Miguel Martín - Academia.edu (original) (raw)

Papers by Miguel Martín

Breast Cancer Research and Treatment, 2019

Background We recently showed PAM50 gene expression data can be represented by five quantitative,... more Background We recently showed PAM50 gene expression data can be represented by five quantitative, orthogonal, multi-gene breast tumor traits. These novel tumor 'dimensions' were superior to categorical intrinsic subtypes for clustering in high-risk breast cancer pedigrees, indicating potential to represent underlying genetic susceptibilities and biological pathways. Here we explore the prognostic and predictive utility of these dimensions in a sub-study of GEICAM/9906, a Phase III randomized prospective clinical trial of paclitaxel in breast cancer. Methods Tumor dimensions, PC1-PC5, were calculated using pre-defined coefficients. Univariable and multivariable Cox proportional hazards (PH) models for disease-free survival (DFS) were used to identify associations between quantitative dimensions and prognosis or response to the addition of paclitaxel. Results were illustrated using Kaplan-Meier curves. Results Dimensions PC1 and PC5 were associated with DFS (Cox PH p = 6.7 × 10 −7 and p = 0.036), remaining significant after correction for standard clinical-pathological prognostic characteristics. Both dimensions were selected in the optimal multivariable model, together with nodal status and tumor size (Cox PH p = 1.4 × 10 −12). Interactions with treatment were identified for PC3 and PC4. Response to paclitaxel was restricted to tumors with low PC3 and PC4 (log-rank p = 0.0021). Women with tumors high for PC3 or PC4 showed no survival advantage. Conclusions Our proof-of-concept application of quantitative dimensions illustrated novel findings and clinical utility beyond standard clinical-pathological characteristics and categorical intrinsic subtypes for prognosis and predicting chemotherapy response. Consideration of expression data as quantitative tumor dimensions offers new potential to identify clinically important patient subsets in clinical trials and advance precision medicine.

Breast Cancer Research and Treatment, 2017

We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independent... more We identified and replicated a novel gene, ETFB, strongly associated with chronic AIC independently of age at tumor onset. Although experimental verification and further studies in larger patient cohorts are required to confirm our finding, we demonstrated that exome array data analysis represents a valuable strategy to identify novel genes contributing to the susceptibility to chronic AIC. KEYWORDS Long-term cancer survivors, anthracycline, chronic cardiotoxicity, low-frequency variants, predictive genes KEY MESSAGE Previous efforts made to understand the interindividual variability in AIC risk have focused exclusively on common variants mainly through a candidate gene strategy. In this study, we evaluated the association of low-frequency variants at genome-wide level by exome-array analysis. We identified and replicated ETFB as a novel gene strongly associated with risk of chronic AIC in cancer patients.

The Oncologist, 2013

Learning Objectives Explain the prognostic value of baseline CTCs. Describe the predictive value ... more Learning Objectives Explain the prognostic value of baseline CTCs. Describe the predictive value of CTCs at day 21 after chemotherapy. Explain the meaning of the change of CTCs from baseline to day 21 after chemotherapy.

New England Journal of Medicine, 2010

BACKGROUND A regimen of docetaxel, doxorubicin, and cyclophosphamide (TAC) is superior to a regim... more BACKGROUND A regimen of docetaxel, doxorubicin, and cyclophosphamide (TAC) is superior to a regimen of fluorouracil, doxorubicin, and cyclophosphamide (FAC) when used as adjuvant therapy in women with node-positive breast cancer. The value of taxanes in the treatment of node-negative disease has not been determined. METHODS We randomly assigned 1060 women with axillary-node-negative breast cancer and at least one high-risk factor for recurrence (according to the 1998 St. Gallen criteria) to treatment with TAC or FAC every 3 weeks for six cycles after surgery. The primary end point was disease-free survival after at least 5 years of follow-up. Secondary end points included overall survival and toxicity. RESULTS At a median follow-up of 77 months, the proportion of patients alive and diseasefree was higher among the 539 women in the TAC group (87.8%) than among the 521 women in the FAC group (81.8%), representing a 32% reduction in the risk of recurrence with TAC (hazard ratio, 0.68; 95% confidence interval [CI], 0.49 to 0.93; P = 0.01 by the log-rank test). This benefit was consistent, regardless of hormonereceptor status, menopausal status, or number of high-risk factors. The difference in survival rates (TAC, 95.2%; FAC, 93.5%) was not significant (hazard ratio, 0.76; 95% CI, 0.45 to 1.26); however, the number of events was small (TAC, 26; FAC, 34). Rates of grade 3 or 4 adverse events were 28.2% with TAC and 17.0% with FAC (P<0.001). Toxicity associated with TAC was diminished when primary prophylaxis with granulocyte colony-stimulating factor was provided. CONCLUSIONS As compared with adjuvant FAC, adjuvant TAC improved the rate of disease-free survival among women with high-risk, node-negative breast cancer. (Funded by GEICAM and Sanofi-Aventis; ClinicalTrials.gov number, NCT00121992.

Cancer Research, 2011

Background Retrospective clinical data suggest that high vascular endothelial growth factor (VEGF... more Background Retrospective clinical data suggest that high vascular endothelial growth factor (VEGF) levels in breast tumors are associated with a decreased response to endocrine therapy. We designed the randomized phase III LEA study of first-line bevacizumab in combination with endocrine therapy, to address the hypothesis that anti-VEGF treatment can prevent resistance to endocrine therapy in patients with advanced breast cancer sensitive to such treatment. Methods: Postmenopausal patients with evaluable locally recurrent or metastatic breast cancer, HER2−negative- and estrogen receptor (ER)-and/or progesterone receptor (PgR)-positive disease, and eligible to receive hormonal treatment are candidates for this study. Patients are randomized to receive letrozole 2.5mg daily or fulvestrant, 250mg every 4 weeks (Arm A) or the same hormonal therapy plus bevacizumab 15mg/kg every 3 weeks (Arm B). The primary objective is to compare progression-free survival (PFS) between the treatment arm...

Breast Cancer Research and Treatment, 2009

Treatment with fluororacil, epirubicin, and cyclophosphamide followed by weekly paclitaxel (FEC-P... more Treatment with fluororacil, epirubicin, and cyclophosphamide followed by weekly paclitaxel (FEC-P) yielded superior disease-free survival than FEC in the adjuvant breast cancer trial GEICAM 9906. We evaluate molecular subtypes predictive of prognosis and paclitaxel response in this trial. Two molecular subtype classifications based on conventional immunohistochemical and fluorescent in situ hybridization determinations were used: #1: Four groups segregated according to the combination of hormone receptor (HR) and HER2 status; #2: Intrinsic subtype classification (Triple Negative (TN), HER2, Luminal B and Luminal A). Results: Both subtype classifications yielded prognostic and predictive information. HR ?/HER2-patients (and Luminal A patients) had a significantly better outcome than the other subgroups of patients. The superiority of FEC-P over FEC was clearly more marked in HR-/HER2-patients (TN patients), particularly in the subset with basal phenotype (TN and either EGFR? or cytokeratins 5/6?). The Luminal A subtype also achieved a significant benefit with FEC-P. The molecular-defined subgroup of TN was clearly predictive of better response to treatment with FEC-P. Luminal A patients had the best prognosis and also have a better outcome with weekly paclitaxel.

Clinical Cancer Research, 2011

Purpose: Hand-foot syndrome (HFS) is one of the most relevant dose-limiting adverse effects of ca... more Purpose: Hand-foot syndrome (HFS) is one of the most relevant dose-limiting adverse effects of capecitabine, an oral prodrug of 5-fluorouracil used in the standard treatment of breast and colorectal cancer. We investigated the association between grade 3 HFS and genetic variations in genes involved in capecitabine metabolism. Experimental Design: We genotyped a total of 13 polymorphisms in the carboxylesterase 2 (CES2) gene, the cytidine deaminase (CDD) gene, the thymidine phosphorylase (TP) gene, the thymidylate synthase (TS) gene, and the dihydropyrimidine dehydrogenase (DPD) gene in 130 patients treated with capecitabine. We correlated these polymorphisms with susceptibility to HFS. Results: We found an association of HFS appearance with rs532545 located in the promoter region of CDD (OR = 2.02, 95% CI = 1.02–3.99, P = 0.039). Because we found no association between the rs532545 genotype and CDD mRNA expression in Epstein-Barr virus lymphoblastoid cells, we explored additional ge...

Mathematics, 2021

Over the last decade, regularized regression methods have offered alternatives for performing mul... more Over the last decade, regularized regression methods have offered alternatives for performing multi-marker analysis and feature selection in a whole genome context. The process of defining a list of genes that will characterize an expression profile remains unclear. It currently relies upon advanced statistics and can use an agnostic point of view or include some a priori knowledge, but overfitting remains a problem. This paper introduces a methodology to deal with the variable selection and model estimation problems in the high-dimensional set-up, which can be particularly useful in the whole genome context. Results are validated using simulated data and a real dataset from a triple-negative breast cancer study.

Journal of Clinical Oncology, 2020

We appreciate the comments and suggestions from Usui et al 1 on our GEICAM/2003-11_CIBOMA/2004-01... more We appreciate the comments and suggestions from Usui et al 1 on our GEICAM/2003-11_CIBOMA/2004-01 trial, recently published in Journal of Clinical Oncology. 2 Arm Capecitabine Observation log-rank P value: .680 FIG 1. Disease-free survival (DFS) for patients without pathological complete response (pCR) after neoadjuvant therapy.

British journal of cancer, 2018

Venous thromboembolism (VTE) is a leading cause of death among patients with cancer. Outpatients ... more Venous thromboembolism (VTE) is a leading cause of death among patients with cancer. Outpatients with cancer should be periodically assessed for VTE risk, for which the Khorana score is commonly recommended. However, it has been questioned whether this tool is sufficiently accurate at identifying patients who should receive thromboprophylaxis. The present work proposes a new index, TiC-Onco risk score to be calculated at the time of diagnosis of cancer, that examines patients' clinical and genetic risk factors for thrombosis. We included 391 outpatients with a recent diagnosis of cancer and candidates for systemic outpatient chemotherapy. All were treated according to standard guidelines. The study population was monitored for 6 months, and VTEs were recorded. The Khorana and the TiC-Onco scores were calculated for each patient and their VTE predictive accuracy VTEs was compared. We recorded 71 VTEs. The TiC-Onco risk score was significantly better at predicting VTE than the Kho...

Clinical and Translational Oncology, 2017

Precision medicine is an emerging approach for disease treatment and prevention that takes into a... more Precision medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle for each person. Precision medicine is transforming clinical and biomedical research, as well as health care itself from a conceptual, as well as a methodological viewpoint, providing extraordinary opportunities to improve public health and lower the costs of the healthcare system. However, the implementation of precision medicine poses ethical-legal, regulatory, organizational, and knowledge-related challenges. Without a national strategy, precision medicine, which will be implemented one way or another, could take place without the appropriate planning that can guarantee technical quality, equal access of all citizens to the best practices, violating the rights of patients and professionals, and jeopardizing the solvency of the healthcare system. With this paper from the Spanish Societies of Medical Oncology, Pathology, and Hospital Pharmacy, we highlight the need to institute a consensual national strategy for the development of precision medicine in our country, review the national and international context, comment on the opportunities and challenges for implementing precision medicine, and outline the objectives of a national strategy on precision medicine in cancer.

The oncologist, Nov 12, 2017

Nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) is an alternative to standard taxanes for ... more Nanoparticle albumin-bound paclitaxel (nab-Paclitaxel) is an alternative to standard taxanes for breast cancer (BC) treatment. We evaluated nab-Paclitaxel efficacy as neoadjuvant treatment for early estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) disease. Women with ER+, HER2-, stage II-III BC were treated preoperatively with four cycles of weekly nab-Paclitaxel (150 mg/m(2)), 3 weeks on and 1 week off. We hypothesized that poor pathological response rate (residual cancer burden [RCB] III; Symmans criteria) would be ≤16%. Eighty-one patients with a median age of 47 years were treated; 64.2% were premenopausal, and 69% of tumors were stage II. Residual cancer burden III rate was 28.4% (95% confidence interval [CI]: 18.6%-38.2%), RCB 0+I (good response) rate was 24.7% (95% CI: 15.3%-34.1%) and RCB 0 (complete response) rate was 7.4% (95% CI: 1.7%-13.1%). Objective response rate by magnetic resonance imaging was 76.5% and rate of conversion t...

Oncotarget, Jan 14, 2017

The anti-HER2 antibody trastuzumab have shown clinical activity in combination with chemotherapy ... more The anti-HER2 antibody trastuzumab have shown clinical activity in combination with chemotherapy in different breast cancer settings. However, most of patients treated with this antibody progress after a period of treatment. Activation of the kinase SRC has been linked with resistance to trastuzumab in several preclinical studies. We designed a phase I clinical study to explore the activity of weekly trastuzumab (2 mg/kg) plus paclitaxel (80 mg/m2) in combination with the anti-SRC kinase inhibitor Dasatinib in the first line treatment of HER2 metastatic breast cancer. The primary objective was to determine the maximum tolerated dose (MTD) and recommended phase II dose (RP2D); secondary objectives included efficacy, objective response rate (ORR), pharmacokinetics and pharmacodynamics. A "3+3" design guided dose escalation with two oral dose levels of dasatinib: 100mg (DL1) and 140 mg (DL2). 10 patients were included in the phase I part. Dasatinib 100 mg q.d. was established...

Journal of the Academy of Nutrition and Dietetics, 2016

Background: Diet is a key modifiable risk for many chronic diseases. But it remains unclear if di... more Background: Diet is a key modifiable risk for many chronic diseases. But it remains unclear if dietary patterns from one study sample are generalizable to other independent populations. Objective: The primary objective of this study was to assess whether data-driven dietary patterns from one study sample are applicable to other populations. The secondary objective was to assess the validity of two criteria of pattern similarity. Methods: Six dietary patterns-"Western" (n=3), "Mediterranean", "Prudent", and "Healthy"from three published studies on breast cancer were reconstructed in a case-control study of 973 breast cancer cases and 973 controls. Three more "internal" patterns ("Western", "Prudent", "Mediterranean") were derived from this case-control study's own data. Statistical Analysis: Applicability was assessed by comparing the six reconstructed patterns with the three internal dietary patterns, using the congruence coefficient (CC) between pattern loadings. If any pair met either of two commonly used criteria for declaring patterns similar (CC≥0.85 or a statistically significant (p<0.05) Pearson correlation), then the true similarity of those two dietary patterns was double-checked by comparing their associations to risk for breast cancer, in order to assess whether those two criteria of similarity are actually reliable. Results: Five of the six reconstructed dietary patterns showed high congruence (CC>0.9) to their corresponding dietary pattern derived from the case-control study's data. Similar associations with risk for breast cancer were found in all pairs of dietary patterns that had high CC but not in all pairs of dietary patterns with statistically significant correlations. Conclusions: Similar dietary patterns can be found in independent samples. The p-value of a correlation coefficient is less reliable than the CC as a criterion for declaring two dietary patterns

Drug Metabolism and Personalized Therapy, 2016

Pharmacogenetics and pharmacogenomics (PGx) are rapidly growing fields that aim to elucidate the ... more Pharmacogenetics and pharmacogenomics (PGx) are rapidly growing fields that aim to elucidate the genetic basis for the interindividual differences in drug response. PGx approaches have been applied to many anticancer drugs in an effort to identify relevant inherited or acquired genetic variations that may predict patient response to chemotherapy and targeted therapies. In this article, we discuss the advances in the field of cancer pharmacogenetics and pharmacogenomics, driven by the recent technological advances and new revolutionary massive sequencing technologies and their application to elucidate the genetic bases for interindividual drug response and the development of biomarkers able to personalize drug treatments. Specifically, we present recent progress in breast cancer molecular classifiers, cell-free circulating DNA as a prognostic and predictive biomarker in cancer, patient-derived tumor xenograft models, chronic lymphocytic leukemia genomic landscape, and current pharmac...

Arbor, 2015

Durante el tratamiento quimioterapéutico contra el cáncer de mama las pacientes deben afrontar la... more Durante el tratamiento quimioterapéutico contra el cáncer de mama las pacientes deben afrontar la caída del cabello y, junto con ésta, la pérdida de ciertos referentes estéticos e identitarios relacionados con el cuerpo femenino, social y cultural. Aunque durante este proceso hay muchos sentimientos involucrados, sobre todo el temor a la muerte, la pérdida de referentes identitarios femeninos es uno de los sentimientos más dolorosos a los que se enfrentan estas mujeres, ya que trastoca la identidad y el autoestima de las mismas, y las estigmatiza como enfermas. Tomando ello en consideración, se considera que el uso de un accesorio de moda, como el sombrero, puede generar más comodidad y bienestar en las pacientes que han perdido sus cabellos. La presente investigación tuvo como objetivo comprender de qué manera el sombrero puede ser un apoyo identitario para las pacientes con cáncer, supliendo la carencia social y personal del cabello durante el tratamiento quimioterapéutico. Teniendo en cuenta los postulados de la antropología aplicada, se elaboró un Taller de Sombreros, en una ciudad del sur de Brasil, dirigido a mujeres con cáncer, que elaboraron y emplearon el accesorio realizado. La recogida de datos se realizó mediante la observación participante y la realización de entrevistas no dirigidas y semiestructuradas. Se concluyó que el sombrero, además de ser un elemento auxiliar en el proceso de reconstrucción identitaria durante el tratamiento quimioterapéutico, también fue un elemento que alejó a las pacientes de los estigmas de la enfermedad.

The Breast, 2008

The development of new anti-tumour drugs without clear cytoreductive activity has necessitated ch... more The development of new anti-tumour drugs without clear cytoreductive activity has necessitated changes in the design of clinical trials. Defining the ''time'' parameter has become the essential objective of the majority of these trials. However, in breast cancer, this parameter is highly variable and, as such, difficult to quantify. We developed a useful tool that takes into account the inter-relatedness of all the variables known to have the capacity to predict the time-to-progression (TTP) in advanced breast cancer. From the Á lamo database (GEICAM), we selected 1798 patients diagnosed as having metastatic breast cancer. Univariate analysis was performed using the method of Kaplan-Meier. Multivariate analysis was with the Cox regression method. The variables that were shown to have independent predictive value for the TTP were: non-visceral metastatic disease, single metastases, hormonal receptor positive N/T ratioo2 and disease-free interval (DFI) X24 months. Taking into account the variables that had reached an independent predictive value, we constructed a model of scoring in which the patients were grouped according to the TTP. Using our new scoring model, it is possible to group patients with metastatic breast cancer according to the predicted TTP. This can be a useful tool at the time of selecting and stratifying patients on entry into new randomised clinical trials.

The Oncologist, 2009

Learning Objectives Analyze the clinical trial data for the treatment of breast cancer. Evaluate ... more Learning Objectives Analyze the clinical trial data for the treatment of breast cancer. Evaluate the risk of cardiotoxicity associated with the use of trastuzumab. Design and conduct a practical approach to managing patients with trastuzumab-associated cardiotoxicity. This article is available for continuing medical education credit at CME.TheOncologist.com.

JAMA, 2011

HERE IS CLINICAL NEED FOR predictive tests for patients with newly diagnosed ERBB2 (HER2 or HER2/... more HERE IS CLINICAL NEED FOR predictive tests for patients with newly diagnosed ERBB2 (HER2 or HER2/neu)-negative breast cancer whose clinicalpathologic risk at presentation favors

Clinical and Translational Oncology, 2011

Melanoma is the deadliest cutaneous malignancy and its incidence continues to grow. Until 2011, t... more Melanoma is the deadliest cutaneous malignancy and its incidence continues to grow. Until 2011, the treatment options for metastatic melanoma were scarce and without any overall survival benefi t. The emergence of new targeted therapies for BRAF mutant melanoma (vemurafenib) and immunotherapy (ipilimumab) has changed the standard of care for this disease. The objective of the present review is to summarise the biological background of the new therapeutic approaches in melanoma, focusing on apoptosis resistance, immune modulation and angiogenesis, and the direct translation into clinical practice.