The NeoPAL trial compares neoadjuvant letrozole-palbociclib (LP) with chemotherapy (CT) in 103 patients with high-risk, early luminal breast cancer. At surgery, the NanoString BC360 proliferation score and Ki67 expression are reduced in both arms, together with upregulation of immune-related signatures. Overall, there is very little difference in the changes observed with LP as compared to CT, even in signatures related to response to estrogen and CDK4/6 manipulation. Deconvolution of bulk RNA sequencing (RNA-seq) data reveals high content at baseline in cancer cells, immunosuppressive cancer-associated fibroblasts, FOXP3+ CD4+ regulatory T lymphocytes, and TREM2+ macrophages. In contrast, myoepithelial cells, normal-like fibroblasts, FOLR2+ macrophages, and SELL+ CD4+ T lymphocytes accumulate after treatment in both arms. A low ROR score is observed at surgery in 63.3% and 43.5% of patients in the LP and CT arms, respectively. No 3-year breast cancer-specific survival events are observed in these patients. These data provide a rationale for CT-sparing trials in this setting.

Despite previous reports of hippocampal alterations in breast cancer patients, the structural evolution of hippocampal subfields in relationship with memory remains to be characterized in this population. We aimed to measure hippocampal subfield volumes and their links with memory performances before and after chemotherapy in breast cancer patients compared to healthy controls. Forty-two middle aged women were evaluated, including 19 patients assessed before (T1), one-month (T2) and one-year (T3) after chemotherapy, and 23 controls assessed at T1 and T3. Using high-resolution MRI, hippocampal subfields were automatically segmented. Derived volumetric measures were compared between groups at T1 and T3 and within the patient group (T1, T2, T3). Both encoding and retrieval memory performances were measured using a dedicated task. At T1 and globally (i.e., T1 and T3 together), patients showed lower retrieval performance and larger subiculum and whole hippocampal volumes compared to controls. Volumes of the whole hippocampus and of the Cornu Ammonis (CA) 4-Dentate gyrus increased over time in controls. Longitudinal comparisons within the patients’ group did not yield significant changes. Volumes were negatively associated with age in controls, and positively with education level in patients. Our results highlight structural differences in the subiculum and whole hippocampus of breast cancer patients both post-surgery and over the adjuvant treatment course. These modifications may reflect a combination of cancer-related and early perioperative factors, while the lack of subsequent longitudinal changes in patients prevents conclusions regarding the specific impact of chemotherapy. Additional studies with larger sample sizes will be of help to further our findings.

Background Breast cancers expressing low (1-9%) immunohistochemistry levels of estrogen and progesterone hormone receptors (HR), remain an uncertain category, being considered either as triple negative (TN) breast cancers or HR-positive (HR+) tumors across guidelines or approvals. Methods ESME is a National real-world cohort of all consecutive patients who initiated a first-line treatment for metastatic breast cancer (MBC) from year 2008 onwards in one of the 18 French Comprehensive Cancer Centers. We analyzed baseline data and outcomes from all patients with HER2-negative MBC and known HR expression levels. Our primary objective was to evaluate overall survival (OS) in HR-low MBC patients compared with those with TN and HR+ disease. Results Out of 30,459 patients in the ESME database who initiated an MBC treatment between 01/2008 and 01/2021, 19,109 were eligible for this analysis: 16768, 2113, 228 respectively with HR+, TN, and HR-low MBC. Median follow-up was 58.0 months (56.6-59.0).Median OS were 44.6 (43.8-45.5), 19.1 (15.5-22.4) and 15.7 (15.0-16.8) months in the HR+, TN, and HR-low groups, respectively. The multivariable analysis identified no difference in OS between HR-low and TN groups (Hazard Ratio 0.93, 95%CI 0.77-1.11). Median PFS under first line chemotherapy were 10.2 (9.9-10.6), 5.3 (5.1-5.6) and 5.1 (4.1-6.2) months for HR+, TN and HR-low groups, respectively. In the multivariable analysis, the HR-low group had a statistically poorer PFS compared to the TN group (Hazard Ratio 1.24, 95% CI 1.04-1.49). Conclusions In this large cohort, patients with HR-low MBC have the same dismal overall survival as those with TN MBC.

BACKGROUND:Aromatase inhibitor-induced arthralgia (AIA) is common in early-stage breast cancer patients on aromatase inhibitors (AI), potentially compromising adherence and outcomes. We developed and validated prediction models for short- and longer-term AIA. METHODS:Postmenopausal patients with stage I-III breast cancer on adjuvant AI in CANTO (NCT01993498) were included. Primary outcome was AIA (any grade articular/muscular pain, Common Terminology Criteria for Adverse Events [CTCAE] v4.0) at year 1 (Y-1) and 4 (Y-4) cohort visits. Baseline clinical, behavioral, treatment-related, patient-reported (EORTC QLQ-C30, HADS) variables were modeled using multivariable logistic regression and bootstrap in development and temporal validation cohorts. Baseline inflammatory markers were examined in a sub-cohort. RESULTS:The Y-1 and Y-4 development cohorts included 3,065 and 2,390 patients (mean age 64.0 [SD 7.2] and 63.7 years [6.9]), respectively. AIA occurred in 61.3% (Y-1) and 66.1% (Y-4) patients. Validation cohorts included 1,313 (Y-1) and 1,009 (Y-4) patients with similar characteristics. Across models, higher BMI, greater baseline fatigue, prior articular/muscular disease, chemotherapy exposure, pre-existing pain were associated with subsequent AIA; anastrozole use was associated with AIA at Y-4. AUC was 0.62-0.65 in development cohorts; 0.61-0.67 in validation cohorts. In the biomarker sub-cohort (n = 637), higher baseline IL-8 was associated with lower Y-1 AIA odds (OR 0.74, 95% CI 0.56-0.98). CONCLUSION:Using baseline clinical and patient-reported data, we generated models identifying patients at increased risk of early and persistent AIA. While performance was modest, risk stratification could help trigger stepped-care pathways to optimize AI adherence and outcomes. IL-8 association requires independent replication.

OBJECTIVE:To evaluate outcomes of first-line ET + CDK4/6i for HR+/HER2 metastatic breast cancer (MBC) based on BRCA/PALB2 mutations status known at treatment initiation. METHODS AND PATIENTS:This cohort study included patients from 18 French comprehensive cancer centers treated with first-line ET and CDK4/6i between August 1, 2013, and December 31, 2023. Multivariable models including a Cox proportional hazard with a time-varying approach and landmark analyses at different timepoints (at the initiation of the first-line therapy and at 6 months after the initiation of the first line) assessed the association between germline and/or somatic BRCA and PALB2 genes alteration (categorized as "BRCA/PALB2m" (mutated) "BRCA/PALB2wt" (wild type), and "untested"), with progression-free (PFS) and overall survival (OS). RESULTS:Among 4283 eligible patients, baseline status was categorized as BRCA/PALB2m in 80 patients (1.9%), BRCA/PALB2wt in 467 patients (10.9%), and untested in 3736 patients (87.2%). Median follow-up was 43.7 months [95%CI, 42.6-44.9]. Median PFS was significantly shorter in BRCA/PALB2m patients (9.9 months [7.6-13.0]) compared to BRCA/PALB2wt (15.4 months [13.9-17.3]) and untested patients (18.3 months [17.6-19.3]). In the multivariable analysis ((including age, number of metastatic sites, presence of visceral metastases, de novo status, and tumor grade), BRCA/PALB2m carriers had a shorter PFS compared to BRCA/PALB2wt (adjusted HR [95% CI] 1.61 [1.24-2.09]; p < 0.001). Time-varying approach, landmark analysis at 6-months and propensity score matching analysis showed consistent results. CONCLUSIONS AND RELEVANCE:In this cohort, using a careful methodology, BRCA1/2 and PALB2 mutation carriers had reduced PFS with first-line ET + CDK4/6i compared to wild-type patients.

Background We proposed in 2005 that androgens replace oestrogens as the driver steroids in a subgroup of triple- negative breast cancer (TNBC) with androgen receptor (AR) expression called molecular apocrine (MA) or luminal androgen receptor (LAR). Here, we report the analysis of a clinical trial evaluating the antitumour activity of the anti- androgen darolutamide in MA breast cancer. Our aim was to assess the clinical benefit in patients with AR-positive TNBCs defined by immunohistochemistry and by RNA profiling. Methods In this multicentre, non-comparative, randomised, phase 2 trial, women aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0-1 and with advanced TNBC that was previously treated with a maximum of one line of chemotherapy were recruited from 45 hospitals in France. After central confirmation of TNBC status and AR positivity (>= 10%; SP107 antibody), participants were randomly assigned (2:1) to receive darolutamide 600 mg orally twice daily or capecitabine minimum 1000 mg/m2 twice daily for 2 weeks on and 1 week off, until disease progression, unacceptable toxicity, lost to follow-up, or withdrawal of consent. Randomisation was done centrally using the minimisation procedure and was stratified according to the number of previous lines of chemotherapy. Transcriptomic analysis was used to classify tumours into groups with high and low AR activity (MAhigh and MAlow). The primary clinical endpoint was clinical benefit rate at 16 weeks (confirmed complete response, partial response, or stable disease). The primary translational endpoint was clinical benefit rate in the darolutamide group in MAhightumours versus all other tumours. Analyses were done per protocol. This trial is registered with ClinicalTrials. gov (NCT03383679), and is closed to recruitment. Findings Between April 9, 2018, and July 20, 2021, 254 women were screened and 94 were randomly assigned to darolutamide (n=61) or capecitabine (n=33), of whom 90 were evaluable for efficacy analyses. Median follow-up at the data cutoff on July 20, 2022, was 225 months (IQR 165-305). The clinical benefit rate was 29% (17 of 58; 90% CI 19-39) with darolutamide and 59% (19 of 32; 90% CI 45-74) with capecitabine. In patients treated with darolutamide, the clinical benefit rate was 57% (12 of 21; 95% CI 36-78) in MAhightumours, and 16% (five of 31; 95% CI 3-29; p=00020) in other tumours. The most common grade 3 adverse events were palmar-plantar erythrodysaesthesia syndrome (none of 60 in the darolutamide group vs two [6%] of 33 in the capecitabine group), and headache (three [5%] vs none). No grade 4 or 5 adverse events were observed. Drug-related serious adverse events occurred in three (5%) patients in the darolutamide group and three (9%) in the capecitabine group, which were toxicoderma (n=1) and headache (n=2) in the darolutamide group, and diarrhoea, general physical deterioration, and hepatic cytolysis in the capecitabine group (n=1 each). Interpretation This study did not reach its prespecified endpoint for darolutamide activity in patients with triple- negative breast cancer selected on the basis of immunohistochemistry for AR. Further studies selecting patients based on RNA profiling might allow better identification of tumours sensitive to anti-androgens. Copyright (c) 2025 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license.

BACKGROUND:Triple negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy (NAC) face high risk of recurrence. BREASTIMMUNE-03 trial evaluates the efficacy of nivolumab and ipilimumab combination compared to capecitabine as adjuvant treatment. METHODS:This multicentre, randomized open-label phase II trial included TNBC patients with Residual Cancer Burden (RCB) of class II-III after NAC and surgery, and allocated them to randomization (1:1) to receive nivolumab plus ipilimumab or capecitabine for 24 weeks. Randomization was stratified by center, ECOG performance status (PS) 0 or 1, and RCB Class. Primary endpoint was disease free survival (DFS), assessed in the intent-to-treat population. Safety analysis according to NCI-CTCAE V5.0 included all patients who received at least one dose of study drug. RESULTS:From July 2019 to October 2021, 95 patients were randomized to the nivolumab plus ipilimumab arm (NIVO + IPI n = 45), or to the capecitabine arm (CT n = 50). With a median follow-up of 34.3 (IQR 33-36) months, 39 events (relapse or death) were reported: 17 (38 %) for NIVO + IPI; 22 (44 %) for CT (HR 0.84, 95 %CI 0.45-1.59; log-rank test p-value 0.5938). 17 (38 %) patients in the NIVO + IPI arm prematurely discontinued treatment due to treatment-related adverse events (AEs), versus 7 (14 %) in the CT arm. CONCLUSION:A 6-month post-operative nivolumab plus ipilimumab treatment did not significantly improve DFS compared to capecitabine in TNBC patients with RCB II-III and resulted in increased immune-mediated AEs. Despite premature trial termination, our results do not support nivolumab plus ipilimumab adjuvant treatment in this setting. TRIAL REGISTRATION:NCT03818685.

Background: Inflammatory breast cancer (IBC) is a rare and highly aggressive clinical entity requiring multimodal treatment, including neoadjuvant chemotherapy, mastectomy, and radiation therapy. With the advent of anti-HER2 agents, significant progress has been made in HER2-positive subtypes but the outcome remains unsatisfactory in HER2-negative IBC. Pembrolizumab in combination with neoadjuvant chemotherapy improves pathological complete response (pCR) and survival in stage II/III triple-negative breast cancer (TNBC) and has become standard of care in this setting. Pembrolizumab also improves pCR in high-grade, HER2-negative, and ER-positive stage II/III breast cancer. Yet, little is known about the specific impact of chemo-immunotherapy in IBC. Methods: We conducted a prospective, national, multicenter, randomized, phase II study evaluating the efficacy of pembrolizumab in HER2-negative IBC (NCT03515798). Patients aged ≥18 years with stage III disease were randomized (1:2) to receive neoadjuvant chemotherapy with epirubicin/cyclophosphamide (EC) +/-5FU x 4 followed by weekly paclitaxel × 12 (arm A) or the same regimen with pembrolizumab administered 3-weekly (arm B). Patients were then subjected to complete mastectomy and axillary lymph node dissection, prior radiation therapy. Randomization was stratified according to hormone receptor (HR) status (HR+, i.e. ER or PR >10%; TNBC, i.e. ER and PR <10%). Primary endpoint was central assessment of pCR rate, as defined as no residual invasive disease in breast and axilla (ypT0/is, ypN0), in arm B. Secondary endpoints included central pCR rate in arm A, local pCR rates and safety. Exploratory objectives included pCR rates according to HR status and PD-L1 expression, as evaluated by combined positive score (CPS). Results: From 29/08/2018 to 22/06/2022, 53 stage III, HER2-negative, IBC patients meeting eligibility criteria were randomized in arm A (n=20, including 9 HR+ and 11 TNBC) and arm B (n=33, including16 HR+ and 17 TNBC). All patients were female, median age was 52 (33-71) and 54 (26-73) in arm A and B, respectively. Histology was of no special type in 70% of patients in both arms. PD-L1 expression on baseline tissue was available in 43 patients: CPS was >10 in 17 (39%) patients, with a non-significant numerical difference between arms (50% and 33% in arm A and B, respectively), and was negatively associated with HR expression. Four patients came off the study before surgery: 3 in arm B (1 consent withdrawal, 2 progressive disease) and 1 in arm A (investigator decision). The central pCR rate in arm B (pembrolizumab) was 24%, 90%CI [12-41] (21%, 90%CI [6-47] in HR+ and 27%, 90%CI [10-51] in TNBC). In arm A (control), the central pCR rate was 35%, 90%CI [17-58] (29%, 90%CI [5-66] in HR+ and 40%, 90%CI [15-70] in TNBC). The pCR rates per local assessment were consistent with central evaluation. There was no significant association between PD-L1 expression and pCR in both arms. Grade >3 treatment-related adverse events (AE) were reported in 65% and 69% of patients (including Serious AE in 20% and 39%) in arms A and B, respectively. Pembrolizumab-related grade >3 AEs were noted in 30% of patients (including SAE in 12%). Immune-related AE included skin rash (n=1, grade 2), myocarditis (n=2, grade 1 and grade 2), adrenal insufficiency (n=2, grade 2 and grade 3), hepatitis (n=2, grade 2 and grade 3), thyroiditis (n=2, grade 2), and diabetes (n=1, grade 3). Conclusions: In HER2-negative IBC, pembrolizumab combined to neoadjuvant EC-paclitaxel chemotherapy induced a moderate pCR rate. Translational studies are ongoing to identify the determinants of therapeutic resistance. Innovative strategies including alternative cytotoxic backbones and novel immune-modulating agents are warranted in this aggressive disease. Citation Format: Alexandre de Nonneville, Florence Lerebours, Christophe Zemmour, Florence Dalenc, Christelle Levy, Thierry Petit, Marianne Leheurteur, Thomas Bachelot, Olivier Tredan, Sylvain Ladoire, Frédéric Viret, Leonor Lopez Almeida, Muge Kaya, Jean-Marie Boher, François Bertucci, Emmanuelle Charafe, Anthony Gonçalves. PELICAN-IPC 2015-016/Oncodistinct-003: a randomized phase II study of pembrolizumab in combination with neoadjuvant chemotherapy in HER2-negative inflammatory breast cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-10-10.

Background: Synchronous bilateral breast cancer (sBBC) is a rare occurrence. There is currently no consensus on the optimal management strategy for this condition, particularly when there is discordance between the clinical or biological presentations. Some studies have reported that sBBC is associated with poorer outcomes compared to unilateral breast cancer. The objective of this study was to describe the incidence, clinical, pathological and biological presentations, treatments and outcomes of sBBC in the prospective CANTO cohort. Methods: We reviewed and included patients (pts) diagnosed with sBBC in CANTO, a French prospective cohort study which enrolled 12012 women with localized invasive breast cancer. Data on clinical and pathological patterns, locoregional and systemic treatments were collected. Pts characteristics were compared with those of patients with unilateral cancers. Survival endpoints were event free survival (EFS) and overall survival (OS). Results: Of the 11341 analyzable pts of the cohort, 259 had sBBC (2.3%). Median age was 60.4y, vs 56.4y in pts with unilateral BC (p<.0001). Of those, 30.9% (79 pts) had a first-degree family history of breast cancer, vs 22.2% in pts with unilateral BC (p=.001). However, the proportion of BRCA mutations was similar in both groups (7.8% out of 90 tested pts vs 10% out of 2592 tested pts, p=.48). Median body mass index was slightly higher in the sBBC pts (25.7 vs 24.8, p=.003). Concordant bilateral stage I and stage II disease was observed in 32% and 13.7% of sBBC pts, respectively. Discordant stage I/II, II/III and I/III disease was observed in 36.3%, 7.8% and 5.5% of pts, respectively. Conversely, pathological subtypes were predominantly concordant: 75.6% of pts had bilateral carcinoma of non-specific type (NST) while 10.5% had bilateral invasive lobular carcinoma. Bilateral ER+ RP+/HER2-, HER2 overexpressed/amplified and triple negative subtypes were identified in 77.4%, 2.8% and 1.6% of pts, respectively. Molecular subtype was discordant in 18.2% of cases. Tumor grade was concordant in 66.9% of pts (grade 2 or 3: 58.4%), while Ki67 was ≤30% in 80.5% of pts. Locoregional and systemic treatments were tailored to stage and pathological subtype of each side. Overall, 22.2% of pts underwent a bilateral mastectomy, 73.6% had bilateral radiotherapy and 64.7% received neoadjuvant and/or adjuvant chemotherapy. After a median follow-up of 60 months, median EFS and OS were not reached: OS and EFS at 5y were approximately 90% and 80%, respectively, regardless of discordance in stage, molecular subtype, or grade. Furthermore, EFS and OS were identical whether patients had bilateral or unilateral BC. Conclusions: Women with sBBC were more likely to be overweight and older, and to have a family history of breast cancer than pts with unilateral BC. However, there was no evidence of a higher frequency of genetic predisposition. Approximately half of sBBC pts had discordant stages at diagnosis, in contrast to the majority of cases, which exhibited similar pathological and biological presentations. It can be observed that the locoregional and systemic treatments were adapted to the stage and presentation of the disease. It is of note that the prognosis was not influenced by stage or pathological discordance, or bilaterality. Citation Format: Augusta d'Huy, Julie Blanc, Anne-Laure Martin, Dominique Delmas, Jean Zeghondy, Laurence Vanlemmens, Courèche Kaderbhai, Anne Kieffer, Baptiste Sauterey, Olivier Tredan, Christelle Levy, Inès Vas-Luis, Aurélie Bertaut, Paul Cottu. Characteristics, treatments and outcomes of localized synchronous bilateral breast cancers in the CANTO French prospective cohort study [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P5-12-18.

Apolipoprotein Ɛ4 genotype (APOE4) has been associated with cancer-related cognitive impairment, but its interaction with treatments remains unclear. This longitudinal study aims to evaluate the association between APOE4 and cognitive impairment in women with breast cancer (BC) undergoing chemotherapy (CT) or endocrine therapy (ET). Patients with stage I–III breast cancer completed cognitive tests at diagnosis (before surgery), then at year-1, year-2, and year-4 post-diagnosis. APOE4 status (APOE4+ [carriers] vs. APOE4− [non-carriers]) was genotyped from blood sample. Cognitive outcomes included episodic memory, working memory, attention, processing speed, and executive functions. Patients were defined as having overall cognitive impairment if ≥ 2 domains were impaired. We fitted logistic and linear mixed models to assess associations of APOE4 status with cognitive impairment over time and interactions of APOE4 with CT and ET. Among 334 patients, 64 (19

Background: In HER2-positive (HER2+) metastatic breast cancer (MBC), the clinical presentation at metastatic diagnosis (dg), de novo (dnMBC) or recurrent (rMBC), is an independent prognostic factor. In contemporary clinical trials, the proportion of patients (pts) with dnMBC is high, likely due to improvements in the efficacy of (neo)adjuvant therapy. ESME-MBC, a national cohort of real-world data, recruiting pts consecutively treated for MBC in all comprehensive cancer centers in France since 2008, allows capturing of this evolution over time. Methods: We selected pts with HER2+ (immunohistochemistry, IHC 3+ or ISH amplified) MBC diagnosed between 2008 and 2022, excluding pts whose hormone receptor (HR) and HER2 status were unknown and those who did not receive systemic treatment for MBC. We compared clinicopathologic characteristics based on presentation at metastatic dg (dnMBC i.e. metastasis found within 6 months from initial diagnosis, or rMBC). We evaluated the trends in presentation according to year of MBC dg (YOD) using a Cochran-Armitage test, and studied factors associated with first-line progression-free survival (PFS1) and overall survival (OS) using multivariable Cox models. Results: Among the 35,687 pts in the ESME MBC cohort, 5,573 pts were treated for HER2+ MBC, including 2,800 (50.2%) with rMBC and 2,773 (49.8%) with dnMBC. Most pts were women (99.4%) with a median age of 57 years (range, 19-97). Compared with rMBC pts, dnMBC pts had significantly more often a premenopausal status (41.6% vs 35.9%, p <0.0001), have a BMI ≥30 (23.5% vs 17.8%; p <0.0001) and have ductal tumors (86.8% vs 78.8%; p <0.0001). In dnMBC pts compared with rMBC pts, there were more visceral involvement in absence of central nervous system (CNS) disease (54.1% vs 42.6%; p <0.0001), and less CNS involvement (4.7% vs 16.9%; p <0.0001), respectively. HR-positive status was similar in both categories (dnMBC vs rMBC, 60.5% vs 59.7%, p= 0.54) while HER2 score 3+ on IHC was more frequent in dnMBC (86.8% vs 82.5%, p <0.0001). Types of therapy by dnMBC and rMBC differed: first-line anti-HER2 treatment + chemotherapy +/- endocrine therapy (ET), anti-HER2 treatment + ET, anti-HER2 treatment alone or no anti-HER2 treatment in 88.4% and 66.6%, 3.2% and 6.6%, 1.6% and 7.6%, and 6.8% and 19.1% of pts, respectively. The proportion of rMBC significantly decreased from 63.5% in 2008 to 32.9% in 2022 (Cochran–Armitage test; p < 0.0001), whereas the proportion of HR+ tumors significantly increased from 53.2% in 2008 to 68.3% in 2022 (Cochran–Armitage test; p < 0.0001) both in dnMBC (50.0% to 67.0%) and rMBC (55.0% to 70.9%) pts from 2008 to 2022 (Cochran–Armitage test; p=0.0197 and 0.0008, respectively). With a median follow-up of 82.8 months (mo) (95%CI: 79.7-84.6), the median OS of dnMBC vs rMBC pts were 72.5 mo (95%CI: 66.4-77.3) vs 43.8 mo (95%CI: 41.6-46.4) and the median PFS1 were 18.9 mo (95%CI: 17.7-20.3) vs 9.4 mo (95%CI: 8.9-9.9). In the multivariable analysis, dnMBC was associated with better OS (adjusted hazard ratio (aHR): 0.65 (95%CI: 0.61-0.70); p < 0.001) and PFS1 (aHR: 0.64 (95% CI: 0.60-0.68); p < 0.001). In both categories of pts, HR- status, older age at metastatic diagnosis, presence of CNS disease, and multiple metastases were independently associated with poorer OS and PFS1. HER2 3+ status was an independent favorable factor for PFS1 in both dnMBC and rMBC pts, and for OS in dnMBC pts only. Conclusion: Between 2008 and 2022, in a large national cohort of pts with HER2+ MBC, we observed an epidemiological shift from a majority of rMBC pts to a vast majority of dnMBC pts, along with an increase in the proportion of HR+ pts among those with HER2+ cancer. Patients with dnMBC experienced significantly longer PFS1 and OS than those with rMBC. Attention to dnMBC vs rMBC enrollment in studies of HER2+ MBC is needed in the design and contextualization of study results. Citation Format: Thomas Grinda, Amélie Lusque, Stefania Morganti, David Pasquier, Aurélie Bertaut, Thierry Petit, Thomas Bachelot, Monica Arnedos, Fanny Le Du, Vincent Massard, Anthony Gonçalves, Caroline Bailleux, Jean-Sebastien Frenel, Paul Cottu, Christelle Levy, Aude-Marie Savoye, Nathalie Olympios, Marie-Ange Mouret-Reynier, Harold J. Burstein, Heather A. Pearsons, Lise Bosquet, Thomas Filleron, Suzette Delaloge, William Jacot, Nancy U. Lin. Trends in Presentation of HER2+ Breast Cancer: A Retrospective study of De Novo Versus Recurrent Metastatic Breast Cancer (MBC) in the Real-World French National ESME Cohort (2008-2022) [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr P3-08-03.

AIM:To describe first-line treatments, overall (OS) and real-world progression-free (rwPFS) survival in women with hormone receptor-positive, HER2-negative (HR+/HER2-) metastatic breast cancer (mBC) following introduction of CDK4/6 inhibitors (CDK4/6i), according to age (<70; 70 +) and diagnostic period (before/after CDK4/6i). METHODS:We extracted data from the ESME database (NCT03275311) which includes consecutive patients starting first-line mBC in one of the 18 French Comprehensive cancer centres. RESULTS:We identified 17,830 eligible women (median age: 62 years). Women aged ≥ 70 years were less likely to present with aggressive disease characteristics. Use of endocrine therapy combined with CDK4/6i increased substantially over time in both age groups, from 0.9 % to 48.9 % in 70 + women, and from 0.8 % to 50.1 % in women < 70 (p < 0.001 for both). In contrast, first-line chemotherapy (alone or in combination) declined from 52.7 % to 30.0 % (p < 0.001), with consistently lower use among women 70 + compared to those < 70: 32.2 % vs. 61.1 % prior to 2016, and 16.4 % vs. 36.5 % after 2017 (p < 0.001 for both). Among 70 + women, OS improved over time (34.0-37.3 months, p = 0.03) but remained shorter than in younger women. rwPFS improved in both age groups: from 12.6 to 14.8 months in 70 + women, and from 12.3 to 14.4 months in women < 70 (p < 0.001 for both). CONCLUSION:ET+CDK4/6i use rose up to ∼50 % after 2017, reaching ∼70 % in recent years among women with good PS, but remained ∼50 % in older patients with poor PS. Broader adoption is needed, with less chemotherapy use. Survival outcomes have improved but, causality cannot be confirmed due to the observational design.