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.

First-in-human phase 1 of YS110, a monoclonal antibody directed against CD26 in advanced CD26-expressing cancers.

BACKGROUND: YS110 is a humanised IgG1 monoclonal antibody with high affinity to the CD26 antigen. YS110 demonstrated preclinical anti-tumour effects without significant side effects. METHODS: This FIH study was designed to determine the maximal tolerated dose (MTD) and recommended phase 2 dose (RP2D) to assess the tolerance, pharmacokinetics (PK) and pharmacodynamics profiles of YS110 and preliminary efficacy. YS110 were initially administered intravenously once every 2 weeks (Q2W) for three doses and then, based on PK data, once every week (Q1W) for five doses in patients with CD26-expressing solid tumours. RESULTS: Thirty-three patients (22 mesothelioma) received a median of 3 (range 1-30) YS110 infusions across six dose levels (0.1-6 mg kg-1). MTD was not reached and two dose-limiting toxicities (infusion hypersensitivity reactions) led to the institution of a systemic premedication. Low-grade asthenia (30.3%), hypersensitivity (27.3%), nausea (15.2%), flushing (15.2%), chills (12.1%) and pyrexia (12.1%) were reported as ADRs. Pharmacokinetic parameters (AUC and Cmax) increased in proportion with the dose. sCD26/DPPIV assays indicated CD26 modulation. Prolonged stable diseases were observed in 13 out of 26 evaluable patients. CONCLUSIONS: YS110 is well tolerated up to 6 mg kg-1 Q1W, which has been defined as the RP2D, with encouraging prolonged disease stabilisations observed in a number of patients with advanced/refractory mesothelioma.

[Reply to « Why is it difficult to implement biomedical policy? The ase of the Cancéropôles, the French cancer organizations ¼, by Audrey Vézian, Med Sci (Paris) 2014 Aug-Sep; 30 (8-9) : 803-7]. / Contribution des responsables des Cancéropôles au Forum/Débat sur le bilan des actions des Cancéropôles - Répartie à l'analyse proposée par Audrey Vézian.

The authors, all in charge of the administration of one of the 7 French Cancéropôles, reply to the article authored by Audrey Vézian, and -provide an alternative and more supportive view of the initiatives -sponsored by these regional cancer research networks.

Open-label uncontrolled pilot study to evaluate complementary therapy with Ruta graveolens 9c in patients with advanced cancer.

BACKGROUND: Patients with advanced metastatic disease are often treated aggressively with multiple lines of chemotherapy, even in the last month of life. The benefit of such an approach remains uncertain. The objective of the study was to investigate whether Ruta graveolens 9c homeopathic medicine can improve quality of life (QoL) and tumour progression in patients with advanced cancer. MATERIAL AND METHODS: This was a single-centre, open-label, uncontrolled, pilot study. Patients (>18-years, life-expectancy ≥3 months, performance status ≤2) with locally-advanced solid tumours or metastases, previously treated with all available standard anti-cancer treatments were recruited. Oral treatment consisted of two 1-mL ampoules of Ruta graveolens (9c dilution) given daily for a minimum of 8 weeks, or until tumour and/or clinical progression. Primary outcome was QoL measured using the EORTC QLQ-C30 questionnaire. Secondary outcome measures were anxiety/depression measured using the Hospital Anxiety and Depression Scale (HADS), WHO performance status (PS), tumour progression assessed using RECIST criteria and tumour markers, survival and tolerance. RESULTS: Thirty-one patients were included (mean age: 64.3 years). Mean duration of treatment was 3.3 months (median: 2.1). QoL global health status improved significantly between baseline and week 8 (P < 0.001) and week 16 (P = 0.035), but was at the limit of significance (P = 0.057) at the end of the study. There was no significant change in anxiety/depression or PS during treatment. Ruta graveolens 9c had no obvious effect on tumour progression. Median survival was 6.7 months [95%CI: 4.8-14.9]. Ruta graveolens 9c was well-tolerated. CONCLUSION: Some patients treated with Ruta graveolens 9c had a transitory improvement in QoL, but the effectiveness of this treatment remains to be confirmed in further studies.

Improving cancer patient care with combined medication error reviews and morbidity and mortality conferences.

BACKGROUND: To reduce the occurrence of medication errors, a systemic approach was developed combining anti-neoplastic medication error reviews and morbidity and mortality conferences (M&MCs). We report the first experience of implementing this strategy in oncology. METHODS: The case reports submitted to combined reviews were prepared by physicians and pharmacists, and medication error(s) were described and chronological and root-cause analyses were performed. RESULTS: Ten combined reviews were conducted, which involved the departments of haematology, medical oncology, pneumology, gastroenterology and clinical oncology pharmacy. A total of 91 errors were analysed, of which 3 had reached the patient. Thirty-four corrective actions were proposed; 53% consisted of changes in practice, 35% in procedural reminders and 12% in on-ward education sessions. CONCLUSIONS: The combination of medication error reviews and M&MCs appears to be an efficient means of improving cancer patient safety and personnel proficiency. This multidisciplinary work is indispensable to improve future patient management through the critical analysis of past medical errors.

A PK-PD model linking biomarker dynamics to progression-free survival in patients treated with everolimus and sorafenib combination therapy, EVESOR phase I trial.

PURPOSE: The objective was to develop a pharmacokinetic-pharmacodynamic (PK-PD) model linking everolimus and sorafenib exposure with biomarker dynamics and progression-free survival (PFS) based on data from EVESOR trial in patients with solid tumors treated with everolimus and sorafenib combination therapy and to simulate alternative dosing schedules for sorafenib. PATIENTS AND METHODS: Everolimus (5-10 mg once daily, qd) and sorafenib (200-400 mg twice daily, bid) were administered according to four different dosing schedules in 43 solid tumor patients. Rich PK and PD sampling for serum angiogenesis biomarkers was performed. Baseline activation of RAS/RAF/ERK (MAPK) pathway was assessed by quantification of mRNA specific gene panel in tumor biopsies. The PK-PD modeling was performed using NONMEM® software. RESULTS: An indirect response PK-PD model linking sorafenib plasma exposure with soluble vascular endothelial growth factor receptor 2 (sVEGFR2) dynamics was developed. Progression-free survival (PFS) was described by a parametric time-to-event model. Higher decreases in sVEGFR2 at day 21 and higher baseline activation of MAPK pathway were associated with longer PFS (p = 0.002 and p = 0.007, respectively). The simulated schedule sorafenib 200 mg bid 5 days-on/2 days-off + continuous everolimus 5 mg qd was associated with median PFS of 4.3 months (95% CI 1.6-14.4), whereas the median PFS in the EVESOR trial was 3.6 months (95% CI 2.7-4.2, n = 43). CONCLUSION: Sorafenib 200 mg bid 5 days-on/2 days-off + everolimus 5 mg qd continuous was selected for an additional arm of EVESOR trial to evaluate whether this simulated schedule is associated with higher clinical benefit. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01932177.

Frequency of depression among oncology outpatients and association with other symptoms.

PURPOSE: Depression occurs among an estimated 15% of cancer patients (range, 1-77.5%). Our main objective was to identify the frequency of reported depression by using the Brief Edinburgh Depression Scale (BEDS) among cancer outpatients. Our secondary objective was to identify associated symptoms of cancer using the Edmonton Symptom Assessment System (ESAS) and to evaluate the screening performance of depression between ESAS and BEDS. METHODS: In this multicenter prospective study conducted, we used the ESAS to collect information on nine symptoms: pain, fatigue, nausea, depression, anxiety, drowsiness, shortness of breath, lack of appetite, and feeling of well-being (each rated from 0 to 10). The BEDS was used to assess for "probable depression" (score >6). Data were analyzed using a parametric and nonparametric test. RESULTS: A total of 146 patients completed the study. The prevalence of probable depression was 43/146 (29%). Probable depression was associated with increased fatigue (p = 0.008), depression (p < 0.0001), anxiety (p < 0.0001), shortness of breath (p = 0.01), and decreased feeling of well-being (p < 0.001). Among patients with probable depression, 42 (98%) patients were not using antidepressants. Regarding the sensitivity and the specificity, we determined that the optimal cutoff for using the ESAS as a depression screening tool was ≥ 2. CONCLUSION: We found significant associations between probable depression as determined with the BEDS and five symptoms as detected with the ESAS. The vast majority of patients with probable depression were not receiving pharmacological treatment. Depression should be suspected in patients with higher symptom distress as for any one of these 5 ESAS items.

Depression assessment by oncologists and palliative care physicians.

OBJECTIVE: Depression is a frequent problem in cancer patients, which is known to reduce quality of life; however, many cancer patients with depression are not treated because of the difficulties in assessing depression in this population. Our aim was to evaluate and improve the depression assessment strategies of palliative care (PC) physicians and oncologists. METHOD: We invited all medical oncologists and PC physicians from three cancer centers to participate in this multicenter prospective study. They were asked to classify 22 symptoms (related and specific to depression in cancer patients, related but not specific, and unrelated) as "very important," "important," "less important," or "not important" for the diagnosis of depression in cancer patients, at three different time points (at baseline, after a video education program, and after 4 weeks). They were also asked to complete a questionnaire exploring physicians' perceptions of depression and of their role in its systematic screening. RESULTS: All 34 eligible physicians participated. Baseline performance was good, with >70% of participants correctly classifying at least seven of nine related and specific symptoms. We found no significant improvement in scores in the immediate and 4-week follow-up tests. Additionally, 24 (83%) and 23 (79%) participants expressed support for systematic depression screening and a role for oncologists in screening, respectively. SIGNIFICANCE OF RESULTS: Oncologists had good baseline knowledge about depression's main symptoms in cancer patients and a positive attitude toward being involved in screening. Underdiagnosis of depression is probably related to problems associated with the oncology working environment rather than the physicians' knowledge.

Assessment of Patient Reported Outcomes (PROs) in Outpatients Taking Oral Anticancer Drugs Included in the Real-Life Oncoral Program.

Background In previous studies, patient-reported outcomes (PROs) have been shown to improve survival in cancer patients. The aim of the present study was to assess symptoms potentially related to adverse events experienced by cancer outpatients treated by oral anticancer agents (OAAs) using PROs. Methods Between September 2018 and May 2019, outpatients starting OAAs were included in a 12-week follow-up to assess 15 symptoms listed in the National Cancer Institute PRO Common Terminology Criteria for Adverse Events, using a 5-point scale of severity or frequency. Patients were requested to alert a referral nurse or pharmacist when they self-assessed high-level (level 3 or 4) symptoms. Results 407 questionnaires were completed by 63 patients in which 2333 symptoms were reported. Almost three-quarters (74.6%) reported at least one high-level symptom. The symptoms that were most commonly experienced were fatigue (>9 in 10 patients; 13.2% of symptoms declared), various psychological disorders (>9 in 10 patients; 28.6% of symptoms declared) and general pain (>8 in 10 patients; 9.4% of symptoms declared). Conclusion PROs are appropriate to detect potential adverse events in cancer outpatients treated by OAAs. This study is the first step for integrating the patient's perspective in a digital e-health device in routine oncology care.

Serum soluble CD26/DPP4 titer variation is a potential prognostic biomarker in cancer therapy with a humanized anti-CD26 antibody.

BACKGROUND: The phase I trial of the humanized anti-CD26 monoclonal antibody YS110 for CD26-expressing tumors was conducted recently. The present study identifies a potential prognostic biomarker for CD26-targeted therapy based on the phase I data. METHODS: Box and Whisker plot analysis, Scatter plot analysis, Peason product moment correlation/Spearman's rank-difference correlation, Bar graph analysis, and Receiver Operating Characteristics (ROC) were used to examine the correlation between sCD26 titer variation with YS110 administration and tumor volume change, RECIST criteria evaluation and progression free survival (PFS). Mechanism for serum sCD26 titer variation was confirmed by in vitro experimentation. RESULTS: Serum sCD26/DPP4 titer was reduced following YS110 administration and gradually recovered until the next infusion. Serum sCD26/DPP4 titer before the next infusion was sustained at lower levels in Stable Disease (SD) cases compared to Progressive Disease cases. ROC analysis defined the cut-off level of serum sCD26/DPP4 titer variation at day 29 pre/post for the clinical outcome of SD as tumor response or PFS. In vitro experimentation confirmed that YS110 addition reduced sCD26 production from CD26-expressing tumor and non-tumor cells. CONCLUSIONS: Our study indicates that serum sCD26/DPP4 titer variation in the early phase of YS110 treatment is a predictive biomarker for evaluating therapeutic efficacy.

Conditions for the Implementation of a Patient Education Program Dedicated to Cancer Patients Treated by Oral Anticancer Therapy.

INTRODUCTION: A patient education program has been developed in the field of cancer for supporting cancer patients undergoing oral anticancer therapies. Its implementation was tested in 3 different settings. The objectives of this study were to 1) identify barriers and facilitators for implementing the patient education program, 2) identify practices encouraging or hindering implementation and 3) produce recommendations for its dissemination. METHODS: Twenty semi-structured interviews were conducted with caregivers from all three establishments. RESULTS: The main factors associated with successful implementation were as follows: prescribers' representations on patient education, considered of low value; on oral anticancer therapies, considered too dangerous to be handled by the patient him/herself, the indefinite legitimacy of certain professions in charge of patient education programs; patients' engagement in their care pathway and provision of caregivers. CONCLUSION: Recommendations include developing patient education culture within the environment of the medical doctors' curriculum, to consider contextual, pre-existing cooperative units for implementing patient education, to systematically send patients to patient education programs without practicing triage. Successful implementation of patient education critically depends on the prescribing physicians' perceived value of patient education. Patient education should become mandatory, integrated as part of the cancer care pathway. Physicians lack the necessary time and/or means to assess patients' capacity for engagement, without adequate strategies for their support. Therefore, physicians should systematically refer all patients to patient education, where nurses can tailor their coaching of cancer patients. TRIAL REGISTRATION: The study protocol was approved by the IRB SUD EST I (N° EudraCT: 2016-A00113-48). All participants were given written and verbal information about the study and gave informed consent to participate.

Methotrexate for 2000 FIGO low-risk gestational trophoblastic neoplasia patients: efficacy and toxicity.

OBJECTIVE: We sought to review efficacy and toxicity of an 8-day methotrexate (MTX) regimen in the treatment of patients with low-risk gestational trophoblastic neoplasia (GTN) from the French Trophoblastic Disease Reference Center. STUDY DESIGN: Between 1999 and 2006, 142 low-risk GTNs were diagnosed according to International Federation of Gynecology and Obstetrics (FIGO) criteria for GTN and to the FIGO scoring system. We report their characteristics, remission/resistance/recurrence rates, and treatment toxicity. RESULTS: The 8-day MTX regimen achieved a 77.5% remission rate. All patients but 1 (99.9%) achieved remission and remained disease free until the time of analysis. Severe (grade 3 or 4) blood/bone marrow toxicity and metabolic/laboratory toxicity was noted in 4.2% of cases, of which 2 (1.4%) were grade 4. CONCLUSION: For patients with GTN diagnosed according to FIGO criteria and considered low risk according to the FIGO scoring system, an 8-day MTX regimen is an adequate treatment associating a high rate of remission to a low rate of toxicity.

Etoposide pharmacokinetics and survival in patients with small cell lung cancer: a multicentre study.

PURPOSE: To investigate the prognostic value of systemic exposure to etoposide (Area Under the concentration Curve (AUC(VP16))) on overall survival (OS) in patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: Data from 52 patients with limited stage (n=17) or metastatic (n=35) SCLC were analysed. They received at least two courses of etoposide (120mg/(m(2)day) on 3 days) combined with either doxorubicin-ifosfamide (AVI, n=29) or platinum compounds (carboplatin: n=16; cisplatin: n=7). Population pharmacokinetic-pharmacodynamic (PK-PD) study was performed using NON-linear Mixed Effect Model (NONMEM) and Splus software with univariate and multivariate analyses. RESULTS: Etoposide plasma concentration vs. time was described by a two compartment model. Etoposide clearance (CL) was significantly dependant on serum creatinine (Scr). Ifosfamide (IFO) coadministration increased etoposide clearance by 28% (median CL(VP16): 2.42L/h vs. 1.89L/h, p<0.0005) leading to a reduced systemic exposure (median AUC(VP16): 260mgh/L vs. 339mgh/L). No influence of body surface area (BSA) on CL(VP16) was observed. Median percent decrease of absolute neutrophil count (ANC) after the first chemotherapy course was greater when etoposide 24h concentration was above 0.33mg/L (88% vs. 0%, p=0.028). Median OS was significantly longer in patients treated without ifosfamide (11.0 months vs. 7.0 months, p=0.049) and in patients with CL(VP16)<2.22L/h (14 months vs. 7 months, p=0.013) and AUC(VP16)>254.8mgh/L (11 months vs. 7 months, p=0.048). The independent prognostic factors regarding OS were LDH, CL(VP16) and AUC(VP16). CONCLUSION: In this study it was found that CL(VP16) is reduced in patients with elevated serum creatinine, whilst ifosfamide coadministration increases CL(VP16) and reduces AUC(VP16), demonstrating the interaction between VP16 and ifosfamide. CL(VP16) and AUC(VP16) correlate significantly with overall survival of patients with SCLC patients receiving etoposide regimens.

Protein abundance of class III beta-tubulin but not Delta2-alpha-tubulin or tau is related to paclitaxel response in carcinomas of unknown primary site.

AIM: To determine the prognostic value of microtubule component expression in tumors of patients with carcinomas of unknown primary site (CUP). PATIENTS AND METHODS: Class III beta-tubulin, Delta2-alpha-tubulin and tau protein were examined immunohistochemically in 51 CUP tumors from patients receiving paclitaxel and compared with their response to treatment. RESULTS: The overall response rate was 18.4% among 49 evaluable patients. Delta2-alpha-Tubulin and tau were not correlated with response or patient outcome. High class III beta-tubulin expression was correlated with both resistance to chemotherapy and shorter overall survival, while there was no relation with progression-free survival. In multivariate analysis taking into account clinical factors, class III beta-tubulin expression was independently correlated with overall survival. CONCLUSION: These findings show that in tumor cells a high level of expression of class III beta-tubulin, but not Delta2-alpha-tubulin or tau, is associated with resistance to paclitaxel and a poor prognosis in CUP patients receiving paclitaxel.

Over-adherence to capecitabine: a potential safety issue in breast and colorectal cancer patients.

PURPOSE: The aim of the OCTO clinical study was to measure patients' adherence to capecitabine-based treatment. METHODS: A cohort of ambulatory patients treated with capecitabine monotherapy for either locally advanced or metastatic, breast or colorectal cancer was monitored for 6 cycles. Adherence was assessed in all patients by self-completed questionnaires on disease, pill-count and pharmacological dosage of FBAL (metabolite of capecitabine); and in half of the cohort by electronic medication event monitoring systems (MEMS™) recording the opening times of the device. RESULTS: Forty patients were enrolled between November 2008 and September 2011 and treated by capecitabine for an average of 4.75 cycles (range 1-6). Hand-foot syndrome (HFS) was the most frequently reported toxicity (35% patients), and to a lesser extent fatigue and/or asthenia (21%), nausea and/or vomiting (13%) and diarrhea (11%). In the MEMS™ cohort, 20 patients were included. Patients' adherence was excellent with very few missing occasions (23/2272 records). Close analysis of MEMS™ data revealed unexpected medication patterns, such as patients taking extra days of medication beyond planned cycle, patients taking extra doses per day and patients missing a day of dosing and "compensating" by taking extra the following day (N = 7, 18%). A trend was found between over-adherence and high-grade toxicity (grades 3 and/or 4): OR 4.74 [0.65-45.2], p = 0.13 and higher AUC (p = 0.16). There was a trend towards increased AUC of FBAL in over-adherent patients (p = 0.16). CONCLUSION: Adherence to oral anticancer chemotherapy was found excellent in this population suggesting over-adherence to capecitabine and potential safety implications for outpatients' drugs.

Oral vinorelbine: role in the management of metastatic breast cancer.

The treatment of advanced breast cancer is continually evolving, with the aim of improving the quality and duration of remission and, in some instances, survival. In this setting, the importance of quality of life cannot be underestimated, and growing attention is being paid to treatment convenience and compliance. New anticancer agents have improved efficacy, but for many of them, toxicity often remains a problem. Vinorelbine seems to represent both an active and a well tolerated treatment for metastatic breast cancer. In particular, the oral formulation has similar efficacy to that of the injectable formulation and has demonstrated generally favourable tolerability, with a high degree of acceptance by both patients and physicians. The availability of this and other novel, well tolerated and effective treatments provides greater potential to tailor treatment to meet individual patient needs and, therefore, also provide the potential to improve patient outcomes. Preliminary data suggest that oral vinorelbine may permit continued, effective chemotherapy when further parenteral therapy with more intensive and more toxic agents is considered inappropriate. Early findings also suggest that oral vinorelbine, when administered together with another new oral agent, capecitabine, may be a valid choice in metastatic breast cancer treatment. Furthermore, vinorelbine plus the monoclonal antibody trastuzumab, with or without oral capecitabine, appears to be another regimen that may be worthy of additional study in patients with human epidermal growth factor-2 positive advanced breast cancer.

First epidemiological data from the French Trophoblastic Disease Reference Center.

OBJECTIVE: The objective of the study was to describe women registered at the new French Trophoblastic Disease Reference Center and particularly the rates of gestational trophoblastic neoplasia (GTN) after molar pregnancies. STUDY DESIGN: Epidemiological data from a prospective cohort of women registered between November 1999 and November 2004 were analyzed. RESULTS: Four hundred forty-eight women were registered. The referent pathologist reclassified 32% and 5% of assumed partial mole (PM) and complete mole (CM), respectively. GTN developed in 30 of 212 patients with singleton CM (14%) and in 5 of 108 with singleton PM (5%). Among 131 patients with GTN (35 women followed up after registration for a mole and 96 registered for a GTN), 115 (88%) were low-risk and 16 (12%) were high-risk patients according to 2000 International Federation of Gynecology and Obstetrics (FIGO) scoring system. CONCLUSION: Creation of trophoblastic disease reference centers is desirable to improve treatment of patients. Our results will have to be compared with future publications based on the new 2000 FIGO oncology committee recommendations.

[Targeted therapies in oncology]. / Nouvelles thérapeutiques ciblées en oncologie.

The development of anticancer targeted therapies is the result of a knowledge transfer from biology research to clinical practice. Indeed these drugs act on proliferation signal pathways involved in oncogenesis. Monoclonal antibodies (antiHER1 or cetuximab, antiHER2 or trastuzimab, antiVEGF or bevacizumab...) or inhibitor proteins (antiHER1 or cetuximab, antityrosine kinase c-Kit or imatinib...) are used in the treatment of several cancers types (breast, colon-rectum, lung, kidney...) alone or in association with chemotherapies since they improve patients' prognosis and survival. However additional clinical studies are still required to optimize their administration.

[Evolution of reimbursement of high-cost anticancer drugs: Financial impact within a university hospital]. / Évolution du remboursement des anticancéreux inscrits sur la liste en sus : impact financier au sein d'un centre hospitalo-universitaire.

INTRODUCTION: In the context of health expenses control, reimbursement of high-cost medicines with a 'minor' or 'nonexistent' improvement in actual health benefit evaluated by the Haute Autorité de santé is revised by the decree of March 24, 2016 related to the procedure and terms of registration of high-cost pharmaceutical drugs. This study aims to set up the economic impact of this measure. METHOD: A six months retrospective study was conducted within a French university hospital from July 1, 2015 to December 31, 2015. For each injectable high-cost anticancer drug prescribed to a patient with cancer, the therapeutic indication, its status in relation to the marketing authorization and the associated improvement in actual health benefit were examined. The total costs of these treatments, the cost per type of indication and, in the case of marketing authorization indications, the cost per improvement in actual health benefit were evaluated considering that all drugs affected by the decree would be struck off. RESULTS: Over six months, 4416 high-cost injectable anticancer drugs were prescribed for a total cost of 4.2 million euros. The costs of drugs with a minor or nonexistent improvement in actual benefit and which comparator is not onerous amount 557,564 euros. DISCUSSION: The reform of modalities of inscription on the list of onerous drugs represents a significant additional cost for health institutions (1.1 million euros for our hospital) and raises the question of the accessibility to these treatments for cancer patients.

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.