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Background: More than half of Breast Cancer (BC) patients take chronically used non-cancer treatments (denoted as comedications) at BC diagnosis. Epidemiological evidence has reported that several non-cancer treatments may modify BC risk, BC recurrence, and overall survival (OS). The ADRENALINE project (Atlas for DRug and brEast caNcer survivAL INtEraction) analyses the impact of the use of each commonly prescribed non-cancer treatment at BC diagnosis on OS using the French social security system data on a comprehensive cohort of French BC patients. Methods: We identified all women diagnosed with an incident BC treated with surgery in France from 2011 to 2017 and affiliated to the general health insurance scheme. Women with concomitant cancer or metastases at diagnosis were discarded from the analyses. Comedication intake was defined as the delivery in pharmacy of at least 3 months of full treatment (e.g. 90 pills) the 6 months preceding BC diagnosis. A Cox proportional hazard model was used to estimate the hazard ratio (HR) for each molecule. The model was adjusted on more than 100 confounding variables: social factors, comorbidities and other comedications by Inverse Probability of Treatment Weighting (IPTW). We assumed that the adjustment was sufficient to control for confounding if the standardized mean difference of each confounder after adjustment did not exceed 0.1. Molecules which did not pass the adjustment quality test were discarded. Results: Overall, 235,368 patients were included in the study. Among 219 selected drugs, 91 passed the adjustment quality test. The full set of results is available on a web application (https://adrenaline.curie.fr). Several drugs or drug classes were associated with an improved survival: statins (e.g. rosuvastatin, HR=0.65, p< 0.001); proton-pump inhibitors (HR=0.93; p=0.002); or beta-blocking agents (atenolol, HR=0.78, p=0.003). Conversely, anti-anemic preparations (folic acid and ferrous sulfate) had a significant deleterious effect (HR = 1.63; p< 0.001). Drugs from the same therapeutic class, could have different effects: within benzodiazepines, bromazepam was protective (HR = 0.91; p = 0.038) while oxazepam was deleterious (HR = 1.37; p < 0.001). Conclusion: ADRENALINE reports the impact on BC survival of 219 widely prescribed drugs. It can be used to identify molecules with a potential protective or deleterious effect relative to BC. Some of them are currently under mechanistical investigation within a drug screening program. This atlas highlights candidates to drug-repurposing trials or pharmacovigilance warnings, and will be extended to cancers of other localizations in a near future. Citation Format: Elise Dumas, Beatriz Grandal, Paul Gougis, Sophie Houzard, Aurélien Latouche, Aullène Toussaint, Samar Alsafadi, Judith Abecassis, Lidia Delrieu, Thierry Dubois, Nadir Sella, Marc Espie, Bernard Asselain, Annabelle Ballesta, Benjamin Marande, Eric Daoud, Enora Laas, Amyn Kassara, Floriane Jochum, Elaine Del Nery, Elodie Anthony, Christine Le Bihan-Benjamin, Philippe-Jean Bousquet, Chloé-Agathe Azencott, Fabien Reyal, Anne-Sophie Hamy. Comedications at Breast Cancer diagnosis impact overall survival: results from the ADRENALINE (Atlas for DRug and brEast caNcer survivAL INtEraction) study (n=235,368) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-07-06.

BackgroundBreast cancer (BC) is the most frequent cancer and the leading cause of cancer-related death in women. The French National Cancer Institute has created a national cancer cohort to promote cancer research and improve our understanding of cancer using the National Health Data System (SNDS). This cohort amalgamates all cancer sites, with no detailed separate data for early BC.ObjectivesWe describe the French Early Breast Cancer Cohort (FRESH).MethodsAll French women aged 18 years or over, with early-stage BC newly diagnosed between January 1, 2011 and December 31, 2017, treated by surgery and registered in the general health insurance coverage plan were included in the cohort. Patients with suspected locoregional or distant metastases at diagnosis were excluded. BC treatments (surgery, chemotherapy, targeted therapy, radiotherapy, endocrine therapy), and diagnostic procedures (biopsy, cytology, imaging) were extracted from hospital discharge reports, outpatient care notes or pharmacy drug delivery data. BC subtype was inferred from the treatments received.ResultsWe included 235,368 patients with early BC in the cohort (median age: 60 years). BC subtype distribution was as follows: luminal (80.2%), triple-negative (TNBC, 9.5%); HER2+ (10.3%), or unidentifiable (n=44,388, 18.9% of the cohort). Most patients underwent radiotherapy (n=200,685, 85.3%) and endocrine therapy (n=165,655, 70.4%), and 38.3% (n=90,252) received chemotherapy. Treatments and care pathways are described.ConclusionThe FRESH Cohort is an unprecedented population-based resource facilitating future large-scale real-life studies aiming to improve care pathways and quality of care for BC patients.

Background Hospitals in the public and private sectors tend to join larger organizations to form hospital groups. This increasingly frequent mode of functioning raises the question of how countries should organize their health system, according to the interactions already present between their hospitals. The objective of this study was to identify distinctive profiles of French hospitals according to their characteristics and their role in the French hospital network. Methods Data were extracted from the national hospital database for year 2016. The database was restricted to public hospitals that practiced medicine, surgery or obstetrics. Hospitals profiles were determined using the k-means method. The variables entered in the clustering algorithm were: the number of stays, the effective diversity of hospital activity, and a network-based mobility indicator (proportion of stays followed by another stay in a different hospital of the same Regional Hospital Group within 90 days). Results Three hospital groups were identified by the clustering algorithm. The first group was constituted of 34 large hospitals (median 82,100 annual stays, interquartile range 69,004 – 117,774) with a very diverse activity. The second group contained medium-sized hospitals (with a median of 258 beds, interquartile range 164 - 377). The third group featured less diversity regarding the type of stay (with a mean of 8 effective activity domains, standard deviation 2.73), a smaller size and a higher proportion of patients that subsequently visited other hospitals (11%). The most frequent type of patient mobility occurred from the hospitals in group 2 to the hospitals in group 1 (29%). The reverse direction was less frequent (19%). Conclusions The French hospital network is organized around three categories of public hospitals, with an unbalanced and disassortative patient flow. This type of organization has implications for hospital planning and infectious diseases control.

To study the use of reimbursed contraceptive methods in France between 2014 and 2019, with an analysis of the profile of users by age group and an analysis by type of prescriber.We conducted a national descriptive study using data from the Assurance Maladie Open Data database on the use of contraceptive methods reimbursed in France from January 1, 2014, to December 31, 2019. We analyzed the number of users by year, by age group (20years, 20-60years), and by prescriber (liberal general practitioner, liberal gynecologist, hospital practitioner, liberal midwife).In 2019, 50.1% (5,345,122) of women of childbearing age used a reimbursed contraceptive method. Hormonal oral contraception was the leading contraceptive method used (42.3%), followed by the intrauterine device (6.2%) and the implant (1.6%). Use of combined estrogen-progestogen oral contraception had been declining since 2015 (-8.1 points), to the benefit of the micro progestin pill (+9.1 points) and the copper intrauterine device (+1.4 points). Among women under 20, the hormonal implant was the second most popular contraceptive method (1.2%), followed by the copper intrauterine device (0.8%) and the hormonal intrauterine system (0.2%). Among women over 20years of age of childbearing age, the copper IUD was the second most-reimbursed contraceptive method (2.4%), followed by the hormonal intrauterine system (1.6%) and the hormonal implant (1.2%). There are disparities in prescribing practices: in 2019, 51% of prescribers were general practitioners and 97% of them prescribed hormonal oral contraception.The contraceptive supply in France is diversifying, although oral contraception remains predominant. Disparities exist between age groups of users and there is great heterogeneity in practices among contraceptive prescribers.

BackgroundAccess to health services plays a key role in cancer survival. Uneven distributions of populations and health facilities lead to geographical disparities. Location-allocation algorithms can address these disparities by finding new locations and capacities for health facilities. However, in oncology, opening new hospitals or moving them is difficult in practice, and should be handled carefully.MethodsWe propose a method to measure the spatial accessibility to oncology care and identify the hospitals to grow to reduce disparities. We first ran a clustering algorithm to automatically label the hospitals in terms of oncology specialization. Then, we computed an accessibility score to these hospitals for every population location. Finally, we introducedCAMION, an optimization algorithm based on Linear Programming that reduces disparities in oncology accessibility by identifying health facilities that should increase their capacities.ResultsWe demonstrate our algorithm in metropolitan France. The clustering step let us identify different oncology specialization levels for hospitals. Most of the population in metropolitan France lived in good accessibility areas, especially in large cities. Lower accessibility zones are often rural or suburban municipalities. The optimization algorithm effectively manages to identify hospitals to grow, based on current oncology specialization and accessibility scores.DiscussionThere is a tradeoff to be found by patients, between care center proximity and care center expertise, which is less likely to happen for patients living in good accessibility areas. The accessibility score is deliberately non-specific to cancer type but can be adapted to more precise pathologies. Our method is replicable in any country, given hospitals and population locations data. We developed a web application intended for healthcare professionals to let them to run the optimization algorithm with the desired parameters and visualize the results.

Although an increasing number of young breast cancer (BC) patients have a pregnancy desire after BC, the time necessary to obtain a pregnancy after treatment and subsequent outcomes remain unknown. We aimed to determine the time to evolutive pregnancy in a cohort of BC survivors and subsequent obstetrical and neonatal outcomes. We analyzed BC patients treated at Institut Curie from 2005–2017, aged 18–43 years old (y.o.) at diagnosis having at least one subsequent pregnancy. 133 patients were included, representing 197 pregnancies. Mean age at BC diagnosis was 32.8 y.o. and at pregnancy beginning was 36.8 y.o. 71% pregnancies were planned, 18% unplanned and 86% spontaneous. 64% pregnancies resulted in live birth (n = 131). Median time from BC diagnosis to pregnancy beginning was 48 months and was significantly associated with endocrine therapy (p &lt, 0.001). Median time to pregnancy was 4.3 months. Median time to evolutive pregnancy 5.6 months. In multivariate analysis, menstrual cycles before pregnancy remained significantly associated with time to pregnancy and endocrine therapy with time evolutive to pregnancy. None of the BC treatments (chemotherapy/endocrine therapy/trastuzumab) was significantly associated with obstetrical nor neonatal outcomes, that seemed comparable to global population. Our findings provide reassuring data for pregnancy counseling both in terms of delay and outcome.

Simple Summary Immune checkpoint inhibitors (ICI) are now part of the therapeutical arsenal for cancers at several sites and in several settings. PD-L1 expression is assessed to predict treatment response. We used immunohistochemistry (E1L3N clone) to assess PD-L1 expression on tumor and immune cells from a cohort of 89 surgical specimens of T1-T3NxM0 triple-negative breast cancers (TNBC) from patients treated with neoadjuvant chemotherapy (NAC) with residual disease. PD-L1 expression levels were low in tumor and immune cells from post-NAC surgical specimens. PD-L1 positivity in tumor cells was significantly associated with aggressive post-NAC tumor characteristics. A small subset of TNBC patients displaying PD-L1 expression in the context of a more extensive post-NAC tumor burden could benefit from ICI treatment after NAC. Abstract The consequences of neoadjuvant chemotherapy (NAC) for PD-L1 activity in triple-negative breast cancers (TNBC) are not well-understood. This is an important issue as PD-LI might act as a biomarker for immune checkpoint inhibitors’ (ICI) efficacy, at a time where ICI are undergoing rapid development and could be beneficial in patients who do not achieve a pathological complete response. We used immunohistochemistry to assess PD-L1 expression in surgical specimens (E1L3N clone, cutoff for positivity: ≥1%) on both tumor (PD-L1-TC) and immune cells (PD-L1-IC) from a cohort of T1-T3NxM0 TNBCs treated with NAC. PD-L1-TC was detected in 17 cases (19.1%) and PD-L1-IC in 14 cases (15.7%). None of the baseline characteristics of the tumor or the patient were associated with PD-L1 positivity, except for pre-NAC stromal TIL levels, which were higher in post-NAC PD-L1-TC-positive than in negative tumors. PD-L1-TC were significantly associated with a higher residual cancer burden (p = 0.035) and aggressive post-NAC tumor characteristics, whereas PD-L1-IC were not. PD-L1 expression was not associated with relapse-free survival (RFS) (PD-L1-TC, p = 0.25, and PD-L1-IC, p = 0.95) or overall survival (OS) (PD-L1-TC, p = 0.48, and PD-L1-IC, p = 0.58), but high Ki67 levels after NAC were strongly associated with a poor prognosis (RFS, p = 0.0014, and OS, p = 0.001). A small subset of TNBC patients displaying PD-L1 expression in the context of an extensive post-NAC tumor burden could benefit from ICI treatment after standard NAC.

Breast cancer (BC) is the most common cancer in women worldwide. Neoadjuvant chemotherapy (NAC) makes it possible to monitor in vivo response to treatment. Several studies have investigated the impact of the seasons on the incidence and detection of BC, on tumor composition, and on the prognosis of BC. However, no evidence is available on their association with immune infiltration and the response to treatment. The objective of this study was to analyze pre- and post-NAC immune infiltration as assessed by TIL levels, the response to treatment as assessed by pathological complete response (pCR) rates, and oncological outcomes as assessed by relapse-free survival (RFS) or overall survival (OS) according to the seasonality of BC diagnoses in a clinical cohort of patients treated with neoadjuvant chemotherapy. Out of 1199 patients, the repartition of the season at BC diagnosis showed that 27.2% were diagnosed in fall, 25.4% in winter, 24% in spring, and 23.4% in summer. Baseline patient and tumor characteristics, including notable pre-NAC TIL levels, were not significantly different in terms of the season of BC diagnosis. Similarly, the pCR rates were not different. No association for oncological outcome was identified. Our data do not support the idea that the seasonality of diagnoses has a major impact on the natural history of BC treated with NAC.

Background: Cancer caused nearly 10 million deaths in 2020. While most of the ongoing research focuses on finding new treatments, accessibility to oncology care receives less attention. However, access to health services plays a key role in cancer survival. Spatial accessibility methods have been successfully applied to measure accessibility to primary care. Yet, little research to date focused on oncology care specifically. Methods: We focused on all care centers with medicine, surgery, or obstetric activity in metropolitan France. We propose a clustering algorithm to automatically label the hospitals in terms of oncology specialization. Then, we computed an accessibility score to these hospitals for every municipality in metropolitan France. Finally, we proposed an optimization algorithm to increase the oncology accessibility by identifying centers which should increase their capacity. Results: We labelled 1,662 care centers into 8 clusters. Half of them were eligible for oncology care and 118 centers were identified as experts. We computed the oncology accessibility score for 34,877 municipalities in metropolitan France. Half of the population lived in the top 20% accessibility areas, and 6.3% in the bottom 20% zones. Accessibility was higher near dense cities, where the experts care centers were located. By combining the care centers clusters and the accessibility distributions, our optimization algorithm could identify hospitals to grow, to reduce accessibility disparities. Conclusion: Our method made it possible to quantify oncology care accessibility across all metropolitan France, as well as to make suggestions on where to increase hospital capacity to improve accessibility, especially in more populated suburban areas. Our approach was deliberately non-specific to cancer type nor to the kind of stays, but it could be adapted to more specific scenarios. We packaged our method into a web application allowing the users to run the algorithms with various parameters and visualize the results. Citation Format: Eric Daoud, Anne-Sophie Hamy, Elise Dumas, Lidia Delrieu, Beatriz Grandal, Christine Le Bihan-Benjamin, Sophie Houzard, Philippe-Jean Bousquet, Judicael Hotton, Aude-Marie Savoye, Christelle Jouannaud, Chloé-Agathe Azencott, Marc Lelarge, Reyal Fabien. Disparities in accessibility to oncology care centers in France [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1022.

Background: Breast cancer (BC) incidence increases with age, as well as the incidence of many other chronic diseases. Between 42 and 68% of BC patients suffer from other chronic conditions -comorbidities- at BC diagnosis. Comorbidities may be associated with the intake of chronic medications -comedications. The French health insurance system routinely collects health care reimbursements of almost 98% of the population: hospital abstracts, long-term diseases, outpatient care (medical consults, drug purchases under prescription⋯) and death status. The project ADRENALINE (Atlas for DRug and brEast caNcer survivAL INtEraction) analyzes the impact of comedications at diagnosis on BC survival on a French cohort using data from the French social security system. Methods: We identified all women diagnosed with an incident BC treated with surgery in France from 2011 to 2017 and affiliated to the general health insurance scheme. Women with concomitant cancer or metastases at diagnosis were discarded from the analyses. Comedication intake was defined as the delivery in pharmacy of at least 3 months of full treatment (e.g. 90 pills) the 6 months preceding BC diagnosis. The analysis was restricted to drugs taken by at least 300 women. A Cox proportional hazard model was used to estimate the hazard ratio (HR) for each molecule. The model was adjusted on more than 100 confounding variables: social factors, comorbidities and other comedications. Two adjustment methods were tested: Inverse Probability of Treatment Weighting (IPTW) and matching. We assumed that the adjustment was sufficient to control for confounding if the standardized mean difference of each confounder after adjustment did not exceed 0.1. Molecules which did not pass the adjustment quality test were discarded. Results: 235,375 patients were included in the study. Among 219 selected drugs, 91 and 171 passed the adjustment quality test for IPTW and for matching, respectively. The full set of results is available on a web application. Among main findings, several drugs or drug classes were associated with an improved survival: proton-pump inhibitors (IPTW; HR=0.93; p=0.002); statins (e.g. rosuvastatin, IPTW, HR=0.65, p Conclusion: ADRENALINE reports the impact on BC survival of 219 widely prescribed drugs. It can be used to identify molecules with a potential protective or deleterious effect relative to BC. Some of them are currently under mechanistical investigation within a drug screening program. This atlas highlights candidates to drug-repurposing trials or pharmacovigilance warnings, and will be extended to cancers of other localizations in a near future. Citation Format: Elise Dumas, Beatriz Grandal, Lucie Laot, Eric Daoud, Lidia Delrieu, Marc Espié, Sophie Houzard, Christine Le Bihan-Benjamin, Philippe-Jean Bousquet, Elodie Anthony, Aurélien Latouche, Nadir Sella, Thierry Dubois, Annabelle Ballesta, Amyn Kassara, Elaine Del Nery, Benjamin Marande, Samar Alsafadi, Paul Gougis, Chloé-Agathe Azencott, Fabien Reyal, Anne-Sophie Hamy. ADRENALINE, an atlas for drug and breast cancer survival interaction: Comedications at diagnosis and impact on breast cancer mortality of the French breast cancer cohort (n=235,375) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 4101.

Context: There is a growing interest in drug repurposing and pathological complete response (pCR) that may influence the progression and treatment of breast cancer (BC). However, few studies focus on the influence of comedications, i.e., non-anticancerous drugs taken for coexisting conditions in cancer patients on neoadjuvant chemotherapy (NAC), and even less regarding the impact of response to treatment and relapse in breast cancer. Objectives: To assess whether the use of comedications modifies pCR and patient relapse probability in BC. Methods: We retrospectively analyzed data from Saint-Louis Hospital (Paris, France). Characteristics from 664 patients with neoadjuvant chemotherapy. Response to chemotherapy was assessed by pathological complete response (pCR). We analyzed comedication according to levels 1 and 2 of the Anatomical Therapeutic Chemical Classification System (ATC). A chronic comedication was defined by a comedication declared at diagnosis, excluding local and/or non-continuous administration. To estimate the average causal effect of comedication on pCR, we employed Inverse Probability Weighting (IPW) and Super Learner strategy to pick the best regression model. We used a Cox multivariate regression model to analyze the average causal effect of comedications on relapse probability. Results: 664 patients were included in this study. The median age at inclusion was 51.4 years. Of 664 patients, 194 patients (29.2%) had at least one comedication (433 total comedications). The repartition of comedications, according to the 1st level of ATC, was as follows: Cardiovascular system (C): 40.2% (n=174), Nervous system (N): 23.8% (n=103) and Alimentary tract and metabolism (A): 15.2% (n=66). Among the population with collected pCR, 112 tumors achieved pCR (18.6%). After IPW adjusted for clinical, pathological, and treatment variables, C03 (Diuretics) was associated with an increased likelihood of positive pCR (C03 versus no C03, OR = 5.0, CI95% [1.25-12.2]). By contrast, N06 (Psychoanaleptics) was associated with a decrease in pCR rates (OR= 0.3, CI95% [0.1-0.6]). The multivariate survival analysis showed a significant effect on the relapse probability of Selective Serotonin reuptake inhibitors (SSRIs, NO6) (OR = 2.3 CI95% [1.2-4.4], p = 0.01). Discussion: In this observational analysis, the use of chronic cardiovascular diuretics (C03) during NAC was associated with improvement of pCR rates. On the contrary, Psychoanaleptics (N06) were significantly associated with lower pCR rates and a higher probability of relapse. This finding prompts for further research on the interactions between chemotherapy, nervous system drugs such as SSRIs, and pathological complete response. Citation Format: Anne-Sophie Hamy, Amyn Kassara, Hamid Hocini, Clementine Garin, Luis Teixeira, Caroline Cuvier, Paul Gougis, Elise Dumas, Fabien Reyal, Beatriz Grandal, Nadir Sella, Eric Daoud, Aurélien Latouche, Thierry Dubois, Annabelle Ballesta, Samar Alsafadi, Elaine Del Nery, Élodie Anthony, Benjamin Marande, Cedric de Bazelaire, Anne de Roquancourt, Catherine Michel, Sylvie Giacchetti, Marc Espie. Impact of comedications on pCR rates and relapse in breast cancer. Analysis of the Saint-Louis observational cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3348.

The consequences of neoadjuvant chemotherapy (NAC) for PD-L1 activity in triple-negative breast cancers (TNBC) are not well understood. This is an important issue as immune checkpoint inhibitors (ICI) are undergoing rapid development and could be beneficial in patients who do not achieve a pathological complete response. We used immunohistochemistry to assess PD-L1 expression (E1L3N clone, cutoff for positivity: ≥ 1%) on both tumor (PD-L1-TC) and immune cells (PD-L1-IC) from a cohort of surgical specimens of T1-T3NxM0 TNBCs treated with NAC. PD-L1-TC was detected in 17 cases (19.1%) and PD-L1-IC in 14 cases (15.7%). None of the baseline characteristics of the tumor or the patient were associated with PD-L1 positivity, except for pre-NAC stromal TIL levels, which were higher in post-NAC PD-L1-TC-positive than in negative tumors. PD-L1-TC were significantly associated with a higher residual cancer burden (p=0.035) and aggressive post-NAC tumor characteristics, whereas PD-L1-IC were not. PD-L1 expression was not associated with DFS (p=0.38) or OS (p=0.48), but high Ki67 levels after NAC were strongly associated with a poor prognosis (DFS p=0.0014 and OS p=0.001). A small subset of TNBC patients displaying PD-L1 expression in the context of an extensive post-NAC tumor burden could benefit from ICI treatment after standard NAC.

IntroductionThe three different breast cancer subtypes (Luminal,HER2-positive and triple negative (TNBCs) display different natural history and sensitivity to treatment, but little is known about whether residual axillary disease after neoadjuvant chemotherapy (NAC) carries a different prognostic value by BC subtype.MethodsWe retrospectively evaluated axillary involvement (0, 1 to 3 positive nodes, ≥ 4 positive nodes) on surgical specimens from a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012. We analyzed the association between nodal involvement (ypN) binned into 3 classes (0; [1-3];4 or more), relapse-free survival (RFS) and overall survival (OS) among the global population, and according to BC subtypes.Results1197 patients were included in the analysis (luminal (n = 526, 43.9%), TNBCs (n = 376, 31.4%),HER2-positive BCs (n = 295, 24.6%)). After a median follow-up of 110.5 months, ypN was significantly associated with RFS, but this effect was different by BC subtype (Pinteraction= 0.004), and this effect was nonlinear. In the luminal subgroup, RFS was impaired in patients with 4 or more nodes involved (HR=2.8; 95% CI [1.93;4.06],pversusypN0,p< 0.001). Similar decreased prognosis were observed among patients withHER2-positive BC (1-3N+: HR=2.7, 95%CI= [1.64; 4.43] and ≥ 4 N+: HR=2.69, 95%CI= [1.24; 5.8] respectively,p=0.003).ConclusionThe prognostic value of residual axillary disease should be considered differently in the 3 BC subtypes to accurately stratify patients with a high risk of recurrence after NAC who should be offered second line therapies.

Context: The majority of BRCA mutation carriers diagnosed with breast cancer (BC) are treated with chemotherapy. The effectiveness of standard neoadjuvant chemotherapy (NAC) in BRCA associated BC compared to noncarriers has been poorly explored. Objectives: To assess whether the BRCA mutation status modifies the immune infiltration, chemosensitivity, and prognosis of breast cancer. Methods: We retrospectively identified in our institutional database all consecutive patients with BRCA germline mutation status available treated with NAC between 2002 and 2012. Microbiopsy specimens and paired surgical samples were evaluated for pre-NAC and post-NAC immune infiltration (stromal TILs, str TILs; intratumoral TILs, IT TILs). Response to chemotherapy was assessed by pathological complete response (pCR) rates. Association of clinical and pathological factors with pCR, overall survival (OS), and relapse free survival (RFS) was assessed by univariate and multivariate analyses. Results: Overall, 267 patients were included in this study (46 BRCA carriers and 221 BRCA noncarriers). The median age at BC diagnosis was 40 years old, and most of the patients (n=227, 85%) were premenopausal. Patients repartition by subtype was as follows: luminal (n=90, 33.7%), TNBC (n=110, 41.2%), HER2-positive (n=67, 25.1%). BRCA mutation carriers were likely to have familial history of BC (73.9% vs. 52.3%, p = 0.012), and be diagnosed with TNBC (58.7% vs 37.6%; p = 0.006), than noncarriers. No pattern was significantly different between BRCA mutation subgroups regarding age, body mass index, histology, tumor size, grade or Ki67. TIL levels were available in 192 patients. Neither pre-NAC stromal TIL levels nor IT TILs were significantly different by BRCA status in the whole population, nor in each BC subtype. PCR rates were significantly higher in BRCA mutation carriers (p= 0.035), and this association remained statistically significant only in the luminal BC subtype (p=0.006) after stratification by BC subtype (Pinteraction= 0.056). After multivariate analysis, only BC subtype and pre-NAC str TILs were independent predictors of pCR. Post-NAC stromal and intra-tumoral TIL levels were significantly higher luminal subtype (p=0.009 and p=0.019, respectively). After a median follow-up of 90 months, RFS and OS were not different between BRCA carriers and noncarriers, neither in the whole population nor after stratification by BC subtype. Discussion: In our study, BRCA status was associated with an enhanced response to standard NAC, particularly in luminal BC patients, in addition to higher post-NAC TIL levels. Whether patients with luminal BC and BRCA mutation derive benefit from second line immunotherapy after NAC completion remains to determine. Citation Format: Beatriz Grandal, Clémence Evrevin, Eric Daoud, Elise Dumas, Nadir Sella, Clara Sebbag, Sonia Rozette, Isabelle Jardin, Lucie Laot, Florence Coussy, Claire Saule, Dominique Stoppa-Lyonnet, Sophie Franck, Claire Sénéchal, Enora Laas, Marick Lae, Diane De Croze, Fabien Reyal, Anne-Sophie Hamy. Impact of BRCA mutation status on immune infiltration, chemosensitivity, and prognosis of breast cancer patients treated with neoadjuvant chemotherapy [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS13-10.

Introduction: The three different breast cancer subtypes (Luminal, HER2-positive, and triple negative (TNBCs) display different natural history and sensitivity to treatment, but little is known about whether residual axillary disease after neoadjuvant chemotherapy (NAC) carries a different prognostic value by BC subtype. Methods: We retrospectively evaluated the axillary involvement (0, 1 to 3 positive nodes, &ge, 4 positive nodes) on surgical specimens from a cohort of T1-T3NxM0 BC patients treated with NAC between 2002 and 2012. We analyzed the association between nodal involvement (ypN) binned into three classes (0, 1 to 3, 4 or more), relapse-free survival (RFS) and overall survival (OS) among the global population, and according to BC subtypes. Results: 1197 patients were included in the analysis (luminal (n = 526, 43.9%), TNBCs (n = 376, 31.4%), HER2-positive BCs (n = 295, 24.6%)). After a median follow-up of 110.5 months, ypN was significantly associated with RFS, but this effect was different by BC subtype (Pinteraction = 0.004), and this effect was nonlinear. In the luminal subgroup, RFS was impaired in patients with 4 or more nodes involved (HR 2.8, 95% CI [1.93, 4.06], p &lt, 0.001) when compared with ypN0, while it was not in patients with 1 to 3 nodes (HR = 1.24, 95% CI = [0.86, 1.79]). In patients with TNBC, both 1-3N+ and &ge, 4 N+ classes were associated with a decreased RFS (HR = 3.19, 95% CI = [2.05, 4.98] and HR = 4.83, 95% CI = [3.06, 7.63], respectively versus ypN0, p &lt, 0.001). Similar decreased prognosis were observed among patients with HER2-positive BC (1-3N +: HR = 2.7, 95% CI = [1.64, 4.43] and &ge, 4 N +: HR = 2.69, 95% CI = [1.24, 5.8] respectively, p = 0.003). Conclusion: The prognostic value of residual axillary disease should be considered differently in the 3 BC subtypes to accurately stratify patients with a high risk of recurrence after NAC who should be offered second line therapies.