LAPATAX: A randomized phase II trial of FEC-docetaxel combined with lapatinib and/or trastuzumab as neoadjuvant therapy of HER2- positive breast cancer-EORTC 10054 trial.

Background: Patients with HER2 +ve breast cancer suitable for neoadjuvant chemotherapy (NAC) have been shown in a series of clinical trials to have the best outcome when treated with anthracyclines (A), taxanes (T), and trastuzumab (Tz). Recent evidence confirms that adjuvant Tz is more effective when given concomitantly rather than sequentially with T (Perez SABCS 2009). Whilst there remains uncertainty as to the most efficacious A-T regimen and duration of Tz, there is widespread use in Europe of FEC-D [3 cycles of 5-FU 500 mg/m2, epirubicin 100 mg/m2 and cyclophosphamide 500 mg/m2 (FEC100) followed by 3 cycles of docetaxel 100 mg/m2 (D) q3w] following the results of PACS-01. The advent of TKI anti-HER2 agents such as L could offer superior outcomes if combined with NAC. However, a phase I study in heavily pre-treated advanced breast cancer reported difficulties in combining lapatinib (L) with D 100 mg/m2 (LoRusso JCO 2008). Methods: EORTC 10054 is designed as a two-part study to compare FEC-D with either Tz, L or their combination as NAC for patients with HER2 +ve large operable or locally advanced breast cancer. Before and on-treatment frozen tumor and blood samples will be taken to better define which tumours are particularly sensitive to either Tz and/or L. Stage 1: (complete) a dose- finding study has confirmed that with primary prophylactic G-CSF, D 100 mg/m2 can be safely and effectively given with L 1,250 mg daily continuously. The dose-limiting toxicity was myelosuppression, and there was no significant diarrhoea or cardiac toxicity (ESMO 2009 abstr P- 5073). Stage 2: (opening Q1 2010) will enroll 150 patients from European centres into a 3-arm randomized trial whose primary endpoint is pathological complete response. All patients will receive FEC-D before primary surgery: 3 cycles of FEC (without anti-HER2 therapy) followed by 3 cycles of D plus either Tz (conventional weekly schedule), monotherapy L, or the combination of Tz and L, using doses based on the EGF100161 dose-finding study in 1st line metastatic therapy of D+L+Tz. After surgery all patients will receive standard 3-weekly Tz, radiotherapy and endocrine therapy as per local guidelines.

Cancer du sein : la pathologie, pierre angulaire de la décision therapeutique [Breast cancer: pathology, the cornerstone of therapeutic decision]

Tailoring adjuvant therapy in breast cancer patients relies on prognostic and predictive factors, most of which are currently established by histopathological analysis of tumors. The quality of the assessment of the former (i.e.: tumor size, lymph node status, tumor grade, HER2 status, and lymphovascular invasion) and the latter (estrogen and progesteron receptors expression, HER2 overexpression or amplification) is an essential prerequisite for an optimal therapeutic decision. If the prognostic and predictive values of multigenes signatures are confirmed by on-going clinical studies, this approach could enter the clinical practice in the coming years and result in improved accuracy of adjuvant therapies in breast cancer patients. This approach might especially allow avoiding overtreatment in patients at low risk of recurrence.

Risk of prostate, breast and colorectal cancer after skin cancer diagnosis.

Ultraviolet radiation is the major cause of skin cancer, but promotes vitamin D synthesis, and vitamin D has been inversely related to the risk of several common cancers including prostate, breast and colorectum. We therefore computed the incidence of prostate, breast and colorectal cancer following skin cancer using the datasets of the Swiss cancer Registries of Vaud and Neuchâtel. Between 1974 and 2005, 6,985 histologically confirmed squamous cell skin cancers, 21,046 basal cell carcinomas and 3,346 cutaneous malignant melanomas were registered, and followed up to the end of 2005 for the occurrence of second primary cancer of the prostate, breast and colorectum. Overall, 680 prostate cancers were observed versus 568.3 expected (standardized incidence ratio (SIR) = 1.20; 95% confidence interval (CI): 1.11-1.29), 440 breast cancers were observed versus 371.5 expected (SIR = 1.18; 95% CI: 1.08-1.30) and 535 colorectal cancers were observed versus 464.6 expected (SIR = 1.15; 95% CI: 1.06-1.25). When basal cell, squamous cell and skin melanoma were considered separately, all the SIRs for prostate, breast and colorectal cancers were around or slightly above unity. Likewise, the results were consistent across strata of age at skin cancer diagnosis and location (head and neck versus others), and for male and female colorectal cancers. These findings, based on a population with a long tradition of systematic histologic examination of all surgically treated skin lesions, do not support the hypothesis that prostate, breast and colorectal cancer risk is decreased following skin cancer.

Prediction of functional outcome 18 months after a first psychotic episode: a proton magnetic resonance spectroscopy study.

CONTEXT: Recent magnetic resonance imaging studies have attempted to relate volumetric brain measurements in early schizophrenia to clinical and functional outcome some years later. These studies have generally been negative, perhaps because gray and white matter volumes inaccurately assess the underlying dysfunction that might be predictive of outcome. OBJECTIVE: To investigate the predictive value of frontal and temporal spectroscopy measures for outcome in patients with first-episode psychoses. DESIGN: Left prefrontal cortex and left mediotemporal lobe voxels were assessed using proton magnetic resonance spectroscopy to provide the ratio of N-acetylaspartate (NAA) and choline-containing compounds to creatine and phosphocreatine (Cr) (NAA/Cr ratio). These data were used to predict outcome at 18 months after admission, as assessed by a systematic medical record audit. SETTING: Early psychosis clinic. PARTICIPANTS: Forty-six patients with first-episode psychosis. MAIN OUTCOME MEASURES: We used regression models that included age at imaging and duration of untreated psychosis to predict outcome scores on the Global Assessment of Functioning Scale, Clinical Global Impression scales, and Social and Occupational Functional Assessment Scale, as well as the number of admissions during the treatment period. We then further considered the contributions of premorbid function and baseline level of negative symptoms. RESULTS: The only spectroscopic predictor of outcome was the NAA/Cr ratio in the prefrontal cortex. Low scores on this variable were related to poorer outcome on all measures. In addition, the frontal NAA/Cr ratio explained 17% to 30% of the variance in outcome. CONCLUSIONS: Prefrontal neuronal dysfunction is an inconsistent feature of early psychosis; rather, it is an early marker of poor prognosis across the first years of illness. The extent to which this can be used to guide treatment and whether it predicts outcome some years after first presentation are questions for further research.

Profiling of counterfeit medicines by vibrational spectroscopy

Counterfeit pharmaceutical products have become a widespread problem in the last decade. Various analytical techniques have been applied to discriminate between genuine and counterfeit products. Among these, Near-infrared (NIR) and Raman spectroscopy provided promising results.The present study offers a methodology allowing to provide more valuable information fororganisations engaged in the fight against counterfeiting of medicines.A database was established by analyzing counterfeits of a particular pharmaceutical product using Near-infrared (NIR) and Raman spectroscopy. Unsupervised chemometric techniques (i.e. principal component analysis - PCA and hierarchical cluster analysis - HCA) were implemented to identify the classes within the datasets. Gas Chromatography coupled to Mass Spectrometry (GC-MS) and Fourier Transform Infrared Spectroscopy (FT-IR) were used to determine the number of different chemical profiles within the counterfeits. A comparison with the classes established by NIR and Raman spectroscopy allowed to evaluate the discriminating power provided by these techniques. Supervised classifiers (i.e. k-Nearest Neighbors, Partial Least Squares Discriminant Analysis, Probabilistic Neural Networks and Counterpropagation Artificial Neural Networks) were applied on the acquired NIR and Raman spectra and the results were compared to the ones provided by the unsupervised classifiers.The retained strategy for routine applications, founded on the classes identified by NIR and Raman spectroscopy, uses a classification algorithm based on distance measures and Receiver Operating Characteristics (ROC) curves. The model is able to compare the spectrum of a new counterfeit with that of previously analyzed products and to determine if a new specimen belongs to one of the existing classes, consequently allowing to establish a link with other counterfeits of the database.

A double-quadrature radiofrequency coil design for proton-decoupled carbon-13 magnetic resonance spectroscopy in humans at 7T

Purpose Carbon-13 magnetic resonance spectroscopy (13C-MRS) is challenging because of the inherent low sensitivity of 13C detection and the need for radiofrequency transmission at the 1H frequency while receiving the 13C signal, the latter requiring electrical decoupling of the 13C and 1H radiofrequency channels. In this study, we added traps to the 13C coil to construct a quadrature-13C/quadrature-1H surface coil, with sufficient isolation between channels to allow simultaneous operation at both frequencies without compromise in coil performance. Methods Isolation between channels was evaluated on the bench by measuring all coupling parameters. The quadrature mode of the quadrature-13C coil was assessed using in vitro 23Na gradient echo images. The signal-to-noise ratio (SNR) was measured on the glycogen and glucose resonances by 13C-MRS in vitro, compared with that obtained with a linear-13C/quadrature-1H coil, and validated by 13C-MRS in vivo in the human calf at 7T. Results Isolation between channels was better than â^'30 dB. The 23Na gradient echo images indicate a region where the field is strongly circularly polarized. The quadrature coil provided an SNR enhancement over a linear coil of 1.4, in vitro and in vivo. Conclusion It is feasible to construct a double-quadrature 13C-1H surface coil for proton decoupled sensitivity enhanced 13C-NMR spectroscopy in humans at 7T. Magn Reson Med, 2014. © 2014 Wiley Periodicals, Inc.

p27 and Skp2 immunoreactivity and its clinical significance with endocrine and chemo-endocrine treatments in node-negative early breast cancer.

BACKGROUND: Low p27 and high Skp2 immunoreactivity are associated with a poor prognosis and other poor prognostic features including resistant phenotypes and antiestrogen drug resistance. We investigated these proteins in two International Breast Cancer Study Group trials studying node-negative early breast cancer. PATIENTS AND METHODS: Trial VIII compared chemotherapy followed by goserelin with either modality alone in premenopausal patients. Trial IX compared chemotherapy followed by tamoxifen with tamoxifen alone in postmenopausal patients. Central Pathology Office assessed p27 and Skp2 expression in the primary tumor by immunohistochemistry among 1631 (60%) trial patients. RESULTS: p27 and Skp2 were inversely related; 13% of tumors expressed low p27 and high Skp2. Low p27 and high Skp2 were associated with unfavorable prognostic factors including larger size and higher grade tumors, absence of estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2 overexpression and high Ki-67 (each P < 0.05). Low p27 and high Skp2 were not associated with disease-free survival (P = 0.42 and P = 0.48, respectively). The relative effects of chemo-endocrine versus endocrine therapy were similar regardless of p27 or Skp2. CONCLUSIONS: We confirm the association of low p27 and high Skp2 with other poor prognostic features, but found no predictive or prognostic value, and therefore do not recommend routine determination of p27 and Skp2 for node-negative breast cancer.

Human chorionic gonadotropin in pregnancy and maternal risk of breast cancer.

Full-term pregnancies are associated with long-term reductions in maternal risk of breast cancer, but the biological determinants of the protection are unknown. Experimental observations suggest that human chorionic gonadotropin (hCG), a major hormone of pregnancy, could play a role in this association. A case-control study (242 cases and 450 controls) nested within the Northern Sweden Maternity Cohort included women who had donated a blood sample during the first trimester of a first full-term pregnancy. Total hCG was determined on Immulite 2000 analyzer. Odds ratios (OR) and 95% confidence intervals (CI) were estimated through conditional logistic regression. Maternal breast cancer risk decreased with increasing hCG (upper tertile OR, 0.67; CI, 0.46-0.99), especially for pregnancies before age 25 (upper tertile OR, 0.41; CI, 0.21-0.80). The association diverged according to age at diagnosis: risk was reduced after age 40 (upper tertile OR, 0.60; CI, 0.39-0.91) and seemed to increase before age 40 (upper tertile OR, 1.78; CI, 0.72-4.38). Risk was reduced among those diagnosed 10 years or longer after blood draw (upper tertile OR, 0.60; CI, 0.40-0.90), but not so among those diagnosed within 10 years (upper tertile OR, 4.33; CI, 0.86-21.7). These observations suggest that the association between pregnancy hCG and subsequent maternal risk of breast cancer is modified by age at diagnosis. Although the hormone seems to be a determinant of the reduced risk around or after age 50, it might not confer protection against, or it could even increase the risk of, cancers diagnosed in the years immediately following pregnancy.

Free β-human chorionic gonadotropin, total human chorionic gonadotropin and maternal risk of breast cancer.

BACKGROUND: We investigated whether the free β-human chorionic gonadotropin (free β-hCG) would provide additional information to that provided by total hCG alone and thus be useful in future epidemiological studies relating hCG to maternal breast cancer risk. MATERIALS & METHODS: Cases (n = 159) and controls (n = 286) were a subset of our previous study within the Northern Sweden Maternity Cohort on total hCG during primiparous pregnancy and breast cancer risk. RESULTS: The associations between total hCG (hazard ratio: 0.79; 95% CI: 0.49-1.27), free β-hCG (hazard ratio: 0.85; 95% CI: 0.33-2.18) and maternal risk of breast cancer were very similar in all analyses and mutual adjustment for either one had minor effects on the risk estimates. CONCLUSION: In the absence of a reliable assay on intact hCG, total hCG alone can be used in epidemiological studies investigating hCG and breast cancer risk, as free β-hCG does not appear to provide any additional information.

Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series.

PURPOSE: Recently, a 76-gene prognostic signature able to predict distant metastases in lymph node-negative (N(-)) breast cancer patients was reported. The aims of this study conducted by TRANSBIG were to independently validate these results and to compare the outcome with clinical risk assessment. EXPERIMENTAL DESIGN: Gene expression profiling of frozen samples from 198 N(-) systemically untreated patients was done at the Bordet Institute, blinded to clinical data and independent of Veridex. Genomic risk was defined by Veridex, blinded to clinical data. Survival analyses, done by an independent statistician, were done with the genomic risk and adjusted for the clinical risk, defined by Adjuvant! Online. RESULTS: The actual 5- and 10-year time to distant metastasis were 98% (88-100%) and 94% (83-98%), respectively, for the good profile group and 76% (68-82%) and 73% (65-79%), respectively, for the poor profile group. The actual 5- and 10-year overall survival were 98% (88-100%) and 87% (73-94%), respectively, for the good profile group and 84% (77-89%) and 72% (63-78%), respectively, for the poor profile group. We observed a strong time dependence of this signature, leading to an adjusted hazard ratio of 13.58 (1.85-99.63) and 8.20 (1.10-60.90) at 5 years and 5.11 (1.57-16.67) and 2.55 (1.07-6.10) at 10 years for time to distant metastasis and overall survival, respectively. CONCLUSION: This independent validation confirmed the performance of the 76-gene signature and adds to the growing evidence that gene expression signatures are of clinical relevance, especially for identifying patients at high risk of early distant metastases.

Identification of prognostic molecular features in the reactive stroma of human breast and prostate cancer.

Primary tumor growth induces host tissue responses that are believed to support and promote tumor progression. Identification of the molecular characteristics of the tumor microenvironment and elucidation of its crosstalk with tumor cells may therefore be crucial for improving our understanding of the processes implicated in cancer progression, identifying potential therapeutic targets, and uncovering stromal gene expression signatures that may predict clinical outcome. A key issue to resolve, therefore, is whether the stromal response to tumor growth is largely a generic phenomenon, irrespective of the tumor type or whether the response reflects tumor-specific properties. To address similarity or distinction of stromal gene expression changes during cancer progression, oligonucleotide-based Affymetrix microarray technology was used to compare the transcriptomes of laser-microdissected stromal cells derived from invasive human breast and prostate carcinoma. Invasive breast and prostate cancer-associated stroma was observed to display distinct transcriptomes, with a limited number of shared genes. Interestingly, both breast and prostate tumor-specific dysregulated stromal genes were observed to cluster breast and prostate cancer patients, respectively, into two distinct groups with statistically different clinical outcomes. By contrast, a gene signature that was common to the reactive stroma of both tumor types did not have survival predictive value. Univariate Cox analysis identified genes whose expression level was most strongly associated with patient survival. Taken together, these observations suggest that the tumor microenvironment displays distinct features according to the tumor type that provides survival-predictive value.

Diffusion-weighted spectroscopy: a novel approach to determine macromolecule resonances in short-echo time 1H-MRS.

Quantification of short-echo time proton magnetic resonance spectroscopy results in >18 metabolite concentrations (neurochemical profile). Their quantification accuracy depends on the assessment of the contribution of macromolecule (MM) resonances, previously experimentally achieved by exploiting the several fold difference in T(1). To minimize effects of heterogeneities in metabolites T(1), the aim of the study was to assess MM signal contributions by combining inversion recovery (IR) and diffusion-weighted proton spectroscopy at high-magnetic field (14.1 T) and short echo time (= 8 msec) in the rat brain. IR combined with diffusion weighting experiments (with δ/Δ = 1.5/200 msec and b-value = 11.8 msec/μm(2)) showed that the metabolite nulled spectrum (inversion time = 740 msec) was affected by residuals attributed to creatine, inositol, taurine, choline, N-acetylaspartate as well as glutamine and glutamate. While the metabolite residuals were significantly attenuated by 50%, the MM signals were almost not affected (< 8%). The combination of metabolite-nulled IR spectra with diffusion weighting allows a specific characterization of MM resonances with minimal metabolite signal contributions and is expected to lead to a more precise quantification of the neurochemical profile.