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Despite considerable progress in understanding the biology and genetics of breast cancer, the development of effective therapies needs physiological and predictive preclinical models. In this context, breast cancer (BC) patient-derived xenograft (PDX) models have become a standard tool as they reproduce the biology of tumors of origin, in term of histology, genotype and response to chemotherapy. They have proven their relevance in the study of pathways leading to the development and progression of cancer, to the mechanisms linked to tumor resistance and to the identification of novel effective therapies. We present a preclinical platform of over 60 fully characterized BC PDX models and their in vitro cell derivatives for preclinical evaluation of new treatment modalities. Our platform consists of a PDX collection of 43 TNBC, 6 ER+, 4 HER2+, 6 Luminal B models (ER+ HER2+) and 14 cellular models derived from these PDXs, representing the variety of BC. PDX models were obtained by transplantation of post-surgery tumor specimens either by grafting of tumor fragments in the interscapular region of nude mice or by injection of tumor cells into the fat pad of NOD-Scid mice. Molecular analyses were done included gene expression, gene copy number, whole exome sequencing and IHC markers staining. In vivo drug efficacy assays were performed with standards of care as single agent or in combinations. This PDX panel mostly reflects the molecular heterogeneity of breast cancer and reproduce accurately the molecular and drug response profile of human tumors. It provides an invaluable tool for translational research. It is widely used to performed standard drug evaluation but also “Mouse Clinical Trials” (MCT) in vivo screens to provide more predictive preclinical data on single-agent or combination drug efficacy. Engrafted on highly immunodeficient mice humanized with human PBMCs or CD34+ cells, these PDX models allow bispecific T-Cell engager antibody testing or immune-checkpoint inhibitors evaluation. In addition to these PDX panel, we derived cellular models (PDXDCs) to offer a time- and cost-effective preclinical screening tool. PDXDCs were obtained from dissociated PDX tumors cultured under different media and matrix conditions. They were characterized by comparison with the parental PDX by Short Tandem Repeat (STR) profiling before performing a master bank. WES and RNASeq molecular analyses were done and in vitro drug sensitivity was compared with their parental PDX in vivo drug response. Overall, the results show that this PDXDC panel reproduced in vitro the in vivo drug response profile of the original PDXs with various therapies. This BC PDX panel and in vitro cell derivatives provide a powerful preclinical platform to improve our knowledge on BC biology and to rapidly evaluate response to new treatments and translate this knowledge to the clinic. Citation Format: Delphine Nicolle, Aurore Gorce, Marie Tavernier, Elisabetta Marangoni, Didier Decaudin, Christophe Ginestier, Emmanuelle Charafe-Jaufret, Judith Passildas, Nina Robin, Robert Clarke, Erwan Corcuff, Anaïs Joachim, Bernard Malissen, Ana Zarubica, Hervé Luche, Jean-Gabriel Judde, Olivier Déas. A preclinical platform of breast cancer PDX and derived cellular models as a tool for pharmacological screening and functional studies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4677.

Background: Triple negative breast cancer (TNBC) is the most heterogeneous subtype of breast cancer. However, the initial treatment of this disease is still dichotomous: 1st-line surgery (Surg1) followed by adjuvant chemotherapy, or neoadjuvant chemotherapy (NACT) followed by surgery. After radiotherapy, most of the patients (pts) are only observed until recurrence. Our team has pointed earlier (SABCS 2017) that some TNBCs recur very rapidly, in less than 12 months (mo) after NACT. Pts with those tumors have a very poor prognosis (overall survival < 6 mo). On the other side, a recent study has revealed a TNBC subgroup with late recurrences (> 5 yrs post-diagnosis, Rueda et al, Nature 2019). Neither of those groups is currently recognized in clinical practice nor specifically managed. In this study, we analyzed pattern and potential clinico-pathological biomarkers of recurrence in a large TNBC patient cohort treated at a specialized cancer center in France, to get a better insight into the need and possibilities for specific prevention of recurrent TNBC. Pts and methods: The study retrospectively included 305 pts, treated between 2000 and 2015 in Centre Jean Perrin, Clermont-Ferrand (stage I-III: 135 pts by Surg1; 146 pts by NACT; stage IV: 24 pts). The following putative biomarkers were evaluated: breast tumor size, number of involved nodes, tumor histograde, presence of lympho-vascular invasion (LVI), tumor-infiltrating lymphocytes (TILs, according to PMIDs 25214542, 29024776), presence of epithelial-mesenchymal transition (expression of Zeb1 protein by immunohistochemistry) - all at the Surg1 and post-NACT residual tumor (RT), as well as pathological complete response to NACT (pCR). Median follow-up of the pts was 4.8 yrs. The biomarkers were evaluated by univariate and multivariate analysis. Results: Recurrence-free survival (RFS) rate was significantly higher in Surg1 than in NACT cohort (76% vs 62%, resp., p=0.016). Early recurrence rate (RR) (< 12 mo post-Dg) was higher in the latter (5.6%) than in the former (2.4%), whereas the standard and the late RRs were comparable (RR 1-5 yrs post-Dg: 21.4% vs. 32.5%, p=0.05; > 5 yrs: 7.0% vs 6.7%, Surg1 vs NACT, resp.) In Surg1 cohort, the independent recurrence biomarkers were pN (pN0 vs pN+, p=0.003) and LVI+ (LVI+ vs LVI-, p=0.005). In NACT cohort, the only independent recurrence biomarkers were post-NACT RT size (p=0.009) and number of the involved nodes (LN) (p1cm≤2cm/LN=0, n=36; any RT/LN=1, n=18; RT≤2cm/LN≥2, n=11; RT>2cm/LN≥2, n=16, with significantly different 5-year RFS rates (92%, 62%, 54%, 30%, 13%, p2cm), with median TILs 5yrs) recurrences exist too, in up to 15% pts. The early recurrences are more frequent in the pts treated by NACT, and reflect high baseline metastatic capacity of the tumors. Big post-NACT RT size (> 2 cm), TILs < 5% and ≥ 2 LN+ are worth validation on larger cohorts as biomarkers of TNBC early and standard (1-5 yrs) recurrence. These 3 parameters, easily assessable in routine clinical practice, could help selecting pts with high risk of recurrence for specific therapies. To discover biomarkers of late TNBC recurrence, additional analyses are needed. Citation Format: Judith Passildas-Jahanmohan, Mona Ouled Dhaou, Fabrice Kwiatkowski, Wilfrid Finck, Camille Poirier, Marie-Ange Mouret-Reynier, Xavier Durando, Catherine Abrial, Frederique Penault-Llorca, Nina Radosevic. Pattern and biomarkers of recurrence in 305 triple negative breast cancer patients treated in a French comprehensive cancer center [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P3-08-45.

Purpose The proportion of older populations living with cancer is on the increase. Maintaining or improving their quality of life (QoL) has become an important goal in the treatment of cancer and has become an endpoint in clinical trials. Melatonin regulates a wide variety of physiological functions and is involved in the initiation of sleep and the improvement of QoL. With age, the secretion of melatonin decreases and could lead to a deterioration in QoL. Methods Literature searches were conducted using the PubMed database. The search terms and derivatives of “metastatic cancer”, “older patients”, “quality of life” and “melatonin” were used. Titles and abstracts were screened to identify whether studies were relevant for full-text screening. Results There is major concern about the symptoms older cancer patients encounter during treatment because they can impact their QoL. Melatonin supplementation presents several benefits for older patients: improvement in survival, decrease in symptoms induced by cancer and cancer treatment, and also improvements in quality of life. Conclusion It therefore seems appropriate to study the impact of melatonin supplementation during cytotoxic therapy on QoL among elderly patients with metastatic cancer. The use of melatonin as a therapeutic strategy seems particularly suitable for elderly patients, a population known to secrete significantly less melatonin. However, to date, no studies have been conducted in this population.

International audience; Background: Meningeal melanocytoma (MM) is a locally aggressive, low-grade primary melanocytic tumor of the central nervous system (PMN-CNS). According to the literature, GNAQ and GNA11 mutations are relatively frequent. In contrast, BRAF and NRAS mutations are very rare. Other series have reported BAP1 mutation, monosomy 3 and gain of chromosome 6. In this paper, we discussed two cases of MM for whom a FoundationOne CDxTM assay was performed.Results: Case report 1: A 48 year old man was diagnosed with intermediate-grade MM based on histological assessment, which is consistent with the clinical evolution. The FoundationOne CDxTM assay detected a SF3B1 mutation, usually found in 15% of uveal melanomas. This mutation is correlated with improved progression-free survival in uveal melanomas. Case report 2: A 39 year old women was diagnosed with MM. Her evolution wasn’t expected based on histology only; her history didn’t match with rather benign histological features microscopically. The FoundationOne CDxTM assay provided two interesting elements: first, the tumour was positive for CDKN2A p16INK4a M52fs*1 and p14ARF H66fs*106 mutations, most commonly found in cutaneous melanomas. Secondly, a GNA11 Q209L mutation, known to be a marker of aggressiveness in uveal melanoma, was detected.Conclusion: The identification of molecular alterations in PMN-CNS, in addition to immunohistochemical analysis could provide a better understanding of the biological and clinical behaviour of these tumours, a better identification of melanocytic melanomas with poor prognosis and a high risk of relapse or metastasis, and the development of novel therapeutic options for these patients.

International audience; Physical activity is known to prevent the occurrence of cancer and decrease the risk of breast cancer. At diagnosis of breast cancer, fewer than half of the patients reach the international recommendation for physical activity. However, breast cancer patients, and particularly HER2+ breast cancer patients, are exposed to treatment-induced cardiotoxicity because of a side effect of 2 molecules used in standard therapy to treat these tumors, i.e., anthracycline and trastuzumab. Cardiotoxicity can sometimes lead to discontinuation of the treatment and even to the development of cardiovascular diseases. Exercise is known to protect the cardiovascular system in the healthy population. Consequently, being physically active during treatment appears to be a way to prevent the negative impact of cancer treatment on the heart in this population. In particular, aerobic exercising could have a protective effect against treatment-induced cardiotoxicity. A supervised physical activity program seems to be the best way for breast cancer patients to be active during treatment. However, there is very little information, and in particular a lack of guidelines, on exercising available to patients. The interventional trials that have been conducted on this topic are very heterogeneous and no standard recommendations have been made available for cancer patients thus far. An effective physical activity program needs to take each patient’s barriers and motivations into account in order to encourage the practice of physical activity throughout treatment. To ensure the success of the program, it is essential to facilitate adherence and especially maintain motivation. Further studies are needed to determine what practice guidelines oncologists should give their patients.

Background Young patients with breast cancer treated with chemotherapy can experience ovarian failure, which can lead to chemotherapy-induced menopause (CIM) impacting the quality of life (QoL). A prospective study was set out to evaluate the impact of CIM on QoL in women of childbearing age with non-metastatic breast cancer, and this article reports results of the interim analysis conducted to evaluate feasibility and to see preliminary results. Patients and Methods A total of 58 women (age, 18-46 years) with newly diagnosed breast cancer and treated with chemotherapy were eligible. QoL was assessed by self-administered questionnaires (Quality of Life Questionnaire-Core 30 [QLQ-C30], Quality of Life Questionnaire-Breast 23 [QLQ-BR23], and Kupperman index) and hormonal variations (anti-Mullerian hormone [AMH], follicle-stimulating hormone, and estradiol) were explored. We compared patients with ≥ 12 months amenorrhea (CIM) (n = 41) to patients with Results A good inclusion rate (approximately 4/month) and sufficient data enabled us to perform this analysis. QLQ-C30 failed to show any difference between CIM and non-CIM patients (P = .5). In contrast, at 6 months post-chemotherapy, CIM patients tended to have lower QoL as shown by QLQ-BR23 (P = .16) and more severe climacteric symptoms (P = .01). Regarding hormonal variations, AMH pre-treatment level was higher in non-CIM patients (P = .0032). We also noted that CIM patients were older (P = .00013), had shorter menstruation cycle (P = .082), and experienced faster amenorrhea (P = .088). Conclusions The study is technically feasible, and our preliminary results underline that age in association with pre-treatment AMH level could be helpful to predict ovarian function. QLQ-BR23 seemed to be stronger, more precise, and appropriate to evaluate QoL changes in patients with breast cancer than the QLQ-C30.

Background Weight changes during adjuvant treatment for early-stage breast cancer has been associated with a poor prognosis. The long-term evolution of body composition during adjuvant treatment for breast cancer, in particular, endocrine therapy, is not well known, and new data on this topic are required. The present study assessed the evolution of weight and body composition among 33 postmenopausal breast cancer patients receiving endocrine therapy after standard adjuvant chemotherapy that included taxanes. Patients and Methods Dual-energy x-ray absorptiometry was used to measure the fat and lean body mass. Body water was assessed using multifrequency bioelectrical impedance analysis. The Hospital Anxiety and Depression questionnaire and the short version of the International Physical Activity Questionnaire were also administered. Results During endocrine therapy, 5 of the 33 patients (15.2%) lost weight and 12 (36.4%) gained weight. The overall average gain was 2.0 ± 5.5 kg (P = .04). During this period, the fat mass, lean body mass, and body water increased. The factors linked to fat mass gain included an excess fat mass (≥ 36%) before treatment and weight loss during chemotherapy. In the overall period of adjuvant cancer treatment, 30% of the population gained > 5% of their initial weight. The average gain was the same as that during the endocrine therapy period (2.0 ± 5.4 kg; P = .031) and was characterized by an increase in total lean body mass, mainly localized in the trunk region. Conclusion Endocrine therapy appears as a pivotal period in weight and body composition management. Overfat and obese patients and those who lose weight during chemotherapy were more subject to weight and fat mass gain during endocrine therapy.