A randomized trial to evaluate the effects of a supervised exercise program on insomnia in patients with non-metastatic breast cancer undergoing chemotherapy: design of the FATSOMCAN study.

BACKGROUND: Up to 70% of breast cancer patients report symptoms of insomnia during and after treatment. Despite the ubiquity of insomnia symptoms, they are under-screened, under-diagnosed and poorly managed in breast cancer patients. Sleep medications treat symptoms but are ineffective to cure insomnia. Other approaches such as cognitive behavioral therapy for insomnia, relaxation through yoga and mindfulness are often not available for patients and are complex to implement. An aerobic exercise program could be a promising treatment and a feasible option for insomnia management in breast cancer patients, but few studies have investigated the effects of such a program on insomnia. METHODS: This multicenter, randomized clinical trial evaluate the effectiveness of a moderate to high intensity physical activity program (45 min, 3 times per week), lasting 12 weeks, in minimizing insomnia, sleep disturbances, anxiety/depression, fatigue, and pain, and in enhancing cardiorespiratory fitness. Patients with breast cancer be recruited from six hospitals in France and randomly allocated to either the "training" or the "control" group. Baseline assessments include questionnaires [Insomnia Severity Index (ISI), Pittsburgh Sleep Quality Index questionnaire (PSQI), Hospital Anxiety Depression Scale (HADS), Epworth Sleepiness Scale (ESS)], home polysomnography (PSG), and 7-day actigraphy coupled with completion of a sleep diary. Assessments are repeated at the end of training program and at six-month follow-up. DISCUSSION: This clinical trial will provide additional evidence regarding the effectiveness of physical exercise in minimizing insomnia during and after chemotherapy. If shown to be effective, exercise intervention programs will be welcome addition to the standard program of care offered to patients with breast cancer receiving chemotherapy. TRIAL REGISTRATION: National Clinical Trials Number (NCT04867096).

Prognostic value of baseline seric Syndecan-1 in initially unresectable metastatic colorectal cancer patients: a simple biological score.

In first-line metastatic colorectal cancer (mCRC), baseline prognostic factors allowing death risk and treatment strategy stratification are lacking. Syndecan-1 (CD138) soluble form was never described as a prognostic biomarker in mCRC. We investigated its additional prognostic value for overall survival (OS). mCRC patients with unresectable disease at diagnosis were treated with bevacizumab-based chemotherapy in two independent prospective clinical trials (development set: n = 126, validation set: n = 51, study NCT00489697 and study NCT00544011, respectively). Serums were collected at baseline for CD138 measurement. OS determinants were assessed and, based on the final multivariate model, a prognostic score was proposed. Two independent OS prognostic factors were identified: Lactate Dehydrogenase (LDH) high level (p = 0.0066) and log-CD138 high level (p = 0.0190). The determination of CD138 binary information (cutoff: 75 ng/mL) allowed the assessment of a biological prognostic score with CD138 and LDH values, identifying three risk groups for death (median OS= 38.9, 30.1 and 19.8 months for the low, intermediate and high risk groups, respectively; p < 0.0001). This score had a good discrimination ability (C-index = 0.63). These results were externally confirmed in the validation set. Our study provides robust evidence in favor of the additional baseline soluble CD138 prognostic value for OS, in mCRC patients. A simple biological scoring system is proposed including LDH and CD138 binary status values.

In the era of genomics, should tumor size be reconsidered as a criterion for neoadjuvant chemotherapy?

BACKGROUND: The Oncotype DX recurrence score (RS) assay has been validated for prediction of 10-year risk of distant recurrence and likelihood of benefit from chemotherapy in patients with estrogen receptor (ER)-positive, HER2-negative early breast cancer. Patients with high RS tumors have substantial benefit, and patients with low RS tumors have minimal if any benefit from chemotherapy. Tumor size is used as a key parameter when selecting patients for neoadjuvant chemotherapy. The aim of this study was to assess the distribution of RS in patients selected for neoadjuvant chemotherapy primarily according to tumor size. PATIENTS AND METHODS: Patients with ER-positive and HER2-negative tumors that were node-negative or had no more than 1 positive node from three trials were included in this study. Oncotype DX was performed at Genomic Health, Inc., blinded to the clinical data. Descriptive statistics were calculated for distribution of RS for all cases. RESULTS: Of 277 patients, 96 met eligibility criteria, and 81 had sufficient material for analysis. Median tumor size was 40 mm (interquartile range [IQR], 30-50 mm). Grade I, II, and III were observed in 13, 49, and 17 cases, respectively. There was a wide distribution of RS with a median of 21.4 (IQR, 16.05-26.75). In total, 23 (28.3%) had high, 28 (34.6%) intermediate, and 30 (37%) low RS results. CONCLUSION: The RS may provide relevant information for neoadjuvant treatment decisions in select patients both in clinical practice and in studies. Inclusion of low RS disease patients in neoadjuvant trials will likely only dilute the ability to look at treatment effects.

Advanced biliary tract carcinomas: a retrospective multicenter analysis of first and second-line chemotherapy.

BACKGROUND: Gemcitabine/Cisplatin (Gem/CDDP) combination has demonstrated a clear survival advantage over gemcitabine alone and has become a new standard in advanced Biliary Tract Carcinoma (aBTC). However, Gemcitabine/Oxaliplatin (GEMOX) combination and Gemcitabine/Carboplatin (Gem/Carb) combination regimens have shown efficacy in phase II trials and there is no comparative study between different platinum salts.We assessed the efficacy and safety of different platinum-based chemotherapies at first line in aBTC patients. We also analysed the second-line chemotherapy. METHODS: Sixty-four consecutive patients with aBTC diagnosed between 1998 and 2010 were included for analysis. At first line chemotherapy, 44 patients received one day GEMOX regimen (gemcitabine 1000 mg/m2 and oxaliplatin 100 mg/m2 Day 1, every 2 weeks), and 20 patients received Gem/Carb regimen (gemcitabine at 1000 mg/m2 Days 1 and 8 with carboplatin delivered according to an area-under-the-curve (AUC) 5 at day 1, every 3 weeks). At second line, a total of 16 patients received a fluoropyrimidine-based chemotherapy. RESULTS: With GEMOX regimen, median progression-free survival (PFS) was 3.7 months (95%CI, 2.4 to 5) and median overall survival (OS) was 10.5 months (95%CI, 6.4 to14.7). The main toxicity was peripheral neuropathy (20% grade 2 and 7% grade 3). Grade 3/4 haematological toxicities were rare.With Gem/Carb regimen, PFS was 2.5 months (95%CI, 2.1 to 3.7) and OS was 4.8 months (95%CI, 3.7 to 5.8). The main grade 3/4 toxicities were haematological: anaemia (45%), thrombocytopenia (45%), and neutropenia (40%).At second-line, fluoropyrimidine-based chemotherapy was feasible in only a fourth of the patients. The median OS was 5.3 months (95%CI, 4.1 to 6.6), and median PFS was 4.0 months (95%CI, 2.6 to 5.5). CONCLUSIONS: One day GEMOX regimen has a favourable toxicity profile and could be an alternative to standard Gem/CDDP regimen, in particular in unfit patients for CDDP.At second-line, selective patients may benefit from fluoropyrimidine-based chemotherapy.

Prognostic Factors for Long-Term Eribulin Response in a Cohort of Patients With HER2-Negative Metastatic Breast Cancer.

CONTEXT AND AIMS: Eribulin is used in taxane and anthracycline refractory HER2-negative metastatic breast cancers (MBC). Patients treated in pivotal clinical trials achieved low survival rates, therefore, the identification of prognostic criteria for long progression-free survival (PFS) is still an unmet medical need. In this study, we sought to determine potential prognostic criteria for long-term eribulin response in HER2-negative MBC. METHODS: Our retrospective cohort includes female patients with HER2-negative MBC treated with eribulin in Franche-Comté, France. We defined a long-term response as at least 6 months of eribulin treatment. The primary endpoint was the analysis of criteria that differ according to the progression-free survival. Secondary outcomes concerned overall survival and response rate. RESULTS: From January 2011 to April 2020, 431 patients treated with eribulin were screened. Of them, 374 patients were included. Median PFS was 3.2 months (2.8-3.7). Eighty-eight patients (23.5%) had a long-term response to eribulin. Four discriminant criteria allowed to separate PFS in 2 arms (PFS < 3 months or > 6 months) with a 78% positive predictive value: histological grade, absence of meningeal metastasis, response to prior chemotherapy, and OMS status. We have developed a nomogram combining these 4 criteria. Median overall survival was 8.5 months (7.0-9.5). CONCLUSION: Eribulin response in MBC can be driven by clinical and biological factors. Application of our nomogram could assist in the prescription of eribulin.

Bifractionated CPT-11 with LV5FU2 infusion (FOLFIRI-3) in combination with bevacizumab: clinical outcomes in first-line metastatic colorectal cancers according to plasma angiopoietin-2 levels.

BACKGROUND: Optimization of chemotherapy effectiveness in metastatic colorectal cancers (mCRC) is a major endpoint to enhance the possibility of curative intent surgery. FOLFIRI3 has shown promising results as second-line chemotherapy for mCRC patients previously exposed to oxaliplatin. The clinical efficacy of FOLFIRI3 was never determined in association with bevacizumab in non-previously treated mCRC patients. METHODS: We conducted a phase II clinical trial to characterize the response rate and toxicity profile of FOLFIRI3-bevacizumab as initial treatment for mCRC. Sixty-one patients enrolled in 3 investigation centers were treated with FOLFIRI3-bevacizumab (median of 10 cycles) followed by a maintenance therapy combining bevacizumab and capecitabine. Levels of plasma angiopoietin-2 (Ang-2) were measured by enzyme-linked immunosorbent assay at baseline. RESULTS: Overall response rate (ORR) was 66.7% (8% of complete and 58% of partial responses). The disease control rate was 91.7%. After a median time of follow-up of 46.7 months, 56 patients (92%) had progressed or died. The median progression free survival (PFS) was 12.7 months (95% confidence interval (CI) 9.7-15.8 months). The median overall survival (OS) was 24.5 months (95% CI: 10.6-38.3 months). Twenty-one patients underwent curative intent-surgery including 4 patients with disease initially classified as unresectable. Most common grade III-IV toxicities were diarrhea (15%), neutropenia (13%), asthenia (10%), and infections (4%). Hypertension-related medications needed to be increased in 3 patients. In multivariate analysis, surgery of metastases and Ang-2 levels were the only independent prognostic factors for PFS and OS. Indeed, baseline level of Ang-2 above 5 ng/mL was confirmed as an independent prognostic factor for progression free survival (HR = 0.357; 95% CI: 0.168-0.76, p = 0.005) and overall survival (HR = 0.226; 95% CI: 0.098-0.53, p = 0.0002). CONCLUSIONS: As front-line therapy, FOLFIRI-3-bevacizumab is associated with an acceptable toxicity and induced promising objective response rates. However, unfavorable clinical outcomes were observed in patients with high levels of angiopoietin-2.

Specific anticancer treatments in the last 3 months of life: a French experience.

PURPOSE: The treatment of patients with advanced cancer is becoming increasingly aggressive near the end of life, whereas poor literature is available. This study analyzes the management of patients with a solid cancer in their last 3 months of life in the Centre Hospitalier Universitaire de Besançon, France. METHODS: This retrospective study includes all adult patients with a solid tumor who died in medical oncology or radiotherapy unit in 2005, 2006, and 2007. Group A had received at least one specific anticancer treatment at the end of life, while group B did not. RESULTS: Of 167 included patients, 139 (83.2 %) received a specific treatment during the last 3 months of life. The reference unit was medical oncology for 76 % and radiotherapy for 24 % patients; overall survival was 18 and 9 months, and median age of metastatic evolution was 59 and 71 in group A and B, respectively. The number of previous lines of chemotherapy was on average 1.96 and 0.39, respectively. In a univariate analysis, differences appear for reference unit, age of death, and number of previous lines of chemotherapy, with a trend for chemosensitivity of the tumor in this small-sized study. No significant difference was found for sex, life-threatening metastases, or performance status. CONCLUSION: These preliminary data suggest that when evaluating the utilization of care at the end of life, one needs to take into account factors such as the age of the patient and the chemosensitivity of the tumor.

Is extracapsular tumour spread a prognostic factor in patients with early breast cancer?

BACKGROUND: This study searched for extra capsular tumour spread (ECS) as a prognostic factor for recurrence in terms of Disease Free Survival (DFS) and Overall Survival (OS). PATIENTS AND METHODS: For this study, from a retrospective database of the Doubs cancer registry, 823 eligible women with node positive breast cancer treated from February 1984 to November 2000 were identified. The following factors were evaluated: ECS, numbers of involved nodes, histological tumour grade, tumour size, status of estrogen and progesterone receptors, and age of patient. A Cox proportional hazards method was used to search for significant factors related to OS and DFS length. RESULTS: In the multivariate analysis, factors related to DFS length were found to be: tumour grade (aHR 0.76, 95 % CI 0.61-0.96, p = 0.02), ECS status (aHR 0.7, 95 % CI 0.49-0.96, p = 0.03), progesterone (PgR) status (aHR 0.63, 95 % CI 0.44-0.85 p = 0.008), number of nodes involved (aHR 0.75, 95 % CI 0.56-1, p = 0.05). The multivariate analysis for OS found as significant factors: tumour grade (aHR 0.76, 95 % CI 0.61-0.95; p = 0.02) and PgR status (aHR 0.8, 95 % CI 0.56-0.99, p = 0.02). CONCLUSIONS: This study might suggest taking into account ECS status in the adjuvant decision-making process.

Cardiotoxicity is mitigated after a supervised exercise program in HER2-positive breast cancer undergoing adjuvant trastuzumab.

Background: Trastuzumab is used, alone or in conjunction with standard chemotherapy, to treat HER2-positive breast cancer (BC). Although it improves cancer outcomes, trastuzumab. can lead to cardiotoxicity. Physical exercise is a safe and effective supportive therapy in the management of side effects, but the cardioprotective effects of exercise are still unclear. Objectives: The primary aim of this study was to test whether trastuzumab-induced cardiotoxicity [left ventricular ejection fraction (LVEF) under 50%, or an absolute drop in LVEF of 10%] was reduced after a supervised exercise program of 3 months in patients with HER2-positive breast cancer. Secondary endpoints were to evaluate (i) cardiotoxicity rates using other criteria, (ii) cardiac parameters, (iii) cardiorespiratory fitness and (iv) whether a change in LVEF influences the cardiorespiratory fitness. Methods: 89 women were randomized to receive adjuvant trastuzumab in combination with a training program (training group: TG; n = 46) or trastuzumab alone (control group: CG; n = 43). The primary and secondary endpoints were evaluated at the end of the supervised exercise program of 3 months (T3). Results: After exercise program, 90.5 % of TG patients and 81.8% of CG patients did not exhibit cardiotoxicity. Furthermore, whatever the used criterion, percentage of patients without cardiotoxicity were greater in TG (97.6 and 100% respectively) than in CG (90.9 and 93.9% respectively). LVEF and GLS values remained stable in both groups without any difference between the groups. In contrast, at T3, peak VO2 (+2.6 mL.min-1.kg-1; 95%CI, 1.8 to 3.4) and maximal power (+21.3 W; 95%CI, 17.3 to 25.3) increased significantly in TG, whereas they were unchanged in CG (peak VO2: +0.2 mL.min-1.kg-1; 95%CI, -0.5 to 0.9 and maximal power: +0.7 W, 95%CI, -3.6 to 5.1) compared to values measured at T0. No correlation between LVEF changes and peak VO2 or maximal power was observed. Conclusion: A 12-week supervised exercise regimen was safe and improved the cardiopulmonary fitness in particular peak VO2, in HER2-positive BC patients treated with adjuvant trastuzumab therapy. The study is under powered to come to any conclusion regarding the effect on cardiotoxicity. Clinical trial registration: www.ClinicalTrials.gov, identifier: NCT02433067.

Low correlation between Ki67 assessed by qRT-PCR in Oncotype Dx score and Ki67 assessed by Immunohistochemistry.

Breast cancers expressing high levels of Ki67 are associated with poor outcomes. Oncotype DX test was designed for ER+/HER2- early-stage breast cancers to help adjuvant chemotherapy decision by providing a Recurrent Score (RS). RS measures the expression of 21 specific genes from tumor tissue, including Ki67. The primary aim of this study was to assess the agreement between Ki67RNA obtained with Oncotype DX RS and Ki67IHC. Other objectives were to analyze the association between the event free survival (EFS) and the expression level of Ki67RNA; and association between RS and Ki67RNA. Herein, we report a low agreement of 0.288 by Pearson correlation coefficient test between Ki67IHC and Ki67RNA in a cohort of 98 patients with early ER+/HER2- breast cancers. Moreover, Ki67RNAhigh tumors were significantly associated with the occurrence of events (p = 0.03). On the other hand, we did not find any association between Ki67IHC and EFS (p = 0.26). We observed a low agreement between expression level of Ki67RNA and Ki67 protein labelling by IHC. Unlike Ki67IHC and independently of the RS, Ki67RNA could have a prognostic value. It would be interesting to better assess the prognosis and predictive value of Ki67RNA measured by qRT-PCR. The Ki67RNA in medical routine could be a good support in countries where Oncotype DX is not accessible.

Duration: escalation study of oral etoposide with carboplatin in patients with varied solid tumors.

Prolonged fractionated oral administration of etoposide may present a theoretical advantage over intravenous administration of the bolus. This phase I trial was carried out to determine the recommended duration of oral etoposide in combination with a fixed dose of carboplatin. Nineteen patients with varied solid tumors, who were not candidates for standard chemotherapy, were administered an escalating duration (6, 9 or 12 consecutive days) of oral etoposide (a 25 mg capsule three times daily) combined with carboplatin AUC5 administered on day 1, by a 30 min intravenous infusion, to define the maximum tolerated dose on the basis of the acute toxicities that were reported. Etoposide was started on day 2; the cycles repeated every 28 days until disease progression or toxicity. Pharmacokinetics was carried out during the two first cycles. The maximum tolerated dose was determined to be the 12-day treatment level, with two cases of grade 4 neutropenia, grade 3 anemia and thrombocytopenia. As no severe toxicity occurred with the 9-day treatment level and in an attempt to explore an optimal combination, a new 10-day treatment plan was studied in three patients. As one patient presented dose-limiting toxicity at that level, five additional patients were included to establish the recommended regimen. Nonhematological toxicities among all patients were moderate, consisting of grade 2 nausea and asthenia. No treatment-related death occurred. Objective responses were observed in four patients and stabilization in three patients. Pharmacokinetics highlighted no interaction between etoposide and carboplatin. Fractionated oral etoposide (3×25 mg/day) for 10 days in combination with carboplatin AUC 5 presents acceptable toxicity and efficacy. The main toxicity remains hematological.

[Prevalence and management of pain in patients with metastatic cancer in Franche-Comté]. / Prévalence et prise en charge de la douleur chez les patients présentant un cancer métastatique en Franche-Comté.

INTRODUCTION: Pain management is a major public health problem, especially in oncology. In order to assess professional practice, the IRFC-FC conducted a survey amongst patients with metastatic osteophilic solid tumor in Franche-Comté. The aims were to assess the pain prevalence, and its characteristics, its management and its impact on patients' quality of life in patients in pain. METHODS: An observational, prospective and multicenter survey was conducted using a self-report questionnaire. Patients with metastatic breast or prostate cancer managed in 5 day-hospitals of the IRFC-FC over a period of three months were included. RESULTS: Two hundred thirty-three questionnaires were analyzed. Pain prevalence rate was 48.5%. Three quarters of patients in pain had chronic background pain, moderate to severe, with or without breakthrough pain. Considering their pain intensity and their analgesic therapy, 42.0% of patients seem to have an inadequate treatment. Eighty-five percent of treated patients reported to be compliant and felt that their pain was well managed despite a strong impact on their quality of life. CONCLUSION: The setting of a specific clinical pathway is essential to secure the standardized, optimal and efficient management of patients in pain. The assessment of patient satisfaction and quality of life must be integrated in clinical practice to identify patients in pain for which the treatment is inappropriate.

Carboplatin-etoposide combination chemotherapy in metastatic castration-resistant prostate cancer: A retrospective study.

The combination of cisplatin or carboplatin and etoposide is the standard treatment for certain poorly differentiated neuroendocrine cancers, such as small-cell lung cancer. The aim of this study was to assess the efficacy and tolerability of the carboplatin-etoposide regimen in metastatic castration-resistant prostate cancer (mCRPC). A total of 27 patients treated by carboplatin [area under the curve (AUC)=5] and etoposide (100 mg/m2 intravenous infusion on days 1-3 or 75 mg orally/day for 10 days) for mCRPC were included for analysis. The median progression-free survival was 3.3 months [95% confidence interval (CI): 1.9-4.2] and the median overall survival (OS) was 8.1 months (95% CI: 4.06-12.36). The main grade 3-4 toxicities were haematological, namely anemia (33.3%), neutropenia (25.9%) and thrombocytopenia (22.2%), whereas the most common non-hematological toxicity was asthenia (22.2%). The efficacy, compliance and safety profile were generally similar between the oral and intravenous etoposide groups. Pretreated patients with mCRPC may benefit from the carboplatin-etoposide regimen in terms of OS. The toxicities were acceptable, without reported treatment-related mortality. Therefore, the oral etoposide regimen may be an viable alternative for improving the quality of life of the patients. However, this regimen requires further prospective investigation to confirm its efficacy.

[Efficacy, safety and cost of eribulin in patients with metastatic breast cancer]. / Efficacité, tolérance et coût de l'éribuline chez des patientes présentant un cancer du sein métastatique.

Eribulin gained its approval in March 2011 for the treatment of patients with locally advanced or metastatic breast cancer (MBC) whose disease has progressed despite anthracycline and taxane-containing regimens. This study retrospectively assessed the efficacy, safety and cost of this treatment for all patients with MBC treated by eribulin in Franche-Comté. Ninety-four patients received eribulin between July 2006 and October 2013. The median age was 62 years (35-83). Median overall survival was 10.3 months [95% CI: 7.6 to 17.9]. Median progression-free-survival was 3.8 months [95% CI: 2.9 to 5.0]. Clinical benefit was obtained in 55% evaluable patients [95% CI: 43.1 to 66.9] by RECIST criteria. Most common grade 3-4 adverse events (AEs) were neutropenia (38%), asthenia (10%) and peripheral neuropathy (7%). Median cost of the treatment was 9767 € per patient (6344-17,517). This analysis found similar results to the EMBRACE study despite less selected population. A medico-economic evaluation cost-utility type would assess the effectiveness of this strategy compared to standard treatments.

Prognostic value of angiopoietin-2 for death risk stratification in patients with metastatic colorectal carcinoma.

BACKGROUND: Baseline prognostic biomarkers stratifying treatment strategies in first-line metastatic colorectal cancer (mCRC) are lacking. Angiopoietin-2 (Ang-2) is proposed as a potential biomarker in several cancers. We therefore decided to establish the additional prognostic value of Ang-2 for overall survival (OS) in patients with first-line mCRC. METHODS: We enrolled 177 patients treated with a bevacizumab containing chemotherapy in two prospective phase II clinical trials. Patient plasma samples were collected at baseline. ELISAs were used to measure Ang-2. RESULTS: The multivariable Cox model identified increased lactate dehydrogenase [HR, 1.60; 95% confidence interval (CI), 1.04-2.45; P = 0.03] and Ang-2 log-transformation level (HR, 1.59; 95% CI, 1.14-2.21; P = 0.0065) as two significant independent OS prognostic factors. It exhibited good calibration (P = 0.8) and discrimination (C-index: 0.64; 95% CI, 0.58-0.68). Ang-2 parameter inclusion in the GERCOR reference model significantly and strongly improved its discriminative ability because the C-statistic increased significantly from 0.61 to 0.63 (bootstrap mean difference = 0.07; 95% CI, 0.069-0.077). Interestingly, the addition of Ang-2 binary information with a 5 ng/mL cutoff value to the GERCOR model allowed the reclassification of intermediate-risk profile patients (41%) into two subsets of low and high risks. CONCLUSIONS: Our study provides robust evidence in favor of baseline Ang-2 prognostic value for OS adding to the conventional factors. Its assessment appears to be useful for the improvement in risk stratification for patients with intermediate-risk profile. IMPACT: Ang-2 ability to predict OS at diagnosis could be of interest in the selection of patients eligible for intermittent or sequential therapeutic strategies dedicated to the optimization of patients' quality of life and chemotherapy cost-effectiveness. Cancer Epidemiol Biomarkers Prev; 24(3); 603-12. ©2015 AACR.

Long-term follow-up of patients with metastatic breast cancer treated by trastuzumab: impact of institutions.

PURPOSE: Trastuzumab in Human Epidermal growth Receptor 2-positive (HER2+) metastatic breast cancer (MBC) was established as standard therapy since 2001. The objective of this study was to search for significant prognostic factors in patients with HER2+ MBC treated by trastuzumab taking into account the institution where the treatment was given. PATIENTS & METHODS: All patients with HER2+ MBC treated by trastuzumab between 2001 and 2010 in the 8 hospitals of Franche Comte region were analysed. Univariate and multivariate analysis were conducted to search for factors related to overall survival (OS). RESULTS: Among 1234 patients with MBC treated by chemotherapy between 2001 and 2010, 217 patients received trastuzumab. In this subset, the median age was 60 years, 8% and 38% had brain and liver metastases at first occurrence of MBC, 36% of, tumours were hormonal receptors positive. Patients were treated in 48% and 52% of cases in specialized and in general hospitals, respectively. The median OS length was 45.2 months (IQR 23.2-89.3 months). In univariate analysis the following factors were significantly related to favourable OS: inclusion in clinical trials, treatment in a specialized hospital, positive hormonal receptors status, age <50. In multivariate analysis remained significant: treatment in specialized hospital (aHR 0.78; 95%CI 0.64-0.94; p = 0.03) and age <50 (aHR 0.76; 95%CI 0.59-0.95; p = 0.02). CONCLUSION: Exposure to trastuzumab erases all established prognostic factors at the metastatic setting. The fact that patients treated in specialized hospitals presented a longer survival emphasizes the dramatic impact of this therapy and the relevance to optimize its use.

[Economic assessment of the routine use of Oncotype DX® assay for early breast cancer in Franche-Comte region]. / Évaluation économique de l'utilisation en routine du test Oncotype DX® dans la prise en charge des cancers du sein en Franche-Comté.

Oncotype DX® has been validated as quantifying the likelihood of distant recurrence at 10 years and overall chemotherapy benefit in patients with estrogen-receptor-positive and HER-2-negative early breast cancer. In 2012, this genomic signature was routinely available for patients in Franche-Comté, France. Patients eligible for Oncotype DX(®) testing had a ER-positive, HER-2-négative early breast cancer with a nodal involvement limited to 0 or 1 positive-node without extracapsular spread; an adjuvant chemotherapy was indicated based on usual prognostic factors. The aim was to assess the economic impact of Oncotype DX(®) testing in a French region. A cost-minimisation analysis from the French Public Healthcare System perspective was performed. The availability of Oncotype DX(®) in Franche-Comté, France, and its use in clinical routine allowed a decrease of 73 % of adjuvant chemotherapy without increase of the cost of the patients' management and with a potential reduction of the cost for the French Public Healthcare System. This strategy was successful and may allow the reimbursement of this test in France for patients with early breast cancer.

Safety and efficacy of cabazitaxel in the docetaxel-treated patients with hormone-refractory prostate cancer.

Prostate cancer (PC) is one of the most common cancers and is a leading cause of death. Its initial growth is dependent on androgens; most patients show an initial response to hormonal therapy but will experience disease progression when PC becomes resistant to castration. In 2004, two key randomized controlled trials demonstrated a benefit for docetaxel-based regimens in the treatment of men with castration-resistant prostate cancer (CRPC). Cabazitaxel (XRP6258, TXD258, and RPR116258A), a tubulin-binding taxane drug as potent as docetaxel in cell lines, was the first treatment able to prolong survival for metastatic CRPC in the post-docetaxel setting. This review describes pharmacologic parameters of this agent followed by a review of clinical trials involving cabazitaxel. Other available treatments and the place of cabazitaxel in metastatic CRPC setting are discussed.

Impact of STAT3 phosphorylation on the clinical effectiveness of anti-EGFR-based therapy in patients with metastatic colorectal cancer.

UNLABELLED: Half of patients with KRAS wild-type colorectal cancer do not benefit from adding anti-epithelial growth factor receptor (EGFR) to standard chemotherapy regimens. This retrospective study was performed in 94 patients with metastatic colorectal cancer (mCRC) treated in the second line with cetuximab and chemotherapy. Signal transducer and activator of transcription 3 (STAT3) phosphorylation in tumor cells was correlated with decreased median progression-free survival and overall survival (OS). These results highlight the potential role of STAT3 as a molecular target to optimize anti-EGFR therapies. BACKGROUND: Signal transducer and activator of transcription 3 (STAT3) is involved in epithelial growth factor receptor (EGFR) signaling in a KRAS-independent manner. Phosphorylated STAT3 (pSTAT3) expression in patients with metastatic colorectal cancer (mCRC) treated with anti-EGFR-containing salvage chemotherapy has never been investigated. PATIENTS AND METHODS: : The first endpoint of this retrospective study was to evaluate the impact of pSTAT3 on the time to progression (TTP) in 94 patients with mCRC treated with anti-EGFR-based therapies in the second- or third-line setting between July 2004 and November 2009. The influence of pSTAT3 on objective response rate and overall survival (OS) was also reported. Nuclear expression of pSTAT3 status was evaluated by immunohistochemical tests on formalin-fixed and paraffin-embedded tumor samples obtained before therapy. RESULTS: Positive expression of pSTAT3 was observed in 24.5% of the tumor samples. The probability of achieving an objective response was 13% among patients with positive nuclear expression of pSTAT3 compared with 41% for patients displaying pSTAT3-negative tumors (P = .02). In a multivariate logistic regression model, high-grade skin rash, wild-type KRAS status, and negative pSTAT3 status significantly improved TTP and OS. CONCLUSION: These results underscore an impact of pSTAT3 on the clinical efficacy of anti-EGFR-containing chemotherapy regimens and support the prospective assessment of this biomarker.

[KIT and KIT: from biology to clinical use]. / KIT et KIT : de la biologie à la clinique.

Scientific knowledge on gastrointestinal stromal tumors (GIST) has highly progressed over the last 10 years. The molecular bases of oncogenic transformation, KIT activating mutations, were identified in 1998 by Hirota et al. The product of KIT proto-oncogene, KIT protein, is a transmembrane receptor with tyrosine kinase activity. Tyrosine kinase inhibitors targeting these mutated activated kinases, namely imatinib and more recently sunitinib, nilotinib, masitinib or sorafenib, have deeply modified GIST prognosis. Molecular biology in GIST is now becoming a routine tool for treatment selection. In patients with advanced GIST, imatinib should be given until progression, and then, other tyrosine kinase inhibitors targeting KIT should be used. In the adjuvant setting, the optimal duration of imatinib treatment remains unknown.