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.

OBJECTIVES:Sacituzumab govitecan, an anti-TROP2 antibody-drug conjugate, is approved for metastatic triple-negative breast cancer (TNBC) from the second-line setting and for hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer from the third line. Radiotherapy is frequently required in metastatic settings for symptom control, but its combination with sacituzumab govitecan has not been formally evaluated. This study aims to assess the safety and tolerability of concurrent sacituzumab govitecan and radiotherapy in metastatic breast cancer patients. METHODS:This retrospective, single-center study included all metastatic breast cancer patients who received sacituzumab govitecan and underwent external beam radiotherapy (EBRT) at Institut Curie. Clinical and pathologic data, treatment details, toxicities graded per CTCAE v5.0, and survival outcomes were analyzed. Overall survival (OS) was estimated using the Kaplan-Meier method. RESULTS:Thirteen patients were included, with a mean age of 54 years. The majority (61.5%) had TNBC. A total of 19 metastatic sites were irradiated, including 10 brain and 9 bone metastases. No radiation-induced toxicity was observed, and no patients required treatment interruption. Grade 3 to 4 toxicities were limited to neutropenia (15.4%). The median OS from radiotherapy completion was 6 months, with a 6-month OS rate of 45.1% and a 12-month OS rate of 16.9%. CONCLUSIONS:The concurrent administration of sacituzumab govitecan and radiotherapy appears well tolerated, with no increased toxicity. This combination may be feasible in metastatic breast cancer patients when clinically indicated. Further studies with larger cohorts are necessary to confirm these findings.

Purpose: Meningeal carcinomatosis (MC) has a dismal prognosis in patients with breast cancer and requires invasive therapies. The aim of the present retrospective study was to determine a prognostic score for overall survival (OS) in patients with breast cancer and treated for MC. Methods: The data of 109 patients with proven breast cancer MC treated with at least one intrathecal (IT) injection of methotrexate or thiotepa at Institut Curie were retrospectively recorded from 2011 to 2019. We developed prognostic clinical scores for OS and 24-week survival. Results: The diagnosis and evaluation of MC were based on a combination of clinical, imaging, and laboratory studies. Three significant prognostic factors for OS were identified. Clinical response or stabilization after one month of IT therapy had a favorable independent prognostic value for both OS and 24-week survival. Additionally, a baseline CSF Cyfra 21-1 concentration lower than 79 ng/mL in the cerebrospinal fluid (CSF) and the absence of 1-month CSF malignant cells had borderline favorable independent prognostic value for OS and 24-week survival, respectively. We constructed 2-class and 3-class prognostic scores for each outcome, identifying a population with a very poor prognosis. Conclusions: To our knowledge, this is the first study to develop a response-based prognosis score for patients with breast cancer-related MC. This one-month prognostic score may help to determine which patient could actually benefit from prolonged IT therapy.

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.

In the UNIRAD phase III trial, evening intake of tamoxifen was previously associated with improved disease-free survival (DFS), while no timing effect was observed for aromatase inhibitors. This sub-study evaluated whether the timing of everolimus intake affects DFS in patients receiving adjuvant endocrine therapy (ET). A total of 1278 patients with high-risk HR+/HER2- early breast cancer were randomized to receive adjuvant ET with either placebo or everolimus. Patients prospectively recorded the timing of both ET and everolimus intake using four time slots: morning (06:00-11:59), afternoon (12:00-17:59), evening (18:00-23:59), and night (00:00-05:59). The relationship between intake timing and DFS was a pre-specified secondary endpoint. Timing data were available for 513 of 632 patients (81.2%) in the everolimus arm. After a median follow-up of 60.6 months, 15 local relapses, 55 metastases, and 36 deaths were reported. Overall, everolimus timing had no significant association with DFS (HR = 0.84, 95% CI 0.53-1.35, P = 0.4). However, a significant interaction was found between everolimus timing and ET type (P = 0.001). Among tamoxifen users, evening/night intake of everolimus significantly improved DFS compared to morning/afternoon intake (HR = 0.17, 95% CI 0.05-0.59, P = 0.005), independently of tamoxifen timing. No timing effect was observed in patients on aromatase inhibitors (HR = 1.56, P = 0.1). In multivariate analysis, evening/night everolimus with tamoxifen remained an independent predictor of improved DFS (HR = 0.13, P = 0.002). Evening or nighttime intake of everolimus may enhance the efficacy of tamoxifen-based adjuvant therapy in high-risk HR+/HER2- early breast cancer.

566 Background: The importance of host anti-tumor immunity in early-stage breast cancer (eBC) is now well recognised. Neutrophil / lymphocyte ratio (NLR) is a peripheral blood-based measure of systemic inflammation and immune status that has been associated with prognosis in other tumour types.We aimed to evaluate the prognostic value of NLR in a large prospective cohort of eBC. Methods: Patients with eBC (stage I-III) in the national French CANTO (NCT01993498) cohort with baseline peripheral blood counts (obtained after diagnosis and before any eBC treatment, including surgery) were included, regardless of systemic (neo)adjuvant therapy. The independent variable of interest was baseline NLR assessed as a continuous variable. Outcomes included invasive- and distant-disease-free survival (iDFS, DDFS) and overall survival (OS). We performed univariable analysis followed by multivariable Cox regression models sequentially adjusting for age, biologic subtype, TNM stage and treatment. Main analyses were conducted in the overall cohort, while additional analyses explored the role of NLR in subtypes (ER+/HER2-, HER2+, TNBC). For a cohort of patients receiving neoadjuvant therapy we tested the impact of NLR or pCR using Wilcoxon test. Sensitivity analyses used NLR as a categorical variable (using median NLR as cutoff to define high vs low NLR). Results: Overall, 10 470 patients were included. Median follow-up was 6.7 years (5.1 – 8.5). The median age at diagnosis was 56.4 years. Most (78%) of patients had stage I/II eBC, 77% ER+/HER2-, 13% HER2+ and 9% TNBC. The median NLR was 2.03. In the univariate analysis, there was a significant association between increasing NLR and worse DDFS in the overall cohort (HR: 1.1, p = 0.004; 95% CI:1.1 – 1.16) and in the ER+/HER2- cohort (HR: 1.1; p = 0.03; 95%CI:1.1 – 1.2 ). In a model adjusted by age and biologic subtype, NLR showed significant associations with DDFS (HR 1.07; p = 0.04) in the global cohort, but these associations did not maintain significance after further adjustment for TNM stage and treatment. Similarly, in the ER+/HER2- cohort, NLR was significantly associated with DDFS when adjusted for age (HR 1.08; p = 0.02), which was no longer significant after adjusting for TNM stage. No statistically significant differences were observed across other subtypes for DDFS, iDFS or OS, nor for pCR in the neoadjuvant cohort. Sensitivity analysis showed consistent results, in particular low NLR was significantly associated with improved DDFS (HR: 0.8, p = 0.03; 95%CI: 0.7 – 0.9) in the ER+/HER2- subgroup. Conclusions: Systemic inflammation, as measured by baseline NLR, was associated with significantly shorter DDFS in the overall CANTO cohort and in the ER+/HER2- subgroup in univariable and age- adjusted analysis. However, this association disappeared after adjustment for known clinicopathologic prognostic characteristics.

Pathological complete response (pCR) after neoadjuvant chemoimmunotherapy (NACi) is associated with improved patient outcomes in early triple-negative breast cancer (TNBC). This study aimed to identify factors associated with pCR after NACi. This cohort included all patients with stage II-III TNBC treated with NACi who underwent surgery at Institut Curie hospitals between 08/2021-06/2023. Among 208 patients, the overall pCR rate was 70% and was similar in ER < 1% (69%) and ER-low TNBC (73%, p = 0.6). In a multivariate model, Ki-67 ≥ 30% (OR 5.19 [1.73–17.3]), centralized TILs ≥ 30% (OR = 3.08 [1.42–7.04]), absence of DCIS at initial biopsy (OR = 2.56 [1.08–6.25]) and germline mutations in homologous recombination genes (OR = 9.50 [2.37–67.7]) remained strong independent predictors of pCR. These findings may guide treatment decisions in patients with TNBC undergoing NACi. Almost all patients with germline mutations in HR genes achieved pCR, supporting de-escalation trials. We suggest that ER-low tumors should be managed as TNBC tumors.

12122 Background: AIMT may lead to treatment discontinuation and detriment on clinical outcomes in pts with EBC. Recommended supportive care (SC) management include adequate physical activity (PA) levels, acupuncture, and physical therapy. Reasonable pharmacologic approaches include duloxetine use and switching AI. We assessed prevalence of AIMT, SC use, and non-adherence to AI. Methods: Postmenopausal pts with EBC treated with adjuvant AI were included from the longitudinal CANTO cohort (NCT01993498). AIMT was defined as any grade (G) articular or muscular pain (CTCAE v4.0) after 3-6 months (Y0), 1 (Y1), 3 (Y3) and 5 years (Y5) of AI. Non-pharmacologic SC included adherence to PA recommendations (≥10 MET-h/week), consulting with an acupuncturist, physical therapist, or osteopath. Pharmacological SC included use of duloxetine, oral complementary-alternative medicine (OCAM), and switching to a different AI. Non-adherence was defined as any interruption and/or permanent discontinuation of AI. Multivariable logistic regressions tested associations of reporting AIMT with subsequent SC use and with non-adherence to AI. Results: Among 4854 pts, 85.9% reported AIMT overall (G3 17.5%): 61.0% at Y0 (G3 9.9%), 68.5% at Y1 (G3 8.7%), 65.4% at Y3 (G3 9.0%), and 57.0% at Y5 (G3 8.8%). Pts with AIMT were younger, with higher rate of previous musculoskeletal problems, and more frequently received chemotherapy. First and second prescribed AIs were mostly letrozole (54%) and exemestane (56%), respectively. Pts reporting AIMT at Y0 were less likely, by Y1, to adhere to PA recommendations (59.3% vs 62.6%), and slightly more likely to consult with an acupuncturist (9.0% vs 7.6%), physical therapist (46.0% vs 35.0%), or osteopath (22.4 vs 16.3%) compared to pts without AIMT. Results were consistent at remaining time-points. In multivariable models, reporting AIMT was consistently associated over time only with subsequent physical therapy consultations (adjusted [a]OR [95%CI]: Y1, 1.48 [1.24-1.78]; Y3, 1.40 [1.13-1.74]; Y5, 1.45 [1.10-1.91]), but not with other non-pharmacological SC. Only 1.4% of pts with AIMT reported duloxetine use, while 25.3% OCAM use. Switching AI was reported by 19.7% of pts with AIMT (aOR of AI switch vs no AIMT 2.47 [1.59-3.83]). 18.4% of pts reporting AIMT were non-adherent to AI: 6.0% had interruptions and 17.8% permanent discontinuations. Reporting overall AIMT was associated with non-adherence to AI (aOR vs no AIMT 2.38 [1.49-3.79]). Conclusions: Despite AIMT was highly prevalent and associated with non-adherence to AI in this prospective cohort, uptake of recommended SC strategies to manage AIMT seemed suboptimal and inconsistent over time. This large study highlights gaps in the implementation of guideline-concordant SC and warrants efforts to maximize treatment retention among pts with EBC treated with adjuvant AI.

BackgroundSexual concerns are a major unaddressed need among survivors of breast cancer (BC) with significant negative effects on quality of life. We longitudinally analyzed sexual health over time, using patient-reported outcomes.MethodsPatients with stage I-III BC prospectively included from the CANcer TOxicity cohort (CANTO) provided data at diagnosis, then 1, 2, and 4 years afterward. Sexual concerns outcomes included poor body image (score ≤91/100), poor sexual functioning (≤16/100), poor sexual enjoyment (≤66/100), and sexual inactivity (EORTC QLQ-B23). Multivariate generalized estimating equation models assessed associations with sexual concerns after diagnosis, adjusting for age, sociodemographic, tumor, treatment, and clinical characteristics.ResultsNearly 78.1% among 7895 patients reported at least one sexual concern between diagnosis and 4 years’ follow-up. Over time, the proportion of patients reporting sexual concerns either increased or remained constant with diagnosis. Less than half (46%, range 11.4-57) of the patients with sexual concerns reported the use of supportive care strategies, including gynecological or psychological consultations (range 11.4-57.4). Factors consistently associated with sexual concerns up to 4 years after diagnosis included already reporting the same concern at diagnosis [odds ratio (OR)poor body image 3.48 [95% confidence interval (CI) 3.11-3.89]; ORsexual inactivity 9.94 (95% CI 8.84-11.18), ORpoor sexual function 9.75 (95% CI 8.67-10.95), ORpoor sexual enjoyment 3.96 (95% CI 3.34-4.69)], endocrine therapy use [ORpoor body image 1.15 (95% CI 1.01-1.31); ORsexual inactivity 1.19 (95% CI 1.02-1.39), ORpoor sexual function 1.17 (95% CI 1.01-1.37), ORpoor sexual enjoyment 1.23 (95% CI 1.00-1.53)], and depression [ORpoor body image 2.00 (95% CI 1.72-2.34); ORsexual inactivity 1.66 (95% CI 1.40-1.97), ORpoor sexual function 1.69 (95% CI 1.43-2.00), ORpoor sexual enjoyment 1.94 (95% CI 1.50-2.51)]. Outcome-specific associations were also identified.ConclusionsSexual concerns seem frequent, persistent, and insufficiently addressed. Pretreatment concerns, endocrine therapy, and emotional distress are commonly associated factors. A proactive evaluation of sexual health across the care continuum is needed, to promptly identify patients suitable for multidisciplinary counseling, referral, and supportive interventions.

Patients’ expectations regarding medical information in advanced stages of cancer are still poorly understood. Tailoring information to advanced cancer patients is a subtle task. We developed a question prompt list (QPL) that serves as a patient-oncologist communication aid in France. A four-step sequential mixed method involving patients with luminal B/triple-negative metastatic breast cancer or metastatic uveal melanoma (N = 110) and patients’ partners, oncologists, and researchers (N = 18) was used. In-depth interviews and questionnaires focused on the information needed at the disclosure of metastasis or resistance to treatment (step 1), the formulation of questions and procedures for use in oncology visits (steps 2 and 3), and the acceptability of the final tool (stage 4). The initial version of the QPL consists of 17 questions covering 5 themes (disease, current treatment, other options, living with cancer, prognosis). In step 2, 13 questions were added, 2 were merged, and 5 were deleted; a short form (4 questions) and recommendations for clinical use were proposed. In step 3, 2 questions were merged, and 6 were deleted. Four oncologists (27

Background We aimed to generate a model of cancer-related fatigue (CRF) of clinical importance two years after diagnosis of breast cancer building on clinical and behavioral factors and integrating pre-treatment markers of systemic inflammation. Methods Women with stage I-III HR+/HER2- breast cancer were included from the multimodal, prospective CANTO cohort (NCT01993498). The primary outcome was global CRF of clinical importance (EORTC QLQ-C30≥40/100) two years after diagnosis (year-2). Secondary outcomes included physical, emotional, and cognitive CRF (EORTC QLQ-FA12). All pre-treatment candidate variables were assessed at diagnosis, including inflammatory markers (interleukin [IL]-1a, IL-1b, IL-2, IL-4, IL-6, IL-8, IL-10, interferon gamma, IL-1 receptor antagonist, TNF-α, and C-reactive protein), and were tested in multivariable logistic regression models implementing multiple imputation and validation by 100-fold bootstrap resampling. Results Among 1208 patients, 415 (34.4%) reported global CRF of clinical importance at year-2. High pre-treatment levels of IL-6 (Quartile 4 vs.1) were associated with global CRF at year-2 (adjusted Odds Ratio [aOR]: 2.06 [95% Confidence Interval 1.40-3.03]; p=0.0002; AUC=0.74). Patients with high pre-treatment IL-6 had unhealthier behaviors, including being frequently either overweight or obese (62.4%; mean BMI 28.0 [SD 6.3] Kg/m2) and physically inactive (53.5% did not meet WHO recommendations). Clinical and behavioral associations with CRF at year-2 included pre-treatment CRF (aOR vs no: 3.99 [2.81-5.66]), younger age (per 1-year decrement: 1.02 [1.01-1.03]), current smoking (vs never: 1.81 [1.26-2.58]), and worse insomnia or pain (per 10-unit increment: 1.08 [1.04-1.13], and 1.12 [1.04-1.21], respectively). Secondary analyses indicated additional associations of IL-2 (aOR per log-unit increment:1.32 [CI 1.03-1.70]) and IL-10 (0.73 [0.57-0.93]) with global CRF and of C-reactive protein (1.42 [1.13-1.78]) with cognitive CRF at year-2. Emotional distress was consistently associated with physical, emotional, and cognitive CRF. Conclusions This study proposes a bio-behavioral framework linking pre-treatment systemic inflammation with CRF of clinical importance two years later among a large prospective sample of survivors of breast cancer.

PURPOSE:Postdiagnosis exercise is associated with lower breast cancer (BC) mortality but its link with risk of recurrence is less clear. We investigated the impact and dose-response relationship of exercise and recurrence in patients with primary BC. METHODS:Multicenter prospective cohort analysis among 10,359 patients with primary BC from 26 centers in France between 2012 and 2018 enrolled in the CANcer TOxicities study, with follow-up through October 2021. Exercise exposure was assessed using the Global Physical Activity Questionnaire-16, quantified in standardized metabolic equivalent of task-hours per week (MET-h/wk). We examined the dose/exposure response of pretreatment exercise on distant recurrence-free interval (DRFI) for all patients and stratified by clinical subtype and menopausal status using inverse probability treatment weighted multivariable Cox models to estimate hazard ratios (HRs). RESULTS:For the overall cohort, the relationship between exercise and DRFI was nonlinear: increasing exercise ≥ 5 MET-h/wk was associated with an inverse linear reduction in DRFI events up to approximately 25 MET-h/wk; increasing exercise over this threshold did not provide any additional DRFI benefit. Compared with <5 MET-h/wk, the adjusted HR for DRFI was 0.82 (95% CI, 0.61 to 1.00) for ≥ 5 MET-h/wk. Stratification by subtype revealed the hormone receptor-/human epidermal growth factor receptor 2- (HR-/HER2-; HR, 0.59 [95% CI, 0.38 to 0.92]) and HR-/HER2+ (HR, 0.37 [95% CI, 0.14 to 0.96]) subtypes were preferentially responsive to exercise. The benefit of exercise was observed especially in the premenopausal population. CONCLUSION:Postdiagnosis/pretreatment exercise is associated with lower risk of DRFI events in a nonlinear fashion in primary BC; exercise has different impact on DRFI as a function of subtype and menopausal status.

Abstract Paclitaxel is a first-line chemotherapy for hormone receptor positive (HR+) metastatic breast cancer patients after progression on a combination of endocrine and CDK4/6 inhibitor therapy. Response rate to paclitaxel ranges between 20-40%, and most patients progress due to intrinsic or acquired resistance, leaving them with limited treatment choices. Therapeutic strategies to overcome paclitaxel resistance and extend its clinical benefit are urgently needed. Paclitaxel-resistant tumors have increased expression of polo-like kinase 1 (PLK1), a serine-threonine-protein kinase that regulates mitosis and cell cycle progression. PLK1 has also been shown to mediate resistance to CDK4/6 inhibitor palbociclib in HR+ breast cancer. Onvansertib is an orally bioavailable, highly potent, and selective PLK1 inhibitor in clinical development. Onvansertib exhibited synergy in vitro and showed potent anti-tumor activity in vivo in combination with paclitaxel in ovarian cancer and triple negative breast cancer (TNBC) preclinical models. A phase 1b/2 clinical trial is ongoing to evaluate the safety and efficacy of onvansertib plus paclitaxel in advanced TNBC (NCT05383196). Here we investigated whether the potential of onvansertib and paclitaxel combination could be extended to HR+ breast cancer. Co-treatment with onvansertib and paclitaxel synergistically inhibited the viability of HR+ breast cancer cell lines (MCF-7, T-47D, EFM-19, CAMA-1, ZR-75-1). Compared to the single agents, the combination induced increased apoptosis. The combination was further tested in vivo in patient-derived xenograft (PDX) models. To this end, six HR+ breast cancer PDXs with intrinsic or acquired resistance to palbociclib were established from primary breast tumors (n=1) or metastatic bone biopsies (n=5). The PDX tumors were engrafted subcutaneously in nude mice and the effect of onvansertib (45 mg/kg, oral, 5 days a week) and paclitaxel (15-25mg/kg, IP, once a week) was investigated as monotherapy and in combination. The combination of onvansertib and paclitaxel was tolerated with minimal toxicity and showed enhanced anti-tumor activity compared to either agent alone in all 6 PDX models. Paclitaxel and onvansertib monotherapies had little to no anti-tumor activity in 4 out of 6 PDX models (HBCx124palboR25, HBCx-139 palboR5, HBCx-202 and HBCx-131). Importantly, the combination of onvansertib and paclitaxel induced strong anti-tumor activity in these 4 models. Tumor regression was observed in the 2 PDX models with acquired resistance to palbociclib, HBCx-124palboR25 and HBCx-139palboR5, with 62% (5/8 mice) and 54% (6/11 mice) complete response rates, respectively. The combination showed tumor stasis in HBCx-131 and induced tumor regression in HBCx-202, established from patient resistant to palbociclib. In 2 of the 6 PDXs, paclitaxel exhibited anti-tumor activity, inducing tumor regression in HBCx-137paboR26 and tumor stasis in HBCx-86. In comparison, the combination of onvansertib and paclitaxel had greater activity, inducing tumor regression in both models with a higher rate of complete response than the monotherapy. Complete response rates for paclitaxel versus the combination were 62% and 100% in the HBCx-137palboR26 model and 0% and 67% in the HBCx-86 model. Notably, the antitumor activity of the onvansertib and paclitaxel combination was very durable, showing a robust delay in tumor relapse after stopping therapy. Together, our data strongly support that combining paclitaxel with the PLK1 inhibitor onvansertib extends its benefit and overcomes paclitaxel resistance, and represents a promising therapeutic strategy for HR+ breast cancer patients after progression on a combination of endocrine and CDK4/6 inhibitor therapy. Citation Format: Maya Ridinger, Pierre Painsec, Sreeja Sreekumar, Dalia Gonzalez, Davis Klein, Laura Sourd, Elodie Montaudon, Paul Cottu, Tod Smeal, Elisabetta Marangoni. PLK1 Inhibitor Onvansertib Extends the Response and Overcomes Resistance to Paclitaxel in Palbociclib-resistant HR+ Breast Cancer Patient-derived Xenografts [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 PO1-04-14.

542 Background: We reported the benefit of taking evening tamoxifen compared to morning/afternoon as adjuvant treatment for high-risk breast cancers in the UNIRAD phase III trial (NCT01805271) (1). Here, we examine the relevance of EVE timing intake in this trial. Methods: 1,277 pts with high-risk HR+/ HER2- primary BC were randomly assigned to adjuvant ET with placebo or EVE (1). Patients prospectively reported in a diary the daily timing for ET and EVE intake among four 6-h slots (06:00 to 11:59 (morning), 12:00 to 17:59 (afternoon), 18:00 to 23:59 (evening), or 24:00 to 05:59 (night). The association between EVE, ET timing and disease-free survival (DFS) was a prespecified secondary endpoint of the trial. Results: EVE timing was recorded by 513 of 632 patients (81.2%). Patients declaring EVE intake in the morning (n= 248, 48 %) or in the afternoon (n=52, 10%) were older than those declaring evening (n=207, 40 %) or night (n=6,1%) intakes ( p<0.001). They were more likely to be postmenopausal (p=0.001) and to take AI rather than tamoxifen (p = 0.03). Only 17 patients (3%) changed EVE intake timing throughout the study. EVE intake dialy times were binned into 2 categories for analyses: morning/afternoon group (n=300) and evening/night group (n = 213). The patients who took morning/afternoon EVE chose another timing for ET in 38% of the cases compared to 17.1% in evening/Night EVE group (p<0.01). The timing of EVE intake was not significantly associated with definitive EVE withdrawal ( p=0.62) in the whole population. Time to EVE withdrawal was significantly longer in the patients taking tamoxifen rather than AI (17.2 vs 10.9 months, p = 0.0047). Prolonged duration of EVE treatment was associated with evening/night intakes of both EVE and tamoxifen, compared to other drug timing modalities (p = 0.04). With a median follow-up of 85months, 15 patients relapsed locally (3%), 55 developed metastases (11%), 36 patients died (7%). Overall, EVE intake timing was not associated with DFS (HR=0.84 [95% CI, 0.53 - 1.35], p=0.4). There was a significant interaction between EVE timing intake and ET type ( P interaction= 0.001). Patients on evening/night EVE combined with tamoxifen had a reduced likelihood of relapse compared to those taking morning/afternoon EVE (HR = 0.17 [0.05- 0.59], p = 0.005). In contrast, no significant EVE effect was found in the AI group (HR = 1.56 [0.92 2.64], p = 0.1). Evening/Night intake of EVE plus tamoxifen was independently associated with DFS (HR 0.13 [0.03-0.6], p = 0.002) after adjustment for age, nodal status, tumor size, ET timing intake, and EVE dose (2.5, 5 or 10 mg). Conclusions: These exploratory results are consistent with a role of circadian rhythm in the efficacy of EVE when given with tamoxifen in pts with high risk early breast cancer. 1. S. Giacchetti et al, Abst 546, ASCO 2023. Clinical trial information: NCT01805271 .

Abstract Background: Higher levels of pre and post-diagnosis physical exercise lead to reduced risk of death among survivors of BC. However, the effect of exercise on recurrence remains unclear. Furthermore, previous studies assumed a linear relationship between exercise and clinical outcomes, used discrete classifications of exercise and did not report results according to BC subtype. The aim of this study was to investigate the dose–response relationship of exercise and clinical outcomes among survivors of BC and by BC subtypes. Methods: We included pts diagnosed with stage I-III BC from the CANTO cohort (NCT01993498). CANTO collects longitudinal data, including self-reported exercise exposure using the Global Physical Activity Questionnaire (GPAQ-16), at diagnosis (dx), 1 (T1), 2 (T2) and 4 (T3) years after dx. Exercise exposure in travel and leisure time was calculated according to GPAQ16 guidelines to derive a total MET-hours per week (MET-h/w) at dx and T1 and absolute change in exercise was computed between these timepoints. Outcome of interest was distant relapse-free interval (DRFI) according to STEEP criteria. Restricted cubic splines from unadjusted Cox models assessed the dose-response relationship between exercise and DRFI in the overall cohort and by BC subtype. Kaplan-Meier estimator, log-rank test and multivariate Cox models assessed the prognostic role of exercise. Results: In the overall cohort with available data on exercise at dx (N=10,359) mean (SD) age and BMI were 56.3 (11.2) years and 25.9 (5.4) kg/m2, 38.7% of pts were premenopausal, 52.9% received chemotherapy and 81.9% hormonal therapy, 57.1% were meeting WHO exercise recommendations at dx. At a median (IQR) follow-up of 5.5 (3.9-6.5) years, 541 DRFI events were observed. In the overall cohort, the spline showed a significant non-linear relationship between exercise at dx and DRFI: exposure greater than ≈5 MET-h/w was associated with an inverse linear risk reduction up to ≈25 MET-h/w. A similar relationship was observed in the HR+/HER2- and HR-/HER2- cohorts. On this basis, exercise was categorized as ‘no exercise’ (0 MET-h/w) and ‘exercise’ (≥ 5 MET-h/w). Pts reporting exercise ≥ 5 MET-h/w had longer DRFI compared to those reporting no exercise in the overall (log-rank p< 0.0001), HR+/HER2- (log-rank p< 0.0113) and HR-/HER2- (log-rank p< 0.0001) cohorts. In multivariate analyses, reporting exercise ≥ 5 MET-h/w was associated with a significant lower risk of DRFI events in the overall (HR 0.75, 95%CI 0.62-0.90) and HR-/HER2- cohorts (HR 0.54, 95%CI 0.37-0.80). Absolute change in exercise exposure from dx to T1 was available in 8,516 pts: 34.2% increased exercise (≥ 5 MET-h/w), 25.9% decreased exercise (≤ -5 MET-h/w) and 39.8% maintained exercise ( > –5 and < +5 MET-h/w). The spline showed a non-significant relationship between change in exercise and risk of DRFI events and change in exercise was not significantly associated with risk of DRFI events in multivariate analyses. Conclusions: In this large, prospective cohort of survivors of BC, higher exercise at diagnosis was associated with reduced risk of DRFI events. The relationship between exercise dose and clinical outcomes appears non-linear and to differ based on subtype. Change in exercise after breast cancer diagnosis does not appear to impact on clinical outcomes. Future studies should aim at validating these findings in independent cohorts. XX XX Citation Format: Davide Soldato, Ines Vaz Luis, Julie Havas, Antonio Di Meglio, Neil Iyengar, Barbara Pistilli, Paul Cottu, Florence Lerebours, Charles Coutant, Aurélie Bertaut, Olivier Trédan, Laurence Vanlemmens, Christelle Jouannaud, Ioana Hrab, Sibille Everhard, Anne-Laure Martin, Fabrice André, Lee Jones. Dose-response association between post-diagnosis exercise and clinical outcomes among survivors of breast cancer (BC) [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 PO3-11-07.

AimsThe purpose of this work was to assess failures in the advanced prescription of parenteral anticancer agents in an adult day oncology care unit with more than 100 patients per day.MethodsAn a priori descriptive analysis was carried out by using the risk matrix approach. After defining the scope in a multidisciplinary meeting, we determined at each step the failure modes (FMs), their effects (E) and their associated causes (C). A severity score (S) was assigned to all effects and a probability of occurrence (O) to all causes. These S and O indicators, were used to obtain a criticality index (CI) matrix. We assessed the risk control (RC) of each failure in order to define a residual criticality index (rCI) matrix.ResultsDuring risk analysis, 14 FMs were detected, and 61 scenarios were identified considering all possible effects and causes. Nine situations (15%) were highlighted with the maximum CI, 18 (30%) with a medium CI, and 34 (55%) with a negligible CI. Nevertheless, among all these critical situations, only three (5%) had an rCI to process (i.e., missed dose adjustment, multiple prescriptions and abnormal biology data); the others required monitoring only. Clinicians' and pharmacists' knowledge of these critical situations enables them to manage the associated risks.ConclusionsAdvanced prescription of injectable anticancer drugs appears to be a safe practice for patients when combined with risk management. The major risks identified concerned missed dose adjustment, prescription duplication and lack of consideration for abnormal biology data.