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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). After adjustment on age, sexual dysfunction was significantly more frequent in women who had a history of BC: they had less frequent SI (OR 0.59 [0.54,0.64], ppConclusions 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.

A subset of cancer-associated fibroblasts (FAP+/CAF-S1) mediates immunosuppression in breast cancers, but its heterogeneity and its impact on immunotherapy response remain unknown. Here, we identify 8 CAF-S1 clusters by analyzing more than 19,000 single CAF-S1 fibroblasts from breast cancer. We validate the five most abundant clusters by flow cytometry and in silico analyses in other cancer types, highlighting their relevance. Myofibroblasts from clusters 0 and 3, characterized by extracellular matrix proteins and TGFβ signaling, respectively, are indicative of primary resistance to immunotherapies. Cluster 0/ecm-myCAF upregulates PD-1 and CTLA4 protein levels in regulatory T lymphocytes (Tregs), which, in turn, increases CAF-S1 cluster 3/TGFβ-myCAF cellular content. Thus, our study highlights a positive feedback loop between specific CAF-S1 clusters and Tregs and uncovers their role in immunotherapy resistance.Significance:Our work provides a significant advance in characterizing and understanding FAP+ CAF in cancer. We reached a high resolution at single-cell level, which enabled us to identify specific clusters associated with immunosuppression and immunotherapy resistance. Identification of cluster-specific signatures paves the way for therapeutic options in combination with immunotherapies.This article is highlighted in the In This Issue feature, p. 1241

Data S2

Background Neoadjuvant chemotherapy followed by interval debulking surgery is today a valid treatment option for advanced epithelial ovarian cancer (EOC). This schema allows in vivo evaluation of the chemosensitivity of the tumor, however there is still no clearly validated marker. The Standardized CA-125 ELIMination rate constant K (Std KELIM) and the Platinum Resistant Recurrence (PtRR) Score have been proposed as markers. The aim of our study was to validate these two tools for predicting platinum sensitivity in a real-world population with advanced EOC. Experimental design: All patients with advanced EOC treated with neoadjuvant chemotherapy followed by interval debulking surgery in Institut Curie between 2000 and 2015 were included. Std KELIM was calculated with the CA-125 concentrations at each cycle. The predictive value of Std KELIM and the validation of the PtRR Score regarding the risk of subsequent platinum-resistant relapse were assessed using ROC curve, logistic regression and calibration curve. Results Std KELIM was calculated for 152 patients. The AUC was 0.67 with an optimal threshold at 0.61. A low Std KELIM was significantly associated with PtRR (odds-ratio = 0.19 (95% CI [0.06, 0.53], p = 0.002) in the univariate analysis but not in the multivariate analysis after adjustment on complete IDS status, which was the only independent predictive factor. The calibration curve of PtRR score presents a slight but significant underestimation (p = 0.02) of the risk of platinum-resistant relapse. Conclusions Std KELIM and PtRR score are early predictive markers of platinum resistance. They could be used in a clinical trial for assisting the clinician in adapting medical treatment.

Intravenous administration of monoclonal antibodies leads to low concentrations in the central nervous system, which is a serious concern in neuro-oncology, especially in leptomeningeal carcinomatosis of HER2-overexpressing breast cancer. Case reports of intrathecal (IT) administrations of trastuzumab have shown promising results in these patients but dosing regimens are empirical in absence of pharmacokinetic study. With a population pharmacokinetic approach, we described the fate of trastuzumab after IT administration in 21 women included in a phase I-II clinical trial. Trastuzumab was administered by IT route every week for 8 weeks and both cerebrospinal fluid (CSF) and serum were sampled to measure trough concentrations. Some patients showed noticeable CSF concentration fluctuations predicted using a target-mediated drug disposition. This target was latent and produced with a delayed feedback. Apparent volumes of distribution were close to physiological volumes (V1 = 3.25 L, V2 = 0.644 L, for serum and CSF, respectively). Estimated (constant) transfer from serum to CSF was very slow (k12 = 0.264 mg.d-1 ) while estimated half-life of transfer from CSF to serum was rapid (2.2 days). From the individual parameters of patients, a single IT administration of 150 mg of trastuzumab corresponded to median mean residence times (MRT) of 3.8 days and 15.6 days in CSF and serum, respectively. Survival without neurological relapse was not related to trastuzumab exposure. This study confirms that transfer of trastuzumab from serum to CSF is very limited and that this monoclonal antibody, when administered by IT route, is rapidly transferred to the serum.

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.

Introduction: The benefits of physical activity (PA) in breast cancer are currently recognized in primary prevention. The World Cancer Research Fund (WCRF) and then the National Cancer Institute (INCa) have reported conflicting results regarding the impact of post-diagnosis PA on breast cancer outcomes. The aim of this systematic review is to assess the association between PA after breast cancer diagnosis and overall mortality, specific mortality and risk of breast cancer recurrence in the literature. Methods: Randomized trials, prospective cohorts and meta-analyses studying post-diagnosis PA and overall mortality, breast cancer mortality or risk of recurrence after breast cancer published between January 1, 2014 and October 1, 2019 were included. The articles selected by the INCa report prior to 2014 were included in the literature review. Results: Eighteen articles have been selected. Studies unanimously concluded that overall mortality was reduced by post-diagnosis PA practice. For specific mortality, 5 meta-analyses showed a significant decrease in breast cancer mortality and 2 found a decrease in the risk of recurrence. Conclusion: Post-diagnosis PA reduces overall mortality and appears to impact specific breast cancer mortality and risk of recurrence. However, these results need to be confirmed by larger randomized trials., Introduction :Les bénéfices de l’activité physique (AP) dans le cancer du sein sont actuellement reconnus en prévention primaire. Le World Cancer Research Fund (WCRF), puis l’Institut national du cancer (INCa) ont rapporté des résultats contradictoires concernant l’impact de l’activité physique après diagnostic sur le pronostic du cancer du sein. L’objectif de cette revue de la littérature est d’évaluer l’association entre l’activité physique après le diagnostic de cancer du sein et la mortalité globale, la mortalité spécifique ainsi que le risque de récidive de cancer du sein dans la littérature.Méthodes :Les essais randomisés, cohortes prospectives et méta-analyses, étudiant l’activité physique postdiagnostic et la mortalité globale, la mortalité liée au cancer du sein ou le risque de récidive après cancer du sein, publiés entre le 1er janvier 2014 et le 1er octobre 2019, ont été inclus. Les articles sélectionnés, par le rapport de l’INCa antérieurs à 2014, ont été intégrés à la revue de la littérature.Résultats :Dix-huit articles ont été sélectionnés. Les études ont conclu de façon unanime à une diminution de la mortalité globale par la pratique d’une activité physique postdiagnostic. Pour la mortalité spécifique, 5 méta-analyses ont montré une diminution significative de la mortalité par cancer du sein et 2 ont retrouvé une diminution du risque de récidive.Conclusion :L’activité physique postdiagnostic d’un cancer du sein diminue la mortalité globale et semble impacter la mortalité spécifique par cancer du sein et le risque de récidive. Ces résultats nécessitent, cependant, d’être confirmés par de plus larges essais randomisés.

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.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.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]).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.

Purpose: Almost all cervical cancers are caused by human papillomavirus (HPV) and patients with advanced stage are at high risk for relapse. Circulating HPV DNA (HPV ctDNA) may serve as a residual tumor marker at the end of chemoradiation or to predict relapse during the follow-up period. Experimental Design: We analyzed serum samples from 94 HPV16- or HPV18-related CCs from the BioRAIDs prospective cohort. Samples were collected before and after treatment and during an 18-month follow-up period. Using digital droplet PCR (ddPCR), we assessed the relevance of circulating HPV E7 gene as a marker for residual disease compared to HPV integration site and PIK3CA mutations. Finally, the prognostic impact of circulating HPV E7 gene was assessed with its prediction value of relapse. Results: HPV E7 gene was the most sensitive tumor marker, superior to both HPV integration sites and PIK3CA mutations in serum. Circulating HPV DNA (HPV ctDNA) was detected in 63% (59/94) of patients, before treatment. HPV ctDNA detection in serum sample was associated with high FIGO stage (P = 0.02) and para-aortic lymph node involvement (P = 0.01). The level of HPV ctDNA was positively correlated with HPV copy number in the tumor (R = 0.39, P < 0.001). Complete clearance of HPV ctDNA by the end of treatment was significantly associated with a longer PFS (P < 0.0001). Patients with persistent HPV ctDNA in serum relapsed with a median time of 10 months (range, 2–15) from HPV ctDNA detection. Conclusions: HPV ctDNA detection is a useful marker to predict relapse in cervical cancer. See related commentary by Wentzensen and Clarke, p. 5733

Objectives Vulvar cancer is a gynecological cancer for which posttreatment morbidity must be known to propose the appropriate medical strategy. The objectives of this article were to review and to summarize the available studies evaluating the impact of vulvar surgery on the quality of sex life. Materials and methods We searched MEDLINE abstracts (source PubMed) and included all studies published between 1990 and 2020 that evaluated the impact of vulvar surgery on the patients' sex life. Articles were selected in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria. We evaluated the quality of the studies using the "study quality assessment tools" established by the National Heart Lung and Blood Institute and the health-related quality-of-life score. Summary statistics were used to report the results of the studies selected. Results A total of 41 articles were screened, and 15 studies were included in this review. Two questionnaires, that is, European Organization for Research and Treatment of Cancer QLC C30 and Female Sexual Function Index, were used in 60% of the studies. The quality of the studies was heterogeneous. None of them had a high level of evidence. Eleven of the 16 studies reported an impairment of quality of sex life, mainly related to the size of the initial lesion and the type of surgery performed. Preoperative sexual status, that is, active sex life, age, and morbidity seemed to be important factors. Conclusions None of the studies had a high level of evidence, and their methodological quality was heterogeneous. More powerful studies using validated questionnaires are necessary. Because this is essential surgery, patients should be informed that if it impacts their sexual life, management strategies will be part of their postoperative care.

Objective The objective of our study was to analyze quality of life (QOL) in an e-cohort of patients treated for breast cancer (BC) by endocrine therapy (ET), by means of validated quality of life questionnaires. Study design and setting A retrospective, observational, e-cohort study was conducted (Seintinelles platform). Female patients treated for nonmetastatic and nonrecurrent BC, treated in France after 2005, filled in online questionnaires concerning: QOL (QLQ-C30 and QLQ-BR23), tolerability of treatment and demographic characteristics. A multivariate analysis including variables significant on univariate analysis (P Results We included 1,198 patients, 1140 of whom declared that they were taking ET (37.7% tamoxifen, 17.1% aromatase inhibitor (AI), 5.6% LHRH-agonist and 39.6% sequential tamoxifen and AI). Different tolerability profiles were observed when comparing the tamoxifen and AI groups. Treatment adherence was similar in the 2 groups. QOL varied slightly according to the type of ET. On multivariate analysis, ET had no impact on QOL. However, individual patient characteristics (socioeconomic, education and age) were significantly associated with QOL Conclusion Using a real-life study questionnaire on a large e-cohort, individual patient characteristics were strongly associated with deterioration of QOL. The use of e-cohorts must be encouraged to modulate the conclusions of randomized trials.

Objective To evaluate the impact of catch-up human papillomavirus (HPV) vaccination on conization rates in France in a large population-based study. Methods We conducted a retrospective real-life cohort study on data collected prospectively by French National Health Insurance. Echantillon généralistes des bénéficiaires (EGB) is a database composed of demographic and health care utilization data for a 1/97th sample of the French population. We extracted data about all women born between 1983 and 1991, corresponding to the catch-up population (vaccination after 14 years old) at the time of implementation of HPV vaccination. The primary outcome was the occurrence of conization (all types of procedures) compared between vaccinated and non-vaccinated women. Results The cohort consisted of 42,452 women. Vaccination coverage (at least one dose) was low (9.8%, n = 4,129), but increased with time from vaccine implementation, from 0% in the 1983 cohort to 31% in the 1991 cohort. The conization rate was 1% for the overall population. The risk of conization for women between the ages of 19 and 30 years was reduced in the vaccinated group with a Hazard Ratio (HR) of 0.59 (95% CI[0.39–0.90]; p = 0.043). Conclusions With a 10-year follow-up, catch-up HPV vaccination is associated with risk reduction of conization between the ages of 19 and 30.

Over the past century, epidemiologic changes and implementation of screening may have had an impact on tumor doubling time in breast cancer. Our study was designed to evaluate changes in tumor doubling time in breast cancer over the past 80 years. A systematic review of published literature and meta‐regression analysis was performed. An online electronic database search was undertaken using the PubMed platform from inception until June 2020. All studies that measured tumor doubling time in breast cancer were included. A total of 151 publications were retrieved. Among them, 16 full‐text articles were included in the qualitative analysis. An exponential growth model was used for quantitative characterization of tumor growth rate. Tumor doubling time has remained stable over the past 80 years. Recent studies have not only identified “fast growing tumor” (grade 3, human epidermal growth factor receptor 2‐positive, triple‐negative, or tumor with an elevated Ki‐67) but also “inactive breast cancer” feeding the ongoing debate of overdiagnosis due to screening programs. The stability of tumor doubling time over the past 80 years, despite increasing and changing risk factors, supports the validity for our screening guidelines. Prospective studies based on more precise measurement of tumor size and adjustment for tumor characteristics are necessary to more clearly characterize the prognostic and predictive impact of tumor doubling time in breast cancer., The stability of tumor doubling time over the past 80 years, despite increasing and changing risk factors, supports the validity of our screening guidelines. Recent studies have not only identified “fast growing tumor” but also “inactive breast cancer” feeding the ongoing debate of overdiagnosis due to screening programs.

Introduction/Background Clinical trials in Epithelial Ovarian Cancer (EOC) frequently examine treatment at a particular phase of the patient’s disease trajectory. Few major studies have examined the management of patients from diagnosis to death. This international network was developed to compare treatment sequencing and outcomes from six centres across Europe and South Korea. Methodology This retrospective cohort study used longitudinal data collected from electronic medical records from 6 European and South Korean treatment centres. A standard protocol & common data model was developed to capture consistent data for patients diagnosed between January 2012 and December 2018, with a minimum of 12 months follow-up. Full treatment data was collected and categorized in programmes of care based on exemplar patient narratives. An extensive data harmonization process was implemented to ensure different country and site medical records were interpreted in a common manner. Overall survival (OS) and time to next treatment (TTNT) were estimated using Kaplan Meier methodology and outcomes stratified by categories of interest. Each site analysed their own EMR data and shared aggregated results for comparison. Results Table 1 demonstrates patient characteristics from six sites. In total the overall study cohort includes 2889 patients. Median age for each centre ranged from 53 to 67 years. The majority of patients were FIGO stage III (range 31% to 66%) and high-grade serous morphology (52% to 69.9%) Additional data on treatment pathways and outcomes for each centre will be presented. Conclusion Preliminary analysis from this network suggests a consistent profile of adults treated for EOC across most contributing treatment centres in Europe, but with some substantial differences compared to patients treated at centres in South Korea and Romania. The establishment of a common data model between sites across five different countries allows for detailed exploration of the factors influencing differences in patient management and treatment outcomes in ovarian cancer patients. Disclosures Sue Cheeseman: I receive consultancy fees from IQVIA Bethany Levick: I am an employee of IQVIA Eunji Nam: I have no conflict of interest to disclose Dongkyu Kim: I have no conflict of interest to disclose Roman Rouzier: I have no conflict of interest to disclose Claire Bonneau: I have no conflict of interest to disclose Paul Kubelac: served on a speaker’s bureau for Roche, Bristol-Myers Squibb, AstraZeneca, Novartis. Patriciu Achimas-Cadariu: I have no conflict of interest to disclose Jean-Marc Classe: I have no conflict of interest to disclose Francois Bocquet: I have no conflict of interest to disclose Sven Becker: I have no conflict of interest to disclose Mariana Guergova-Kuras: I am an employee of IQVIA Geoff Hall: I receive grant support and consultancy fees from IQVIA

High-grade serous ovarian cancer is one of the deadliest gynecological malignancies and remains a clinical challenge. There is a critical need to effectively define patient stratification in a clinical setting. In this study, we address this question and determine the optimal number of molecular subgroups for ovarian cancer patients. By studying several independent patient cohorts, we observed that classifying high-grade serous ovarian tumors into four molecular subgroups using a transcriptomic-based approach did not reproducibly predict patient survival. In contrast, classifying these tumors into only two molecular subgroups, fibrosis and non-fibrosis, could reliably inform on patient survival. In addition, we found complementarity between transcriptomic data and the genomic signature for homologous recombination deficiency (HRD) that helped in defining prognosis of ovarian cancer patients. We also established that the transcriptomic and genomic signatures underlined independent biological processes and defined four different risk populations. Thus, combining genomic and transcriptomic information appears as the most appropriate stratification method to reliably subgroup high-grade serous ovarian cancer patients. This method can easily be transferred into the clinical setting.

Ovarian cancer is mostly diagnosed at advanced stage. Better survival is achieved through complete debulking surgery and chemotherapy. Historically, neoadjuvant chemotherapy (NAC) has been introduced for unresectable disease to decrease tumor load and perform a unique complete surgery. Four randomized control trials have compared primary debulking surgery to NAC, but there is still controversy about the use of neoadjuvant chemotherapy and questions about its modalities. Areas covered: We made a review of knowledge on benefits of NAC compared to primary debulking chemotherapy, in terms of survival and morbidity, methods of administration, new drugs in early and late phase trials, the selection of patients. Similar survival was observed after NAC and interval debulking surgery or primary debulking surgery. Morbidity of surgery was decreased after interval debulking compared primary debulking surgery. Conventional drugs are carboplatin and paclitaxel. Safety of bevacizumab was evaluated in phase 2 trials associated with conventional drugs. Immunotherapy trials are enrolling patients in phase 1 study. Expert commentary: NAC followed by debulking surgery is the best treatment for patients with advanced ovarian cancer.

Neuroendocrine breast carcinomas represent a rare subtype of breast cancer. Their definition, prevalence, and prognosis remain controversial in the literature. The 2012 WHO classification of breast cancer categorizes neuroendocrine carcinomas into three morphologically distinct subtypes: well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and invasive breast carcinomas with neuroendocrine differentiation. We aimed to gain insight into the clinical, morphologic, phenotypic, and molecular features of 47 neuroendocrine breast carcinomas. Targeted next-generation sequencing by an AmpliSeq 22 cancer gene hotspot panel and the Prosigna assay were performed on 42/47 and 35/47 cases, respectively. Average age at diagnosis was 69 years. All tumors were estrogen receptor-positive and the large majority expressed progesterone receptor (89%), GATA3 (98%), FOXA1 (96%), and CK8/18 (98%). There was an almost equal distribution of luminal A (52%) and B (48%) carcinomas. Almost half of the cohort (49%) displayed a high risk of recurrence score with the Prosigna test. Patients with a neuroendocrine carcinoma had a shorter disease-free survival compared with those affected by carcinomas of no special type matched for age, size, grade, and estrogen receptor status. No significant differences were observed in terms of overall survival. Stratification of neuroendocrine carcinomas using the 2012 WHO criteria did not reveal statistically significant differences among the distinct categories (well-differentiated neuroendocrine tumors, poorly differentiated neuroendocrine carcinomas, and invasive breast carcinomas with neuroendocrine differentiation), in terms of either progression-free or overall survival. Our targeted sequencing analysis found three cases (7%) harboring a PIK3CA mutation, and in three other cases (7%) TP53 mutations were detected. This study showed that neuroendocrine breast carcinoma is a distinct subtype of luminal carcinoma with a low rate of PIK3CA mutations and with an aggressive clinical behavior. An accurate identification of neuroendocrine differentiation may be useful to better tailor patient adjuvant therapy within luminal carcinomas.Modern Pathology advance online publication, 8 September 2017; doi:10.1038/modpathol.2017.107.

Resume Introduction On observe un engouement croissant pour les regimes alimentaires et leurs effets sur le pronostic du cancer. En 2014, un rapport du « World Cancer Research Fund » concernant l’alimentation et les femmes avec un antecedent de cancer du sein a ete publie sans impact evident retrouve. L’objectif de cette revue de la litterature etait d’actualiser les connaissances. Methodes Les essais randomises, cohortes prospectives et meta-analyses publiees entre 2012 et 2018 etudiant l’impact d’un regime alimentaire sur le risque de recidive et/ou la mortalite apres cancer du sein etaient inclus afin de repondre a l’objectif. La qualite des etudes a ete evaluee (selon les criteres de la Haute Autorite de Sante), les regimes etudies ont ete categorises : macronutriments, micronutriments et aliments selectifs. Resultats Dix-huit articles ont ete selectionnes. Concernant les macronutriments, un regime pauvre en matieres grasses etait associe a une meilleure survie. Concernant les micronutriments, une alimentation riche en phyto-œstrogene diminuait le risque de recidive du cancer. Enfin, l’adoption d’une alimentation saine n’etait pas associee a une amelioration du pronostic du cancer du sein mais a une amelioration de la survie globale et du risque de deces par maladie cardiovasculaire. Discussion Cette revue de la litterature suggerait une influence de la nutrition sur le pronostic du cancer du sein. Neanmoins, le niveau de preuve des resultats etait insuffisant pour emettre des recommandations. Un regime alimentaire sain et equilibre devrait etre encourage afin de diminuer la mortalite toutes causes confondues.

A subset of cancer-associated fibroblasts (FAP+/CAF-S1) mediates immunosuppression in breast cancers, but its heterogeneity and its impact on immunotherapy response remain unknown. Here, we identify 8 CAF-S1 clusters by analyzing more than 19,000 single CAF-S1 fibroblasts from breast cancer. We validate the five most abundant clusters by flow cytometry and in silico analyses in other cancer types, highlighting their relevance. Myofibroblasts from clusters 0 and 3, characterized by extracellular matrix proteins and TGFβ signaling, respectively, are indicative of primary resistance to immunotherapies. Cluster 0/ecm-myCAF upregulates PD-1 and CTLA4 protein levels in regulatory T lymphocytes (Tregs), which, in turn, increases CAF-S1 cluster 3/TGFβ-myCAF cellular content. Thus, our study highlights a positive feedback loop between specific CAF-S1 clusters and Tregs and uncovers their role in immunotherapy resistance. Significance: Our work provides a significant advance in characterizing and understanding FAP+ CAF in cancer. We reached a high resolution at single-cell level, which enabled us to identify specific clusters associated with immunosuppression and immunotherapy resistance. Identification of cluster-specific signatures paves the way for therapeutic options in combination with immunotherapies. This article is highlighted in the In This Issue feature, p. 1241

Centrosome amplification has been described as a common feature of human cancers and it is known to promote tumorigenesis when induced in animals. However, little is known about the real status of centrosome numbers in human cancers and whether numerical alterations are solely associated with poor prognosis. To address this question, we have analyzed a large cohort of human epithelial ovarian cancers (EOCs) from 100 patients using state-of-the-art microscopy to determine the Centrosome-Nucleus Index (CNI) of each tumor. We found that EOCs are highly heterogeneous, with infrequent but strong centrosome amplifications leading to higher CNI than in healthy tissues. Strikingly, while a correlation between CNI and genomic alterations, such as aneuploidy or chromosome rearrangements could not be established, we found that high CNI correlates with increased patient survival and sensitivity to chemotherapy. Using ovarian cancer cellular models to manipulate centrosome numbers and Patient-Derived Xenografts (PDXs), we found that higher CNIs can positively impact the response to chemotherapy and inhibit cell dissemination. Our findings highlight a novel paradigm linking centrosome amplification to the inhibition of tumor progression.

There is a growing interest in diets and their effects on cancer prognosis. In 2014, a report from the World Cancer Research Fund on diet and women with a history of breast cancer did not demonstrate a major effect on breast cancer prognosis. The aim of this literature review was to provide an update of knowledge in this area.Randomized trials, prospective cohorts and meta-analyses published between 2012 and 2018 examining the impact of diet on recurrence risk and/or mortality after breast cancer were included, to achieve the objective. We evaluated study quality (according to Haute Autorité de Santé criteria) and the studied diets were categorized: macronutrients, micronutrients and selective foods.We selected eighteen articles that met levels of evidence 1 to 3. For macronutrients, a low-fat diet was associated with better survival. With regard to micronutrients, a diet rich in phytœstrogen reduced the risk of cancer recurrence. Finally, the adoption of a healthy diet was not associated with an improved prognosis for breast cancer but with an improvement in overall survival and risk of death from cardiovascular disease.This review suggests that nutrition influences the prognosis of breast cancer. Nevertheless, the level of evidence of the results was insufficient to make recommendations. Ultimately, a healthy and balanced diet could be encouraged in order to reduce global mortality.

Background Chemoradiotherapy (CRT) is the standard of care for patients diagnosed with locally advanced cervical cancer (LACC), a human papillomavirus (HPV)-related cancer that relapses in 30%-60% of patients. This study aimed to (i) design HPV droplet digital PCR (ddPCR) assays for blood detection (including rare genotypes) and (ii) monitor blood HPV circulating tumor DNA (HPV ctDNA) levels during CRT in patients with LACC. Methods We analyzed blood and tumor samples from 55 patients with HPV-positive LACC treated by CRT in a retrospective cohort (n = 41) and a prospective cohort (n = 14). HPV-ctDNA detection was carried out by genotype-specific ddPCR. Results HPV ctDNA was successfully detected in 69% of patients (n = 38/55) before CRT for LACC, including nine patients with a rare genotype. HPV-ctDNA level was correlated with HPV copy number in the tumor (r = 0.41, P < 0.001). HPV-ctDNA positivity for HPV18 (20%, n = 2/10) was significantly lower than for HPV16 (77%, n = 27/35) or other types (90%, n = 9/10, P = 0.002). HPV-ctDNA detection (positive versus negative) before CRT was associated with tumor stage (P = 0.037) and lymph node status (P = 0.02). Taking into account all samples from the end of CRT and during follow-up in the prospective cohort, positive HPV-ctDNA detection was associated with lower disease-free survival (DFS) (P = 0.048) and overall survival (OS) (P = 0.0013). Conclusion This is one of the largest studies to report HPV-ctDNA detection before CRT and showed clearance of HPV ctDNA at the end of treatment in most patients. Residual HPV ctDNA at the end of CRT or during follow-up could help to identify patients more likely to experience subsequent relapse., Highlights • HPV ctDNA can be detected before CRT in patients with LACC (69%). • HPV-ctDNA detection was associated with tumor stage and lymph node status. • A lower detection rate of HPV ctDNA was observed for HPV18 genotype. • Residual ctDNA levels after CRT and during follow-up had a prognostic impact.

Background: Recent molecular biology technologies reveals insight into tumor heterogeneity but quantification and impact on reproducibility of tests is not well known. The objective of this study was to assess the extent to which tumor heterogeneity may affect the prognosis of patients assessed by Prosigna™ (PAM50) gene signature assay compared to test reproducibility. Methods: Reproducibility was measured by testing replicate tissue sections from 186 FFPE breast tumor blocks across 2 sites (Institut Curie, Centre Jean Perrin) following independent pathology review at each site. Consecutive slides came from blocks of patients included in the Decision Impact prospective study which examined whether the Prosigna™ test influences adjuvant treatment decision (Clinical trial information: NCT02395575). To evaluate heterogeneity and its impact in terms of outcome, we selected among T1N0 patients treated in Institut Curie between 2003 and 2008, 32 patients who did recur and 28 matched control group who did not (2 'controls' recurred during the study). Analyses were performed on two parts of each tumor. NanoString's Prosigna™ outputs (risk of recurrence (ROR) score, 10 year probability of distant recurrence, risk category, and intrinsic subtype (Luminal A/B, HER2-enriched, Basal-like)) were measured and compared to evaluate heterogeneity (defined as difference in terms of subtype and/or risk category between the two parts) and reproducibility. Correlation between heterogeneity and outcome was performed. Impact was assessed by tumor board analysis. Results: Pearson correlation coefficients for ROR score and probability of distant recurrence predicted were .95 and .97, respectively in the reproducibility study and .82 and .86, in the tumor heterogeneity study. The measured standard deviation (SD) was 5.4 and 8.1 ROR units corresponding to 1.6% and 2.8% in terms of risk of distant metastasis free survival within the reproducibility study and the tumor heterogeneity study, respectively. Kappa coefficients for intrinsic subtype and risk category agreement were 0.88 and 0.87 in the reproducibility study, and 0.67 and 0.58 in the tumor heterogeneity study. Tumor board analysis of discordant cases showed that the impact, in terms of decision of chemotherapy administration, concerns 3% of patients because of reproducibility and 8% because of tumor heterogeneity, comparing favorably with the discordance between Prosigna™ and immunohistochemistry (27%). Probability of distant recurrence was higher in the cases (15%) compared to control (9%) (p=.001) in the tumor heterogeneity study confirming the performance of the Prosigna™ test. Conclusion: We validated in the prospective Decision Impact study the analytical performance of NanoString's Prosigna™ assay across multiple clinical testing laboratories. We showed in these two studies that tumor heterogeneity has more impact than reproducibility performance. The clinical impact on the decision making based on tumor heterogeneity is however limited, since it does not correlate to outcomes, whereas the Prosigna™ ROR score has been shown to correlate very well to outcomes. Citation Format: Rouzier R, Bonneau C, Cayre A, Hequet D, Gentien D, Bonhomme A, Mouret-Reynier M-A, Dubot C, Cottu P, Roulot A, Morel P, Salomon A, Callens C, Guinebretiere J-M, Penault-Llorca F. Evaluation of intra-tumor heterogeneity, test reproducibility and their impact in breast cancer samples assessed by Prosigna™: Results from a decision impact prospective study and a matched case-control study [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P2-05-04.

L’insorgenza di un cancro durante la gravidanza e rara , ma solleva una duplice problematica materna e fetale. L’approccio deve essere multidisciplinare. I trattamenti devono essere quanto piu vicini possibile a quelli proposti al di fuori della gravidanza. La chemioterapia deve essere differita dopo il primo trimestre, per quanto possibile, e la radioterapia deve essere rimandata fino al post-partum. L’interruzione della gravidanza deve essere ipotizzata quando e necessario un trattamento immediato e incompatibile con la gravidanza.

Summary Background and aim Persistent postsurgical pain (PPP) has been reported by patients following various surgeries. Body contouring procedures are being performed more frequently, but no data are available regarding the effects of these procedures. Long-term disability occurring after performing "functional" procedures on healthy subjects is a particular concern. The aim of this study was to describe the risk factors, prevalence, characteristics, and effects of persistent pain after body contouring procedures. Methods Patients who underwent body contouring surgery (e.g., abdominoplasty, lower body lift, medial thigh lift, brachioplasty, and abdominal liposuction) between January 1 2009 and December 31 2013 were included in this retrospective, monocentric cohort study. Pain evaluation was performed using a visual analog pain scale (VAS) and the Douleur Neuropathique 4 (DN4) questionnaire. Major risk factors previously identified in the literature were evaluated. Results The study included 199 patients. Pain was reported by 42 patients (21%). Seventy-one percent ( n = 30) of these 42 patients presented with neuropathic pain. Risk factors that were significantly associated with PPP were acute postoperative pain ( p = 0.0003), medical history of bariatric surgery ( p = 0.002), longer period of hospitalization ( p = 0.04), depressive status during the operative period ( p = 0.03), substantial stress before surgery ( p = 0.03), and major complications after surgery ( p = 0.03). Conclusion Persistent chronic pain is frequent after body contouring procedures. Preemptive approaches and early postoperative diagnosis are important measures that can be used to limit the effects of this complication on the patient's quality of life.

Epithelial ovarian cancer (EOC) is the most lethal gynecologic malignancy. The most common subtype of EOC is high-grade serous (HGSOC), which responds at least initially to chemotherapy but has a worse overall prognosis. Genomic, transcriptomic, and proteogenomic profiling of HGSOC suggested a whole spectrum of molecular diversity, including homologous recombination pathway deficiencies (HRD). The centrosome is the main microtubule (MT)-organizing center of animal cells. It facilitates the accuracy of chromosome segregation during mitosis and influences cell polarity and migration. The presence of more than two centrosomes in a cell, centrosome amplification, has long been associated with tumorigenesis. However, little is known about the real status of centrosome numbers in human cancers and whether numerical alterations are solely associated with poor prognosis. We screened 100 samples of primary EOCs including 88 HGSOC, using immunofluorescence and state-of-the-art microscopy, to determine the centrosome-nucleus index (CNI). We integrated these data with genomic alterations, HRD status, and patient outcome. We found that EOCs are highly heterogeneous, with infrequent but strong centrosome amplifications leading to higher CNI than in healthy tissues. Strikingly, while a correlation between CNI and genomic alterations, such as aneuploidy or chromosome rearrangements, could not be established, we found that high CNI correlates with increased patient survival and sensitivity to chemotherapy, independently of HRD status. Using ovarian cancer cellular models to manipulate centrosome numbers and patient-derived xenografts (PDXs), we found that higher CNIs can positively impact the response to chemotherapy and inhibit peritoneal cell dissemination. Citation Format: Jean-Philippe Morretton, Aurelie Herbette, Camille Cosson, Bassirou Mboup, Aurelien Latouche, Pierre Gestraud, Tatiana Popova, Marc-Henri Stern, Fariba Nemati, Didier Decaudin, Guillaume Bataillon, Veronique Becette, Didier Meseure, Andre Nicolas, Odette Mariani, Claire Bonneau, Jorge Barbazan, Anne Vincent-Salomon, Fatima Mechta-Grigoriou, Sergio Roman-Roman, Roman Rouzier, Xavier Sastre-Garau, Oumou Goundiam, Renata Basto. Centrosome amplification favors survival and impairs ovarian cancer progression [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr A43.

High-grade serous ovarian cancers (HGSOC) have been subdivided into molecular subtypes. The mesenchymal HGSOC subgroup, defined by stromal-related gene signatures, is invariably associated with poor patient survival. We demonstrate that stroma exerts a key function in mesenchymal HGSOC. We highlight stromal heterogeneity in HGSOC by identifying four subsets of carcinoma-associated fibroblasts (CAF-S1-4). Mesenchymal HGSOC show high content in CAF-S1 fibroblasts, which exhibit immunosuppressive functions by increasing attraction, survival, and differentiation of CD25+FOXP3+ T lymphocytes. The beta isoform of the CXCL12 chemokine (CXCL12β) specifically accumulates in the immunosuppressive CAF-S1 subset through a miR-141/200a dependent-mechanism. Moreover, CXCL12β expression in CAF-S1 cells plays a crucial role in CAF-S1 immunosuppressive activity and is a reliable prognosis factor in HGSOC, in contrast to CXCL12α. Thus, our data highlight the differential regulation of the CXCL12α and CXCL12β isoforms in HGSOC, and reveal a CXCL12β-associated stromal heterogeneity and immunosuppressive environment in mesenchymal HGSOC., Cancer-associated fibroblasts (CAFs) are an important part of the tumor microenvironment. Here the authors characterize four subsets of CAFs across human samples of ovarian cancer subtypes and show in the mesenchymal subtype a specific CAF-S1 population that attracts immunosuppressive Tregs via CXCL12β.