Genome-wide association studies (GWAS) and large-scale replication studies have identified common... more Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P…
Background: A previous phase 2 study in metastatic breast cancer compared treatment with intraven... more Background: A previous phase 2 study in metastatic breast cancer compared treatment with intravenously delivered oncolytic reovirus, pelareorep (pela), in combination with paclitaxel (PTX) versus PTX alone. This study demonstrated a statistically significant improvement in overall survival (OS), without differences in objective response or progression-free survival. We hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive immune response triggered by pela. To test this hypothesis, and examine if pela can mediate the priming of an anti-tumor immune response, we designed a study called AWARE-1 (A window-of-opportunity study of pela in Early Breast Cancer), which is currently enrolling and for which initial translational research results are presented. Methods: AWARE-1 is evaluating the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, whil...
Background: A previous phase 2 study in metastatic breast cancer demonstrated a statistically sig... more Background: A previous phase 2 study in metastatic breast cancer demonstrated a statistically significant improvement in overall survival (OS) in patients treated with pelareorep (pela), an intravenously delivered immuno-oncolytic reovirus, given in combination with paclitaxel (PTX) versus PTX alone [1]. We hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive T cell response triggered by pela. To examine if pela can mediate the priming of an anti-tumor immune response, and the impact of checkpoint blockade therapy on this response, we and SOLTI research group are conducting the AWARE-1 study (NCT04102618) in patients with early breast cancer. The initial translational research results from this study are presented here. Methods: AWARE-1 is a window-of-opportunity study to evaluate the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, an...
Supplemental material, InhibCDK-Supplementary_Material_v2_01012019 for Palbociclib and ribociclib... more Supplemental material, InhibCDK-Supplementary_Material_v2_01012019 for Palbociclib and ribociclib in breast cancer: consensus workshop on the management of concomitant medication by Meritxell Bellet, Faten Ahmad, Rafael Villanueva, Carolina Valdivia, Julián Palomino-Doza, Ada Ruiz, Xavier Gonzàlez, Encarna Adrover, Analía Azaro, Maria Valls-Margarit, Josep Lluís Parra, Juan Aguilar, Maria Vidal, Anastasi Martín, Joaquíín Gavilá, Santiago Escrivá-de-Romaní, Antonia Perelló, Cristina Hernando, Ainhara Lahuerta, Pilar Zamora, Victoria Reyes, María Alcalde, Helena Masanas, Pamela Céliz, Isabel Ruíz, Miguel Gil, Miguel Àngel Seguí and Lorena de la Peña in Therapeutic Advances in Medical Oncology
Drug–drug interactions are of significant concern in clinical practice in oncology, particularly ... more Drug–drug interactions are of significant concern in clinical practice in oncology, particularly in patients receiving Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are typically exposed to long-term regimens. This article presents the highlights from the ‘First Workshop on Pharmacology and Management of CDK4/6 Inhibitors: Consensus about Concomitant Medications’. The article is structured into two modules. The educational module includes background information regarding drug metabolism, corrected QT (QTc) interval abnormalities, management of psychotropic drugs and a comprehensive review of selected adverse effects of palbociclib and ribociclib. The collaborative module presents the conclusions of the five working groups, each of which comprised five experts from different fields. From these conclusions positive lists of drugs for treating common comorbid conditions that can be safely administered concomitantly with palbociclib and/or ribociclib were developed.
Previous studies have identified common germline variants nominally associated with breast cancer... more Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium. A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer specific survival, overall survival and disease-free survival. All associations which reached the nominal significance level of…
Background: The presence of bone metastases (BMe) alters the balance of bone remodeling and conse... more Background: The presence of bone metastases (BMe) alters the balance of bone remodeling and consequently, levels of bone turnover markers (BTM). Increased levels of these biomarkers are related to the risk of skeletal-related events (SREs), disease progression and death. Treatment with bisphosphonates reduces the probability of SREs through osteoclastic activity inhibition. The aim of this study was to determine the relation between BTM, bone metastasis development and SREs, disease progression and death in patients with breast cancer (BC) and BMe. Patients and methods: Observational, prospective and multicenter study. Patients with BC and BMe; no previous bone treatment in the last 6 months prior to study entry. Urinary aminoterminal telopeptide of collagen I (NTX, Osteomark NTx Urine, Wampole Laboratories, USA); urinary alpha-alpha-isomer of carboxyterminal telopeptide of collagen I (αα-CTX, ALPHA Crosslaps EIA, ids, UK) and serum bone alkaline phosphatase (BALP, OSTASE BAP, ids, ...
GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mappin... more GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the…
The approved capecitabine regimen as monotherapy in metastatic breast cancer (MBC) is 1,250 mg/m(... more The approved capecitabine regimen as monotherapy in metastatic breast cancer (MBC) is 1,250 mg/m(2) twice daily for 2 weeks on and 1 week off (Cint). Dose modifications are often required because of severe hand-foot syndrome (HFS). We tested a continuous regimen with a lower daily dose but a similar cumulative dose in an attempt to reduce the severity of adverse events (AEs) while maintaining efficacy. We randomized 195 patients with HER-2/neu-negative MBC to capecitabine 800 mg/m(2) twice daily throughout the 21-day cycle (Ccont) or to Cint to assess noninferiority in the percentage of patients free of progression at 1 year. Secondary endpoints included efficacy and safety. Associations between polymorphisms in capecitabine metabolism-related genes and drug response were assessed. The percentage of patients free of progression at 1 year was 27.3% with Cint versus 25.3% with Ccont (difference of -2.0%; 95% confidence interval: -15.5% to 11.5%, exceeding the 15% deemed noninferior). ...
Using the Breast Cancer Association Consortium, the authors previously reported that the single n... more Using the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case-control studies.
Breast cancer is a heterogeneous disease. In clinical practice, tumors are classified as hormonal... more Breast cancer is a heterogeneous disease. In clinical practice, tumors are classified as hormonal receptor positive, Her2 positive and triple negative tumors. In previous works, our group defined a new hormonal receptor positive subgroup, the TN-like subtype, which has a prognosis and a molecular profile more similar to triple negative tumors. In this study, proteomics and Bayesian networks were used to characterize protein relationships in 106 breast tumor samples. Components obtained by these methods had a clear functional structure. The analysis of these components suggested differences in processes such as metastasis or proliferation between breast cancer subtypes, including our new subtype TN-like. In addition, one of the components, mainly related with metastasis, had prognostic value in this cohort. Functional approaches allow to build hypotheses about regulatory mechanisms and to establish new relationships among proteins in the breast cancer context.Author SummaryBreast can...
Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the... more Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval ...
Anthracyclines are among the most used chemotherapeutic agents in breast cancer (BC). However the... more Anthracyclines are among the most used chemotherapeutic agents in breast cancer (BC). However their use is hampered by anthracycline-induced cardiotoxicity (AIC). The currently known clinical and genetic risk factors do not fully explain the observed inter-individual variability and only have a limited ability to predict which patients are more likely to develop this severe toxicity. To identify novel predictive genes, we conducted a two-stage genome-wide association study in epirubicin-treated BC patients. In the discovery phase, we genotyped over 700,000 single nucleotide variants in a cohort of 227 patients. The most interesting finding was rs62134260, located 4kb upstream of POLRMT (OR = 5.76, P = 2.23 × 10−5). We replicated this association in a validation cohort of 123 patients (P = 0.021). This variant regulates the expression of POLRMT, a gene that encodes a mitochondrial DNA-directed RNA polymerase, responsible for mitochondrial gene expression. Individuals harbouring the r...
Genome-wide association studies (GWAS) and large-scale replication studies have identified common... more Genome-wide association studies (GWAS) and large-scale replication studies have identified common variants in 79 loci associated with breast cancer, explaining ∼14% of the familial risk of the disease. To identify new susceptibility loci, we performed a meta-analysis of 11 GWAS, comprising 15,748 breast cancer cases and 18,084 controls together with 46,785 cases and 42,892 controls from 41 studies genotyped on a 211,155-marker custom array (iCOGS). Analyses were restricted to women of European ancestry. We generated genotypes for more than 11 million SNPs by imputation using the 1000 Genomes Project reference panel, and we identified 15 new loci associated with breast cancer at P…
Background: A previous phase 2 study in metastatic breast cancer compared treatment with intraven... more Background: A previous phase 2 study in metastatic breast cancer compared treatment with intravenously delivered oncolytic reovirus, pelareorep (pela), in combination with paclitaxel (PTX) versus PTX alone. This study demonstrated a statistically significant improvement in overall survival (OS), without differences in objective response or progression-free survival. We hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive immune response triggered by pela. To test this hypothesis, and examine if pela can mediate the priming of an anti-tumor immune response, we designed a study called AWARE-1 (A window-of-opportunity study of pela in Early Breast Cancer), which is currently enrolling and for which initial translational research results are presented. Methods: AWARE-1 is evaluating the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, whil...
Background: A previous phase 2 study in metastatic breast cancer demonstrated a statistically sig... more Background: A previous phase 2 study in metastatic breast cancer demonstrated a statistically significant improvement in overall survival (OS) in patients treated with pelareorep (pela), an intravenously delivered immuno-oncolytic reovirus, given in combination with paclitaxel (PTX) versus PTX alone [1]. We hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive T cell response triggered by pela. To examine if pela can mediate the priming of an anti-tumor immune response, and the impact of checkpoint blockade therapy on this response, we and SOLTI research group are conducting the AWARE-1 study (NCT04102618) in patients with early breast cancer. The initial translational research results from this study are presented here. Methods: AWARE-1 is a window-of-opportunity study to evaluate the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, an...
Supplemental material, InhibCDK-Supplementary_Material_v2_01012019 for Palbociclib and ribociclib... more Supplemental material, InhibCDK-Supplementary_Material_v2_01012019 for Palbociclib and ribociclib in breast cancer: consensus workshop on the management of concomitant medication by Meritxell Bellet, Faten Ahmad, Rafael Villanueva, Carolina Valdivia, Julián Palomino-Doza, Ada Ruiz, Xavier Gonzàlez, Encarna Adrover, Analía Azaro, Maria Valls-Margarit, Josep Lluís Parra, Juan Aguilar, Maria Vidal, Anastasi Martín, Joaquíín Gavilá, Santiago Escrivá-de-Romaní, Antonia Perelló, Cristina Hernando, Ainhara Lahuerta, Pilar Zamora, Victoria Reyes, María Alcalde, Helena Masanas, Pamela Céliz, Isabel Ruíz, Miguel Gil, Miguel Àngel Seguí and Lorena de la Peña in Therapeutic Advances in Medical Oncology
Drug–drug interactions are of significant concern in clinical practice in oncology, particularly ... more Drug–drug interactions are of significant concern in clinical practice in oncology, particularly in patients receiving Cyclin-dependent kinase (CDK) 4/6 inhibitors, which are typically exposed to long-term regimens. This article presents the highlights from the ‘First Workshop on Pharmacology and Management of CDK4/6 Inhibitors: Consensus about Concomitant Medications’. The article is structured into two modules. The educational module includes background information regarding drug metabolism, corrected QT (QTc) interval abnormalities, management of psychotropic drugs and a comprehensive review of selected adverse effects of palbociclib and ribociclib. The collaborative module presents the conclusions of the five working groups, each of which comprised five experts from different fields. From these conclusions positive lists of drugs for treating common comorbid conditions that can be safely administered concomitantly with palbociclib and/or ribociclib were developed.
Previous studies have identified common germline variants nominally associated with breast cancer... more Previous studies have identified common germline variants nominally associated with breast cancer survival. These associations have not been widely replicated in further studies. The purpose of this study was to evaluate the association of previously reported SNPs with breast cancer specific survival using data from a pooled analysis of eight breast cancer survival genome-wide association studies (GWAS) from the Breast Cancer Association Consortium. A literature review was conducted of all previously published associations between common germline variants and three survival outcomes: breast cancer specific survival, overall survival and disease-free survival. All associations which reached the nominal significance level of…
Background: The presence of bone metastases (BMe) alters the balance of bone remodeling and conse... more Background: The presence of bone metastases (BMe) alters the balance of bone remodeling and consequently, levels of bone turnover markers (BTM). Increased levels of these biomarkers are related to the risk of skeletal-related events (SREs), disease progression and death. Treatment with bisphosphonates reduces the probability of SREs through osteoclastic activity inhibition. The aim of this study was to determine the relation between BTM, bone metastasis development and SREs, disease progression and death in patients with breast cancer (BC) and BMe. Patients and methods: Observational, prospective and multicenter study. Patients with BC and BMe; no previous bone treatment in the last 6 months prior to study entry. Urinary aminoterminal telopeptide of collagen I (NTX, Osteomark NTx Urine, Wampole Laboratories, USA); urinary alpha-alpha-isomer of carboxyterminal telopeptide of collagen I (αα-CTX, ALPHA Crosslaps EIA, ids, UK) and serum bone alkaline phosphatase (BALP, OSTASE BAP, ids, ...
GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mappin... more GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the fine mapping of this locus using data from 101,943 subjects from 50 case-control studies. We genotype 276 SNPs using the…
The approved capecitabine regimen as monotherapy in metastatic breast cancer (MBC) is 1,250 mg/m(... more The approved capecitabine regimen as monotherapy in metastatic breast cancer (MBC) is 1,250 mg/m(2) twice daily for 2 weeks on and 1 week off (Cint). Dose modifications are often required because of severe hand-foot syndrome (HFS). We tested a continuous regimen with a lower daily dose but a similar cumulative dose in an attempt to reduce the severity of adverse events (AEs) while maintaining efficacy. We randomized 195 patients with HER-2/neu-negative MBC to capecitabine 800 mg/m(2) twice daily throughout the 21-day cycle (Ccont) or to Cint to assess noninferiority in the percentage of patients free of progression at 1 year. Secondary endpoints included efficacy and safety. Associations between polymorphisms in capecitabine metabolism-related genes and drug response were assessed. The percentage of patients free of progression at 1 year was 27.3% with Cint versus 25.3% with Ccont (difference of -2.0%; 95% confidence interval: -15.5% to 11.5%, exceeding the 15% deemed noninferior). ...
Using the Breast Cancer Association Consortium, the authors previously reported that the single n... more Using the Breast Cancer Association Consortium, the authors previously reported that the single nucleotide polymorphism 7q21-rs6964587 (AKAP9-M463I) is associated with breast cancer risk. The authors have now assessed this association more comprehensively using 16 independent case-control studies.
Breast cancer is a heterogeneous disease. In clinical practice, tumors are classified as hormonal... more Breast cancer is a heterogeneous disease. In clinical practice, tumors are classified as hormonal receptor positive, Her2 positive and triple negative tumors. In previous works, our group defined a new hormonal receptor positive subgroup, the TN-like subtype, which has a prognosis and a molecular profile more similar to triple negative tumors. In this study, proteomics and Bayesian networks were used to characterize protein relationships in 106 breast tumor samples. Components obtained by these methods had a clear functional structure. The analysis of these components suggested differences in processes such as metastasis or proliferation between breast cancer subtypes, including our new subtype TN-like. In addition, one of the components, mainly related with metastasis, had prognostic value in this cohort. Functional approaches allow to build hypotheses about regulatory mechanisms and to establish new relationships among proteins in the breast cancer context.Author SummaryBreast can...
Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the... more Genetic variations, such as single nucleotide polymorphisms (SNPs) in microRNAs (miRNA) or in the miRNA binding sites may affect the miRNA dependent gene expression regulation, which has been implicated in various cancers, including breast cancer, and may alter individual susceptibility to cancer. We investigated associations between miRNA related SNPs and breast cancer risk. First we evaluated 2,196 SNPs in a case-control study combining nine genome wide association studies (GWAS). Second, we further investigated 42 SNPs with suggestive evidence for association using 41,785 cases and 41,880 controls from 41 studies included in the Breast Cancer Association Consortium (BCAC). Combining the GWAS and BCAC data within a meta-analysis, we estimated main effects on breast cancer risk as well as risks for estrogen receptor (ER) and age defined subgroups. Five miRNA binding site SNPs associated significantly with breast cancer risk: rs1045494 (odds ratio (OR) 0.92; 95% confidence interval ...
Anthracyclines are among the most used chemotherapeutic agents in breast cancer (BC). However the... more Anthracyclines are among the most used chemotherapeutic agents in breast cancer (BC). However their use is hampered by anthracycline-induced cardiotoxicity (AIC). The currently known clinical and genetic risk factors do not fully explain the observed inter-individual variability and only have a limited ability to predict which patients are more likely to develop this severe toxicity. To identify novel predictive genes, we conducted a two-stage genome-wide association study in epirubicin-treated BC patients. In the discovery phase, we genotyped over 700,000 single nucleotide variants in a cohort of 227 patients. The most interesting finding was rs62134260, located 4kb upstream of POLRMT (OR = 5.76, P = 2.23 × 10−5). We replicated this association in a validation cohort of 123 patients (P = 0.021). This variant regulates the expression of POLRMT, a gene that encodes a mitochondrial DNA-directed RNA polymerase, responsible for mitochondrial gene expression. Individuals harbouring the r...
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