Paclitaxel plus bevacizumab or paclitaxel as first-line treatment for HER2-negative metastatic breast cancer in a multicenter national observational study.

BACKGROUND: Bevacizumab combined with paclitaxel as first-line chemotherapy for patients with HER2-negative metastatic breast cancer (MBC) has led to mixed results in randomized trials, with an improvement in progression-free survival (PFS) but no statistically significant overall survival (OS) benefit. Real-life data could help in assessing the value of this combination. PATIENTS AND METHODS: This study aimed to describe the outcome following first-line paclitaxel with or without bevacizumab in the French Epidemiological Strategy and Medical Economics (ESME) database of MBC patients, established in 2014 by Unicancer. The primary and secondary end points were OS and PFS, respectively. RESULTS: From 2008 to 2013, 14 014 MBC patient files were identified, including 10 605 patients with a HER2-negative status. Of these, 3426 received paclitaxel and bevacizumab (2127) or paclitaxel (1299) as first-line chemotherapy. OS adjusted for major prognostic factors was significantly longer in the paclitaxel and bevacizumab group compared with paclitaxel [hazard ratio (HR) 0.672, 95% confidence interval (CI) 0.601-0.752; median survival time 27.7 versus 19.8 months]. Results were consistent in all supportive analyses (using a propensity score for adjustment and as a matching factor for nested case-control analyses) and sensitivity analyses. Similar results were observed for the adjusted PFS, favoring the combination (HR 0.739, 95% CI 0.672-0.813; 8.1 versus 6.4 months). CONCLUSIONS: In this large-scale, real-life setting, patients with HER2-negative MBC who received paclitaxel plus bevacizumab as first-line chemotherapy had a significantly better OS and PFS than those receiving paclitaxel. Despite robust methodology, real-life data are exposed to important potential biases, and therefore, results need to be treated with caution. Our data cannot therefore support extension of current use of bevacizumab in MBC.

De novo metastatic breast cancer in patients with a small locoregional tumour (T1-T2/N0): Characteristics and prognosis.

INTRODUCTION: The estimated rate of de novo metastatic breast cancer (dnMBC) at the time of diagnosis is between 5 to 12%. International guidelines recommend metastatic work-up (MWU) only in women with advanced breast cancer. The purpose of this study was to describe the characteristics and prognosis of patients with dnMBC diagnosed without an initial indication for MWU. METHODS: We conducted a retrospective, comparative study in dnMBC patients selected from the ESME-MBC cohort. Patients were treated in France between 2008 and 2016. We compared two populations: patients in whom dnMBC was diagnosed by staging although not indicated by guidelines (non-guideline staging [NGS]) and those in whom dnMBC was diagnosed by guideline staging (GS). RESULTS: During the study period, 22,463 patients with MBC were included in the ESME cohort. Among them, 6698 were dnMBC patients. In 247 of these patients (6% of dnMBC and 1% of the overall population), dnMBC was diagnosed by non-guideline staging. Women in this group were significantly younger (57 vs. 59 years, p = 0.02) and had fewer metastatic sites at diagnosis than dnMBC-GS patients. The two groups were not significantly different in terms of the other characteristics. Overall survival (OS) and progression-free survival (PFS) were better in the dnMBC-NGS group than in the dnMBC-GS group. The impact on survival was confirmed by univariate and multivariate analysis (HR 1.83 [1.31-2.57], p < 0.01). CONCLUSION: This study provides the first description of a very specific population. These patients with dnMBC-NGS were younger and more likely to have oligometastatic disease with a better prognosis.

Evolution of overall survival and receipt of new therapies by subtype among 20 446 metastatic breast cancer patients in the 2008-2017 ESME cohort.

BACKGROUND: Treatment strategies for metastatic breast cancer (MBC) have made great strides over the past 10 years. Real-world data allow us to evaluate the actual benefit of new treatments. ESME (Epidemio-Strategy-Medico-Economical)-MBC, a nationwide observational cohort (NCT03275311), gathers data of all consecutive MBC patients who initiated their treatment in 18 French Cancer Centres since 2008. PATIENTS AND METHODS: We evaluated overall survival (OS) in the whole cohort (N = 20 446) and among subtypes: hormone receptor positive, human epidermal growth factor 2 negative (HR+/HER2-; N = 13 590), HER2+ (N = 3919), and triple-negative breast cancer (TNBC; N = 2937). We performed multivariable analyses including year of MBC diagnosis as one of the covariates, to assess the potential OS improvement over time, and we described exposure to newly released drugs at any time during MBC history by year of diagnosis (YOD). RESULTS: The median follow-up of the whole cohort was 65.5 months (95% CI 64.6-66.7). Year of metastatic diagnosis appears as a strong independent prognostic factor for OS [Year 2016 HR 0.89 (95% CI 0.82-0.97); P = 0.009, using 2008 as reference]. This effect is driven by the HER2+ subcohort, where it is dramatic [Year 2016 HR 0.52 (95% CI 0.42-0.66); P < 0.001, using 2008 as reference]. YOD had, however, no sustained impact on OS among patients with TNBC [Year 2016 HR 0.93 (95% CI 0.77-1.11); P = 0.41, using 2008 as reference] nor among those with HR+/HER2- MBC [Year 2016 HR 1.02 (95% CI 0.91-1.13); P = 0.41, using 2008 as reference]. While exposure to newly released anti-HER2 therapies appeared very high (e.g. >70% of patients received pertuzumab from 2016 onwards), use of everolimus or eribulin was recorded in less than one-third of HR+/HER2- and TNBC cohorts, respectively, whatever YOD. CONCLUSION: OS has dramatically improved among HER2+ MBC patients, probably in association with the release of several major HER2-directed therapies, whose penetrance was high. This trend was not observed in the other subtypes, but the impact of CDK4/6 inhibitors cannot yet be assessed.

Endocrine therapy or chemotherapy as first-line therapy in hormone receptor-positive HER2-negative metastatic breast cancer patients.

BACKGROUND: For hormone receptor-positive (HR+) human epidermal growth factor receptor 2 (HER2-) negative metastatic breast cancer (MBC), international guidelines recommend endocrine therapy as first-line treatment, except in case of 'visceral crisis'. In the latter case, chemotherapy is preferred. Few studies have compared these two strategies. We used the Epidemiological Strategy and Medical Economics (ESME) programme, UNICANCER, a large national observational database (NCT03275311), to address this question. METHODS: All patients who initiated treatment for a newly diagnosed HR+ HER2-negative MBC between January 2008 and December 2014 in any of the 18 French Comprehensive Cancer Centers participating to ESME were selected. Patients should be aromatase inhibitor (AI)-sensitive (no previous AI or relapse occurring more than 1 year after last adjuvant AI). Objectives of the study were evaluation of progression-free and overall survival (OS) according to the type of first-line treatment adjusted on main prognostic factors using a propensity score. RESULTS: Six thousand two hundred sixty-five patients were selected: 2733 (43.6%) received endocrine therapy alone, while 3532 (56.4%) received chemotherapy as first-line therapy. Among the latter, 2073 (58.7%) received maintenance endocrine therapy. Median OS was 60.78 months (95% confidence interval [CI], 57.16-64.09) and 49.64 months (95% CI, 47.31-51.64; p < 0.0001) for patients receiving endocrine therapy alone and chemotherapy ± maintenance endocrine therapy, respectively. However, this difference was not significant after adjusting on the propensity score (hazard ratio: 0.943, 95% CI 0.863-1.030, p = 0.19). CONCLUSION: In this large retrospective cohort of patients with AI-sensitive metastatic luminal BC, OS was similar, whether first-line treatment was chemotherapy or endocrine therapy. In agreement with international guidelines, endocrine therapy should be the first choice for first-line systemic treatment for MBC in the absence of visceral crisis.

Sexual behavior changes and protease inhibitor therapy. SEROCO Study Group.

OBJECTIVE: To examine changes in sexual activity and unprotected sexual intercourse among HIV-infected patients before and after the initiation of protease inhibitor therapy. DESIGN: An analysis of data from the SEROCO Study, a French prospective cohort. METHODS: All 191 patients who initiated protease inhibitor therapy after 1 January 1996, who were interviewed within one year before the initiation of therapy (Time 1), and who had at least 6 months of follow-up after therapy initiation (Time 2) were included. Patients provided information about sex partner characteristics and unprotected sexual intercourse. RESULTS: Eighty-one (42%) were gay or bisexual men, 46 (24%) were heterosexual men, and 64 (34%) were women. No significant increases were found in either the number of patients reporting anal or vaginal sex or the number reporting unprotected sexual intercourse after protease inhibitor initiation. However, in matched pair analysis, gay or bisexual men were three times more likely to report having had unprotected sexual intercourse with partners who were of HIV-negative or unknown serostatus after protease inhibitor initiation [relative risk (RR) = 3.0, 95% confidence interval (CI) = 1.2-7.6]. Non-significant decreases in unprotected sexual intercourse among both heterosexual men and women were also observed. No relationship between plasma viral load after protease inhibitor initiation and unprotected sexual intercourse was found in these data. CONCLUSIONS: A relapse in sex risk practices among some HIV-infected gay or bisexual men cannot be ruled out and requires both continued monitoring and immediate secondary preventative intervention.

Cytomegalovirus seroconversion as a cofactor for progression to AIDS.

OBJECTIVE: To study the impact of cytomegalovirus (CMV) seroconversion on HIV-1 disease progression. DESIGN: Follow-up of CMV-seronegative subjects enrolled in the French SEROCO/HEMOCO cohorts of HIV-infected subjects. METHODS: A total of 290 subjects were CMV-seronegative at enrolment in the cohort. Serological testing for CMV infection was done at enrolment and then every 6 months in CMV-seronegative subjects. The person-years method was used to calculate the incidence of CMV seroconversion. After adjustment for age, the CD4+ cell count at enrolment and the HIV exposure group in a Cox model, we studied CMV seroconversion as a time-dependent variable in progression to a CD4+ cell count below 200 x 10(6) cells/l and to clinical AIDS. RESULTS: Overall, 61 CMV seroconversions were observed. The overall incidence rate was 4.4 per 100 person-years [95% confidence interval (CI), 3.3-5.5]. The risk of progression to a CD4+ cell count below 200 x 10(6) cells/l was not increased in CMV seroconverters. However, the risk of progression to AIDS was increased two-fold in CMV seroconverters compared with subjects who remained CMV-seronegative [relative risk (RR) = 2.09; 95% CI, 1.16-3.74; P = 0.01]. CONCLUSION: This analysis of 61 CMV seroconversions, the largest study in the literature, confirms the impact of recent CMV infection on progression to AIDS.

Predictive factors of response to first-line chemotherapy in 1426 women with metastatic breast cancer.

Since response to chemotherapy is a major determinant of survival in metastatic breast cancer, the purpose of our study was to analyse the predictive factors of response. 1426 patients enrolled into eight consecutive randomised trials of anthracycline-based first-line chemotherapy in metastatic breast cancer, between 1977 and 1992, were analysed. A forward stepwise logistic regression analysis was used. The objective response rate (ORR) to chemotherapy in the total population was 63.6% (95% confidence interval (CI): 61.5-67.7). The complete response rate was 17.5%. Multivariate analysis defined adjuvant chemotherapy, lactate dehydrogenase (LDH), Karnofsky index (KI), and pleural and lung metastases to be the five main variables correlated with ORR. A predictive score was calculated using the coefficient of these five variables, The score was established as follows: -1.32+0.54 (if prior adjuvant chemotherapy) +0.80 (low KI) +0.75 (raised LDH) +0.49 (lung metastases) +0.51 (pleural metastases). A low score (less than -0.78) was associated with an ORR greater than 70.0%, representing 41.2% of our population. An intermediate score (between -0.78 and 0) was associated with an ORR of 50 to 70%, representing 37.5% of our population and a positive score was associated with an ORR of less than 50%, representing 21.3% of our population. This score can be used to predict objective response rates to first-line anthracycline-based chemotherapy. This method now needs to be evaluated prospectively in phase II trials. Identification of various risk groups may also be useful for interpretation and design of clinical trials.

A multicentric study of 41 cases of B-prolymphocytic leukemia: two evolutive forms.

B-prolymphocytic leukemia (B-PLL) is an infrequent disease with a poor prognosis. We present the clinical and biological features of 41 patients. Median age was 67 years [42-89] and male-female sex ratio was 2.4. The immunophenotyping revealed B-cell phenotype, with a high level expression of surface IgM and/or IgD in all cases, FMC7+ in 76 % of cases and CD5+ in 67%. Marked spontaneous in-vitro apoptosis was observed in most cases tested (n = 12). The median overall survival time was 5 years and the event-free survival time was 37 months. As detected by univariate and multivariate analysis, the only variables associated with a poor prognosis were advanced age and anemia. No significant difference was observed between de novo PLL (n = 27) and prolymphocytoid transformation of chronic lymphocytic leukemia (n = 14). Two groups of patients were individualized according to their clinical course: patients who died within one year of diagnosis (n = 14) and patients who had a prolonged survival (n = 23) without any treatment in some cases. The comparison between the 2 groups showed that they differed in age (p = 0.01) and anemia (p = 0.02). We also observed that the patients with p53 mutations had a worse clinical outcome. Taken together these data confirm that B-PLL should be regarded as a distinct form of chronic lymphoproliferative disorder and suggest the existence of two patterns of clinical evolution.

[Reliability and validity of the French version of the first part of the Appropriateness Evaluation Protocol (AEPf): pertinent criteria of hospitalization stay]. / Reproductibilité et validité de la version française de la première partie de l'Appropriateness Evaluation Protocol (AEPf): critères de pertinence des journées d'hospitalisation.

BACKGROUND: The Appropriateness Evaluation Protocol (AEP) is a tool used to identify hospitalization days that are appropriate with respect to simple technical criteria, and the reasons for hospitalization days that do not meet these criteria. The goal of the study was to validate the clinical criteria of AEPf, required for identifying the reasons which explain these inappropriate hospital days. METHODS: The validity of a French version of criteria of appropriateness (AEPf) was assessed in a sample of 502 hospital days in medical and surgical wards of six French teaching hospitals. The reliability of the AEPf-based conclusions was studied by the measure of the concordance between two independent measures of AEPf for the same hospital day. Validity of AEPf was studied by the measure of the concordance between AEPf-based conclusions and the judgments of physicians using implicit criteria to assess the necessity of the hospital day studied. The degree of concordance was estimated by the Kappa coefficient. RESULTS: AEPf reproducibility was high (Kappa coefficient: 0.81; 95% confidence interval (95% CI): 0.76-0.87). Validity was also high (Kappa coefficient: 0.61; 95% CI: 0.53-0.68). CONCLUSION: The French version of the AEP was thus shown to be both reliable and valid to identify hospitalisation days appropriate with respect to hospital's technical equipment and specific resources. However, the reproducibility of the assessment of reasons for hospital days that did not meet AEP criteria will require a validation.

[Invasive group A streptococcal infections in France]. / Infections invasives A streptocoque du groupe A en France.

OBJECTIVES: Following the recent report of necrosing fasciitis cases in Great Britain, we conducted a study of group A streptococci infections in France to evaluate the frequency and severity of the different clinical presentations, particularly necrosing fasciitis. METHODS: Thirteen hospital laboratories were selected because of the large number of group A streptococci blood cultures they observed in 1993. The microbiologists in these hospitals, in relation with clinicians, identified 83 patients with a group A streptococci bacteraemia between January 1, 1993 and June 30, 1994. RESULTS: Sixty-three percent of the patients had an underlying condition: 39% had a chronic general or local disease and 24% had severe immunodepression. The skin portal of entry was found for 70% of the cases. Patients were divided into 4 groups according to the clinical picture: there were 16 cases of streptococci shock syndrome, 13 with deep infections, 25 infections of soft tissue (including 3 cases of fasciitis) and 29 cases of isolated bacteraemia. CONCLUSION: Overall, one-fourth of the patients died due to the streptococci infection, one-half of whom had a toxic shock syndrome. Mortality was correlated with age and health status, but also with the clinical presentation of the disease. Compared with former years, there was no increase in the number of group A streptococci infections, nor in the number of necrotizing fasciitis in France in 1993. However, streptococci shock syndrome is of particular importance because of its frequency and poor outcome.

[Prevalence and incidence of cytomegalovirus infection in patients infected with HIV-1. SEROCO group]. / Prévalence et incidence de l'infection par le cytomégalovirus chez les sujets infectés par le VIH-1. Le groupe SEROCO.

OBJECTIVES: To study prevalence of the cytomegalovirus (CMV) infection as well as incidence of the CMV seroconversions in HIV-infected subjects enrolled in the French multicentric cohort SEROCO. METHOD: Prevalence of CMV infection at inclusion in the cohort was estimated from 1504 HIV-infected subjects. Incidence of the CMV seroconversion was estimated from 184 subjects CMV seronegative at inclusion. Cox model was used to identify independent factors related to CMV seroconversion. RESULTS: CMV prevalence was high (87.2%) mainly in homosexual men. The incidence of the CMV seroconversions was also high (9, 18/100 person-years), particularly in homosexual men, in subjects declaring sexual intercourse with occasional partner, and in those declaring a sexually transmitted disease during the follow-up. CONCLUSION: The risk to develop serious disease related to CMV in subjects with AIDS being particularly high when the CMV primary infection occurs during the course of the HIV infection, the prevention of CMV primary infections is thus a major element in the counselling of HIV-infected subjects.

Is cytomegalovirus infection a co-factor in HIV-1 disease progression?

The influence of cytomegalovirus (CMV) infection as a co-factor in HIV-1 disease progression has mainly been studied in haemophiliacs and remains controversial. Based on the files of 1683 HIV-1-infected patients in the Seropositive Cohort (SEROCO) and Haemophiliacs Cohort (HEMOCO) cohorts, we studied the role of CMV infection in progression to CD4+ cell counts of less than 200 microl, AIDS onset and death, in various HIV exposure groups. Adjusted relative risk (aRR) of progression to AIDS and to death was respectively 1.30 (P = 0.05) and 1.58 (P = 0.007). In the sexual exposure group the influence of CMV infection on the risk of progression to AIDS was of borderline significance (aRR = 1.50; P = 0.07) and was more marked on the risk of death (aRR = 2.00; P = 0.03). No such influence of CMV infection was observed in the transfusion and intravenous drug use exposure groups. When we studied the influence of CMV infection according to the stage of HIV disease, the main effect was on progression from AIDS to death, probably because CMV disease is a late event. Sexual CMV transmission and frequent re-exposure to CMV may explain why CMV infection emerged as an important co-factor for HIV progression only in the sexual exposure group.

Sexual factors associated with cytomegalovirus seropositivity in human immunodeficiency virus-infected men. The Seroco Study Group.

BACKGROUND: Many people infected by human immunodeficiency virus (HIV) acquire severe cytomegalovirus (CMV) diseases. Factors associated with CMV seropositivity are poorly documented in sexually active HIV-infected men. GOAL: To study CMV seroprevalence in HIV-infected men according to sexual behavior before the diagnosis of HIV seropositivity. STUDY DESIGN: Cross-sectional study. CMV seroprevalence was studied at enrollment in a prospective cohort of homosexual and heterosexual men infected by HIV through sexual contact. RESULTS: In the study population (n = 723), age, sexual preference, previous lifetime history of sexually transmitted diseases, and multiple sexual partners were independently related to CMV seropositivity. Furthermore, routine condom use during the 6 months before diagnosis of HIV seropositivity was significantly related to CMV seropositivity (adjusted odds ratio [OR]: 0.4, 95% confidence interval [CI]: 0.1-1.0), occasional condom use being of borderline significance [adjusted OR: 0.5, CI: 0.2-1.3]. CONCLUSIONS: This study confirms the importance of sexual factors in the acquisition of CMV infection by HIV-infected men and suggests a protective effect of condom use.

Incidence and sexual risk factors of cytomegalovirus seroconversion in HIV-infected subjects. The SEROCO Study Group.

BACKGROUND: Data on incidence of cytomegalovirus (CMV) seroconversion in HIV-infected (HIV(+)) subjects was sparse. GOAL: To determine the incidence of CMV seroconversion in sexually active HIV(+) subjects and sexual factors associated with CMV seroconversion. STUDY DESIGN: One hundred eighty four persons not infected by CMV at enrollment in a cohort of HIV(+) persons were studied. A case-control study within the cohort was conducted to determine the effect of sexual behavior in the 6 months prior to CMV seroconversion. Thirty seven cases of CMV seroconversion were compared with 136 controls. RESULTS: The overall incidence of CMV seroconversion was 9.18 per 100 person-years (95% confidence interval (CI), 6.67-12.28) and was particularly high among homosexual men. After adjustment for age, socio-professional category, sexual orientation, and casual sex, the risk of CMV seroconversion was higher in subjects who never used condoms than in those who used them systematically (adjusted odds ratio (OR) 3.37;95% CI, 1.05-11.00). CONCLUSIONS: In addition to the need to protect their sexual partners from HIV infection, HIV(+) subjects free of CMV infection should use condoms to avoid CMV infection and its complications.

Response to chemotherapy is a major parameter-influencing long-term survival of metastatic breast cancer patients.

BACKGROUND: In cancer patients, correlation between response to chemotherapy and gain in survival remains debated. We addressed this question in a multivariate analysis evaluating response to chemotherapy as a factor influencing survival of patients with metastatic breast cancer. PATIENTS AND METHODS: From 1977 to 1992, 1430 patients included in eight consecutive prospective trials of anthracycline-based first-line chemotherapy in metastatic breast cancer, were available for assessment. Median follow-up was 155 months. RESULTS: Median survival from the date of randomisation was 24 months. Objective response rate was 63.6%. A complete response (CR) was achieved in 17% (249 patients). In a stepwise forward progression analysis objective response was the first independent prognostic factor for survival. Median survival time was 43 months for complete responders (CR), 29 months for partial responders (PR), 18 months for stable disease (SD), 5 months for progressive disease (PD). The probability of survival at 5 and 10 years was 35% and 15% for CR's and decreased to 18% and 6% for PR's. The timing of best response (at 4 or 8 months) was not related to outcome. CONCLUSIONS: Response to an anthracycline-based chemotherapy is a major independent prognostic factor in metastatic breast cancer. The use of this factor to investigate new drugs seems to be pertinent. The good prognosis of complete responders justifies further evaluation of new treatment strategies for this patient population.