Alberto Ocaña

Centro de Investigación Biomédica en Red de Cáncer

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Document Type

Co-Authors

Atanasio Pandiella

Centro de Investigación Biomédica en Red de Cáncer

222

Eitan Amir

University of Toronto

159

BŠ

Boštjan Šeruga

Institute of Oncology Ljubljana

117

Verónica Corrales‐Sánchez

Complejo Hospitalario Universitario de Albacete

Arnoud J. Templeton

St. Claraspital

Cristina Nieto‐Jiménez

Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

Juan Carlos Montero

Complejo Hospitalario de Salamanca

Eva María Galán‐Moya

University of Castilla-La Mancha

Francisco Vera-Badillo

Queen's University

Ian F. Tannock

Princess Margaret Cancer Centre

Cooperative Institutions

Centro de Investigación Biomédica en Red de Cáncer

131

Instituto de Salud Carlos III

127

University of Toronto

123

Hospital Clínico San Carlos

107

Instituto de Investigación Sanitaria del Hospital Clínico San Carlos

105

Princess Margaret Cancer Centre

Universidad de Salamanca

Hospital General Universitario de Albacete

University of Castilla-La Mancha

Centro de Investigación Biomédica en Red

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Impact of comorbidity on the outcome in men with advanced prostate cancer treated with docetaxel

Radiology and Oncology (2015)

Andrej Žist Eitan Amir Alberto Ocaña Boštjan Šeruga

Men with metastatic castrate-resistant prostate cancer (mCRPC) may not receive docetaxel in everyday clinical practice due to comorbidities. Here we explore the impact of comorbidity on outcome in men with mCRPC treated with docetaxel in a population-based outcome study.Men with mCRPC treated with docetaxel at the Institute of Oncology Ljubljana between 2005 and 2012 were eligible. Comorbidity was assessed by the age-adjusted Charlson comorbidity index (aa-CCI) and adult comorbidity evaluation (ACE-27) index. Hospital admissions due to the toxicity and deaths during treatment with docetaxel were used as a measure of tolerability. Association between comorbidity and overall survival (OS) was tested using the Cox proportional hazards analysis.Two hundred and eight men were treated with docetaxel. No, mild, moderate and severe comorbidity was present in 2%, 32%, 53% and 13% using aa-CCI and in 27%, 35%, 29% and 8% when assessed by ACE-27. A substantial dose reduction of docetaxel occurred more often in men with moderate or severe comorbidity as compared to those with no or mild comorbidity. At all comorbidity levels about one-third of men required hospitalization or died during treatment with docetaxel. In univariate analysis a higher level of comorbidity was not associated with worse OS (aa-CCI HR 0.99; [95% CI 0.87-1.13], p = 0.93; ACE-27: HR 0.96; [95% CI 0.79-1.17], p = 0.69).Men with mCRPC, who have comorbidities may benefit from treatment with docetaxel.

Tolerability

10.1515/raon-2015-0038

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Citations (7)

Cardiovascular Toxicity of Multi-Tyrosine Kinase Inhibitors in Advanced Solid Tumors: A Population-Based Observational Study

PLoS ONE (2015)

Amirrtha Srikanthan Josée-Lyne Ethier Alberto Ocaña Boštjan Šeruga Monika K. Krzyzanowska

Background Treatment with small molecule tyrosine kinase inhibitors (TKIs) has improved survival in many cancers, yet has been associated with an increased risk of adverse events. Warnings of cardiovascular events are common in drug labels of many TKIs. Despite these warnings, cardiovascular toxicity of patients treated with TKIs remains unclear. Here, we evaluate the cardiovascular outcomes of advanced cancer patients treated with small molecule tyrosine kinase inhibitors. Methods A population based cohort study was undertaken involving adults aged >18 years in Ontario, Canada, diagnosed with any advanced malignancy between 2006 and 2012. Data were extracted from linked administrative governmental databases. Adults with advanced cancer receiving TKIs were identified and followed throughout the time period. The main outcomes of interest were rates of hospitalization for ischemic heart disease (acute myocardial infarction and angina) or cerebrovascular accidents and death. Results 1642 patients with a mean age of 62.5 years were studied; 1046 were treated with erlotinib, 166 with sorafenib and 430 with sunitinib. Over the 380 day median follow-up period (range 6-1970 days), 1.1% of all patients had ischemic heart events, 0.7% had cerebrovascular accidents and 72.1% died. Rates of cardiovascular events were similar to age and gender-matched individuals without cancer. In a subgroup analysis of treatment patients with a prior history of ischemic heart disease, 3.3% had ischemic heart events while 1.2% had cerebrovascular accidents. Conclusions TKIs do not appear to increase the cause-specific hazard of ischemic heart disease and cerebrovascular accidents compared to age and gender-matched individuals without advanced cancer.

Stroke

10.1371/journal.pone.0122735

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Citations (17)

Breast Cancer Heterogeneity and Response to Novel Therapeutics

Cancers (2020)

Mariona Baliu‐Piqué Atanasio Pandiella Alberto Ocaña

Targeted cancer therapies against oncogenic drivers are actively being developed and tested in clinical trials. Targeting an oncogenic driver may only prove effective if the mutation is present in most tumoral cells. Therefore, highly heterogeneous tumors may be refractory to these therapies. This makes tumor heterogeneity a major challenge in cancer therapy. Although heterogeneity has traditionally been attributed to genetic diversity within cancer cell populations, it is now widely recognized that human cancers are heterogeneous in almost all distinguishable phenotypic characteristics. Understanding the genetic variability and also the non-genetic influences of tumor heterogeneity will provide novel insights into how to reverse therapeutic resistance and improve cancer therapy.

Tumor Heterogeneity

Tumour heterogeneity

10.3390/cancers12113271

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Citations (56)

Toxicity of Extended Adjuvant Therapy With Aromatase Inhibitors in Early Breast Cancer: A Systematic Review and Meta-analysis

JNCI Journal of the National Cancer Institute (2017)

Hadar Goldvaser T. Barnes Boštjan Šeruga David W. Cescon Alberto Ocaña

A number of randomized controlled trials (RCTs) have reported improvement in breast cancer outcomes from extending treatment with aromatase inhibitors (AIs) beyond the initial five years after diagnosis. However, the toxicity profile of extended AIs is uncertain.We identified RCTs that compared extended AIs to placebo or no treatment using MEDLINE and a review of abstracts from key conferences between 2013 and 2016. Odds ratios (ORs), 95% confidence intervals (CIs), absolute risks, and the number needed to harm (NNH) were computed for prespecified safety and tolerability outcomes including cardiovascular events, bone fractures, second cancers (excluding new breast cancer), treatment discontinuation for adverse events, and death without recurrence. All statistical tests were two-sided.Seven trials comprising 16 349 patients met the inclusion criteria. Longer treatment with AIs was associated with increased odds of cardiovascular events (OR = 1.18, 95% CI = 1.00 to 1.40, P = .05, NNH = 122), bone fractures (OR = 1.34, 95% CI = 1.16 to 1.55, P < .001, NNH = 72), and treatment discontinuation for adverse events (OR = 1.45, 95% CI = 1.25 to 1.68, P < .001, NNH = 21). Longer treatment with AIs did not influence the odds of either second malignancy (OR = 0.93, 95% CI = 0.73 to 1.18, P = .56) or deaths without breast cancer recurrence (OR = 1.11, 95% CI = 0.90 to 1.36, P = .34).Extended treatment with AIs is associated with an increased risk of cardiovascular events and bone fractures. There is no statistically significant increase in deaths without breast cancer recurrence among patients receiving longer treatment with AIs. These data should be taken into account when considering extended adjuvant AIs.

Discontinuation

Tolerability

Aromatase inhibitor

10.1093/jnci/djx141

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Citations (152)

Expression of MHC class I, HLA-A and HLA-B identifies immune-activated breast tumors with favorable outcome

OncoImmunology (2019)

María del Mar Noblejas‐López Cristina Nieto‐Jiménez Sara Morcillo García Javier Pérez‐Peña Miriam Nuncia‐Cantarero

Antigen recognition by MHC class I molecules is a key step for the initiation of the immune response. We hypothesized that expression of these molecules could be a marker of immune-activated breast cancers. Data from KM Plotter were extracted to develop an exploratory cohort. Information from Cancer Genome Atlas (TCGA) and METABRIC was used to create two validation cohorts. Raw data were re-processed and analyzed using plyr R and Bioconductor. We predicted epitope-HLA binding to MHC I molecules by using NetMHC 4.0. Cox proportional hazards regression was computed to correlate gene expression and survival outcome. There was a weak but positive correlation between mutational burden and the expression of most MHC class I molecules. In the exploratory cohort, expression of HLA-A and HLA-B was associated with favorable relapse-free survival (RFS) and overall survival (OS) in the basal-like subgroup. This was confirmed in the METABRIC and TCGA dataset. Expression of HLA-A and HLA-B was associated with biomarkers of T cell activation (GZMA, GZMB, and PRF1) and improved the predictive capacity of known immunologic signatures. Several neopeptides expressed in breast cancer were also identified including FUK, SNAPC3, GC, ANO8, DOT1L, HIST1H3F, MYBPH, STX2, FRMD6, CPSF1, or SMTN, among others. Expression of HLA A and B is associated with T cell activation and identifies immune activated, basal-like breast cancers with favorable prognosis. Antigen recognition markers should be incorporated into the assessment of the tumor immune state of basal-like breast patients.

10.1080/2162402x.2019.1629780

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Citations (46)

Effect of Multikinase Inhibitors on Caspase-Independent Cell Death and DNA Damage in HER2-Overexpressing Breast Cancer Cells

JNCI Journal of the National Cancer Institute (2010)

Samuel Seoane Juan Carlos Montero Alberto Ocaña Atanasio Pandiella

The receptor tyrosine kinase, HER2, is overexpressed in approximately 25% of patients with breast cancer and is implicated in the aggressiveness of cancer. Targeting of HER2 signaling with trastuzumab, a monoclonal antibody that inhibits HER2 activity, has demonstrated clinical benefits.We investigated whether the antitumor activity of trastuzumab can be potentiated by dasatinib, a small-molecule tyrosine kinase inhibitor, on breast cancer cell lines that overexpress HER2 (BT474 and SKBR3) or have normal HER2 expression (MCF7 and T47D). Functional, biochemical, and gene expression microarray studies were performed to test the effect of trastuzumab, dasatinib, or a combination of trastuzumab and dasatinib on cell proliferation; HER activation; cell cycle; DNA damage; and apoptosis. The effect of drugs on mice (n = 6 per group) bearing xenograft tumors originating from HER2-overexpressing BT474 cells was assessed, and tumors were evaluated for an effect on volume, HER signaling, and DNA damage. All statistical tests were two-sided.Trastuzumab and dasatinib combination showed a synergistic effect on the proliferation of HER2-overexpressing breast cancer cells (combination index = 0.44, 95% confidence interval = 0.30 to 0.58). The drug combination also induced a stronger inhibitory effect on HER2 activation than the individual drugs, decreased the level of proteins involved in DNA damage response, induced DNA double-strand breaks, cell cycle arrest, and caspase-independent apoptosis. Mice (n = 6 per group) bearing xenograft tumors originating from HER2-overexpressing BT474 cells showed statistically significantly reduced tumor volume on day 28 when treated with the drug combination (control vs trastuzumab and dasatinib combination; mean volume = 2.6 vs 0.5 cm(3), difference = 2.1 cm(3), 95% confidence interval = 0.76 to 3.51 cm(3), P = .01) and total regression of tumors by day 36 with no later relapse.Results showed that HER2 and dasatinib-sensitive tyrosine kinases act in a synergistic manner to safeguard the breast cancer cells from DNA damage. The therapeutic targeting of multikinase inhibition opens new avenues for the treatment of HER2-positive breast cancer patients.

SKBR3

10.1093/jnci/djq315

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Identification of a stemness-related gene panel associated with BET inhibition in triple negative breast cancer

Annals of Oncology (2019)

Eva María Galán‐Moya Miriam Nuncia‐Cantarero Leticia Serrano‐Oviedo Sara Morcillo-García Cristina Nieto‐Jiménez

Triple-negative breast cancer

CD24

Matrigel

10.1093/annonc/mdz268.068

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