Phase 1 trial of ralimetinib (LY2228820) with radiotherapy plus concomitant temozolomide in the treatment of newly diagnosed glioblastoma.

BACKGROUND AND PURPOSE: This phase 1 trial aimed to determine the maximum tolerated dose (MTD; primary objective) of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. MATERIALS AND METHODS: The study was designed as an open-label dose-escalation study driven by a Tite-CRM design and followed by an expansion cohort. Ralimetinib was administered orally every 12 h, 7 days a week, for 2 cycles of 2 weeks at a dose of 100, 200 or 300 mg/12 h. Patients received ralimetinib added to standard concurrent RT (60 Gy in 30 fractions) with TMZ (75 mg/m2/day) and 6 cycles of adjuvant TMZ (150-200 mg/m2 on days 1-5 every 28 days). RESULTS: The MTD of ralimetinib was 100 mg/12 h with chemoradiotherapy. The three patients treated at 200 mg/12 h presented a dose-limiting toxicity: one patient had a grade 3 face edema, and two patients had a grade 3 rash and grade 3 hepatic cytolysis (66%). Of the 18 enrolled patients, 15 received the MTD of ralimetinib. At the MTD, the grade ≥ 3 adverse events during concomitant chemoradiotherapy were hepatic cytolysis (2/15 patients), dermatitis/rash (1/15), lymphopenia (1/15) and nausea/vomiting (1/15). No interaction of TMZ and ralimetinib when administrated concomitantly has been observed. Inhibition of pMAPKAP-K2 (-54%) was observed in peripheral blood mononuclear cells. CONCLUSION: This phase 1 trial is the first trial to study the combination of a p38-MAPK inhibitor, ralimetinib, with radiotherapy (RT) and chemotherapy (TMZ), in the treatment of newly diagnosed glioblastoma (GBM) patients. The MTD of ralimetinib was 100 mg/12 h. The most frequent dose-limiting toxicities were hepatic cytolysis and rash.

[Tolerance of hypofractionated stereotactic radiotherapy for hepatic tumours]. / Tolérance de l'irradiation stéréotaxique hypofractionnée des tumeurs hépatiques.

PURPOSE: The purpose of the study was to evaluate the outcomes of stereotactic radiation therapy for primary and secondary liver tumours in Jean-Perrin cancer centre (Clermont-Ferrand, France) in terms of efficacy and safety. MATERIALS AND METHODS: Between December 2013 and June 2016, 25 patients were included. Treatment was performed on a linear accelerator Novalis TX®. The prescription dose was 42 to 60Gy in three to five fractions. Local control at 1 year was evaluated with modified Response Evaluation Criteria in Solid Tumours (mRECIST) and RECIST criteria. Acute and late toxicity were evaluated with Common Terminology Criteria for Adverse Events (CTCAE) v4.0 criteria. RESULTS: Median follow-up was 10.5 months. Treatment tolerance was good with few side effects grade 3 or above, no acute toxicity and only one late toxicity. We have highlighted that hepatic artery haemorrhage was associated with the presence of a biliary prosthesis in contact with the artery (P=0.006) and in the irradiation field. There was no correlation with the dose delivered to the artery and hepatic artery haemorrhage. CONCLUSION: Stereotactic radiation therapy for liver tumours allows a good local control with few secondary effects. Caution should be exercised when treating patients with biliary prostheses in the vicinity of the target volume because there is a risk of haemorrhage of the hepatic artery in contact with the prosthesis.

[Toxicity of docetaxel, platine, 5-fluorouracil-based induction chemotherapy for locally advanced head and neck cancer: The importance of nutritional status]. / Toxicité de la chimiothérapie d'induction par docétaxel, platine, 5-fluorouracile (TPF) pour les cancers des voies aérodigestives supérieures localement évolués en routine clinique : importance du statut nutritionnel.

PURPOSE: The objective of this study was to identify predictive factors of toxicity of docetaxel, platin, 5-fluorouracil (TPF) induction chemotherapy for locally advanced head and neck cancers. PATIENTS AND METHODS: From July 2009 to March 2015, 57 patients treated consecutively with TPF were included retrospectively. There were 47 males (83%), the median age was 56 years [40-71 years]. Thirty-eight patients (67%) were treated for inoperable cancer (highly symptomatic and/or high tumor burden) and 19 (33%) were treated for laryngeal preservation. There were 47% stage IVa, 32% stage III and 21% stage IVb. At diagnosis, there were 53% stable weight, 28% grade 1 weight loss, 17% grade 2 weight loss and 2% grade 3 weight loss. RESULTS: Forty-seven percent of patients were in partial response after TPF, 28% in complete response, 7% stable, 2% progressing and 2% discordant response. The possibility of oral feeding without a feeding tube was predictive of a better response (P=0.02). Thirty-nine percent of patients increased weight during TPF, 35% were stable, 18% in grade 1 weight loss, 6% in grade 2 and 2% in grade 3. Six of the patients (10.5%) died during chemotherapy: four from febrile neutropenia, one from pneumopathy and one of unknown cause. Age 57years and older was associated with a higher risk of grade≥3 anemia and thrombocytopenia. There was a higher risk of grade≥3 infection for weight loss at diagnosis (P=0.04) and feeding tube (P=0.05). There was a higher risk of grade≥3 neutropenia for weight loss during TPF (P=0.03). CONCLUSION: Induction chemotherapy by TPF has an strong anti-tumor efficacy (75.5% objective response) but an important morbidity with 10% toxic deaths in our very symptomatic population with a very important tumor burden. Age and nutritional status are important factors to consider.

[Description of the GORTEC 2017-03 study: Postoperative stereotactic radiotherapy for early stage oropharyngeal and oral cavity cancer with high risk margin (PHRC-K-16-164)]. / Présentation de l'étude Gortec 2017-03 : radiothérapie en conditions stéréotaxiques postopératoire des cancers localisés de l'oropharynx et de la cavité buccale avec marges à risque (PHRC-K-16-164).

The GORTEC 2017-03-Stereo-postop study is a phase 2, multicentric, nationwide study, funded by the hospital clinical research program (PHRC). The sponsor is Centre Jean-Perrin in Clermont-Ferrand, in partnership with the GORTEC. The principal investigators are Dr J Biau and Dr M Lapeyre. The main objective is to study severe late toxicity of postoperative stereotactic radiotherapy (6×6Gy) for early stage oropharyngeal and oral cavity cancer with high risk margins. The secondary objectives include acute toxicity, efficacy, nutritional impact and quality of life. The population is adult patients, with pT1 or pT2 squamous cell carcinoma of the oropharynx or oral cavity (except lips), without indication of neck irradiation or concomitant chemotherapy, with at risk margin (R1, less than 5mm or uncertain). Ninety patients will be included over a 2-year period; this was calculated to limit the rate of 2-year severe toxicity at 5 to 15%, with a 2-year local control of at least 80 to 90%. If this study is considered as positive, stereotactic radiotherapy (6×6Gy) could become the third therapeutic option, with brachytherapy and normofractionated intensity-modulated radiotherapy (IMRT), for postoperative irradiation of oropharyngeal and oral cavity cancer with high risk margins.

Quality of life after mastectomy with or without immediate breast reconstruction.

BACKGROUND: Mastectomy with immediate breast reconstruction (IBR) is a surgical strategy in breast cancer when breast-conserving surgery is not an option. There is a lack of evidence showing an advantage of mastectomy plus IBR over mastectomy alone on health-related quality of life (QoL). METHODS: A large prospective multicentre survey, STIC-RMI (support of innovative and expensive techniques - immediate breast reconstruction), was undertaken to study the changes in QoL in patients treated by mastectomy with or without IBR. Patients were recruited between 2007 and 2009. European Organisation for Research and Treatment of Cancer QLQ-C30 and QLQ-BR23 instruments were used to assess QoL before operation, and at 6 and 12 months after surgery. A propensity score was used to compare QoL between mastectomy alone and mastectomy plus IBR, with limited bias. RESULTS: A total of 595 patients were included from 22 French academic hospitals, of whom 407 (68·4 per cent) underwent IBR. One-year data were available for 71·1 per cent of patients. Factors associated with IBR were age, histological tumour type, palpable nodes and an attempt at breast-conserving surgery. At inclusion, QoL was significantly better in the IBR group (P < 0·001) and there was no significant change in either group during 1 year compared with baseline. Results for the QLQ-BR23 functional dimension varied according to propensity score quartiles; IBR had no influence in the lowest quartile. In the upper quartiles, QoL increased slightly over the year among patients who had IBR, whereas it decreased among those who had mastectomy alone (P = 0·037). Satisfaction with the cosmetic outcome strongly influenced QoL, especially in upper quartiles (P < 0·001). However, an unsatisfactory outcome after IBR was still considered a better condition than simple mastectomy. CONCLUSION: The QoL benefit provided by IBR depends on patients' life status at inclusion; young active women with an in situ tumour are more likely to preserve their QoL after IBR.

Prevalence of aortic valve dystrophy and insufficiency in a cohort of 255 HIV-positive patients followed-up in a cardiology department between 2012 and 2014.

OBJECTIVES: To study valve appearance and the presence of valve disease in a cohort of people living with HIV (PLHIV). DESIGN: A prospective study of PLHIV examined at the cardiology department of the Clermont Ferrand university hospital group (CHU) between January 1, 2012, and December 31, 2014. Were excluded those with a history of infection associated with a possible endocarditis. METHODS: Demographic, medical characteristics and cardiovascular disease risk factors at time of cardiovascular examination and Doppler-echocardiography were recorded and analyzed. RESULTS: In total, 903 PLHIV were examined in the infectious diseases department, 255 of whom were included. These consisted of 67 women (26.3%) and 188 men, of a mean age of 51.2±9.7years, in whom coronary artery disease was diagnosed in 18 patients (7.0%), two women and 16 men, representing a prevalence of 3.0% in females and 8.5% in males. The appearance of the aortic cusps was considered dystrophic in 14.1% of cases (36/255), dysplastic in two cases (0.8%), exhibiting a bicuspid deformity in one case. The prevalence of aortic valve abnormality was therefore 6.0% in the women (4/67) and 17.0% in the men (32/188). On facing off this data with the Kora Monica study findings, an increase in prevalence appears only to truly manifest after 50years of age. We registered 35 aortic insufficiency cases (13.7%), representing a higher incidence than that of the Framingham cohort, with age and masculine gender being the determining factors. CONCLUSION: Valve disease, along with coronary artery disease, should be closely monitored in PLHIV.

Multicentric neoadjuvant pilot Phase II study of cetuximab combined with docetaxel in operable triple negative breast cancer.

Systemic therapy for triple negative breast cancer (TNBC) is mostly based upon chemotherapy. Epithelial Growth Factor Receptor (EGFR) is overexpressed in around 50% of TNBC and may play a role in its pathogenesis. Consequently, we performed a multicentric pilot Phase II neoadjuvant trial of cetuximab (anti-EGFR antibody) combined with docetaxel for patients with operable, Stage II-III TNBC. Therapy consisted of weekly cetuximab (first infusion: 400 mg/m(2), then 250 mg/m(2)) combined with six cycles of docetaxel (T: 100 mg/m(2)) q.3 weeks. Subsequently, all patients underwent surgery. The primary endpoint was pathological complete response (pCR) while clinical response, toxicity and ancillary studies were secondary endpoints. Paraffin-embedded and frozen tumor samples were systematically collected in order to identify predictive biomarkers of efficacy and resistance. From a total of 35 accrued patients, 25 were assessable for pathologic response. The pCR rate was 24% [95% CI: 7.3-40.7]. Complete clinical response rate (cCR) was observed in 22% of cases. Conservative surgery was performed in 75% of patients. Toxicity, mostly cutaneous and hematologic, was manageable. The pre-therapy ratio between CD8+ and FOXP3+ tumor-infiltrating lymphocytes equal or higher than 2.75 was predictive of pCR: 43% versus 0%, p = 0.047. Cetuximab in combination with docetaxel displays a modest activity, but acceptable toxicity as neoadjuvant therapy of operable TNBC. Similarly to previous observations using panitumumab, another anti-EGFR antibody, the immune component of the tumor microenvironment may play an important role in predicting TNBC response to the neoadjuvant therapy.

Immunonutrition stimulates immune functions and antioxidant defense capacities of leukocytes in radiochemotherapy-treated head & neck and esophageal cancer patients: A double-blind randomized clinical trial.

BACKGROUND: Immunonutrition has been reported to improve the immune status of perioperative cancer patients, thereby reducing complications and length of hospital stay. AIM: This study aimed to assess whether immunonutrition enriched in arginine, EPA & DHA and nucleotides could impact the immune cells responses in head & neck and esophageal cancer patients treated by radiochemotherapy (RCT). METHODS: A double-blind clinical trial was carried out in 28 patients randomized into two groups, receiving either an immunomodulating enteral nutrition formula (IEN, n = 13, Impact(®), Nestlé) or an isoenergetic isonitrogenous standard enteral nutrition formula (SEN, n = 15) throughout RCT (5-7 weeks). After isolation from whole blood, immune cells metabolism and functions were assessed at the beginning (Db) and at the end (De) of RCT. RESULTS: Immunonutrition maintained CD4(+)/CD8(+) T-lymphocyte counts ratio and CD3 membrane expression between Db and De. Polymorphonuclear cells CD62L and CD15 densities and ROS production were increased in IEN patients. Peripheral blood mononuclear cells (PBMC) production of pro-inflammatory prostaglandin-E2 was stable in IEN patients and lower than in SEN patients at De. Genes coding for immune receptors, antioxidant enzymes and NADPH oxidase subunits were overexpressed in the PBMC of IEN vs SEN patients at De. CONCLUSION: Immunonutrition can enhance immune cell responses through the modulation of their phenotypes and functions. By modulating the gene expression of immune cells, immunonutrition could make it easier for the organism to adapt to the systemic inflammation and oxidative stress induced by RCT. CLINICAL TRIAL REGISTRATION: This clinical trial has been registered on ClinicalTrial.gov website: NCT00333099.

The role of tomosynthesis in breast cancer staging in 75 patients.

OBJECTIVES: Compare tomosynthesis to mammography, ultrasound, MRI, and histology for the detection and staging of BI-RADS 4-5 anomalies, as a function of breast composition, lesion location, size, and histology. PATIENTS AND METHODS: Seventy-five patients underwent mammography, tomosynthesis, ultrasound, and MRI. The diagnostic accuracy of the different examinations was compared. RESULTS: The sensitivities for detection were as follows: 92.5% with MRI, 79% for ultrasound, 75% for tomosynthesis, and 59.5% for mammography. Tomosynthesis improves the sensitivity of mammography (P=0.00013), but not the specificity. The detection of multifocality and multicentricity was improved, but not significantly. Tomosynthesis identified more lesions than mammography in 10% of cases and improved lesion staging irrespective of the density, but was still inferior to MRI. The detection of ductal neoplasia was superior with tomosynthesis than with mammography (P=0.016), but this was not the case with lobular cancer. The visualization of masses was improved with tomosynthesis (P=0.00012), but not microcalcifications. Tomosynthesis was capable of differentiating lesions of all sizes, but the smaller lesions were easier to see. Lesion sizes measured with tomosynthesis, excluding the spicules, concurred with histological dimensions. Spicules lead to an overestimation of the size. CONCLUSION: In our series, tomosynthesis found more lesions than mammography in 10% of patients, resulting in an adaption of the surgical plan.

Shear wave elastography contribution in ultrasound diagnosis management of breast lesions.

PURPOSE: To determine the diagnosis performance of shear wave elastography in the differentiation of benign and malignant breast lesions and the factors influencing the elasticity values. To suggest an appropriate management of breast lesions using the ultrasound-elastography combination. PATIENTS AND METHODS: Monocentric retrospective study of 167 breast lesions classified by conventional ultrasound as BI-RADS category 3 or higher that underwent an elastography study and histological analysis. RESULTS: The analysis of qualitative parameters, according to the classification established in this study, allows us to obtain a sensitivity of 91.1% and a specificity of 92.3%. These values are very close to or better than the quantitative parameters Emax and Emean. Different Emax thresholds values were established based on the long axis of the lesion and its palpable character, which appeared to be significant factors influencing elasticity. The management of breast lesions by combining ultrasound and elastography, as proposed here, allows us to keep the sensitivity of an ultrasound (96%), while doubling its specificity (86.2% versus 43.1%). CONCLUSION: With the complementary nature of their performance, the combination of conventional ultrasound and shear wave elastography can improve the management of breast lesions. The qualitative classification proposed appears to be relevant assistance in lesion characterization.

Adenocarcinoma of the pancreas: Does prognosis depend on mode of lymph node invasion?

BACKGROUND: Lymph node (LN) invasion in pancreatic ductal adenocarcinoma (PDAC) is the most important prognostic factor after surgical resection. The mechanisms of LN invasion include lymphatic spreading and/or direct extension from the main tumor. However, few studies have assessed the impact of these different patterns of invasion on prognosis. PATIENTS AND METHODS: Pathologic reports of pancreatic resections for PDAC from 1997 to 2007 were retrospectively analyzed. The mode of LN invasion was defined as follows: standard lymphatic metastases (S), contiguous from the main tumor (C) and standard with extracapsular invasion (EI). Clinical outcomes were compared according to the mode of invasion and the number of invaded LN. RESULTS: 306 patients were reviewed. Median age at resection was 61 years (range, 34-81). Eighty seven patients were N- (28.9%) and 214 were N+ (71.1%). Of the N+ patients, 195 (91.1%) were S+, 35 (16.3%) were C+, and 24 (12.3% of the S+ patients) were EI+. Median survival in N+ patients was lower than in N- patients (29 vs. 57 months, p < 0.001). In patients without standard involvement, C+ patients (n = 19) had worse survival than C- patients (n = 47) (34 vs. 57 months, p = 0.037). In S+ patients, C status was correlated with prognosis when the number of LN S+ was <2 (p = 0.07). EI status had no influence on prognosis. On multivariate analysis, only perineural invasion (p = 0.02) and LN ratio (p = 0.042) were independent prognostic factors. CONCLUSION: Direct invasion of LN by the tumor is predictive of reduced survival, but has little impact compared to standard LN involvement and perineural invasion.

Multicentric neoadjuvant phase II study of panitumumab combined with an anthracycline/taxane-based chemotherapy in operable triple-negative breast cancer: identification of biologically defined signatures predicting treatment impact.

BACKGROUND: Triple-negative breast cancer (TNBC) is a heterogeneous group of tumors for some of which the epithelial growth factor receptor (EGFR) pathway may play an important role. We investigated the efficacy and toxicity of an anti-EGFR antibody (panitumumab) combined with a standard neoadjuvant anthracycline-taxane-based chemotherapy in patients with operable, stage II-III, TNBC. PATIENTS AND METHODS: Treatment in this multicentric neoadjuvant pilot study consisted of panitumumab (9 mg/kg) for eight cycles q.3 weeks combined with four cycles of 5-fluorouracil, epidoxorubicin and cyclophosphamide (FEC100: 500/100/500 mg/m(2)) q.3 weeks, followed by four cycles of docetaxel (T: 100 mg/m(2)) q.3 weeks. Following therapy, all patients underwent surgical resection. Pathologic complete response (pCR) in assessable patients was the main end point while clinical response, toxicity and ancillary studies were secondary end points. Paraffin-embedded and frozen tumor samples were systematically collected with the aim to identify predictive biomarkers of efficacy and resistance in order to select biologically defined subpopulations for potential further clinical development of the anti-EGFR antibody. RESULTS: Sixty patients were included with 47 assessable for pathologic response. The pCR rates were 46.8% [95% confidence interval (CI): 32.5% to 61.1%] and 55.3% [95% CI: 41.1% to 69.5%] according, respectively, to Chevallier and Sataloff classifications. The complete clinical response (cCR) rate was 37.5%. Conservative surgery was carried out in 87% of cases. Toxicity was manageable. The association of high EGFR and low cytokeratin 8/18 expression in tumor cells on one hand and high density of CD8+ tumor-infiltrating lymphocytes on the other hand were significantly predictive of pCR. CONCLUSIONS: Panitumumab in combination with FEC100 followed by docetaxel appears efficacious, with acceptable toxicity, as neoadjuvant therapy of operable TNBC. Several biomarkers could help define large subsets of patients with a high probability of pCR, suggesting a potential interest to further develop this combination in biologically defined subgroups of patients with TNBC. CLINICAL TRIAL NUMBER: NCT00933517.

Immunonutrition improves functional capacities in head and neck and esophageal cancer patients undergoing radiochemotherapy: a randomized clinical trial.

BACKGROUND & AIMS: Malnutrition is frequent in head and neck (HN) and esophageal cancer patients and aggravated by radiochemotherapy (RCT), increasing morbi-mortality and treatment toxicity. Our goal was to investigate the effect of immunonutrition consisting of an arginine, omega-3 fatty acid, nucleotides-enriched diet on nutritional status, and functional capacity in HN or esophageal cancer patients undergoing RCT. METHODS: 37 patients were randomized in a double-blind clinical trial. 5 days before and until the end of RCT (5-7 weeks), they received either an Immunomodulating Enteral Nutrition (IEN) or an isonitrogenous, isoenergetic Standard Enteral Nutrition (SEN). Anthropometrical parameters, nutritional risk index (NRI), serum albumin, plasma antioxidant capacity, and functional capacity were recorded between the beginning and the end of RCT. RESULTS: A significant gain in total body weight (+2.1 ± 3.1 kg) was observed in IEN patients. Albuminemia and NRI were improved concomitantly in IEN malnourished patients. Plasma antioxidant capacity was improved (+100 ± 13 µM EqTrolox) in IEN patients. Functional capacity measured by WHO Performance Status and Karnofsky index was maintained in IEN patients but significantly reduced in SEN patients. CONCLUSIONS: These preliminary data show that immunonutrition could improve the nutritional status together with functional capacity in HN and esophageal cancer patients undergoing RCT. CLINICAL TRIAL REGISTRATION: This clinical trial promoted by the University Hospital Center of Clermont-Ferrand has been registered at ClinicalTrial.gov website under the following reference: NCT00333099.

Long term improved quality of life by a 2-week group physical and educational intervention shortly after breast cancer chemotherapy completion. Results of the 'Programme of Accompanying women after breast Cancer treatment completion in Thermal resorts' (PACThe) randomised clinical trial of 251 patients.

BACKGROUND: Quality of life (QoL) after breast cancer is nowadays a major challenge. Complementary interventions are necessary because of frequent depression symptoms after treatment and also to favour return to activity. Besides, radio-chemotherapy has side-effects like weight gain and fatigue. Several strategies including group behavioural-educational interventions, physical training and/or dietary education, have been tested to answer these difficulties with moderate success in the long run. METHODS: Two hundred and fifty-one non-metastatic patients were accrued after chemotherapy in a prospective randomised multicenter trial between 2008 and 2010, testing a 2-week intervention in SPA centres. Intervention comprised group physical training, dietary education and physiotherapy. Selected patients were in complete remission. QoL was evaluated with SF36 questionnaire, anxiety and depression with the hospital anxiety and depression (HAD) one. Anthropometric measures and QoL evaluations were obtained before randomisation and every 6 months during 3 years. RESULTS: Two hundred and twenty patients were evaluable at 1 year. Intervention increased SF36 score by 9.5 points (p=0.000006), 4.6 (p=0.032) and 6.2 (p=0.028) respectively at 6, 12 and 24 months. Effect size (ES) was 0.63 [0.37; 0.90], 0.29 [0.03; 0.55] and 0.41 [0.04; 0.78]. Anxiety score was shortly minored by intervention (6-month ES=-0.24 [-0.42; -0.05]) and depression score more durably: ES=-0.45 [-0.72; -0.18], -0.34 [-061; -0.08], and -0.26 [-0.63; 0.11] at 6, 12 and 24 months. CONCLUSION: This 2-week group intervention seemed to durably influence QoL of breast cancer patients treated by chemotherapy. Differences, smaller at 12 months than at six, suggest that a second but shorter intervention could help maintain the 6-month benefits.

Adherence with oral oncologic treatment in cancer patients: interest of an adherence score of all dosing errors.

PURPOSE: Patient nonadherence to oral antineoplastic therapy is a well-recognized barrier to effective treatment. In order to identify patients who may need additional support to become adherent, it is important to have a useful tool that takes into account all the parameters of adherence to prescription. The aim of this prospective study was to evaluate adherence of oral antineoplastic agents and to investigate two calculation methods of adherence score. PATIENTS AND METHODS: Twenty-nine cancer patients were enrolled in this study. Fourteen were treated by capecitabine and 15 patients by aromatase inhibitors. Adherence was measured using a medication event monitoring system and adherence score was calculated by a usual method and a composite adherence score that takes into account missed doses and also intake interval errors (between 2 doses and between meals). RESULTS: Across the 6-month evaluation period, average adherence was 95% with the standard calculation (capecitabine group: 89%; aromatase inhibitor group: 99%) versus 83% with the composite index (capecitabine group: 62%; aromatase inhibitor group: 99%) (p = 0.030). The composite calculation permits to highlight more nonadherent patients (29.6 vs. 7.4%), particularly in the capecitabine group (73 vs. 18%, p = 0.001). We report 2 cases identified as nonadherent with composite adherence rate. CONCLUSION: The composite adherence score permits to better evaluate adherence to prescription and to identify barriers to adherence and persistence.

[Analysis of gene expression data regulated by clock-genes: methodological approach and optimization]. / Analyse de données d'expression transcriptomiques rythmées par des gènes-horloge: approche méthodologique et optimisation.

BACKGROUND: In microarray data, wide-scale correlations are numerous and increase the number of genes correlated to a test condition (phenotype, mutation status, etc.) either positively or negatively. Several methods have been developed to limit the effect of such correlations on the false discovery rate, but these may reject too many genes that have a mild or indirect impact on the studied condition. We propose here a simple methodology to correct this spurious effect without eliminating weak but true correlations. RESULTS: This methodology was applied to a microarray dataset designed to distinguish heterozygous BRCA1 mutation carriers from non-carriers. As our samples were collected at different times in the morning, we evaluated the effect of correlations due to circadian rhythm. The circadian system is a well-known correlation network, regulated by a small number of period genes whose expression varies throughout the day in predictable ways. The downstream effects of this variation on the expression of other genes, however, are incompletely characterized. We used two different strategies to correct this correlation bias, by either dividing or multiplying the expression of correlated genes by the expression of the considered period gene according to the sign of the correlation between the period gene and correlated gene (respectively positive or negative). CONCLUSIONS: We observed a linear relationship between the number of false-positive/negative genes and the strength of the correlation of the candidate gene to the test condition. BRCA1 was highly correlated to the period gene Per1; our correction methodology enabled us to recover genes coding for BRCA1-interacting proteins which were not selected in the initial direct analysis. This methodology may be valuable for other studies and can be applied very easily in case of well-known correlation networks.

Prognostic value of initial tumor parameters after metastatic relapse.

Classical prognostic factors of breast cancer are correlated to disease-free survival and overall survival (OS); their precise role is less known on metastatic disease. A total of 511 breast cancer patients without initial metastasis were treated. OS was divided in time to distant recurrence and metastatic survival (MS). Age, Scarff-Bloom-Richardson (SBR) grade, hormone receptor, axillary node involvement, and Nottingham prognostic index predicted MS in univariate analysis. Multivariate analysis retained age, SBR grade, and axillary lymph node involvement as significant independent prognostic factors. Interactions are still present between initial parameters and MS. The clinician has to take into account for treatment choice.

Late lines of treatment benefit survival in metastatic breast cancer in current practice?

Metastatic breast cancer is mostly incurable. Progressively overall survival (OS) has improved but few authors have studied treatment globally versus for each line and demonstrated the interest of chemotherapy (CT) after the third line. We selected recent patients treated during the "taxane/anti-aromatase era" for each line given. 529 received CT and 383 hormonotherapy. OS was assessed; from the date of first metastasis and from Day 1 of each CT line. Median OS was 34.1 months; 226 patients received >3 lines of CT with a steady median OS for late lines, 11.4 months per line (range 10.4-12.6). Clinical benefit after the third line of CT was obtained for 29.2-36.6% of patients. CT lasted 11.7 months "on"versus 20.6 months "off" CT. These results may support the use of more than 3 CT lines; each line can contribute to a longer survival.