Residual ANTXR1+ myofibroblasts after chemotherapy inhibit anti-tumor immunity via YAP1 signaling pathway.

Although cancer-associated fibroblast (CAF) heterogeneity is well-established, the impact of chemotherapy on CAF populations remains poorly understood. Here we address this question in high-grade serous ovarian cancer (HGSOC), in which we previously identified 4 CAF populations. While the global content in stroma increases in HGSOC after chemotherapy, the proportion of FAP+ CAF (also called CAF-S1) decreases. Still, maintenance of high residual CAF-S1 content after chemotherapy is associated with reduced CD8+ T lymphocyte density and poor patient prognosis, emphasizing the importance of CAF-S1 reduction upon treatment. Single cell analysis, spatial transcriptomics and immunohistochemistry reveal that the content in the ECM-producing ANTXR1+ CAF-S1 cluster (ECM-myCAF) is the most affected by chemotherapy. Moreover, functional assays demonstrate that ECM-myCAF isolated from HGSOC reduce CD8+ T-cell cytotoxicity through a Yes Associated Protein 1 (YAP1)-dependent mechanism. Thus, efficient inhibition after treatment of YAP1-signaling pathway in the ECM-myCAF cluster could enhance CD8+ T-cell cytotoxicity. Altogether, these data pave the way for therapy targeting YAP1 in ECM-myCAF in HGSOC.

Genomic signature to guide adjuvant chemotherapy treatment decisions for early breast cancer patients in France: a cost-effectiveness analysis.

Introduction: Chemotherapy (CT) is commonly used as an adjuvant treatment for women with early breast cancer (BC). However, not all patients benefit from CT, while all are exposed to its short- and long-term toxicity. The Oncotype DX® test assesses cancer-related gene expression to estimate the risk of BC recurrence and predict the benefit of chemotherapy. The aim of this study was to estimate, from the French National Health Insurance (NHI) perspective, the cost-effectiveness of the Oncotype DX® test compared to standard of care (SoC; involving clinicopathological risk assessment only) among women with early, hormone receptor-positive, human epidermal growth factor receptor 2-negative BC considered at high clinicopathological risk of recurrence. Methods: Clinical outcomes and costs were estimated over a lifetime horizon based on a two-component model that comprised a short-term decision tree representing the adjuvant treatment choice guided by the therapeutic decision support strategy (Oncotype DX® test or SoC) and a Markov model to capture long-term outcomes. Results: In the base case, the Oncotype DX® test reduced CT use by 55.2% and resulted in 0.337 incremental quality-adjusted life-years gained and cost savings of €3,412 per patient, compared with SoC. Being more effective and less costly than SoC, Oncotype DX® testing was the dominant strategy. Discussion: Widespread implementation of Oncotype DX® testing would improve patient care, provide equitable access to more personalized medicine, and bring cost savings to the health system.

Prevalence of sexual dysfunction after breast cancer compared to controls, a study from CONSTANCES cohort.

PURPOSE: Sexuality, a substantial factor in quality of life, may be altered after breast cancer (BC) treatments as they intimately afflict femininity. This study aimed to assess the prevalence of sexual dysfunction in women with a history of BC and to compare it with women without a BC history. METHODS: The French general epidemiological cohort CONSTANCES includes more than 200,000 adults. All inclusion questionnaires from CONSTANCES non-virgin adult female participants were analyzed. Women reporting a history of BC were compared to controls in univariate analysis. Multivariate analysis was performed to highlight any demographic risk factor for sexual dysfunction. RESULTS: Among the 2,680 participants who had a history of BC, 34% did not engage in sexual intercourse (SI) in the month preceding the completion of the questionnaire (n = 911), 34% had pain during SI (n = 901) and 30% were not satisfied with their sex life (n = 803). Sexual dysfunction was significantly more frequent in women who had a history of BC: they had less sexual interest (OR 1.79 [1.65;1.94], p < 0.001), experienced more pain during SI (OR 1.10 [1.02;1.19], p < 0.001) and were more dissatisfied with their sex life (OR 1.58 [1.47;1.71], p < 0.001). This stayed true after adjustment on multiple demographic factors such as age, menopausal status, body mass index and depression. CONCLUSIONS: Overall, in this real-life study in a large national cohort, history of BC appeared to be a risk factor for sexual disorders. IMPLICATIONS FOR CANCER SURVIVORS: Efforts to detect sexual disorders in BC survivors and offer quality support must be pursued.

Ovarian Real-World International Consortium (ORWIC): A multicentre, real-world analysis of epithelial ovarian cancer treatment and outcomes.

Introduction: Much drug development and published analysis for epithelial ovarian cancer (EOC) focuses on early-line treatment. Full sequences of treatment from diagnosis to death and the impact of later lines of therapy are rarely studied. We describe the establishment of an international network of cancer centers configured to compare real-world treatment pathways in UK, Portugal, Germany, South Korea, France and Romania (the Ovarian Real-World International Consortium; ORWIC). Methods: 3344 patients diagnosed with EOC (2012-2018) were analysed using a common data model and hub and spoke programming approach applied to existing electronic medical records. Consistent definition of line of therapy between sites and an efficient approach to analysis within the limitations of local information governance was achieved. Results: Median age of participants was 53-67 years old and 5-29% were ECOG >1. Between 62% and 84% of patients were diagnosed with late-stage disease (FIGO III-IV). Sites treating younger and fitter patients had higher rates of debulking surgery for those diagnosed at late stage than sites with older, more frail patients. At least 21% of patients treated with systemic anti-cancer therapy (SACT) had recurrent disease following second-line therapy (2L); up to 11 lines of SACT treatment were recorded for some patients. Platinum-based SACT was consistently used across sites at 1L, but choices at 2L varied, with hormone therapies commonly used in the UK and Portugal. The use (and type) of maintenance therapy following 1L also varied. Beyond 2L, there was little consensus between sites on treatment choice: trial compounds and unspecified combinations of other agents were common. Discussion: Specific treatment sequences are reported up to 4L and the establishment of this network facilitates future analysis of comparative outcomes per line of treatment with the aim of optimizing available options for patients with recurrent EOC. In particular, this real-world network can be used to assess the growing use of PARP inhibitors. The real-world optimization of advanced line treatment will be especially important for patients not usually eligible for involvement with clinical trials. The resources to enable this analysis to be implemented elsewhere are supplied and the network will seek to grow in coverage of further sites.

Detection, resection and cure: a systematic review and meta-analysis of 18F-choline PET in primary hyperparathyroidism.

INTRODUCTION: Primary hyperparathyroidism (pHPT) is a common endocrine disorder caused by an autonomous overproduction of parathyroid hormone (PTH) by a parathyroid gland. Over the last decade, 18F-choline (FCH) PET has emerged as a highly performant imaging technique for guiding parathyroidectomy. As cure is the goal of surgery, the main aims of this study were to summarize patient-based sensitivity, positive predictive value (PPV), and cure rate of FCH PET guided surgery in the surgical management of pHPT. EVIDENCE ACQUISITION: We conducted a systematic review and metaanalysis according to the PRISMA Guidelines. A literature search was performed in the PubMed, Web of Science and Cochrane databases, last updated November 2022. Original articles on choline PET in patients with pHPT mentioning patient-based sensitivity, PPV and cure rate were retained. Quality of included studies was assessed using the QUADAS-2 Tool. Patient-based sensitivity, PPV and cure rate were pooled by using a random-effects model. EVIDENCE SYNTHESIS: Twenty-three studies including 1716 patients were included for quantitative assessment. FCH PET showed a pooled patient-based sensitivity of 93.8% (95% CI: 89.8-96.3) and PPV of 97% (95% CI: 92.8-98.8) in patients with pHPT. Parathyroid surgery was performed in 1129 patients. The pooled cure rate of PET-guided surgery was 92.8% (95% CI: 87.4-96.0). Heterogeneity was shown to be moderate for all effect sizes. CONCLUSIONS: FCH PET showed a high patient-based sensitivity, PPV and cure rate of PET guided surgery in patients with pHPT.

Current perspectives for external control arms in oncology clinical trials: Analysis of EMA approvals 2016-2021.

Leveraging external control data, especially real-world data (RWD), has drawn particular attention in recent years for facilitating oncology clinical development and regulatory decision-making. Medical regulators have published guidance on accelerating the use of RWD and external controls. However, few systematic discussions have been conducted on external controls in cancer drug submissions and regulatory feedback. This study aimed to identify European oncology drug approvals using external control data to demonstrate clinical efficacy. We included 18 eligible submissions employing 24 external controls and then discussed the use of external control, data sources, analysis methods, and regulators' feedback. The external controls have been actively submitted to the European Medical Agency (EMA) recently. We found that 17 % of the EMA-approved cancer drugs in 2016-2021 used external controls, among which 37 % of the cases leveraged RWD. However, nearly one-third of the external controls were not considered supportive evidence by EMA due to limitations regarding heterogeneous patient populations, missing outcome assessment in RWD, and inappropriate statistical analysis. This study highlighted that proper use of external controls requires a careful assessment of clinical settings, data availability, and statistical methodology. For better use of external controls in oncology clinical trials, we recommend: prospective study designs to avoid selection bias, sufficient baseline data to ensure the comparability of study populations, consistent endpoint measurements to enable outcome comparison, robust statistical methodology for comparative analysis, and collaborative efforts of sponsors and regulators to establish regulatory frameworks.

[Bisphenol A and breast cancer: State of knowledge and meta-analysis]. / Bisphénol A et cancer du sein : état des lieux des connaissances et méta-analyse.

INTRODUCTION: Bisphenol A is an endocrine disruptor used in the composition of food containers. It was partially banned in France in 2015 and classified as a "very high-risk substance" in 2017. Bisphenol A's carcinogenic effects have been demonstrated in animal testing. Bisphenol A acts through estrogen-dependent and estrogen-independent pathways. It induces epigenetic changes and impacts the microenvironment of the mammary gland. However, the role of bisphenol A exposure in the development of breast cancer in humans remains controversial. This study documents the current thinking on bisphenol A with an analysis of the mechanisms and a meta-analysis. MATERIALS AND METHODS: A literature review and a statistical analysis of linear regression type, with the creation of a Forest plot, were used to perform the meta-analysis of 9 studies including 10,695 patients. RESULTS: Nine case-control studies, published between 1990 and 2021, investigating the association between breast cancer and mean urinary, blood or tissue bisphenol A levels were selected. The meta-analysis did not find a significant association between bisphenol A exposure and the development of breast cancer with an OR=(1 IC95% [0.92-1.08]). DISCUSSION: This meta-analysis does not show a link between breast cancer and bisphenol A exposure. Nevertheless, the analysis of a pathogenic link between bisphenol A and breast cancer requires additional cohort studies to conclude because of methods of available studies.

Sexuality after breast cancer, how to provide a global and contemporary approach.

Patients' sexuality is one of the major and most neglected impact of breast cancer (BC) and its treatment. Even though research is ongoing on the subject, sexuality issues are rarely taken into account and efficiently dealt with in clinical practice. The objective is to review the impact of BC and its treatment on modern women sexuality. In the literature, a heterogeneous level of advancement is notable in the different publishing countries depending on the cultural background; some countries simply do not publish on the matter, others mainly discuss the male partners and practicians experience, and lastly, the most progressive countries have moved up to studying niches of patients such as sexual and gender minorities. A multidisciplinary approach, including pharmacologic and nonpharmacologic management, appears most efficient. There is a need for greater inclusion of partners and for providing a specific training to first-line health care providers. This review provides a general contemporary worldwide overview of the state of the art in sexuality issues in BC patients and survivors.

[Prophylaxis and management of cancer-associated thrombosis: Practical issues about anticoagulant use]. / Prévention et prise en charge des thromboses associées au cancer: questions pratiques à propos de l'anticoagulation.

Cancer-associated thrombosis (CAT) is a common complication resulting from various vascular mechanisms related to cancer, antitumoral therapy and patient status, and is associated with a poor prognosis. Anticoagulants recommended for CAT treatment or prevention mainly include low molecular weight heparin (LMWH) and direct oral anticoagulants (DOACs). Regarding thromboprophylaxis, a situation for which LMWH is a preferred option due to a lower risk of hemorrhage especially in patients with unresected gastro-intestinal and genito-urinary malignancies, the identification of patients at risk is a major issue. For patients with established CAT, the main issue is the choice of the most appropriate anticoagulant therapy. Because of the convenience of oral formulation, DOACs are an attractive option, and their efficacy has been shown in randomized trials. However, such studies are limited by selection biases, which make the analyzed population not representative of the real-life setting, as for instance cancers associated with a high risk of hemorrhage, or antitumoral therapies (e.g., tyrosine kinase inhibitors) known to interact with DOACs and then modifying their bioavailability. Caution associated with DOAC use is highlighted by most updated guidelines that recommend a case-by-case-based approach. The aim of the present paper is to help the oncologists make the most appropriate decision regarding the choice of anticoagulant therapy in a context of thromboprophylaxis or established CAT management in a patient with a solid tumor. The main issues are addressed through key practical questions, the answers of which are based on the current guidelines and additional published data or expert opinions.

The need to tailor the omission of axillary lymph node dissection to patients with good prognosis and sentinel node micro-metastases.

BACKGROUND: Results of IBCSG-23-01-trial which included breast cancer patients with involved sentinel nodes (SN) by isolated-tumor-cells or micro-metastases supported the non-inferiority of completion axillary-lymph-node-dissection (cALND) omission. However, current data are considered insufficient to avoid cALND for all patients with SN-micro-metastases. METHODS: To investigate the impact of cALND omission on disease-free-survival (DFS) and overall survival (OS), we analyzed a cohort of 1421 patients <75 years old with SN-micro-metastases who underwent breast conservative surgery (BCS). We used inverse probability of treatment weighting (IPTW) to obtain adjusted Kaplan-Meier estimators representing the experience in the analysis cohort, based on whether all or none had been subject to cALND omission. RESULTS: Weighted log-rank tests comparing adjusted Kaplan-Meier survival curves showed significant differences in OS (p-value = 0.002) and borderline significant differences in DFS (p-value = 0.090) between cALND omission versus cALND. Cox's regression using stabilized IPTW evidenced an average increase in the risk of death associated with cALND omission (HR = 2.77, CI95% = 1.36-5.66). Subgroup analyses suggest that the rates of recurrence and death associated with cALND omission increase substantially after a large period of time in the half sample of women less likely to miss cALND. CONCLUSIONS: Using IPTW to estimate the causal treatment effect of cALND in a large retrospective cohort, we concluded cALND omission is associated with an increased risk of recurrence and death in women of <75 years old treated by BCS in the absence of a large consensus in favor of omitting cALND. These results are particularly contributive for patients treated by BCS where cALND omission rates increase over time.

Erector spinae plane block versus thoracic paravertebral block for the prevention of acute postsurgical pain in breast cancer surgery: A prospective observational study compared with a propensity score-matched historical cohort.

BACKGROUND: Preventing acute postsurgical pain (PSP) following breast cancer surgery is a major issue. Thoracic paravertebral block (TPVB) has been widely studied for this indication. Erector spinae plane block (ESPB) has been assumed to be effective. We aimed to compare the efficacy and safety of ESPB over TPVB in preventing acute PSP. METHODS: In this prospective observational study, 120 patients admitted for unilateral major oncologic breast surgery received T2/T3 ESPB (ropivacaine 0.75%, 0.35 ml.kg-1), and 102 were analysed. Then, the ESPB cohort was compared to a TPVB cohort from the experimental arm of a randomized controlled study with the same protocol (NCT02408393) using propensity score matching analysis. The primary outcome was the need for morphine consumption in the PACU. Secondary outcomes were the morphine total dose, the incidence of ESPB and TPVB complications, and discontinuous visual analogue scale measurement trends at rest and at mobilization in the 24 hours after surgery. RESULTS: A total of 102 patients completed the study between December 2018 and August 2019. Propensity score matching formed 94 matched pairs. The proportion of morphine titration in the PACU was higher in the ESPB group than in the TPVB group (74.5% vs. 41.5%, p<0.001), with a between-group difference of 33.0% (95% CI [19.3%, 46.7%]). No ESPB-related complications were observed. CONCLUSION: ESPB is less effective in preventing morphine consumption in the PACU than TPVB. Our findings do not support the use of ESPB as the first-line regional anaesthesia for major breast cancer surgery. Randomized trials comparing ESPB and TPVB are needed.

[Impact of the COVID-19 pandemic on breast cancer management: Experience of a French Comprehensive Cancer Center]. / Impact de la pandémie de COVID-19 sur la prise en charge du cancer du sein : retour d'expérience d'un centre de lutte contre le cancer.

INTRODUCTION: The COVID-19 pandemic had a profound impact on health-care systems and reduced access to care. This study assays the mid-term effects of the COVID-19 pandemic on breast cancer management over a 2-year-period in a single French Comprehensive Cancer Center. METHODS: We performed, in a French comprehensive cancer center, an observational study including all patients with newly diagnosed breast cancer between 2019 and 2021. We collected the number of first consultations for breast cancer, the number of breast and axillary surgeries, pTNM and ypTNM cancer staging, the therapeutic sequence (surgery or neoadjuvant chemotherapy as a primary treatment), patients' age and their place of residence. RESULTS: In total, 14,772 patients had a first consultation for breast cancer. Among these 9058 breast and axillary surgeries were performed, 1798 patients had neoadjuvant chemotherapy as a primary treatment. During the first COVID-19 lockdown ( March17, 2020-May 10, 2020), we observed a reduction in the number of first consultations for breast cancer and breast cancer surgeries giving respectively a 42.3% and 27% rate of change. Subsequently, we observed a resumption of consultations and surgeries with a slight increase in early 2021 compared to 2019. In addition, we did not find any difference in terms of therapeutic sequence, pTNM and ypTNM stages, age at diagnosis or place of residence between the reference year 2019 and the years 2020 and 2021. CONCLUSION: Our study shows a decrease in activity during the first lockdown of 2020, then a resumption of activity. These reassuring results only concern patients with breast cancer, and are specific to our institution, whose oncology activity was preserved during the COVID-19 pandemic.

Contribution of endocrine therapy in oestrogen receptor-positive pT1a-b breast cancer: Results of a retrospective study.

INTRODUCTION: Few data have been reported regarding endocrine therapy (ET) in patients with small pT1a-b ER-postive breast cancer (BC). Thus, we conducted a study to detect possible survival improvements due to ET in such patients. METHODS: Our retrospective observational study included 5545 patients with pT1a-b ER-positive BC treated in 15 French centres, excluding patients with HER2-positive status, neoadjuvant chemotherapy, ER-negative status, unknown pN status or in situ BC. We estimated disease-free survival (DFS), recurrence-free survival (RFS) and overall survival (OS) via univariate analysis and multivariate Cox regression. RESULTS: Most patients (80.3%: 4453) received ET and-when compared to those without ET-experienced increases of 2.5% and 3.3% in DFS and 1.9% and 4.3% in RFS after 5 and 7 years of follow-up, respectively, with little difference in OS. In Cox regression analysis, no ET was significantly associated with decreased DFS (hazard ratio, HR = 1.275, p = 0.047, 95% CI[1.003-1.620]) but not OS or RFS in all patients, while in 2363 patients with pT1a-b ER-positive grade 2-3 BC, no ET was significantly associated with decreased DFS (HR = 1.502, p = 0.049, 95% CI[1.001-2.252]), but not OS (HR = 1.361, p = 0.272). ET omission was not significantly associated with decreased survival in 3047 patients with pT1a-b ER-positive grade 1 BC. CONCLUSION: Our results indicate that while ET provided a beneficial impact on survival to patients with pT1a-bN0 ER-positive BC-and especially in those with grade 2-3 tumours-no such impact was observed in grade 1 tumours. Consequently, ET should be discussed with these patients, particularly in those with pT1a grade 1 tumours.

A catalog of numerical centrosome defects in epithelial ovarian cancers.

Centrosome amplification, the presence of more than two centrosomes in a cell is a common feature of most human cancer cell lines. However, little is known about centrosome numbers in human cancers and whether amplification or other numerical aberrations are frequently present. To address this question, we have analyzed a large cohort of primary human epithelial ovarian cancers (EOCs) from 100 patients. We found that rigorous quantitation of centrosome number in tumor samples was extremely challenging due to tumor heterogeneity and extensive tissue disorganization. Interestingly, even if centrosome clusters could be identified, the incidence of centrosome amplification was not comparable to what has been described in cultured cancer cells. Surprisingly, centrosome loss events where a few or many nuclei were not associated with centrosomes were clearly noticed and overall more frequent than centrosome amplification. Our findings highlight the difficulty of characterizing centrosome numbers in human tumors, while revealing a novel paradigm of centrosome number defects in EOCs.

Real-World Data on Newly Diagnosed BRCA-Mutated High-Grade Epithelial Ovarian Cancers: The French National Multicenter ESME Database.

BACKGROUND: In spite of the frequency and clinical impact of BRCA1/2 alterations in high-grade epithelial ovarian cancer (HGEOC), real-world information based on robust data warehouse has been scarce to date. METHODS: Consecutive patients with BRCA-mutated HGEOC treated between 2011 and 2016 within French comprehensive cancer centers from the Unicancer network were extracted from the ESME database. The main objective of the study was the assessment of clinicopathological and treatments parameters. RESULTS: Out of the 8021 patients included in the ESME database, 266 patients matching the selection criteria were included. BRCA1 mutation was found in 191 (71.8%) patients, while 75 (28.2%) had a BRCA2 mutation only; 95.5% of patients received a cytoreductive surgery. All patients received a taxane/platinum-based chemotherapy (median = six cycles). Complete and partial response were obtained in 53.3% and 20.4% of the cases, respectively. Maintenance therapy was administered in 55.3% of the cases, bevacizumab being the most common agent. After a median follow up of 51.7 months, a median progression-free survival of 28.6 months (95% confidence interval (CI) [26.5; 32.7]) and an estimated 5-year median overall survival of 69.2% (95% CI [61.6; 70.3]) were reported. Notably, BRCA1- and BRCA2-mutated cases exhibited a trend towards different median progression-free survivals, with 28.0 (95% CI [24.4; 32.3]) and 33.3 months (95% CI [26.7; 46.1]), respectively (p-value = 0.053). Furthermore, five-year OS for BRCA1-mutated patients was 64.5% (95% CI [59.7; 69.2]), while it was 82.5% (95% CI [76.6; 88.5]) for BRCA2-mutated ones (p-value = 0.029). CONCLUSIONS: This study reports the largest French multicenter cohort of BRCA-mutated HGEOCs based on robust data from the ESME, exhibiting relevant real-world data regarding this specific population.

Optimal timing of interval debulking surgery for advanced epithelial ovarian cancer: A retrospective study from the ESME national cohort.

OBJECTIVE: Interval debulking surgery is recommended after 3-4 cycles (standard IDS) of neoadjuvant chemotherapy (NACT) for epithelial ovarian cancer (EOC) not able to received upfront complete debulking surgery. However, real world practices frequently report performing IDS after ≥5 NAC cycles (delayed IDS). The aim of this work was to evaluate the impact on survival of the number of NACT cycles before IDS. METHODS: We identified from a French national database, women with newly diagnosed EOC who underwent IDS from January 2011 to December 2016. Progression free survival (PFS) and overall survival (OS) were compared using Cox model with adjustments for confounding factors provided by two propensity score methods: inverse probability of treatment weighting (IPTW) and matched-pair analysis. RESULTS: 928 patients treated by IDS for which our propensity score could be applied were identified. After a median follow-up of 49.0 months (95% CI [46.0;52.9]); from the IPTW analysis, median PFS was 17.6 months and 11.5 months (HR = 1.42; CI 95% [1.22-1.67]; p < 0.0001); median OS was 51.2 months and 44.3 months (HR = 1.29; CI 95% [1.06-1.56]; p = 0.0095) for the standard and delayed IDS groups. From the matched-pair analysis (comparing 352 patients for each group), standard IDS was associated with better PFS (HR = 0,77; CI 95% [0.65-0.90]; p = 0.018) but not significantly associated with better OS (HR = 0,84; CI 95% [0.68-1,03]; p = 0.0947). CONCLUSIONS: Carrying IDS after ≥5 NACT cycles seems to have a negative effect on patients survival. The goal of IDS surgery is complete resection and should not be performed after >3-4 NACT cycles.

Variation over time of the factors influencing return to work and work capacities after a diagnosis of breast cancer: a study on the behalf of the Seintinelles research network.

PURPOSE: To evaluate the dynamics of the determinants of returning to work (RTW) in a population of patients treated for breast cancer (BC) in a real-world setting. METHOD: We conducted a retrospective study including 1278 BC patients working or looking for work at the time of diagnosis. We performed a focused principal component analysis to highlight the dimensions of a persistent decline in work capacity. Logistic regression analyses were performed to identify correlates of non-RTW 1 and 2 years after treatment. RESULTS: One-third (31%, n = 389) of patients continued working during treatment. At study inclusion, 1100 patients had returned to work (89%). Three-quarters (n = 508, 75%) of the women reported a decline in work capacity 1 year after RTW and 22% (n = 148) presented a persistent decline in work capacity 2 years after the diagnosis. The odds ratio for non-RTW at 1 year was significantly higher for patients treated with a combination of chemotherapy and trastuzumab (OR = 1.72, 95% CI [1.07-2.76]), manual workers (OR = 3.99, 95% CI [1.54-10.81]), patients with lower incomes (OR = 2.33, 95% CI [1.29-4.19]), and patients experiencing fatigue (OR = 1.81, 95% CI [1.34-2.48]). The odds ratio for non-RTW at 2 years was higher for various occupational categories (OR = 3.49, 95% CI [1.89-6.74] for clerks, OR = 4.58, 95% CI [1.48-12.82] for self-employed workers, OR = 8.98, 95% CI [2.69-27.89] for manual workers), patients with comorbidities (OR = 2.80, 95% CI [1.61-4.93]), and patients experiencing anxiety symptoms (OR = 2.54, 95% CI [1.18-5.76]), while the impact of the type of treatment was no longer significantly associated with RTW. CONCLUSION: The determinants of RTW change over time. Patients should be offered supportive interventions tailored to risk factors and time from diagnosis.