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Synchronous bilateral breast cancer (sBBC) occurs after both breasts have been affected by the same germline genetics and environmental exposures. Little evidence exists regarding immune infiltration and response to treatment in sBBCs. Here we show that the impact of the subtype of breast cancer on levels of tumor infiltrating lymphocytes (TILs, n = 277) and on pathologic complete response (pCR) rates (n = 140) differed according to the concordant or discordant subtype of breast cancer of the contralateral tumor: luminal breast tumors with a discordant contralateral tumor had higher TIL levels and higher pCR rates than those with a concordant contralateral tumor. Tumor sequencing revealed that left and right tumors (n = 20) were independent regarding somatic mutations, copy number alterations and clonal phylogeny, whereas primary tumor and residual disease were closely related both from the somatic mutation and from the transcriptomic point of view. Our study indicates that tumor-intrinsic characteristics may have a role in the association of tumor immunity and pCR and demonstrates that the characteristics of the contralateral tumor are also associated with immune infiltration and response to treatment.

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.

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 ERpositive 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 pT1ab 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. 2022 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Breast cancer (BC) is the leading cause of cancer and cancer mortality among women worldwide. Surgery is the primary therapeutic strategy of BC in most of the cases. Efficient carcinologic and aesthetic resection requires breast surgeons to accurately understand medical images. Virtual reality (VR) is a promising avenue to improve surgical diagnosis and planning by producing high-precision images. Hereafter we report three cases of patients for which using AVATAR medical device for 3D visualization with VR would have helped to decide surgical strategy and adapt surgical procedure. The three cases are real-life examples of using the VR-AVATAR medical device for breast cancer surgery treatment: evaluation of the tumor response to neoadjuvant chemotherapy, decision for breast conservative or radical treatment, decision for loco-regional treatment in metastatic setting. Through these three real-life cases, we describe the potential impact of VR-AVATAR medical device use in clinical daily practice in breast cancer surgery. It seems like a useful tool, easy to use, providing high-quality images, helping with surgery planning and decisions.

Background: Invasive lobular carcinoma (ILC) represents up to 15% of all breast carcinomas. The majority of ILC express the estrogen receptor (ER) and have no amplification/overexpression of the human epidermal growth factor receptor 2 (HER2). A high body mass index (BMI) has been associated with an increased risk of developing ILC in postmenopausal women, similar to what is seen for breast cancer of no special type (NST). It is however unknown if BMI impacts the clinicopathological features and the prognosis of ILC. Methods: We performed a multicentric retrospective study in 5 European centers of patients diagnosed between January 2000 and December 2020 with ER+/HER2- non-metastatic pure (i.e., not mixed) ILC. Patient and tumor characteristics and event-related data were collected. BMI was categorized into underweight (≤18.5kg/m2), lean (>18.5kg/m2 and < 25kg/m2), overweight (≥25kg/m2 and < 30kg/m2) and obese (≥30kg/m2). The association of BMI as either a continuous or a categorical variable with clinicopathological variables was assessed using linear regression or ordinal logistic regression, respectively. Median follow-up was calculated using the reverse Kaplan-Meier estimator. Survival analyses using univariable (stratified by center) and multivariable (adjusted for all included variables and stratified by center) Cox regression were performed to evaluate the association of BMI with disease free survival (DFS), distant recurrence free survival (DRFS) and overall survival (OS). DFS and DRFS were analyzed in the presence of death without event as the competing risk. Results: The data of 2476 patients were collected and BMI was available for 2346 patients. In total, 1299 (55%) patients were lean, 638 (27%) overweight and 339 (14%) obese. Underweight patients only represented 3% of all patients and were thus excluded from further analyses. A higher age at diagnosis, higher grade, larger tumor size, nodal involvement and multifocality were significantly associated with higher BMI (Table 1). The median follow-up was 8,5 years (interquartile range 59.24 – 142.13 months). In univariable analysis, higher BMI was associated with worse survival outcomes (Table 2). However, this association was not seen in multivariable analysis while grade, tumor size and nodal involvement were still prognostic for all endpoints. Similar results were seen with BMI as a continuous variable. Conclusion: Larger tumors and nodal involvement were more likely to be found in patients with ER+/HER2- ILC with higher BMI which might be explained by a delayed diagnosis in these patients. Higher grade also seemed to be associated with higher BMI. In multivariable analyses, BMI was not found to be an independent prognostic factor. Tumor grade, tumor size, and nodal status remained strongly prognostic for survival outcomes in multivariable survival analyses which is consistent with their known prognostic importance in luminal tumors. We hypothesize that the prognostic effect of BMI is mediated through these variables for patients with ER+/HER2- ILC. Table 1. Association of clinicopathological features of ER+/HER2- ILC with categorical BMI. Table 2. Association of categorical BMI and other clinicopathological features of ER+/HER2- ILC with survival. Citation Format: Karen Van Baelen, Ha-Linh Nguyen, François Richard, Anne-Sophie Hamy, Aullène Toussaint, Fabien Reyal, Anne Salomon, Luc Dirix, Peter Vermeulen, Hilde Wuyts, Maria Karsten, Adam D. Dordevic, Guilherme Nader Marta, Evandro de Azambuja, Christos Sotiriou, Denis Larsimont, Ottavia Amato, Marion Maetens, Maxim De Schepper, Tatjana Geukens, Sileny Han, Thaïs Baert, Kevin Punie, Hans Wildiers, Chantal Remmerie, Ann Smeets, Ines Nevelsteen, Giuseppe Floris, Elia Biganzoli, Patrick Neven, Christine Desmedt. Association of body mass index with clinicopathological features and survival in patients with primary ER+/HER2- invasive lobular breast cancer [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 P3-05-40.

The high frequency of homologous recombination deficiency (HRD) is the main rationale of testing platinum-based chemotherapy in triple-negative breast cancer (TNBC), however, the existing methods to identify HRD are controversial and there is a medical need for predictive biomarkers. We assess the in vivo response to platinum agents in 55 patient-derived xenografts (PDX) of TNBC to identify determinants of response. The HRD status, determined from whole genome sequencing, is highly predictive of platinum response. BRCA1 promoter methylation is not associated with response, in part due to residual BRCA1 gene expression and homologous recombination proficiency in different tumours showing mono-allelic methylation. Finally, in 2 cisplatin sensitive tumours we identify mutations in XRCC3 and ORC1 genes that are functionally validated in vitro. In conclusion, our results demonstrate that the genomic HRD is predictive of platinum response in a large cohort of TNBC PDX and identify alterations in XRCC3 and ORC1 genes driving cisplatin response.

Several randomized controlled trials have demonstrated the benefit of a boost to the tumor bed (TB) to reduce the risk of ipsilateral breast tumor recurrence. Recent technological progress has facilitated improved conformation of isodoses around the target volume. The accuracy and reproducibility of TB delineation have become even more essential. The purpose of this study is to review the extant knowledge on the boost delineation in breast cancer, focusing on interobserver variability (IOV) and the influence of various factors, such as the presence of clips or different imaging modalities to improve IOV. Most studies investigating IOV for boost delineation have shown poor reproducibility (with comparison indices such as the dice similarity index around 0.5). Clips in the lumpectomy cavity (LC), postoperative fluid accumulation in the LC and/or high cavity visualization score appeared to be associated with improved IOV. Likewise, the use of preoperative imaging (CT and/or MRI) may also be useful in improving the accuracy of TB definition but without any real gain in terms of IOV. Moreover, the delineation of boost has become even more challenging since the development of oncoplastic surgery. To improve the reproducibility and the accuracy of boost delineation, this review suggests that within each center, a group of multidisciplinary experts, including surgeons, radiation oncologists, pathologists, and radiologists, should convene to develop local guidelines, which may include the choice of preoperative imaging, the number and location of surgical clips, pathological margins, and orientation. The elaboration of contouring atlas is certainly of great assistance.

Women with pathogenic germline BRCA1 or BRCA2 variants have a higher risk of breast cancer than in the general population. International guidelines recommend specific clinical and radiological breast follow-up. This specific breast screening program has already been shown to be of clinical benefit, but no information is available concerning the use of prognostic factors or specific survival to guide follow-up decisions. We evaluated "high-risk" screening in a retrospective single-center study of 520 women carrying pathogenic germline variants of the BRCA1 or BRCA2 gene treated for breast cancer between January 2000 and December 2016. We compared two groups of women: the incidental breast cancer group (IBCG) were followed before breast cancer diagnosis (N = 103), whereas the prevalent breast cancer group (PBCG) (N = 417) had no specific follow-up for high risk before breast cancer diagnosis. Breast cancers were diagnosed at an earlier stage in the IBCG than in the PBCG: T0 in 64% versus 19% of tumors, (p 0.00001), and N0 in 90% vs. 75% (p 0.00001), respectively. Treatment differed significantly between the 2 groups: less neoadjuvant chemotherapy (7.1% vs. 28.5%, p 0.00001), adjuvant chemotherapy (47.7% vs. 61.9%, p = 0.004) and more mastectomies (60% vs. 42% p 0.0001) in the IBCG vs PBCG groups respectively. Overall and breast cancer-specific mortality were similar between the two groups. However, the patients in the IBCG had a significantly longer metastasis-free survival than those in the PBCG, at three years (96.9% [95% CI 93.5-100] vs. 92.30% [95% CI 89.8-94.9]; p = 0.02), suggesting a possible long-term survival advantage.

Supplementary Table 11

List of genes differentially regulated between resistant and responder PDX.

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Purpose: Triple-negative breast cancer (TNBC) patients with residual disease after neoadjuvant chemotherapy have a poor outcome. We developed patient-derived xenografts (PDX) from residual tumors to identify efficient chemotherapies and predictive biomarkers in a context of resistance to anthracyclines- and taxanes-based treatments.Experimental Design: PDX were established from residual tumors of primary breast cancer patients treated in neoadjuvant setting. TNBC PDX were treated by anthracyclines, taxanes, platins, and capecitabine. Predictive biomarkers were identified by transcriptomic and immunohistologic analysis. Downregulation of RB1 was performed by siRNA in a cell line established from a PDX.Results: Residual TNBC PDX were characterized by a high tumor take, a short latency, and a poor prognosis of the corresponding patients. With the exception of BRCA1/2-mutated models, residual PDX were resistant to anthracyclines, taxanes, and platins. Capecitabine, the oral prodrug of 5-FU, was highly efficient in 60% of PDX, with two models showing complete responses. Prior treatment of a responder PDX with 5-FU increased expression of thymidylate synthase and decreased efficacy of capecitabine. Transcriptomic and IHC analyses of 32 TNBC PDX, including both residual tumors and treatment-naïve derived tumors, identified RB1 and TYMP proteins as predictive biomarkers for capecitabine response. Finally, RB1 knockdown in a cell line established from a capecitabine-responder PDX decreased sensitivity to 5-FU treatment.Conclusions: We identified capecitabine as efficient chemotherapy in TNBC PDX models established from residual disease and resistant to anthracyclines, taxanes, and platins. RB1 positivity and high expression of TYMP were significantly associated with capecitabine response. Clin Cancer Res; 24(11); 2605–15. ©2018 AACR.

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Supplementary Table S4 from Integrated Genomic and Transcriptomic Analysis of Ductal Carcinoma In situ of the Breast

Boxplot of the expression of genes encoding proteins involved in capecitabine metabolism (TYMP, TYMS, TK1, DPYD) and cell-cycle control (RB1, CDKN2A, CCND1).

Purpose: To gain insight into genomic and trancriptomic subtypes of ductal carcinomas in situ of the breast (DCIS).Experimental Design: We did a combined phenotypic and genomic analysis of a series of 57 DCIS integrated with gene expression profile analysis for 26 of the 57 cases.Results: Thirty-two DCIS exhibited a luminal phenotype; 21 were ERBB2 positive, and 4 were ERBB2/estrogen receptor (ER) negative with 1 harboring a bona fide basal-like phenotype. Based on a CGH analysis, genomic types were identified in this series of DCIS with the 1q gain/16q loss combination observed in 3 luminal DCIS, the mixed amplifier pattern including all ERBB2, 12 luminal and 2 ERBB2-/ER- DCIS, and the complex copy number alteration profile encompassing 14 luminal and 1 ERBB2-/ER- DCIS. Eight cases (8 of 57; 14%) presented a TP53 mutation, all being amplifiers. Unsupervised analysis of gene expression profiles of 26 of the 57 DCIS showed that luminal and ERBB2-amplified, ER-negative cases clustered separately. We further investigated the effect of high and low copy number changes on gene expression. Strikingly, amplicons but also low copy number changes especially on 1q, 8q, and 16q in DCIS regulated the expression of a subset of genes in a very similar way to that recently described in invasive ductal carcinomas.Conclusions: These combined approaches show that the molecular heterogeneity of breast ductal carcinomas exists already in in situ lesions and further indicate that DCIS and invasive ductal carcinomas share genomic alterations with a similar effect on gene expression profile.

Table S3

A)Response to cisplatin in the HBcx-66 (BRCA1-mutated) and HBCx-92 (BRCA2-mutated) PDX. B) KM survival analysis of the HBCx-95 PDX

Clinical characteristics of patients

Supplementary Table S1 from Integrated Genomic and Transcriptomic Analysis of Ductal Carcinoma In situ of the Breast

A) Disease histories of individual patients. Time 0 corresponds to surgery, and each line of chemotherapy is shown. Primary tumors are distinguished from residual disease. B) Circle distribution of vital status, lymphovascular invasion and metastatic status, according to type of tumor (primary or residual), showing that a large proportion of the patients with residual disease died from their cancer, with most of these patients presenting LVI and metastases. By contrast, 50% of the patients for whom PDXs were derived from primary tumors died from their disease, with metastasis noted in a large proportion. However, the proportion of these patients with LVI was similar amongst the patient still alive and those who died. C) Distribution of the the sites at which the first metastasis was detected.

Supplementary Table S2 from Integrated Genomic and Transcriptomic Analysis of Ductal Carcinoma In situ of the Breast

A) Immunohistochemistry analysis of HER2, Rb and TYMP (20X) in the HBCx-73 PDX B) response to trastuzumab and capecitabine in the HBCx-73 PDX

Table S1

Purpose:High levels of tumor-infiltrating lymphocytes (TIL) before neoadjuvant chemotherapy (NAC) are associated with higher pathologic complete response (pCR) rates and better survival in triple-negative breast cancer (TNBC) and HER2-positive breast cancer. We investigated the value of TIL levels by evaluating lymphocyte infiltration before and after NAC.Experimental Design:We assessed stromal TIL levels in 716 pre- and posttreatment matched paired specimens, according to the guidelines of the International TIL Working Group.Results:Pre-NAC TIL levels were higher in tumors for which pCR was achieved than in cases with residual disease (33.9% vs. 20.3%, P = 0.001). This was observed in luminal tumors and TNBCs, but not in HER2-positive breast cancers (PInteraction = 0.001). The association between pre-NAC TIL levels and pCR was nonlinear in TNBCs (P = 0.005). Mean TIL levels decreased after chemotherapy completion (pre-NAC TILs: 24.1% vs. post-NAC TILs: 13.0%, P < 0.001). This decrease was strongly associated with high pCR rates, and the variation of TIL levels was strongly inversely correlated with pre-NAC TIL levels (r = −0.80, P < 0.001). Pre-NAC TILs and disease-free survival (DFS) were associated in a nonlinear manner (P < 0.001). High post-NAC TIL levels were associated with aggressive tumor characteristics and with impaired DFS in HER2-positive breast cancers (HR, 1.04; confidence interval, 1.02–1.06; P = 0.001), but not in luminal tumors or TNBCs (PInteraction = 0.04).Conclusions:The associations of pre- and post-NAC TIL levels with response to treatment and DFS differ between breast cancer subtypes. The characterization of immune subpopulations may improve our understanding of the complex interactions between pre- or post-NAC setting, breast cancer subtype, response to treatment, and prognosis.

Levels of expression for the TYMS, TK1, CCNA2, CCNB1, TOPO2A, TTK, PLK1 and AURKA genes in control and capecitabine-treated xenografts. Mean {plus minus} SD, n=5 xenografts. Statistical significance was determined in multiple t-tests with an alpha risk of 0.05.

Supplementary Data from Integrated Genomic and Transcriptomic Analysis of Ductal Carcinoma In situ of the Breast

Supplementary Table S5 from Integrated Genomic and Transcriptomic Analysis of Ductal Carcinoma In situ of the Breast

Table S2

Supplementary Table S3 from Integrated Genomic and Transcriptomic Analysis of Ductal Carcinoma In situ of the Breast

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supplementary material

Supplementary Table S4. Cytokine measurements in digested unstimulated primary breast tumor (Unst) or tumors stimulated with anti-CD3/CD28 microbeads (αCD3/CD28).

Supplementary Figure Legends 1-4 from Characterization of the Recurrent 8p11-12 Amplicon Identifies PPAPDC1B, a Phosphatase Protein, as a New Therapeutic Target in Breast Cancer

Supplementary Figures 1-4 from Characterization of the Recurrent 8p11-12 Amplicon Identifies PPAPDC1B, a Phosphatase Protein, as a New Therapeutic Target in Breast Cancer

Supplementary Figure 1 from MicroRNA Sequence and Expression Analysis in Breast Tumors by Deep Sequencing

PDF file - 158K, Involvement of the immune system in differential growth of TS/A, 4T1, and their sh27a-expressing counterparts; A-Examples of FACS stainings and cytospin analysis of CD11b, CD11c, Ly6C and Ly6G in spleens of tumor-bearing mice. B, C- Growth of Scr- and sh27a-4T1 in Rag2-/- or CD4+ T cell-depleted hosts

PDF file - 77K, Metastasis formation after i.v. injection and in vitro growth of 4T1; Metastasis formation by 4T1 after i.v. injection is decreased (A), whereas growth of 4T1 tumors in vitro is not affected (B) by Rab27a inhibition

PDF file - 113K

Supplementary Figure 2A from MicroRNA Sequence and Expression Analysis in Breast Tumors by Deep Sequencing

Supplementary Table 1 from Visualizing Chromosomes as Transcriptome Correlation Maps: Evidence of Chromosomal Domains Containing Co-expressed Genes—A Study of 130 Invasive Ductal Breast Carcinomas

Supplementary Figure 6 from MicroRNA Sequence and Expression Analysis in Breast Tumors by Deep Sequencing

Supplementary Methods, Figure and Table Legends from MicroRNA Sequence and Expression Analysis in Breast Tumors by Deep Sequencing

Supplementary Tables 1-8C from MicroRNA Sequence and Expression Analysis in Breast Tumors by Deep Sequencing

Supplementary Figure 2 from Visualizing Chromosomes as Transcriptome Correlation Maps: Evidence of Chromosomal Domains Containing Co-expressed Genes—A Study of 130 Invasive Ductal Breast Carcinomas

Supplementary Figure 1 from Visualizing Chromosomes as Transcriptome Correlation Maps: Evidence of Chromosomal Domains Containing Co-expressed Genes—A Study of 130 Invasive Ductal Breast Carcinomas