Assignment of tumor subtype by genomic testing and pathologic-based approximations: implications on patient's management and therapy selection

BACKGROUND: Breast cancer subtypes can be identified by genomic testing or pathology-based approximations. However, these classifications are not equivalent and the clinical relevance of both classifications needs to be fully explored. METHODS: Ninety-four patients were randomized to neoadjuvant single agent doxorubicin or docetaxel. Tumor subtype was assessed by pathology-based classification and by gene expression using the PAM50 plus the claudin-low predictor (CLP). Kappa Cohen's coefficient (κ) was used to test the agreement between methods. Multivariate Cox proportional hazards analyses were used to determine the significance of each methodology in the prediction of prognosis. Likelihood ratio statistics of both classifications were evaluated. RESULTS: The agreement between pathology-based classification and PAM50 was moderate [κ = 0.551, 95 % confidence interval (95 % CI) 0.467-0.641]. Tumor subtype assessed by both classifications were prognostic for overall survival (OS) and relapse-free survival (P < 0.05). However, PAM50 + CLP provided more prognostic information, in terms of OS, than the pathology-based classification (P < 0.05). Patients with triple negative tumors as well as basal-like tumors had worse OS when first treated with doxorubicin (HR = 5.98, 95 % CI 1.25-28.67, and HR = 5.02, 95 % CI 0.96-26.38, respectively). However, claudin-low tumors did not show significant differences in OS according to neoadjuvant treatment branch. Indeed, we found that claudin-low tumors treated with pre-operative doxorubicin had significantly better OS than basal-like tumors treated with neoadjuvant doxorubicin (adjusted HR = 0.16, 95 % CI 0.04-0.69, P = 0.014). CONCLUSIONS: The assignment of tumor subtype can differ depending on the methodology, which might have implications on patient's management and therapy selection (AU)

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Study of KRAS new predictive marker in a clinical laboratory

BACKGROUND: The presence of somatic mutations in the KRAS gene has been identified as a reliable strong negative predictor for the response to targeting the epidermal growth factor receptor (EGFR), in patients with metastatic colorectal cancer and the use of anti-EGFR monoclonal antibodies such as Cetuximab and Panitumumab is now restricted to patients with no detectable KRAS mutations. Between 30 and 40 % of colorectal cancers contain a mutated KRAS oncogene. The aim of this study was to evaluate concordance between three methods to analyze KRAS mutational status in regard to clinical testing. METHODS: We analyzed KRAS mutations in codons 12 and 13 of exon 2 in one hundred formalin-fixed paraffin-embedded (FFPE) colorectal cancer samples by three different methods: Direct Sequencing and two commercial kits on allele-specific oligonucleotide hybridization (KRAS StripAssay, Vienna Lab.) and Amplification Refractory Mutation System/Scorpions (ARMS/S; TheraScreen KRAS Mutation kit DxS) based on q-PCR. RESULTS: We have found similar frequencies of KRAS mutations by TheraScreen and Strip-Assay (44 and 48 %), with a κ value of 0.90, indicating almost perfect agreement between methods. The frequency by direct sequencing was much lower (26 %) and the κ values were 0.67 (compared to TheraScreen) and 0.57 (compared to Strip-Assay) indicating low sensitivity. CONCLUSIONS: On analyzing KRAS mutation in FFPE tumor samples, direct sequencing sensitivity is too low to be used in a clinical setting. Choosing between ARMS/S; TheraScreen KRAS Mutation kit DxS and KRAS StripAssay, Vienna Lab, will depend on laboratory facilities and expertise (AU)

Risk-reduction surgery in BRCA mutation carriers in a Spanish population: adherence and results

OBJECTIVE: To analyse the level of adherence to prophylactic surgery of breast and/or ovarian cancer in female carriers of the BRCA1 or BRCA2 mutation in a referential genetic counselling unit in Spain. METHODS: Between January 1998 and November 2006, a total of 684 families with several cases of breast and/or ovarian cancer were selected by the Genetic Counselling Unit at the Hospital Clínico Universitario San Carlos. Some of them opted for prophylactic surgery after genetic counselling and genetic testing. RESULTS: The pathogenic mutation was found in 57 families out of a total of 449 families who fulfilled the hereditary breast/ovarian cancer criteria. Out of a total of 238 individuals who were carriers of the mutation, 136 (57%) were offered risk-reducing prophylactic surgery. Prophylactic surgery was chosen by 58 (43%) women out of a total of 136 who were offered this possibility; the histological findings observed 7% malignant lesions in the breast and, in the ovarian-fallopian complex, 2 cases (8%) of a borderline tumour and one case (4%) of papillary adenocarcinoma. CONCLUSION: This is the first study published on the role of prophylactic surgery in BRCA mutation carriers in the Spanish population. The incidence of occult carcinoma in these cases is lower than in other series (AU)

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Consejo genético: modelo de predicción de riesgo de mutación en familias con cáncer de mama/ovario / Genetic counselling: prediction model of mutation in breatslovarian cancer families

El objetivo de este estudio es el desarrollo de un modelo logístico de riesgo pretest de ser portador de mutación en familias españolas con cáncer de mama/ovario, y la evaluación de su valor predictivo. Para ello se desarrolló un estudio con 48 familias con síndrome mama/ovario. Este estudio consistió en el análisis mutacional completo de los genes BRCA1 y BRCA2, y en la realización de un estudio retrospectivo de distintos parámetros en las familias con/sin mutación para discriminar cuáles de las variables influyen en el riesgo de ser portador y en qué medida. El resultado es un modelo estadístico que estima el riesgo (R) pretest atribuible a cada familia en función de características fenotípicas, como el número de cánceres de ovario y la edad de diagnóstico de cáncer de mama. El punto de corte estadísticamente óptimo para la realización del test genético en una familia es R>=30%. Además, la eficacia del modelo en la predicción del riesgo es superior a la capacidad predictiva de un consejero genético experto que se basa en criterios subjetivos. En conclusión, podemos decir que el modelo propuesto constituye una herramienta muy útil para el consejo genético, ya que asigna el riesgo de ser portador de mutación sobre la base de criterios clínicos valorables y objetivos. Permite, por tanto, la personalización del consejo gen ético y la optimización de los recursos de estas unidades

The aim of this study is to develop a statistical model to calculate pre-test probability of being a BRCA1/2 mutation carrier in Spanish breast/ovarian families, and its prediction capability. 148 breast ovarian families participated in the study. This, consisted in the complete mutational screening of BRCA1 and BRCA2 genes and the development of a retrospective analysis of different variables for predicting the probability of harbouring a mutation in either BRCA1 or BRCA2 as a function of the cancer phenotype present in the family. The result is a pre-test logistic model that consider some clinical elements as number of ovarian cancer in the family or the mean age at diagnosis of breast cancel: The statistical cut-off for risk value is 30%. Also, the model in crease the discriminarían power of an experienced risk counsellor; suggesting that the use is valuable in the context of clinical counselling and genetic testing to optimise selection of patients for screening and allowing for more focused management