) p=0.64. There was no difference between histological subtypes at 8-years regarding DFS rate: 80.5% (95% CI 74.3%-87.2%) in luminal HER2-low patients and 76.3% (95% CI 60.8%-95.7%) in luminal HER2-zero patients, p=0.22; 83.8% in TNBC HER2-low (95% CI 74.5%-94.2%) and 77.5% in TNBC HER2-zero patients (95% CI 69.4%-86.6%) p=0.26. We also didn´t find significant differences in terms of OS. For HER2-low patients, the 8-year OS was 90.9% (95% CI 87%-94.9%) and for HER2-zero patients, it was 86.4% (95% CI 80.8%- 92.5%) p=0.46. There were also no differences in OS for different histological subgroups with an 8-year OS in luminal HER2-low breast cancer patients of 92.5% (95% CI 88%-96.7%) and 87% in HER2-zero (95% CI 78.9%-96.1%) p=0.91. In patients with triple-negative breast cancer phenotype, the OS was 84.2% for HER2-low (95% CI 74.5%-95.2%) and 85.3% for HER2-zero (95% CI 77.9%-93.4%) p=1. Conclusions: We found no difference in survival outcomes and response rate to conventional NAT between HER2-low and HER2-zero expression levels. Therefore, our data do not support the hypothesis of HER2-low as a biologically specific breast cancer subtype. Further research on this approach with HER2 antibody-drug conjugate schemes as an alternative to traditional NAT schemes is warranted. Citation Format: Ana Gil-Torralvo, Yeray Rodriguez, Alejandro Falcon, David Morales, Mónica Cejuela, Isabel Miras, Marta Amérigo, Manuel Ruíz - Borrego, Juan Bayo, Francisco Javier Salvador Bofill. Is HER2-low a biologically distinct breast cancer (BC) subtype? Prognosis and pathological complete response rate after neoadjuvant treatment (NAT) in early breast cancer (BC) HER2 negative [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 PO1-27-07.

Abstract PO2-16-07: Real-world eligibility for adjuvant CDK4/6 inhibitors among patients without genomic risk for chemotherapy: a GBECAM multicenter retrospective study

Abstract Background: Oncotype DX (ODX) is a genomic signature (GS) for the prediction of risk of recurrence and benefit of chemotherapy (CT) in both node negative (N0) and positive (N1), hormone receptor positive (HR+), HER2 negative (HER2-) early breast cancer (eBC). ODX was not an inclusion criterion in the MonarchE but was one in the Natalee study, in which trials most patients received neo-adjuvant chemotherapy. We aim to evaluate the proportion of patients potentially eligible for adjuvant CDK4/6 inhibitors (CDK4/6i) without CT indication by genomic risk using real-world data from a large dataset of patients from various Brazilian institutions. Methods: Clinicopathologic and ODX information were reviewed for patients with T1-T3, N0-N1, HR+/HER2- eBC who had an ODX performed between 2005 and 2020. Projections of CT indication by genomic criteria were based on TAILORx and RxPONDER data. Projections of adjuvant CDK4/6i indication were based on the MonarchE and Natalee criteria. Results: Of 636 patients, 27.5%/51.8%/20.8% were T1mic-a-b/T1c/T2-3, respectively. 19.5% were grade 1 (G1), 66.9% G2 tumors and 12.9% G3. 74 (11.6%) were N1. The ODX indicated low (&amp;lt; 11), intermediate (11-25) and high ( &amp;gt;25) risk in 117 (18.4%), 408 (64.1%) and 111 (17.5%) patients, respectively. 408 patients (64.2%) had low clinical risk and 228 patients (35.8%) had high clinical risk disease. In the overall cohort, 439 (69%) did not have genomic indication for CT, 25 (3.9%) and 133 (21%) were eligible for adjuvant abemaciclib and ribociclib, respectively. Among patients eligible for adjuvant CDK4/6i, greater than 50% did not meet genomic criteria for recommendation of CT (Table 1). Conclusions: In times of rapid incorporation of both GES (as valuable treatment de-escalation tools) and adjuvant CDK4/6i, our results suggest that a meaningful proportion of patients could be eligible for adjuvant abemaciclib and/or ribociclib independently of CT indication. However, little is currently known about the role of these agents in patients not treated with chemotherapy because they were largely unrepresented in these studies. Proportion of patients eligible for adjuvant CDK4/6i in the overall and non-CT eligible population. CT: chemotherapy Citation Format: Leandro Oliveira, Thais Megid, Daniela Rosa, Daniele Assad-Suzuki, Daniel Argolo, Solange Sanches, Laura Testa, José Bines, Rafael Kaliks, Débora Gagliato, Romualdo Barroso-Sousa, Tatiana Correa, Andrea Shimada, Daniel Batista, Daniel Musse, Marcelle Cesca, Débora Gaudêncio, Larissa Moura, Julio Araujo, Renata Colombo Bonadio, Artur Katz, Max Mano. Real-world eligibility for adjuvant CDK4/6 inhibitors among patients without genomic risk for chemotherapy: a GBECAM multicenter retrospective study [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 PO2-16-07.

Abstract PO2-14-05: COMPARISON OF HER2 mRNA PCR LEVELS AND IMMUNOHISTOCHEMISTRY (IHC) IN HORMONE RECEPTOR POSITIVE (HR+)/HER2 NEGATIVE (HER2-) EARLY BREAST CANCER

Abstract BACKGROUND IHC assays were developed to identify HER2-positive breast cancers deemed to be treated with trastuzumab-based therapies. However, these assays lack sensitivity to reliably identify tumors with low levels of HER2 protein on the cell surface. HR+/HER2-low may benefit from Trastuzumab Deruxtecan (TDxd) and therefore accurate quantification of HER2 expression levels becomes a critical issue. As a result, additional technologies are needed to achieve a quantitative and reproducible detection of HER2 in the low range expression compared with the standard IHC testing. METHODS We conducted a retrospective study of all incident stage I-II HR +/HER2- breast cancer patient whose genomic risk was assessed with the Oncotype 21 gene assay from 2009 to 2022 in Hospital Clínico San Carlos (Spain). Local HER2 expression (IHC w/wo cerbB2 FISH) was performed in all patients according to ASCO/CAP guidelines available during the different periods. HER2 mRNA expression levels by RT-PCR were obtained from OncotypeDx patient reports. The primary objective was to determine the distribution of HER2 mRNA levels across the different HER2 expression groups. Other objectives were to compare the clinicopathological characteristics, management and OncotypeDX Recurrence Score (RS) in the different HER2 expression groups. Qualitative variables are presented with their frequency distribution. Quantitative variables are summarized in their mean and standard deviation (SD). Welch’s F-test ANOVA was used to measure association between the two HER2 measuring methods. RESULTS 500 early breast cancer patients with HER2 IHC 0, 1+ and 2+ (FISH negative) and HER2 mRNA expression by RT-PCR tumors were included. Among them, 169 (34%) were IHC 0, 211(42%) were IHC 1+ and 120 (24%) were IHC 2+ (FISH negative). The distribution of clinicopathological characteristics was similar between different IHC HER2 expression groups, and the distribution of chemotherapy treatment was also similar among them (Table 1). All patients had undergone surgery, and most of them had received hormone therapy (487, 97%) and radiotherapy when indicated (375, 77%). The mean OncotypeDx® recurrence score across HER2 IHC 0, 1, 2 showed not significant difference between groups (16,85, 17,36 and 17,89 respectively). The mean OncotypeDx® HER2 gene score expression across the different levels of HER2 (0, 1+, 2+) determined by IHC were 9.07, 9.25 and 9.51, respectively. One-way ANOVA and Games-Howell post-hoc test revealed that differences between all the groups were significant. The ranges of HER2 gene score data for the 3 IHC groups were widely overlapped, with IQR of [8,5-9,5], [8,83-9,7] and [9,07-10] respectively. CONCLUSIONS Our data show statistically significant differences between HER2 mRNA expression levels and IHC groups. This suggests that RT-qPCR could complement the data obtained by IHC. However, the wide range and dispersion of mRNA expression within groups limits its clinical utility. Clinicopathological characteristics and management between different IHC HER2 expression groups. Citation Format: Julia Tejerina-Peces, Marta Amann-Arévalo, Pablo Ballestín, Beatriz González-Diez, Mateo Paz-Cabezas, Alejandro Pascual, Alicia de Luna, Vanesa García-Barberán, Alfonso López de Sá, Jose Angel García-Sáenz, Fernando Moreno. COMPARISON OF HER2 mRNA PCR LEVELS AND IMMUNOHISTOCHEMISTRY (IHC) IN HORMONE RECEPTOR POSITIVE (HR+)/HER2 NEGATIVE (HER2-) EARLY BREAST CANCER [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 PO2-14-05.

Abstract PO2-01-13: Clinico-Pathological and Molecular Characterization of Early Hormone Receptor-Positive Breast Cancer in Young Women

Abstract Introduction Premenopausal women diagnosed with hormone receptor-positive (HR+)/HER2-negative (HER2-) early breast cancer (EBC) face a significantly higher risk of cancer recurrence and mortality compared to older women, particularly those diagnosed under the age of 40. The underlying causes behind this disparity remain largely unknown. Material and methods We retrospectively select tumour samples from patients (pts) diagnosed with HR+/HER2- EBC at Hospital Clinic (Barcelona, Spain) from May 2014 to March 2020 who had a PAM50/Prosigna assay (Veracyte) previously performed. This assay examines the expression of 50 genes involved in important breast cancer signaling pathways, as well as the intrinsic subtypes (IS) and the Risk of Recurrence (ROR) score. Our primary objective was to compare the distinct clinicopathological and molecular characteristics of HR+/HER2- EBC between two age groups: patients under 40 years old (Young EBC or YEBC) and those 40 years old and above (Older EBC or OEBC). Disease-free survival (DFS) was defined as the time between diagnosis and the first recurrence. Comparisons between groups were carried out using chi-square tests (categorical variables). Additionally, we performed a two-class unpaired Significance Analysis of Microarrays (SAM) with a false discovery rate (FDR) less than 5% to identify genes with significantly different expression between YEBC and OEBC. The statistical significance level was set at less than 0.05. Results A total of 441 tumor samples from 420 patients were included in the analysis, with 5% (22/441) corresponding to YEBC. With a median follow-up of 64.5 months, there were 20 breast cancer (BC) recurrences (4.8%), 12 second cancers (2.9%) and 5 BC-related deaths (1.2%), all occurring in the OEBC group. Table 1 provides an overview of the main clinico-pathological and molecular characteristics. YEBC tended to have larger tumors, with 45.5% (10/22) measuring over 2 cm compared to 36.1% (151/419) in OEBC (p=0.376). YEBC also had a higher proportion of grade 3 tumors (18.18% versus 3.1% in OEBC, p=0.418) and lower expression of estrogen receptor (ER) as determined by immunohistochemistry (mean of 72.28% vs 88.36%, p=0.004). Regarding the PAM50 IS, there was a difference observed between YEBC and OEBC (p &amp;lt; 0.001). Specifically, YEBC patients exhibited a tendency towards a higher proportion of Luminal B tumors (54.6% versus 38.9% in OEBC, p=0.144), as well as non-Luminal subtypes such as Basal-like (18.2% versus 0.95% in OEBC, p&amp;lt; 0.001) and HER2E (4.6% versus 0.7% in OEBC, p=0.186). YEBC tended to have higher ROR (p=0.167), and to receive chemotherapy in a higher proportion, especially in the intermediate-risk group (p=0.004). In YEBC tumours, SAM analysis (p &amp;lt; 0.05) showed an overexpression of genes mainly related with proliferation (i.e., RRM2, MELK, MIK67), cell cycle progression (i.e., KNTC2, CDC20, MYBL2) and apoptosis inhibition (i.e., BIRC5). In OEBC there were an overexpression of genes related with the oestrogen receptor-signalling pathway (i.e., ESR1, NAT1, FOXA1, PGR). Luminal B tumours in YEBC showed an upregulation of genes related to proliferation, migration, and poor prognosis (i.e., KRT17, KRT5) compared to OEBC. However, since there were no recurrences in the YEBC group, differences in terms of DFS between the groups could not be calculated. Principio del formulario Final del formulario Conclusions YEBC exhibited a more advanced stage and a more aggressive intrinsic phenotype compared to OEBC. Additionally, these tumors showed a tendency to upregulate genes involved in proliferation, cell cycle progression, and survival, while downregulating genes related to hormone signaling pathways. These molecular characteristics may help explain the worse prognosis of YEBC compared to OEBC. However, further research is necessary to delve into the differential genomic characteristics that contribute to the unfavorable prognosis observed in patients diagnosed with HR+ EBC before the age of 40. Key clinical and molecular features in 441 biopsies Citation Format: Francisco Javier Muñoz-Carrillo, José Antonio Sola, Carme Crous, Esther Sanfeliu, Isabel Garcia-Fructuoso, Elia Seguí, Teresa Gorría, Raquel Gómez-Bravo, Barbara Adamo, Tomás Pascual, Olga Martínez-Sáez, Francesco Schettini, Pablo Rivera, Rosalía Cayuela, Montserrat Muñoz, Núria Chic, Maria Vidal. Clinico-Pathological and Molecular Characterization of Early Hormone Receptor-Positive Breast Cancer in Young Women [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 PO2-01-13.

Abstract PO2-19-07: PROOFS – Pre-/perimenopausal patients with HR+/HER2- EBC with intermediate to high clinical and low genomic risk, treated by endocrine treatment (ET) plus ovarian function suppression (OFS) or chemotherapy followed by ET

Abstract Background During the past years, clinical routine has shifted away from relying solely on clinicopathologic factors toward increasing use of multigene expression assays in guiding treatment decisions regarding adjuvant chemotherapy (CT) for hormone receptor-positive (HR+), HER2-negative (HER2-) early breast cancer (EBC) with 0 to 3 positive lymph nodes. In case of a low genomic risk, there is strong consensus in favor of endocrine treatment (ET) alone for postmenopausal patients, regardless of clinical risk (supported by data from planB, ADAPT, RxPonder, TailorX, MINDACT). However, there is still uncertainty regarding optimal therapy for pre- and perimenopausal patients with a similar clinical/genomic risk profile. Since the observed benefit of CT in this patient group may be partly attributable to CT-induced ovarian function suppression (OFS), some of these patients could be spared CT by adding OFS to endocrine therapy. The West German Study Group (WSG) initiated the PROOFS-registry to create a real-world database on how to optimally treat these patients. Eligibility Criteria PROOFS (NCT05792150) aims at the long-term follow up of pre- or perimenopausal patients with HR+/HER2- EBC with an intermediate to high clinical risk of recurrence and low genomic risk measured by MammaPrint(R). Additional endocrine response assessment (Ki67) after a short preoperative endocrine therapy is encouraged. Up to 25% of the study population may have node-positive disease. Participants undergo standard-of-care treatment at physician´s discretion and according to clinical routine, which may include CT neoadjuvant or adjuvant + ET, ET + OFS in premenopausal, or ET +/- OFS in perimenopausal women. Specific Aims PROOFS aims to give insights in the real-world use of OFS and to confirm an excellent outcome in pre-/perimenopausal women with HR+/HER2- early BC with an intermediate to high clinical risk of recurrence and low genomic risk treated by ET +/- OFS alone (without CT). In addition, quality of life is captured. Statistical Methods The primary objective is to demonstrate the 5-year distant recurrence-free interval (dRFI) in patients treated by ET +/- OFS alone. The null hypothesis H(0) is: 5-year dRFI &amp;lt; 92%. Secondary endpoints for all patients are 5- and 10-year dRFI, distant disease-free survival (dDFS), overall survival (OS), breast cancer-free interval (BCFI), quality of life (QLQ BR23 and QLQ-C30) and therapy adherence. Cox regression models, Kaplan-Meier method and log-rank tests will be applied for survival analysis. Linear mixed models will be utilized to quantitatively describe the course of quality of life-scores as well as therapy adherence, and to conduct group comparisons. Present and Target Accrual The study is open for recruitment of 1500 patients (approximately 20% receiving CT and 80% receiving ET +/- OFS) at up to 100 centers in Germany (June 2023: 24 open for recruitment). Funding AGENDIA N.V., Amsterdam Contact Information rachel.wuerstlein@med.uni-muenchen.de Citation Format: Rachel Wuerstlein, Lotta Ada Fischer, Nadia Harbeck, Monika Graeser, Ulrike Nitz, Matthias Christgen, Sherko Kuemmel, Christine zu Eulenburg, Matthias Warm, Oleg Gluz. PROOFS – Pre-/perimenopausal patients with HR+/HER2- EBC with intermediate to high clinical and low genomic risk, treated by endocrine treatment (ET) plus ovarian function suppression (OFS) or chemotherapy followed by ET [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 PO2-19-07.

Abstract PO3-19-08: A phase 2 randomized pre-operative,window of opportunity trial investigating the effect of elacestrant with/without triptorelin in premenopausal patients with HR+/HER2- breast cancer – SOLTI-2104-PremiÈRe trial

Abstract Background. Premenopausal women diagnosed with HR+/HER2- breast cancer (BC) often have a different biology and worse prognosis. The SOFT and TEXT studies demonstrated an increase diseasefree survival (DFS) with ovarian function suppression (OFS) plus tamoxifen or exemestane compared to tamoxifen alone. Of note, high-risk clinicopathologic features, adjuvant chemotherapy, or aged ≤35 years correlated with greater OFS benefit. However, adding OFS in this context has intrinsic issues as higher toxicity, which led to treatment discontinuation (20% in SOFT trial), and suboptimal OFS was found in around 25% of patients (pts) with exemestane plus monthly triptorelin (SOFT-EST sub-study). Thus, new effective ET options without OFS are needed for premenopausal patients (pts). Elacestrant is the first oral, non-steroidal, selective estrogen receptor degrader (SERD) to demonstrate improved efficacy to SOC treatments and specifically compared to fulvestrant in postmenopausal pts with HR+/HER2- metastatic BC at the phase III EMERALD trial. In menopausal patients with HR+/HER2- early BC, the window of opportunity SOLTI-1905 ELIPSE trial (NCT04797728), showed that elacestrant was associated with a 27.3% rate of Complete Cell Cycle Arrest (CCCA) and a statistically significant suppression of Ki-67. Among Luminal A tumors, the CCCA rate was 45% and the average decrease in Ki-67 was 64.6%, while no CCCA was reported and the suppression of Ki-67 was less pronounced (31.7%) in the Luminal B population. There is still a need for investigating elacestrant without OFS in the premenopausal scenario. We hypothesize that elacestrant as a single agent or in combination with triptorelin is an effective and safe treatment regimen in premenopausal pts with HR+/HER2-negative early BC capable of achieving an equivalent CCCA rate as a subrogate of effectiveness regardless the use of OFS Study design. PREMIERE is a parallel, non-comparative, two-arm, randomized 1:1, open-label, multicenter, exploratory study in premenopausal women with primary operable HR+/HER2-negative BC. The study aims to evaluate the biological effects of elacestrant with or without triptorelin. Participants must have histologically confirmed HR+ (≥ 10%) and HER2- operable early BC stage I to stage IIB &amp;gt;1 cm with a Ki-67 between 10-35%. The primary objective is to assess the ability of each treatment arm to induce CCCA determined by central assessment of Ki-67 (% Ki-67 ≤ 2.7%). No formal comparison between treatment arms is intended. Secondary objectives include evaluating the biological activity of elacestrant with or without OFS, antiproliferative activity, changes in gene expression including PAM50 subtype changes, and the effect of optimal vs suboptimal suppression on CCCA . Serum E2 and FSH levels will also be evaluated. Safety and tolerability will be assessed based on adverse events and clinical laboratory test results. Pts will undergo screening and randomization, with stratification by PAM50 subtype (Luminal A vs Non-luminal A). Treatment will be elacestrant 400 mg once daily or elacestrant 400 mg once daily plus triptorelin 3.75 mg days +1 and +29 for 30 (+7) days. Surgery or biopsy will be performed after treatment completion, and a post-surgery visit will mark the end of the active follow-up period. Patients will receive SOC treatment after surgery. 48 patients will be recruited in 9 sites within SOLTI Spanish network in 9 months period. This study is financially supported by Menarini-Stemline. Citation Format: Meritxell Bellet- Ezquerra, Cristina Hernando, Pablo Tolosa, Maria Vidal, Yolanda Fernández, Santiago González-Santiago, Pilar Sanchez, Susana De La Cruz, Vanesa Ortega, Xavier Gonzalez-Farré, Milana Bergamino, Alejandra Espinosa, Tomás Pascual. A phase 2 randomized pre-operative,window of opportunity trial investigating the effect of elacestrant with/without triptorelin in premenopausal patients with HR+/HER2- breast cancer – SOLTI-2104-PremiÈRe trial [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 PO3-19-08.

Abstract PO4-20-03: HIPEx: Adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative early breast cancer with high recurrence score according to GenesWellTM BCT; a multi-center single arm phase II clinical trial (KCSG BR 19-13)

Abstract Background: In estrogen receptor (ER)-positive human epidermal growth factor receptor2 (HER2)-negative early breast cancer (EBC) patients, NCCN treatment guideline recommend 21-gene tests for decision of adjuvant chemotherapy if tumor size is over 0.5cm or node positive disease. In addition, GenesWellTM BCT is a prognostic assay that predict the risk of recurrence in patients with ER-positive HER2-negative and nodal stage 0-1 EBC. According to gene tests, EBC patients with high recurrence risk would have help from adjuvant chemotherapy to increase the rate of disease free survival but toxicities of chemotherapy are not negligible. Therefore, the effort for escaping adjuvant chemotherapy has been performed and currently CDK4/6 inhibitor would be considered as the substitute for cytotoxic chemotherapy in ER-positive HER2-negative EBC patients. Methods: HIPEx trial is a multi-center, phase II clinical trial to determine the efficacy of adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative EBC with high recurrence score according to GenesWellTM BCT (NCT04247633). Eligible patients are women who received curative surgery and diagnosed as ER-positive, HER2-negative and pathologic stage T1b-T2 and/or N0-1. Clinical recurrence risk is high according to the modified Adjuvant! Online guideline and GenesWellTM BCT score is 4 or more which being genomic high risk. Other criteria include ECOG performance status ≤1, adequate organ functions and availability of an archival surgical specimens. Patients receive palbociclib 125mg once daily for 21 days of 28-day cycle plus tamoxifen or aromatase inhibitor (anastrozole, letrozole or exemestane) once daily for every day. Palbociclib would be taken for two years and endocrine therapy for five years or more. If adjuvant radiotherapy is required, palbociclib should be taken two weeks after the end date of radiotherapy. If patients are premenopausal status, GnRH agonist is allowed. Primary endpoint is 3-year event free survival (EFS) rate of high clinical and genetic risk ER-positive EBC. Secondary endpoints include 3-year overall survival, quality of life, safety and tolerability of palbociclib with endocrine therapy as an adjuvant setting, exploratory analysis of predictive and prognostic biomarkers and the performance of GenesWellTM BCT for 3-year EFS rate. In total, 578 patients would be enrolled in this trial. Based on the previous results of GenesWell™ BCT in Korea, the 3-year EFS rate for the past control group (chemotherapy followed by endocrine therapy) is 87.0% and the treatment group in this clinical trial is assumed to be 90.5%.(hazard ratio for EFS = 0.717). Null hypothesis is the 3year-EFS rate in patients received adjuvant palbociclib and endocrine therapy is not less than that of the past control group. Alternative hypothesis is the 3year-EFS rate of this trial is less than that of the past control group (one-sided). Significance level is 0.025, power is 0.80. Considering 10% drop out rate, 4-years of accrual patient enrollment and 3-years of follow up period, 578 patients were required in this clinical trial. Citation Format: Ji-Yeon Kim, Sung Hoon Sim, Jieun Lee, In Hae Park, Kyong Hwa Park, Seock-Ah Im, Jee Hung Kim, Kyoung Eun Lee, Jeong Eon Lee, Jai Min Ryu, Young Kee Shin, Yeon Hee Park. HIPEx: Adjuvant palbociclib plus endocrine therapy in ER-positive HER2-negative early breast cancer with high recurrence score according to GenesWellTM BCT; a multi-center single arm phase II clinical trial (KCSG BR 19-13) [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 PO4-20-03.

Abstract PO5-02-09: Discordance of the PAM50 intrinsic subtypes with the immunohistochemistry-based subtypes in HER2-negative early breast cancer treated with neoadjuvant chemotherapy

Abstract Background The PAM50 (Prosigna Breast Cancer Gene Signature Assay) can be used to assess the expression levels of 50 genes in early breast cancer biopsies, including formalin-fixed paraffin-embedded (FFPE) tissue from human epidermal growth factor receptor 2 (HER2)-negative patients. However, there is currently no practical molecular assay for intrinsic subtype in real-world practice that addresses the problems of cost and run-time. Methods In the phase 2 HER2E-PAM/PAMILIA study (NCT04817540), we prospectively analyzed molecular subtyping through the PAM50 test in low HER2 (HER2 IHC 1+ or 2+ SISH-) breast cancer patients. PAM50 intrinsic subtypes were determined according to 50 cancer genes using the NanoString nCounter Analysis System. This study was originally designed to determine whether adding HER2-targeted treatment in HER2 enriched molecular subtype increases the pathologic complete rate (pCR). We aimed to analyze the discordance between immunohistochemistry (IHC)-based surrogate subtyping of pre- &amp; post-operative tissues and PAM50 intrinsic subtypes, and to assess the pCR according to the discordance. Results In a total 82 patients, the proportions of HR+/HER2- and triple negative breast cancer (TNBC) in the preoperative tissue were 85.4% (n=70) and 14.6% (n=12), respectively. According to PAM50 intrinsic subtypes, 11.0% (n=9) were basal, 8.5% (n=7) were HER2-enriched, 34.1% (n=28) were luminal A, 36.6% (n=30) were luminal B, and 3.7% (n=3) were normal-like type. In total, 32 patients (41.5%) were discordant between IHC-based preoperative subtype and PAM50 intrinsic subtype. Among the 70 patients with HR+/HER2-, non-luminal A, B type was found in 12.9% with basal-like, 8.6% with HER2-enriched, and 4.3% with normal-like type, respectively. Of 12 TNBC patients, 83.3% were luminal A, B type, and 8.3% were HER2-enriched. In the other hands, 6 patients (13.0%) were discordant between IHC-based post-operative subtype and PAM50 intrinsic subtype. Among the 40 patients with HR+/HER2- postoperative subtype, non-luminal A, B type was found in 2.5% with basal-like, 2.5% with HER2-enriched, and 5.0% with normal-like type, respectively. Of 6 TNBC postoperative patients, 16.7% were normal-like. Most received anthracycline- and taxane-based neoadjuvant chemotherapy. During data analysis (June 2023), 54 cases underwent surgery after neoadjuvant chemotherapy. 4 of 54 patients (7.4%) achieved a pCR, of which one was HER2-enriched, one was luminal B-like, and two were basal-like PAM50 intrinsic subtype. However, discordance of IHC based subtype with intrinsic subtype was not considerable and was not correlated with pCR. Conclusion A substantial portion of patients showed discrepancy between preoperative and postoperative IHC subtype and PAM50 intrinsic subtype in our study. Citation Format: Jee Hung Kim, Soong June Bae, Sung Gwe Ahn, Jeonghee Lim, Min Hwan Kim, Gun Min Kim, Joo Hyuk Sohn, Joon Jeong. Discordance of the PAM50 intrinsic subtypes with the immunohistochemistry-based subtypes in HER2-negative early breast cancer treated with neoadjuvant chemotherapy [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 PO5-02-09.

Abstract PO5-01-14: Genomic risk analyses in patients with clinical low risk ER-positive HER2-negative early breast cancer developing an early metastatic event

Abstract Background: Over the past decade, there have been notable changes in the definition of risk estimation in patients with early-stage breast cancer (EBC). Specifically, within the timeframe of 2000 to 2017, following Estrogen Receptor (ER) positive and HER2-negative EBC cases were classified as low risk according to the University Hospitals of Leuven (UHL) criteria of that time: if ER H-score was &amp;gt;200: all patients with tumors N0 and Grade (G) 1, ≤pT2; or G2-3 pT1a-b; in patients ≥40 years with tumors N0 and G2 pT1c-2 or G3 pT1c; in patients ≥ 55 years with tumors N0 G3 pT2 or N1 any Grade, pT≤2. For lower H-scores, other criteria applied. However, despite undergoing endocrine therapy, a subset of these patients with clinically low-risk tumors unexpectedly experienced metastasis within five years of initial diagnosis. This unforeseen outcome may indicate potential undertreatment, as these patients did not receive adjuvant chemotherapy. We have conducted a case-cohort study of those patients with early relapse and performed the current clinical risk assessment methods and genomic risk analyses. Methods: In this study, we included patients with ER-pos, HER2-neg early-stage breast cancer diagnosed between 1-1-2000 and 31-12-2017, who were classified as low-risk tumors by UHL guidelines at that time, who were older than 35 but younger than 71 years, had an unilateral, unifocal breast tumor with tumor size up to 5 cm. These patients did not receive adjuvant chemotherapy. We selected the patients that experienced early distant recurrence, defined as distant recurrence (DR) within 5 years after the initial diagnosis. To ensure comparability for the analyses they were matched to controls for grade, menopausal status, tumor size, lymphovascular invasion, progesterone receptor status, and the year of diagnosis. For each patient, we have calculated the clinical risk score according to the criteria outlined by Mymammaprint.com, based on the modified Adjuvant Online tool used in the MINDACT trial. For the analysis, formalin-fixed paraffin-embedded (FFPE) breast tumor tissue samples were subjected to in-house validated targeted RNA-based Mammaprint(MP) analysis by NGS (MP Agendia). Results: Of the 3190 patients with EBC at UHL during the study period, 2476 patients were considered for this analysis and fitted the clinical low-risk criteria defined low-risk at UHL. Among those, only 42 or 1.7% of the eligible cohort had developed metastasis within 5 years. Tissue for MP analysis was available for 35 of these cases and for their matched control. Due to technical failure, the 1:1 matching was lost and MP results were known for 28 cases and 27 controls. The patient and tumor characteristics of both groups were comparable. In this UHL clinical low-risk group, 21/28 (75%) cases would be identified as clinical high-risk by MyMammaprint.com and 18/27 (67%) controls. We identified 13 patients (46.43%) with high genomic risk within the group with DR and 9 (33.33%) within the control group. There was no statistically significant difference (p=0.412) in the proportion of genomically high-risk patients within the group with DR compared to the control group. Conclusions: In a database of patients with EBC of whom 98% did not develop metastasis within 5 years, we observed in a small series of chemotherapy naïve patients with early DR and UHL-defined clinical low-risk tumors, that nearly half had a genomically high risk of distant metastasis. Albeit numerically higher than the matched-control group, this observation was not significant and would warrant a larger sample size and power to confirm these results. Table. Genomic versus Clinical Risk by MyMammaprint.com Citation Format: Josephine Van Cauwenberge, Hava Izci, Hans Wildiers, Sileny Han, Christine Desmedt, Giuseppe Floris, Sara Vander Borght, Ann Smeets, Ines Nevelsteen, Isabelle Vanden Bempt, Patrick Neven. Genomic risk analyses in patients with clinical low risk ER-positive HER2-negative early breast cancer developing an early metastatic event [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 PO5-01-14.

Abstract PO3-16-06: Perceptions and experiences of patients and healthcare providers on genetic testing and treatment of early breast cancer: qualitative findings

Abstract Background: Olaparib is approved as adjuvant therapy for high-risk HER2-negative early breast cancer (eBC) patients with germline BRCA mutations (BRCAm). Understanding patients’ preferences for genetic testing and treatment in the context of shared decision-making is needed to support optimal care in eBC. This study elicited the perspectives of patients with eBC and healthcare providers (HCP) treating eBC regarding treatment decision-making, and drivers and barriers to BRCA testing. Methods: Semi-structured interviews were conducted in the United States from Jan-Feb 2023 with women (n=12) diagnosed with eBC from 2017-2021. Community and academic oncologists treating eBC (n=12) and genetic counselors (GCs; n=8) were also interviewed. Patients who were tested (n=7) and untested (n=5) for BRCAm were included. A content and thematic analysis was performed which identified key factors from the data; these analyses provided both a range and common responses that may influence BRCA testing and treatment decisions. Results: BRCA-tested patients considered testing beneficial. In choosing to receive testing, &amp;gt;50% of patients reported HCP recommendation (n=7) and the opportunity to have “all of the information” about their eBC (n=7) as strong influencers. Patients declined genetic testing noting fear around negative impact to their insurance coverage (n=2) or mental health (n=3), or if they did not have family who would benefit from the information. Cost did not strongly influence testing choice. In choosing a treatment, patients sought to maintain their quality of life (QoL) with fewer side effects while minimizing chance of recurrence. They expressed the dual goals of normalcy during treatment, including curtailing side effects that impact QoL, and returning to normalcy after treatment (n=7). Patients were willing to accept unpleasant side effects to have a more effective treatment if those side effects do not severely impact their QoL and the treatment is highly effective (n=9). Side effects that may lead to hospitalization were the least accepted as they disrupt normalcy. HCPs reported that patients eagerly accept testing and face minimal familial or access barriers to testing. HCPs observed that among their non-Medicare patients, testing is usually covered by insurance with minimal out-of-pocket costs, thus alleviating financial constraints observed in previous years. HCPs believe BRCA testing is driven by updated hereditary cancer testing guidelines (e.g., NCCN), lower testing costs, closer collaborations of physicians and genetic counselors, and greater awareness among patients. HCPs reported that they embrace patient-led decision-making in eBC, especially as it relates to patients with BRCAm considering additional prophylactic surgery, and GCs further emphasized patient autonomy. Oncologists mentioned that they discuss risk status starting at diagnosis and these conversations evolve over the patient journey as new information emerges. In HR+ eBC, oncologists offered most patients with BRCAm adjuvant olaparib, which they perceive as well tolerated. In triple-negative eBC, oncologists opted for neoadjuvant Keytruda regimen prior to considering adjuvant olaparib for gBRCAm patients. Conclusions: Patients value information that empowers them to achieve their goals of normalcy and remission that can be achieved by addressing QoL, side effects, and patients' goals of living “normally”. Though prior research highlighted insurance coverage and costs as significant barriers to BRCA testing, results from this study suggest that cost was not a major factor in testing decisions. Prior barriers to testing access have been mitigated making it more available and affordable than in the past, which could be broadly communicated to patients and HCPs to minimize misperception. Citation Format: Jagadeswara Earla, Emily Mulvihill, Josh Lankin, Lauren Howell, Alex Kissling, Weiyan Li, Jaime Mejia. Perceptions and experiences of patients and healthcare providers on genetic testing and treatment of early breast cancer: qualitative findings [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 PO3-16-06.

Abstract PO5-21-04: Leveraging Digital Twins for Patient Stratification and Treatment Optimization in geriatric oncology: A Breast Cancer Multivariate Clustering Analysis

Abstract Context: Geriatric oncology necessitates an accurate evaluation of a patient's health status and cancer characteristics. Digital twins, virtual replicas of a patient and their cancer, can aid in predicting real-world behaviors and support therapeutic decision-making. Objectives: This study aims to demonstrate how digital twins can optimize treatments by simulating various scenarios based on the individual characteristics of patients and their cancers. Methods: Creation of a digital twin relies on the use of advanced manifold learning technologies. A model is built to represent the variability present in the reference cohort, capturing complex relationships and inherent data structures. A reference digital twin is generated by drawing samples from this model, thus reflecting the characteristics distribution of the reference population. Stratification (MeanShift algorithm) enables cohort structure visualization and classical statistics estimation for each stratum. Multivariate analysis was performed on a French monocentric population of 1345 patients aged over 70 years who underwent surgery for HER2-negative early breast cancer. Results: 8 cluster, created by manifold learning based on biological, demographic, and tumoral variables, exhibits unique five-year survival rates and influential factors. The clusters represent specific patient subgroups, each with its distinct set of characteristics and prognostic indicators. Table 1 provides a summary of these variables' averages within each cluster. we can thus see that the variables of clusters 3 and 6 (including only HR+ cancers) do not show statistically significant differences, unlike their 5-year survival rates (cluster 3 : 80,9% (CI95 :70-88.5) and 63.9% (CI95 :47.6-77.5) for cluster 6, p= 0,04). Provided with model results, the relative importance of these variables varies from one cluster to another, underscoring the heterogeneity among patient subgroups. Interestingly, Hormonal receptor status, nodal involvement and tumoral grade were not the predominant variables in these clusters, which challenges traditional perspectives. Table 1 : Mean value of variables per cluster (SBR grade 0=grade 1 and 2 ; 1= grade 3) Discussion: The findings underscore the vast variability of individual variable importance across clusters. Digital twins enabled the modeling of these complex interactions, providing valuable insights for clinical decision-making. Conclusion: Digital twins offer a valuable tool for personalizing care in oncogeriatrics, facilitating the identification of patient subgroups, yielding more accurate treatment outcomes, and guiding future research directions. The results affirm that incorporating digital twins into oncogeriatric care could potentially lead to the enhanced personalization of therapeutic approaches, ultimately improving patient outcomes. Table. Citation Format: Pierre Heudel, Mashal Ahmed, Felix Renard. Leveraging Digital Twins for Patient Stratification and Treatment Optimization in geriatric oncology: A Breast Cancer Multivariate Clustering 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 PO5-21-04.