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.

Cardiotoxicity

Discontinuation

10.1634/theoncologist.2008-0137

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Citations (146)

Re-interpretation of PAM50 gene expression as quantitative tumor dimensions shows utility for clinical trials: application to prognosis and response to paclitaxel in breast cancer

Breast Cancer Research and Treatment (2019)

Nicola J. Camp Michael J. Madsen Jesús Herránz Álvaro Rodríguez-Lescure Amparo Ruı́z

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. 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. Dimensions PC1 and PC5 were associated with DFS (Cox PH p = 6.7 $$\times$$ 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 $$\times$$ 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. 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.

Categorical variable

10.1007/s10549-018-05097-5

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Citations (18)

Impairment of Mossy Fiber Long-Term Potentiation and Associative Learning in Pituitary Adenylate Cyclase Activating Polypeptide Type I Receptor-Deficient Mice

Journal of Neuroscience (2001)

Christiane Otto Yury Kovalchuk David P Wolfer Peter Gass Miguel Martín

The pituitary adenylate cyclase activating polypeptide (PACAP) type I receptor (PAC1) is a G-protein-coupled receptor binding the strongly conserved neuropeptide PACAP with 1000-fold higher affinity than the related peptide vasoactive intestinal peptide. PAC1-mediated signaling has been implicated in neuronal differentiation and synaptic plasticity. To gain further insight into the biological significance of PAC1-mediated signaling in vivo, we generated two different mutant mouse strains, harboring either a complete or a forebrain-specific inactivation of PAC1. Mutants from both strains show a deficit in contextual fear conditioning, a hippocampus-dependent associative learning paradigm. In sharp contrast, amygdala-dependent cued fear conditioning remains intact. Interestingly, no deficits in other hippocampus-dependent tasks modeling declarative learning such as the Morris water maze or the social transmission of food preference are observed. At the cellular level, the deficit in hippocampus-dependent associative learning is accompanied by an impairment of mossy fiber long-term potentiation (LTP). Because the hippocampal expression of PAC1 is restricted to mossy fiber terminals, we conclude that presynaptic PAC1-mediated signaling at the mossy fiber synapse is involved in both LTP and hippocampus-dependent associative learning.

Mossy fiber (hippocampus)

Associative learning

10.1523/jneurosci.21-15-05520.2001

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Citations (185)

Biomarker Analyses of Response to Cyclin-Dependent Kinase 4/6 Inhibition and Endocrine Therapy in Women with Treatment-Naïve Metastatic Breast Cancer

Clinical Cancer Research (2019)

Richard S. Finn Yuan Liu Zhou Zhu Miguel Martín Hope S. Rugo

Abstract Purpose: Preclinical data identified the cyclin-dependent kinase 4/6 (CDK4/6) inhibitor palbociclib as synergistic with antiestrogens in inhibiting growth of hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2−) human breast cancer models. This observation was validated clinically in the randomized, placebo-controlled, phase III PALOMA-2 study. Experimental Design: To determine markers of sensitivity and resistance to palbociclib plus letrozole, we performed comprehensive biomarker analyses, investigating the correlation with progression-free survival (PFS), on baseline tumor tissues from PALOMA-2. Results: Despite a broad biomarker search, palbociclib plus letrozole demonstrated consistent PFS gains versus placebo plus letrozole, with no single biomarker or cassette of markers associated with lack of benefit from combination treatment. Palbociclib plus letrozole confers efficacy on both luminal A and B patients. Higher CDK4 levels were associated with endocrine resistance which was mitigated by the addition of palbociclib, whereas lower PD-1 levels were associated with greater palbociclib plus letrozole benefit. Tumors with more active growth factor signaling, as exemplified by increased expression of FGFR2 and ERBB3 mRNA, appeared to be associated with greater PFS gain from the addition of palbociclib. Conclusions: These data underscore the importance of CDK4/6 signaling in HR+/HER2− breast cancer and suggest that the interplay between steroid hormone and peptide growth factor signaling could drive dependence on CDK4/6 signaling. See related commentary by Anurag et al., p. 3

Palbociclib

Letrozole

Cyclin-dependent kinase 4

Fulvestrant

10.1158/1078-0432.ccr-19-0751

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Citations (155)

El cáncer de mama

Arbor (2015)

Miguel Martín Ana Herrero Isabel Echavarría

RESUMEN: El cáncer de mama es un problema socio-sanitario de primer orden en España debido a su elevada incidencia.En las últimas tres décadas se han producido notables mejoras en la supervivencia debidas tanto a la introducción de las campañas de cribado mamográfico como a los nuevos tratamientos médicos.Pese a estos datos optimistas, no hay que olvidar que aún quedan pacientes que recaen tras el tratamiento del tumor mamario (cerca del 20%) y fallecen a causa de la enfermedad, por lo que es importante continuar con los esfuerzos de investigación en cáncer de mama hasta conseguir una tasa de recaída cero

10.3989/arbor.2015.773n3004

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Supplementary Figure S8 from CCNE1 and PLK1 Mediate Resistance to Palbociclib in HR+/HER2− Metastatic Breast Cancer

Ángel Guerrero-Zotano Stefania Belli Christoph Zielinski Miguel Gil‐Gil Antonio Fernández‐Serra

Effects of PLK1 gene modulation on cell sensitivity to palbociclib alone or in combination with fulvestrant in ER+ breast cancer cell lines

Palbociclib

Fulvestrant

10.1158/1078-0432.22633147.v1

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Supplementary Figure 3 from Phase I Study of CC-486 Alone and in Combination with Carboplatin or nab-Paclitaxel in Patients with Relapsed or Refractory Solid Tumors

Daniel D. Von Hoff Drew Rasco Elisabeth I. Heath Pamela N. Münster Jan H.M. Schellens

Correlation analysis between pharmacodynamic and pharmacokinetic findings in part 1

Carboplatin

Pharmacodynamics

Refractory (planetary science)

Nab-paclitaxel

10.1158/1078-0432.22469370.v1

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Clinical and Sociodemographic Determinants of Adherence to World Cancer Research Fund/American Institute for Cancer Research (WCRF/AICR) Recommendations in Breast Cancer Survivors—Health-EpiGEICAM Study

Cancers (2022)

Virginia Lope Ángel Guerrero-Zotano Emma Ruiz Begoña Bermejo Silvia Antolín

Breast cancer (BC) survivors are advised to follow the WCRF/AICR cancer prevention recommendations, given their high risk of developing a second tumour. We aimed to explore compliance with these recommendations in BC survivors and to identify potentially associated clinical and sociodemographic factors. A total of 420 BC survivors, aged 31-80, was recruited from 16 Spanish hospitals. Epidemiological, dietary and physical activity information was collected through questionnaires. A 7-item score to measure compliance with the recommendations was built according to the 2018 WCRF/AICR scoring criteria. Standardized prevalences and standardized prevalence ratios of moderate and high compliance across participant characteristics were estimated using multinomial and binary logistic regression models. The mean score was 3.9 (SD: 1.0) out of 7 points. Recommendations with the worst adherence were those of limiting consumption of red/processed meats (12% of compliance, 95% CI: 8.2-15.0) and high fibre intake (22% of compliance, 95% CI: 17.6-27.0), while the best compliance was observed for the consumption of fruits and vegetables (73% of compliance, 95% CI: 69.2-77.7). Overall, adherence was worse in women with university education and in those with first-degree relatives with BC. This information may be of interest to design and implement personalized preventive measures adapted to the characteristics of these patients.

Limiting

Cancer Prevention

10.3390/cancers14194705

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Abstract OT3-1-06: CIBOMA/2004-01_GEICAM/2003-11: A randomised phase III trial assessing adjuvant capecitabine (Cap) maintenance therapy after standard chemotherapy for triple-negative early breast cancer (EBC)

Cancer Research (2013)

C.H. Barrios Aña Lluch Manuel Ruíz‐Borrego José Bines Laura Torrecillas

Abstract Background: The ideal adjuvant treatment of triple negative EBC remains to be defined. CIBOMA/2004-01_GEICAM/2003-11 is a multinational randomized phase III trial exploring adjuvant Cap after the conclusion of conventional chemotherapy in triple-negative EBC patients. Materials and Methods: Patients with operable, node-positive (or node-negative with tumour diameter ≥1 cm), hormone receptor-negative, HER2-negative EBC that have received 6–8 cycles of standard anthracycline and/or taxane-containing chemotherapy in the (neo)adjuvant setting (doxorubicin–cyclophosphamide x 4 allowed for node-negative disease), followed by radiotherapy (if indicated) are eligible. After central confirmation of triple negativity by immunohistochemistry, patients were randomised to either 8 cycles of Cap (1,000 mg/m2 bid, d1–14 q21d) or observation. Stratification factors: centre, prior taxane (yes vs. no), involved nodes (0 vs. 1–3 vs. ≥4) and phenotype (basal vs. non-basal). The primary endpoint is disease-free survival (DFS). Secondary endpoints include 5-year DFS, overall survival and safety. An optional pharmacogenetic sub-study will explore polymorphisms of thymidylate synthase and methylenetetrahydrofolate reductase in relation to efficacy and tolerability of Cap. Present Status: Recruitment of 876 randomized patients was completed in September 2011. Statistical assumptions: expected 30% reduction in the risk of recurrence at 5 years (64.7% to 73.7%, HR 0.701), power of 80% and 0.05 two-sided significance level. Final efficacy analysis will be triggered by 255 events. Baseline characteristics are well balanced and shown in the table below. 75.0% of the patients completed the 8 cycles of adjuvant Cap. Baseline patients characteristics Capecitabine (n = 448)Observation (n = 428)Median Age, years (range)51 (20-79)50 (24-83)Basal Phenotype,%70.772.2Histology,% Ductal87.786.1Lobular1.82.3Other9.811.4Unknown0.70.2Grade,% 13.32.8218.119.0371.969.6Not determinable6.08.4Unknown0.70.2Chemotherapy received,% Adjuvant (only)78.982.2Neoadjuvant (only)15.615.0Adjuvant + Neoadjuvant4.22.6Unknown1.30.2Postmenopausal,%69.267.3Prior Chemotherapy Agents,% Anthracyclines without taxanes32.132.2Anthracyclines and taxanes67.267.6Unknown0.70.2 Conclusions: This randomized phase III adjuvant trial in triple negative EBC patients has completed accrual and event follow up is ongoing. The trial is sponsored by CIBOMA/GEICAM. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr OT3-1-06.

Triple-negative breast cancer

Taxane

Tolerability

Clinical endpoint

10.1158/0008-5472.sabcs13-ot3-1-06

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Citations (3)

Data from Analysis of Fcγ Receptor IIIa and IIa Polymorphisms: Lack of Correlation with Outcome in Trastuzumab-Treated Breast Cancer Patients

Sara A. Hurvitz David J. Betting Howard M. Stern Emmanuel Quinaux Jeremy Stinson

<div>AbstractPurpose: The mechanisms by which trastuzumab imparts clinical benefit remain incompletely understood. Antibody-dependent cellular cytotoxicity via interactions with Fcγ receptors (FcγR) on leukocytes may contribute to its antitumor effects. Single-nucleotide polymorphisms (SNP) in FCGR3A and FCGR2A genes lead to amino acid substitutions at positions 158 and 131, respectively, and affect binding of antibodies to FcγR such that 158V/V and 131H/H bind with highest affinity. This study aimed to determine whether high-affinity SNPs are associated with disease-free survival (DFS) among patients with HER2-positive nonmetastatic breast cancer.Experimental Design: Genomic DNA was isolated from 1,286 patients enrolled in a trial of adjuvant trastuzumab-based chemotherapy. Genotyping was conducted using Sanger sequencing and Sequenom mass spectrometry.Results: Patient samples (N = 1,189) were successfully genotyped for FCGR3A and 1,218 for FCGR2A. Compared with the overall results of the BCIRG006 study, in the subset of patients genotyped in this analysis, a less robust improvement in DFS was observed for the trastuzumab arms than control arm (HR, 0.842; P = 0.1925). When stratified for prognostic features, the HR in favor of trastuzumab was consistent with that of the overall study (HR, 0.74; P = 0.036). No correlation between DFS and FCGR3A/2A genotypes was seen for trastuzumab-treated patients (158V/V vs. V/F vs. F/F, P = 0.98; 131H/H vs. H/R vs. R/R, P = 0.76; 158V/V and/or 131H/H vs. others, P = 0.67).Conclusion: This analysis evaluating the association between FCGR3A/2A genotypes and trastuzumab efficacy in HER2-positive breast cancer did not show a correlation between FCGR3A-V/F and FCGR2A-H/R SNPs and DFS in patients treated with trastuzumab. Clin Cancer Res; 18(12); 3478–86. ©2012 AACR.</div>

10.1158/1078-0432.c.6519876

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