Pregnancy, fertility concerns and fertility preservation procedures in a national study of French breast cancer survivors.

RESEARCH QUESTION: What are the real-life oncofertility practices in young women diagnosed with breast cancer? DESIGN: The FEERIC (FErtility, prEgnancy, contRaceptIon after breast Cancer in France) study is a web-based cohort study launched with the French collaborative research platform Seintinelles. The current work is based on the enrolment self-administered questionnaire of 517 patients with prior breast cancer diagnosis, free from relapse and aged 18 to 43 years at inclusion (from 12 March 2018 to 27 June 2019). RESULTS: Median age at breast cancer diagnosis was 33.6 years and 424 patients (82.0%) received chemotherapy. Overall, 236 (45.6%) patients were offered specialized oncofertility counselling, 181 patients underwent at least one fertility preservation procedure (FPP); 125 (24.2%) underwent one or more FPP with material preservation (oocytes n = 108, 20.9%; embryos n = 31, 6.0%; ovarian cryopreservation n = 6, 1.2%) and 78 patients received gonadotrophin-releasing hormone agonists (15.1%). With a median follow-up of 26.9 months after the end of treatments, 133 pregnancies had occurred in 85 patients (16.4%), including 20 unplanned pregnancies (15.0%). Most of the pregnancies were natural conceptions (n = 113, 87.6%), while 16 (12.4%) required medical interventions. For the planned pregnancies, median time to the occurrence of an ongoing pregnancy was 3 months. Patients who had an unplanned pregnancy reported lower rates of information on the consequences of the treatments on fertility (P = 0.036) at diagnosis. CONCLUSIONS: Most of the patients were not offered proper specialized oncofertility counselling at the time of breast cancer diagnosis. Naturally conceived pregnancies after breast cancer were much more frequent than pregnancies resulting from the use of cryopreserved gametes. Adequate contraceptive counselling seems as important as information about fertility and might prevent unplanned pregnancies.

Optimization of G-CSF dosing schedule in patients treated with eribulin: a modeling approach.

BACKGROUND: Granulocyte colony-stimulating factors (G-CSF) are commonly given to limit chemotherapy-induced neutropenia, but, in case of weekly chemotherapy such as eribulin, their administration schedules remain empirical. OBJECTIVES: This pharmacokinetic/pharmacodynamic (PK/PD) study was conducted to establish the effect of different G-CSF regimens on neutropenia's incidence for patients treated by eribulin, to propose an optimal G-CSF dosing schedule. METHODS: A population PK/PD model was developed to describe absolute neutrophil counts' (ANC) time course in 87 cancer patients receiving eribulin. The structural model considered ANC dynamics, neutropenic effect of eribulin and stimulating effect of G-CSF. Final model estimates were used to calculate neutropenia's incidence following different G-CSF dosing schedules for 1000 virtual subjects. RESULTS: The final model successfully described most of the ANC time course for all patients. Simulations showed that a single G-CSF administration 48 h after each eribulin injection reduced the risk of severe neutropenia from 29.7 to 5.2%. Five days of G-CSF only after the second eribulin injection or no G-CSF administration induces similar incidence of neutropenia. CONCLUSION: Simulations showed a single G-CSF administration 48 h after the end of each eribulin injection seems to be the optimal schedule to reduce eribulin-induced neutropenia. However, the new administration scheme should be tested in real life to evaluate its pertinence. TRIAL REGISTRATION: Eudract 2015-001753-32, 2015/01/26.

[Adapting to the SARS-CoV2 pandemic: Experience of the Curie Institute]. / S'adapter face à la pandémie SARS-CoV2 : l'expérience de l'Institut Curie.

The Curie Institute exclusively cares for cancer patients, who were considered particularly "vulnerable" from the start of the SARS-CoV 2 pandemic. This pandemic, which took the medical world by surprise, suddenly required the Institute's hospital to undergo rapid and multimodal restructuring, while having an impact on everyone to varying degrees. We will examine here how this hospital has coped, with the concern for a new benefit-risk balance, in times of greater medical uncertainty and scarcity of certain resources, for these "vulnerable" patients but also for their relatives and staff. We will highlight by theme the positive aspects and difficulties encountered, and then what could be useful for other hospitals as the pandemic is ongoing.

6 months versus 12 months of adjuvant trastuzumab in early breast cancer (PHARE): final analysis of a multicentre, open-label, phase 3 randomised trial.

BACKGROUND: In 2013, the interim analysis of the Protocol for Herceptin as Adjuvant therapy with Reduced Exposure (PHARE) trial could not show that 6 months of adjuvant trastuzumab was non-inferior to 12 months. Here, we report the planned final analysis based on the prespecified number of occurring events. METHODS: PHARE is an open-label, phase 3, non-inferiority randomised trial of patients with HER2-positive early breast cancer comparing 6 months versus 12 months of trastuzumab treatment concomitant with or following standard neoadjuvant or adjuvant chemotherapy. The study was undertaken in 156 centres in France. Eligible patients were women aged 18 years or older with non-metastatic, operable, histologically confirmed adenocarcinoma of the breast and either positive axillary nodes or negative axillary nodes but a tumour of at least 10 mm. Participants must have received at least four cycles of a chemotherapy for this breast cancer and have started receiving adjuvant trastuzumab-treatment. Eligible patients were randomly assigned to either 6 months or 12 months of trastuzumab therapy duration between the third and sixth months of adjuvant trastuzumab. The randomisation was stratified by concomitant or sequential treatment with chemotherapy, oestrogen receptor status, and centre. The primary objective was non-inferiority in the intention-to-treat population in the 6-month group in terms of disease-free survival with a prespecified hazard margin of 1·15. This trial is registered with ClinicalTrials.gov, number NCT00381901. FINDINGS: 3384 patients were enrolled and randomly assigned to either 12 months (n=1691) or 6 months (n=1693) of adjuvant trastuzumab. One patient in the 12-month group and three patients in the 6-month group were excluded, so 1690 patients in each group were included in the intention-to-treat analysis. At a median follow-up of 7·5 years (IQR 5·3-8·8), 704 events relevant to disease-free survival were observed (345 [20·4%] in the 12-month group and 359 [21·2%] in the 6-month group). The adjusted hazard ratio for disease-free survival in the 12-month group versus the 6-month group was 1·08 (95% CI 0·93-1·25; p=0·39). The non-inferiority margin was included in the 95% CI. No differences in effects pertaining to trastuzumab duration were found in any of the subgroups. After the completion of trastuzumab treatment, rare adverse events occurred over time and the safety analysis remained similar to the previously published report. In particular, we found no change in the cardiac safety comparison, and only three additional cases in which the left ventricular ejection fraction decreased to less than 50% have been reported in the 12-month group. INTERPRETATION: The PHARE study did not show the non-inferiority of 6 months versus 12 months of adjuvant trastuzumab. Hence, adjuvant trastuzumab standard duration should remain 12 months. FUNDING: The French National Cancer Institute.

Long-Term Gynecological Cancer Survivors in Côte d'Or: Health-Related Quality of Life and Living Conditions.

BACKGROUND: The likelihood that health-related quality of life (HRQoL) could depend on factors other than clinical data increases with the duration of follow-up since diagnosis. The aim of this study was to identify determinants of long-term HRQoL in women with cervical, endometrial, and ovarian cancer. Secondary objectives were to describe their living conditions (sexual function, psychological distress, social and professional reinsertion). MATERIALS AND METHODS: In a cross-sectional survey, women diagnosed with cervical, endometrial, and ovarian cancers from 2006 to 2013 were selected through the French gynecological cancers registry of Côte d'Or. Validated questionnaires exploring HRQoL (short-form health survey; SF-12), anxiety and depression (Hospital Anxiety and Depression Scale), social support (Sarason's Social Support Questionnaire), sexual function (Female Sexual Function Index), and living conditions (EPICES questionnaire) were used to assess HRQoL and its determinants. Social and professional reinsertion were also investigated using study-specific questionnaires. Determinants of HRQoL were identified using a multivariable mixed-regression model for each composite score of the SF-12. RESULTS: In total, 195 gynecological cancer survivors participated in the survey. HRQoL was deteriorated for almost all the SF-12 dimensions. The main determinants of poor HRQoL were comorbidities, deprivation, lack of availability and satisfaction with social support, and psychological outcomes. Thirty-four percent of survivors of gynecological cancer reported a negative impact of cancer on their work, and 73% reported an impaired ability to work after treatment. CONCLUSIONS: Long-term HRQoL of survivors of gynecological cancer is not impacted by stage of disease. Specific interventions should focus on issues that promote social and professional reintegration and improve HRQoL. IMPLICATIONS FOR PRACTICE: This study shows that women with gynecological cancer have problems related to work and sexual dysfunction, even 5 years after diagnosis. The results of this study will help improve clinicians' awareness of the factors affecting the lives of gynecological cancer survivors, even long after diagnosis and treatment. They will also highlight for clinicians the areas that are of importance to gynecological cancer survivors, making it possible to guide management of these patients with a view to preventing deteriorated health-related quality of life after treatment. For the health authorities, the results of this study underline that more than 5 years after gynecological cancer, the initial stage of disease no longer affects quality of life, but there is a clear need for actions targeting socio-professional reintegration of survivors.

FDG PET/CT for prognostic stratification of patients with metastatic breast cancer treated with first line systemic therapy: Comparison of EORTC criteria and PERCIST.

AIM: Evaluate response and predict prognosis of patients with newly diagnosed metastatic breast cancer treated with first line systemic therapy using European Organization for Research and Treatment of Cancer (EORTC) criteria and PET Response Criteria in solid Tumours (PERCIST). METHODS: From December 2006 to August 2013, 57 women with newly diagnosed metastatic breast cancer were retrospectively evaluated. FDG-PET/CT was performed within one month before treatment and repeated after at least 3 cycles of treatment. Metabolic response evaluation was evaluated by two readers according to both EORTC criteria and PERCIST, classifying the patients into 4 response groups: complete metabolic response (CMR), partial metabolic response (PMR), stable metabolic disease (SMD), and progressive metabolic disease (PMD). RESULTS: With EORTC criteria, 22 patients had CMR, 17 PMR, 6 SMD and 12 PMD. With PERCIST, 20 patients had CMR, 15 PMR, 10 SMD and 12 PMD. There was agreement between EORTC and PERCIST in 84% of the patients. By log-rank analysis, metabolic response evaluated with both EORTC criteria and PERCIST was able to predict overall survival (p = 0.028 and 0.002 respectively). CMR patient group had longer median OS than patients in the combined PMR+SMD+PMD group (60 vs 26 months both with EORTC and PERCIST; p = 0.009 and 0.006 respectively). By multivariate analysis, CMR either with EORTC or PERCIST remained an independent predictor of survival. CONCLUSION: Metabolic response evaluation with EORTC criteria and PERCIST gave similar prognostic stratification for metastatic breast cancer treated with a first line of systemic therapy.

Fluctuation of the left ventricular ejection fraction in patients with HER2-positive early breast cancer treated by 12 months of adjuvant trastuzumab.

BACKGROUND: Cardiac toxicity with a decrease of the left ventricular ejection fraction (LVEF) is the main side effect induced by trastuzumab. This study reports the fluctuation of LVEF over the 12 months of adjuvant trastuzumab in PHARE trial (NCT00381901). METHODS: LVEF assessment was performed every 3 months while patients received trastuzumab and after completion of treatment over the first 2 years and then every 6 months afterwards. The fluctuations of LVEF over time were described and a logistic regression model was performed investigating associated factors to LVEF perfect recovery at baseline value. RESULTS: A total of 1631 patients who received 12 months of trastuzumab from PHARE trial, were considered in the analysis. A total of 13 881 LVEF measurements were assessed. Baseline mean LVEF was 66.08% (standard error (SE): 0.15) and the mean relative LVEF decrease observed at 12-month was 3.61% (SE: 0.31). No clinical characteristic was significantly associated to LVEF fluctuation. After completion of trastuzumab, the relative difference progressively disappeared with beyond 30 months a relative difference value of 0.08% (SE: 0.42). Nevertheless, at 30 months, 48.53% of patients with available measures (379/781) did not fully recover their baseline LVEF value. CONCLUSION: The LVEF decreased during treatment with trastuzumab and rose up after the completion of treatment without coming back to the initial values for a substantial subset. These results would suggest investigating some strategies aimed to improve the ability to achieve a full recovery.

The 21-gene Recurrence Score® assay predicts distant recurrence in lymph node-positive, hormone receptor-positive, breast cancer patients treated with adjuvant sequential epirubicin- and docetaxel-based or epirubicin-based chemotherapy (PACS-01 trial).

BACKGROUND: The 21-gene Recurrence Score (RS) result predicts outcome and chemotherapy benefit in node-negative and node-positive (N+), estrogen receptor-positive (ER+) patients treated with endocrine therapy. The purpose of this study was to evaluate the prognostic impact of RS results in N+, hormone receptor-positive (HR+) patients treated with adjuvant chemotherapy (6 cycles of FEC100 vs. 3 cycles of FEC100 followed by 3 cycles of docetaxel 100 mg/m2) plus endocrine therapy (ET) in the PACS-01 trial (J Clin Oncol 2006;24:5664-5671). METHODS: The current study included 530 HR+/N+ patients from the PACS-01 parent trial for whom specimens were available. The primary objective was to evaluate the relationship between the RS result and distant recurrence (DR). RESULTS: There were 209 (39.4%) patients with low RS (< 18), 159 (30%) with intermediate RS (18-30) and 162 (30.6%) with high RS (≥ 31). The continuous RS result was associated with DR (hazard ratio = 4.14; 95% confidence interval: 2.67-6.43; p <  0.001), adjusting for treatment. In multivariable analysis, the RS result remained a significant predictor of DR (p <  0.001) after adjustment for number of positive nodes, tumor size, tumor grade, Ki-67 (immunohistochemical status), and chemotherapy regimen. There was no statistically significant interaction between RS result and treatment in predicting DR (p = 0.79). CONCLUSIONS: After adjustment for clinical covariates, the 21-gene RS result is a significant prognostic factor in N+/HR+ patients receiving adjuvant chemoendocrine therapy. TRIAL REGISTRATION: Not applicable.

Breast Cancer Blood Flow and Metabolism on Dual-Acquisition 18F-FDG PET: Correlation with Tumor Phenotype and Neoadjuvant Chemotherapy Response.

Early changes in tumor glucose metabolism (SUVmax) and in tumor blood flow (BF) have been evaluated separately for monitoring breast cancer response to neoadjuvant chemotherapy (NAC). This study used a single 18F-FDG dual-acquisition PET examination to simultaneously assess these two imaging features and to determine whether they correlate with the same pretherapy tumor phenotypic features and whether they are comparable or complementary in predicting pathologic complete response (pCR). Methods: This prospective study included 150 women with breast cancer and an indication for NAC. A 2-min chest-centered dynamic PET acquisition was performed at the time of 18F-FDG injection, followed by a delayed static PET acquisition 90 min later. Tumor BF was calculated from the dynamic acquisition using a validated first-pass model, and tumor SUVmax was calculated from the delayed acquisition. This dual acquisition was repeated after the first cycle of NAC to measure early changes in tumor BF and SUVmaxResults: A weak correlation was found between SUVmax and BF at baseline (r = 0.22; P = 0.006). A high baseline SUVmax was associated with all biologic markers of tumor aggressiveness, including the triple-negative breast cancer subtype (P < 0.0001). In contrast, a high baseline BF was associated only with obesity (P = 0.002). The change in SUVmax (mean, -44.6% ± 27.4%) varied depending on the Scarff-Bloom-Richardson grade, overexpression of human epidermal growth factor receptor 2 (HER2-positive), and lack of hormone receptor expression (P = 0.04, P < 0.001, and P = 0.01, respectively). BF (mean change, -26.9% ± 54.3%) showed a drastic reduction only in HER2-positive subtypes (-58.7% ± 30.0%), supporting the antiangiogenic effect of trastuzumab. Changes in SUVmax outperformed changes in BF for predicting pCR in all tumor subtypes: the areas under the curve for change in SUVmax were 0.82, 0.65, and 0.90 in the triple-negative, HER2-positive, and luminal subtypes, respectively. Conclusion: Of the two biologic hallmarks of cancer evaluated in this study, a reduction in tumor glucose metabolism was more accurate than a reduction in tumor BF for predicting pCR in the different subtypes of breast cancer.

Nuclear Imaging Study of the Pharmacodynamic Effects of Debio 1143, an Antagonist of Multiple Inhibitor of Apoptosis Proteins (IAPs), in a Triple-Negative Breast Cancer Model.

Background: Debio 1143, a potent orally available SMAC mimetic, targets inhibitors of apoptosis proteins (IAPs) members and is currently in clinical trials. In this study, nuclear imaging evaluated the effects of Debio 1143 on tumor cell death and metabolism in a triple-negative breast cancer (TNBC) cell line (MDA-MB-231)-based animal model. Methods: Apoptosis induced by Debio 1143 was assessed by FACS (caspase-3, annexin 5 (A5)), binding of 99mTc-HYNIC-Annexin V, and a cell proliferation assay. 99mTc-HYNIC-Annexin V SPECT and [18F]-FDG PET were also performed in mice xenografted with MDA-MB-231 cells. Results: Debio 1143 induced early apoptosis both in vitro and in vivo 6 h after treatment. Debio 1143 inhibited tumor growth, which was associated with a decreased tumor [18F]-FDG uptake when measured during treatment. Conclusions: This imaging study combining SPECT and PET showed the early proapoptotic effects of Debio 1143 resulting in a robust antitumor activity in a preclinical TNBC model. These imaging biomarkers represent valuable noninvasive tools for translational and clinical research in TNBC.

Assessment of the prognostic role of a 94-single nucleotide polymorphisms risk score in early breast cancer in the SIGNAL/PHARE prospective cohort: no correlation with clinico-pathological characteristics and outcomes.

BACKGROUND: Genome-wide association studies (GWAS) have to date identified 94 genetic variants (single nucleotide polymorphisms (SNPs)) associated with risk of developing breast cancer. A score based on the combined effect of the 94 risk alleles can be calculated to measure the global risk of breast cancer. We aimed to test the hypothesis that the 94-SNP-based risk score is associated with clinico-pathological characteristics, breast cancer subtypes and outcomes in early breast cancer. METHODS: A 94-SNP risk score was calculated in 8703 patients in the PHARE and SIGNAL prospective case cohorts. This score is the total number of inherited risk alleles based on 94 selected SNPs. Clinical data and outcomes were prospectively registered. Genotyping was obtained from a GWAS. RESULTS: The median 94-SNP risk score in 8703 patients with early breast cancer was 77.5 (range: 58.1-97.6). The risk score was not associated with usual prognostic and predictive factors (age; tumor, node, metastasis (TNM) status; Scarff-Bloom-Richardson grade; inflammatory features; estrogen receptor status; progesterone receptor status; human epidermal growth factor receptor 2 (HER2) status) and did not correlate with breast cancer subtypes. The 94-SNP risk score did not predict outcomes represented by overall survival or disease-free survival. CONCLUSIONS: In a prospective case cohort of 8703 patients, a risk score based on 94 SNPs was not associated with breast cancer characteristics, cancer subtypes, or patients' outcomes. If we hypothesize that prognosis and subtypes of breast cancer are determined by constitutional genetic factors, our results suggest that a score based on breast cancer risk-associated SNPs is not associated with prognosis. TRIAL REGISTRATION: PHARE cohort: NCT00381901 , Sept. 26, 2006 - SIGNAL cohort: INCa RECF1098, Jan. 28, 2009.

Clinical value of CA 15-3 for detection of distant metastases in newly diagnosed breast cancer.

The aim of the study is to investigate the clinical value of CA 15-3 for detection of distant metastases (DM) in newly diagnosed breast cancer. This retrospective study focuses on a population of 1,007 patients with locally advanced breast cancer (n=561) or metastatic breast cancer (n=446) diagnosed at the CGFL (Centre Georges Francois Leclerc) from March 1998 to October 2013. These patients underwent a measurement of CA 15-3 and an assessment of extension before any treatment. The cut-off value of CA 15-3 was determined and verified on two independents subpopulations determined in drawing lots. The ROC curve shows an AUC of 0.85 (p<0.0001). At the threshold of 50 kU/L, CA 15-3 before treatment has a predictive value on the existence of DM independently of the other prognostics factors. This predictive value has been found in every molecular subtype (AUC≥ 0.70; p≤ 0,085). The rate of false negative is of 38% and depends on the number and the type of the metastatic localization. Among the 28 patients without DM and a CA 15-3> 50 kU/L, 13 have developed DM and 11 died of cancer. In conclusion, these facts confirm the independently predictive value of CA 15-3 before treatment on the existence of DM and the complementarity of the marker with the assessment of extension by imagery.

Constitutional variants are not associated with HER2-positive breast cancer: results from the SIGNAL/PHARE clinical cohort.

Human epidermal growth factor receptor 2-positive breast cancer is a subtype of interest regarding its outcome and the impressive impact of human epidermal growth factor receptor 2 targeted therapy. Constitutional variants may be involved in the aetiology of human epidermal growth factor receptor 2-positive breast cancer, and we propose a case-case study to test the hypothesis that single nucleotide polymorphisms may be associated with human epidermal growth factor receptor 2 status. A Genome-Wide Association Study was used in a cohort of 9836 patients from the SIGNAL/PHARE study (NCT00381901-RECF1098). The main goal was to identify variants specifically related to human epidermal growth factor receptor 2-positive breast cancer. A two-staged genotyping strategy was carried out to cover as large a proportion of the genome as possible. All subjects were genotyped using the Illumina HumanCore Exome chip set. Principal Components Analysis and k-means were then used to characterize the ancestry of the participants. A random sample of subjects from the main "European" cluster was genotyped with the Omni5 chip set. These data were then used to impute missing genotypes from the remaining subjects genotyped only using the HumanCore Exome array. From the 9836 patients, a total of 8703 cases including 3230 patients with human epidermal growth factor receptor 2-positive breast cancer were analyzed. Despite having 80% power to detect an odds ratio of 1.23 in this population, no variant achieved genome-wide significance for association with the occurrence of human epidermal growth factor receptor 2-positive breast cancer vs. any other subtype of breast tumour. Our study was unable to identify constitutional polymorphisms that are strongly associated with human epidermal growth factor receptor 2-positive status among breast cancer patients.

Superimposable outcomes for sequential and concomitant administration of adjuvant trastuzumab in HER2-positive breast cancer: Results from the SIGNAL/PHARE prospective cohort.

AIM: Adjuvant clinical trials in early human epidermal growth factor receptor 2 (HER2)-positive breast cancer have assessed either sequential or concomitant incorporation of trastuzumab with chemotherapy; only the North Central Cancer Treatment Group (NCCTG)-N9831 trial prospectively compared both modalities. In routine trastuzumab has been incorporated into a concurrent regimen with taxane chemotherapy instead of sequential modality on the basis of a positive risk-benefit ratio. This present study assessed sequential versus concomitant administration of adjuvant trastuzumab. METHODS: A population combining patients from Protocol for Herceptin® as Adjuvant therapy with Reduced Exposure (PHARE) a randomised phase III clinical trial (NCT00381901) and SIGNAL (RECF1098) a prospective study specifically designed for Genome-wide Association Studies (GWAS) analyses was studied. In this cohort with 58 months of median follow-up, the comparison in the HER2-positive group of adjuvant trastuzumab and chemotherapy modalities was based on a propensity score methodology. Treatment modalities were based on physician's choice and comparisons adjustment were made by a propensity score methodology. Overall Survival (OS) and Disease-Free Survival (DFS) were estimated using the Kaplan-Meier method, and comparisons between groups were based on the log rank test. RESULTS: The SIGNAL/PHARE cohort included 11,728 breast cancer cases treated in adjuvant setting; some 5502 of them with HER2-positive tumour: 34.5% (1897/5502) were treated by sequential and 65.5% (3605/5502) by concomitant modality of administration for taxane-chemotherapy and trastuzumab. The adjusted comparison found similar OS (HR = 1.01; 95% CI: 0.86-1.19) and similar DFS (HR = 1.08; 95% CI: 0.96-1.21). CONCLUSION: These results suggest that the sequential administration of trastuzumab given after the completion of adjuvant chemotherapy might be as valid as the concomitant administration of trastuzumab and taxane chemotherapy in the adjuvant setting.

Exosomes in cancer theranostic: Diamonds in the rough.

During the last 10 years, exosomes, which are small vesicles of 50-200 nm diameter of endosomal origin, have aroused a great interest in the scientific and clinical community for their roles in intercellular communication in almost all physiological and pathological processes. Most cells can potentially release these nanovesicles that share with the parent cell a similar lipid bilayer with transmembrane proteins and a panel of enclosed soluble proteins such as heat shock proteins and genetic material, thus acting as potential nanoshuttles of biomarkers. Exosomes surface proteins allow their targeting and capture by recipient cells, while the exosomes' content can modify the physiological state of recipient cells. Tumor derived exosomes by interacting with other cells of the tumor microenvironment modulate tumor progression, angiogenic switch, metastasis, and immune escape. Targeting tumor-derived exosomes might be an interesting approach in cancer therapy. Furthermore, because a key issue to improve cancer patients' outcome relies on earlier cancer diagnosis (metastases, as opposed to the primary tumor, are responsible for most cancer deaths) exosomes have been put forward as promising biomarker candidates for cancer diagnosis and prognosis. This review summarizes the roles of exosomes in cancer and clinical interest, focusing on the importance of exosomal heat shock proteins (HSP). The challenges of clinical translation of HSP-exosomes as therapeutic targets and biomarkers for early cancer detection are also discussed.

[The anti-tumor immune response in breast cancer: Update and therapeutic perspectives]. / La réponse immunitaire anti-tumorale dans le cancer du sein : état des lieux et perspectives thérapeutiques.

The role of the immune response in breast cancer is now well recognized and increasingly taken in account. The goal of this article is, in the first part, to underline its prognostic impact and to precise the immunosurvelliance, immunoselection and the immunosubversion concepts involved in the control and evasion of breast carcinoma. In the second part, therapeutic strategies for the restauration of anti-tumor immunity are developed. Vaccination strategies and checkpoints inhibitors blockade strategies are discussed as well as the immunogenic death linked to the conventional treatments of breast cancer.

The transfer of multigene panel testing for hereditary breast and ovarian cancer to healthcare: What are the implications for the management of patients and families?

Until recently, the molecular diagnosis of hereditary breast and ovarian cancer (HBOC) was mostly based on BRCA1/2 testing. Next generation sequencing and the recent discovery of new genes involved in HBOC now permit the transfer of genomic capture targeting multiple candidate genes from research to clinical use. However, the implications for the management of patients and their families have not been extensively studied, in particular since some of these genes are not well-established cancer predisposing genes. We studied 583 consecutive patients from Burgundy (France) fulfilling the criteria for BRCA testing using a next generation sequencing 25-genes panel including 20 well-established high-risk cancer genes as well as more recently identified predisposing HBOC cancer. A pathogenic BRCA1/2 mutation was found in 51 patients (9%). Besides, we found 37 pathogenic or likely pathogenic mutations in 10 different high to low-risk genes in 34 patients (6%). The most frequently mutated genes were CHEK2 (n = 12; 2%), ATM (n = 9; 1.5%), and PALB2 (n = 4; 0.6%). Three patients had a mutation in two different predisposing genes. The analysis of clinical actionability conducted in mutation-positive individuals revealed that additional disease-specific screening and/or prevention measures beyond those based on personal and family history alone had been recommended in 69% of cases. In conclusion, multigene panel testing is a powerful tool to identifying high to low-risk HBOC susceptibility genes. The penetrance and spectrum of cancers with these other genes are sometimes undefined, and further collaborative work is crucial to address this question.

GWAS in the SIGNAL/PHARE clinical cohort restricts the association between the FGFR2 locus and estrogen receptor status to HER2-negative breast cancer patients.

Genetic polymorphisms are associated with breast cancer risk. Clinical and epidemiological observations suggest that clinical characteristics of breast cancer, such as estrogen receptor or HER2 status, are also influenced by hereditary factors. To identify genetic variants associated with pathological characteristics of breast cancer patients, a Genome Wide Association Study was performed in a cohort of 9365 women from the French nationwide SIGNAL/PHARE studies (NCT00381901/RECF1098). Strong association between the FGFR2 locus and ER status of breast cancer patients was observed (ER-positive n=6211, ER-negative n=2516; rs3135718 OR=1.34 p=5.46×10-12). This association was limited to patients with HER2-negative tumors (ER-positive n=4267, ER-negative n=1185; rs3135724 OR=1.85 p=1.16×10-11). The FGFR2 locus is known to be associated with breast cancer risk. This study provides sound evidence for an association between variants in the FGFR2 locus and ER status among breast cancer patients, particularly among patients with HER2-negative disease. This refinement of the association between FGFR2 variants and ER-status to HER2-negative disease provides novel insight to potential biological and clinical influence of genetic polymorphisms on breast tumors.

A whole-genome sequence and transcriptome perspective on HER2-positive breast cancers.

HER2-positive breast cancer has long proven to be a clinically distinct class of breast cancers for which several targeted therapies are now available. However, resistance to the treatment associated with specific gene expressions or mutations has been observed, revealing the underlying diversity of these cancers. Therefore, understanding the full extent of the HER2-positive disease heterogeneity still remains challenging. Here we carry out an in-depth genomic characterization of 64 HER2-positive breast tumour genomes that exhibit four subgroups, based on the expression data, with distinctive genomic features in terms of somatic mutations, copy-number changes or structural variations. The results suggest that, despite being clinically defined by a specific gene amplification, HER2-positive tumours melt into the whole luminal-basal breast cancer spectrum rather than standing apart. The results also lead to a refined ERBB2 amplicon of 106 kb and show that several cases of amplifications are compatible with a breakage-fusion-bridge mechanism.

18F-FDG PET-Derived Tumor Blood Flow Changes After 1 Cycle of Neoadjuvant Chemotherapy Predicts Outcome in Triple-Negative Breast Cancer.

Previous studies have suggested that early changes in blood flow (BF) in response to neoadjuvant chemotherapy and evaluated with 15O-water are a surrogate biomarker of outcome in women with breast cancer. This study investigates, in the triple-negative breast cancer subtype, the prognostic relevance of tumor BF changes (ΔBF) in response to chemotherapy, assessed using a short dynamic 18F-FDG PET acquisition. METHODS: Forty-six consecutive women with triple-negative breast cancer and an indication for neoadjuvant chemotherapy were prospectively included. Women benefited from a baseline 18F-FDG PET examination with a 2-min chest-centered dynamic acquisition, started at the time of 18F-FDG injection. Breast tumor perfusion was calculated from this short dynamic image using a first-pass model. This dynamic PET acquisition was repeated after the first cycle of chemotherapy to measure early ΔBF. Delayed static PET acquisitions were also performed (90 min after 18F-FDG injection) to measure changes in tumor glucose metabolism (ΔSUVmax). The association between tumor BF, clinicopathologic characteristics, and patients' overall survival (OS) was evaluated. RESULTS: Median baseline tumor BF was 21 mL/min/100 g (range, 6-46 mL/min/100 g) and did not significantly differ according to tumor size, Scarf-Bloom-Richardson grade, or Ki-67 expression. Median tumor ∆BF was -30%, with highly scattered values (range, -93% to +118%). A weak correlation was observed between ΔBF and ∆SUVmax (r = +0.40, P = 0.01). The median follow-up was 30 mo (range, 6-73 mo). Eight women developed recurrent disease, 7 of whom died. Low OS was associated with menopausal history (P = 0.03), persistent or increased tumor vascularization on the interim PET (ΔBF cutoff = -30%; P = 0.03), non-breast-conserving surgery (P = 0.04), and the absence of a pathologic complete response (pCR) (P = 0.01). ΔBF and pCR provided incremental prognostic stratification: 3-y OS was 100% in pCR women, 87% in no-pCR women but achieving an early tumor BF response, and only 48% in no-pCR/no-BF-response women (ΔBF cutoff = -30%, P < 0.001). CONCLUSION: This study suggests the clinical usefulness of an early user- and patient-friendly 2-min dynamic acquisition to monitor breast tumor ΔBF to neoadjuvant chemotherapy using 18F-FDG PET/CT. Monitoring tumor perfusion and angiogenesis response to treatment seems to be a promising target for PET tracers.