Miguel A Martín

A Genomic Predictor of Response and Survival Following Taxane-Anthracycline Chemotherapy for Invasive Breast Cancer

CONTEXT Prediction of high probability of survival from standard cancer treatments is fundamental for individualized cancer treatment strategies. OBJECTIVE To develop a predictor of response and survival from chemotherapy for newly diagnosed invasive breast cancer. DESIGN, SETTING, AND PATIENTS Prospective multicenter study conducted from June 2000 to March 2010 at the M. D. Anderson Cancer Center to develop and test genomic predictors for neoadjuvant chemotherapy. Patients were those with newly diagnosed ERBB2 (HER2 or HER2/neu)-negative breast cancer treated with chemotherapy containing sequential taxane and anthracycline-based regimens (then endocrine therapy if estrogen receptor [ER]-positive). Different predictive signatures for resistance and response to preoperative (neoadjuvant) chemotherapy (stratified according to ER status) were developed from gene expression microarrays of newly diagnosed breast cancer (310 patients). Breast cancer treatment sensitivity was then predicted using the combination of signatures for (1) sensitivity to endocrine therapy, (2) chemoresistance, and (3) chemosensitivity, with independent validation (198 patients) and comparison with other reported genomic predictors of chemotherapy response. MAIN OUTCOME MEASURES Distant relapse-free survival (DRFS) if predicted treatment sensitive and absolute risk reduction ([ARR], difference in DRFS between 2 predicted groups) at median follow-up (3 years). RESULTS Patients in the independent validation cohort (99% clinical stage II-III) who were predicted to be treatment sensitive (28%) had 56% (95% CI, 31%-78%) probability of excellent pathologic response and DRFS of 92% (95% CI, 85%-100%), with an ARR of 18% (95% CI, 6%-28%). Survival was predicted in ER-positive (30% predicted sensitive; DRFS, 97% [95% CI, 91%-100%]; ARR, 11% [95% CI, 0.1%-21%]) and ER-negative (26% predicted sensitive; DRFS, 83% [95% CI, 68%-100%]; ARR, 26% [95% CI, 4%-48%]) subsets and was significant in multivariate analysis. Other genomic predictors showed paradoxically worse survival for patients predicted to be responsive to chemotherapy. CONCLUSION A genomic predictor combining ER status, predicted chemoresistance, predicted chemosensitivity, and predicted endocrine sensitivity identified patients with high probability of survival following taxane and anthracycline chemotherapy.

Evaluation of a 30-Gene Paclitaxel, Fluorouracil, Doxorubicin, and Cyclophosphamide Chemotherapy Response Predictor in a Multicenter Randomized Trial in Breast Cancer

Purpose: We examined in a prospective, randomized, international clinical trial the performance of a previously defined 30-gene predictor (DLDA-30) of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil, doxorubicin, and cyclophosphamide (T/FAC) chemotherapy, and assessed if DLDA-30 also predicts increased sensitivity to FAC-only chemotherapy. We compared the pCR rates after T/FAC versus FACx6 preoperative chemotherapy. We also did an exploratory analysis to identify novel candidate genes that differentially predict response in the two treatment arms. Experimental Design: Two hundred and seventy-three patients were randomly assigned to receive either weekly paclitaxel × 12 followed by FAC × 4 (T/FAC, n = 138), or FAC × 6 (n = 135) neoadjuvant chemotherapy. All patients underwent a pretreatment fine-needle aspiration biopsy of the tumor for gene expression profiling and treatment response prediction. Results: The pCR rates were 19% and 9% in the T/FAC and FAC arms, respectively (P < 0.05). In the T/FAC arm, the positive predictive value (PPV) of the genomic predictor was 38% [95% confidence interval (95% CI), 21-56%], the negative predictive value was 88% (95% CI, 77-95%), and the area under the receiver operating characteristic curve (AUC) was 0.711. In the FAC arm, the PPV was 9% (95% CI, 1-29%) and the AUC was 0.584. This suggests that the genomic predictor may have regimen specificity. Its performance was similar to a clinical variable–based predictor nomogram. Conclusions: Gene expression profiling for prospective response prediction was feasible in this international trial. The 30-gene predictor can identify patients with greater than average sensitivity to T/FAC chemotherapy. However, it captured molecular equivalents of clinical phenotype. Next-generation predictive markers will need to be developed separately for different molecular subsets of breast cancers. Clin Cancer Res; 16(21); 5351–61. ©2010 AACR.

Motesanib, or open-label bevacizumab, in combination with paclitaxel, as first-line treatment for HER2-negative locally recurrent or metastatic breast cancer: a phase 2, randomised, double-blind, placebo-controlled study

BACKGROUND Vascular endothelial growth factor (VEGF) has a crucial role in angiogenesis, and is a valid target in metastatic breast cancer. Motesanib is an investigational oral inhibitor of VEGF receptors. We aimed to determine whether treatment with motesanib plus paclitaxel is better than placebo plus paclitaxel in patients with HER2-negative locally recurrent or metastatic breast cancer. METHODS Between Dec 1, 2006, and July 4, 2008, patients with untreated HER2-negative metastatic breast cancer were randomly assigned (using a randomisation list created by personnel not associated with the study) in a 1:1:1 ratio to paclitaxel (90 mg/m(2) on days 1, 8, and 15 every 3 weeks) plus either masked motesanib 125 mg orally once per day (n=91), masked placebo orally once per day (n=94), or open-label bevacizumab 10 mg/kg intravenously on days 1 and 15 of each 28-day cycle (n=97), after stratification according to adjuvant or neoadjuvant chemotherapy (taxane-containing regimens vs other regimens vs none), number of metastatic sites (<3 vs ≥3), and hormone receptor status (positive vs negative). Placebo was provided as a replica of motesanib 25 mg tablets. The primary endpoint was objective response rate (ORR) based on the population as assigned to treatment. This trial is registered with ClinicalTrials.gov, number NCT00356681. FINDINGS ORRs for the motesanib group and the placebo group did not differ significantly (49%vs 41%; absolute difference 8% [95% CI -6 to 22]; p=0.31). The ORR in the bevacizumab group (52%) was similar to that in the motesanib group. The most common grade 3 or higher adverse events included diarrhoea (18 of 92 patients in the motesanib group, none of 89 patients in the placebo group, and four of 96 patients in the bevacizumab group), fatigue (11, eight, and six), hypertension (11, one, and seven), and peripheral sensory neuropathy (ten, seven, and 19). More patients in the motesanib group had serious adverse events than did those in the placebo or bevacizumab groups (34, 26, and 21 patients, respectively); the most common of these in the motesanib group were gastrointestinal in nature. INTERPRETATION Data from this trial do not support the further investigation of motesanib at this dose and schedule in this population. FUNDING Amgen.

Evaluation of the Predictive Performance and Regimen Specificity of a 30-Gene Predictor of Pathologic Complete Response in a Prospective Randomized Neoadjuvant Clinical Trial for Stage I-III Breast Cancer.

Purpose: To prospectively evaluate in a randomized trial if a previously reported multigene predictor of pathologic complete response (pCR) to preoperative weekly paclitaxel and fluorouracil-doxorubicin-cyclophosphamide (T/FAC) chemotherapy can accurately predict pCR to neoadjuvant T/FAC chemotherapy, and if it also predicts pCR to FAC only chemotherapy. Furthermore, it is unknown if the T/FAC regimen is superior to 6 courses of FAC; therefore we compare the pCR rates for patients who receive T/FAC versus FACx6 preoperative chemotherapy. Materials and Methods: Patients with stage I-III breast cancer (n=273) were randomly assigned to receive either 12 courses of weekly paclitaxel followed by 4 courses of FAC (T/FAC, n=138), or 6 courses of FAC (FACx6, n=135) neoadjuvant chemotherapy. All patients underwent a pretreatment FNA biopsy of the tumor for gene expression profiling on oligonucleotide microarrays, and treatment response prediction (pCR versus residual disease, RD) was performed using the multigene predictor. Predicted and observed pathologic responses were compared independently in the two treatment arms. Results: The pCR rate was 19% with T/FAC and 9% with FACx6 (p Discussion: Pathologic complete response rate was significantly higher in the T/FAC arm compared to the FACx6 arm indicating a higher efficacy of the paclitaxel containing arm. Patients who were predicted to achieve pCR to T/FAC had a significantly higher pCR rate (38%) than unselected patients (19%) or patients predicted to have RD (12%) when treated with this regimen. These results confirm that the multigene predictor can identify patients with greater than average sensitivity to T/FAC chemotherapy. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 101.

Missense mutations have unexpected consequences: The McArdle disease paradigm

McArdle disease is a disorder of muscle glycogen metabolism caused by mutations in the PYGM gene, encoding for the muscle‐specific isoform of glycogen phosphorylase (M‐GP). The activity of this enzyme is completely lost in patients’ muscle biopsies, when measured with a standard biochemical test which, does not allow to determine M‐GP protein levels. We aimed to determine M‐GP protein levels in the muscle of McArdle patients, by studying biopsies of 40 patients harboring a broad spectrum of PYGM mutations and 22 controls. Lack of M‐GP protein was found in muscle in the vast majority (95%) of patients, irrespective of the PYGM genotype, including those carrying missense mutations, with few exceptions. M‐GP protein biosynthesis is not being produced by PYGM mutations inducing premature termination codons (PTC), neither by most PYGM missense mutations. These findings explain the lack of PYGM genotype–phenotype correlation and have important implications for the design of molecular‐based therapeutic approaches.

A milder phenotype of megaconial congenital muscular dystrophy due to a novel CHKB mutation

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Mitochondrial Complex III Deficiency of Nuclear Origin

Mitochondrial respiratory chain complex III enzyme deficiency is associated with a heterogeneous group of neuromuscular and multisystemic disorders of variable severity that are present in childhood and adulthood. Despite being considered a relatively uncommon defect of the OXPHOS system, interest has recently shifted toward the Mendelian inheritance of mitochondrial complex III-related disease due to the increasing number of nuclear genetic defects that affect its biogenesis and function. Not only are most complex III subunits encoded by nuclear genes, but also are an increasing number of specific regulatory proteins and assembly factors involved in the biosynthesis of this respiratory chain complex, which have been described in different organisms. From a clinic-genetic point of view, inherited complex III enzyme deficiency can be classified into disorders due to mutations in complex III structural constituents, or those caused by mutations in assembly chaperones, such as BCS1L and TTC19. The first part of this review will focus on the relationships between the nuclear genetic alterations that lead to complex III deficiency and their clinical manifestations. The second part will explain what is known so far about the cellular pathophysiological consequences of complex III dysfunction with regards to defects in the activity and assembly of the respirasome, and the alterations in the production of reactive oxygen species and mitochondrial dynamics. The final part of this review will describe the development and experimental advances in new mammalian models of complex III deficiency with a special emphasis on the GRACILE mouse, which has arisen as a powerful approach to better understand complex III enzyme deficiency of nuclear origin.

Elegibilidad de pacientes con esquizofrenia ingresados en una unidad de hospitalización psiquiátrica para participar en ensayos clínicos

INTRODUCTION This study assesses the potential eligibility of patients admitted to a psychiatric hospitalisation unit to take part in the major clinical trials based on schizophrenia treatment in clinical practice (CATIE, CUtLASS and EUFEST). MATERIAL AND METHODS A retrospective evaluation by consulting the medical records of 241 subjects (59.8% males and 40.2% females, mean age 39.7±13.0 years), admitted consecutively over one year to psychiatric hospitalisation unit with a diagnosis of schizophrenia or another psychosis. The influence of the factors involved in the non-eligibility in each of the clinical trials is analysed using logistic regression analysis. RESULTS Only 20.7%, 22.3%, and 22.5% of patients with schizophrenia or another psychosis would be eligible to participate in the CATIE, CUtLASS and EUFEST studies, respectively. The main factors involved in the non-eligibility were polytherapy with anti-psychotics (2 or more) (Odds Ratio (OR): 7.64, 95% confidence interval (CI): 3.06-19.06, P<.001), mental retardation (OR: 16.67, 95% CI: 1.75-166.67, P=.014), and resistance, intolerance or contraindication to any of the anti-psychotics of the study (OR: 3.68, 95% CI: 1.13-11.99, P=.030). CONCLUSIONS Three out of every four patients with schizophrenia or another psychosis admitted to a psychiatric hospitalisation unit are not represented in the major clinical trials on schizophrenia treatment.

Abstract PD07-03: A Genomic Predictor of Survival Following Taxane-Anthracycline Chemotherapy for Breast Cancer

Background: There is currently no predictive assay for patients with clinical Stage II-III breast cancer from which predicted sensitivity to treatment is associated with high probability of survival following chemotherapy. Patients & Methods: We performed Affymetrix gene expression microarrays of prospectively collected tumor biopsies from 508 patients with newly diagnosed HER2-normal invasive breast cancer prior to neoadjuvant taxane-anthracycline chemotherapy followed by adjuvant endocrine therapy (if hormone receptor-positive). The predictor was developed from 310 samples (from MDACC & I-SPY) by combining: 1) a signature to predict sensitivity to endocrine therapy (SET); 2) estrogen receptor (ER)-stratified predictive signatures of resistance to chemotherapy, defined as extensive residual cancer burden (RCB-III) or relapse within 3 years; and 3) ER-stratified predictive signatures of response to chemotherapy, defined as pathologic complete response (pCR) or minimal RCB (RCB-I). The predictor classified tumors as treatment sensitive if high or intermediate SET, or if predicted to be responsive (and not resistant) to chemotherapy. Otherwise, tumors were classified as treatment insensitive. The predictor was then tested on an independent cohort (N= 198, 98% with clinical Stage II-III) who received neoadjuvant (N= 180) or adjuvant (N= 18) taxane-anthracycline chemotherapy (from MDACC, USO, GEICAM, Peru, LBJ). Distant relapse-free survival (DRFS) was evaluated at a 3-year median follow up using negative predictive value (NPV, absence of event if predicted to be sensitive), and absolute risk reduction (ARR) for those predicted to be sensitive (versus insensitive), with 95% confidence interval (CI). The independent predictive value was assessed in multivariate Cox regression analysis based on the likelihood ratio test (P≥0.05). Results: Patients in the independent validation cohort who were predicted to be treatment sensitive (28%) had excellent DRFS, with NPV 92% (CI 85-100) and significant absolute risk reduction (ARR 18%, CI 6-28) at 3 years, compared to those predicted to be insensitive. This was similar to the DRFS observed in patients who achieved pCR after they completed neoadjuvant chemotherapy (NPV 93%, CI 85-100). Predictions were accurate in each phenotypic subset: ER+/HER2- (30% predicted sensitive, NPV 97%, CI 91-100; ARR 11%, CI 0.1-21) and ER-/HER2- (26% predicted sensitive, NPV 83%, CI 68-100; ARR 26%, CI 4-28). Predicted treatment sensitivity (HR 0.20, CI 0.07-0.57), ER+ status (HR 0.32, CI 0.17-0.63), clinical tumor stage T3-4 (HR 2.04, CI 1.07-3.88) and age >50 (HR 0.50, CI 0.25-0.98) were significant in a multivariate model that also included clinical nodal status, grade, and type of taxane used. Conclusion: We report validation results for the first molecular predictor of sensitivity to neoadjuvant/adjuvant systemic therapy for clinical Stage II-III breast cancer that is independently associated with excellent DRFS in those predicted to be sensitive. Predictions were accurate for both ER+/HER2- and ER-/HER2- invasive breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr PD07-03.