Integrated analysis of RNA and DNA from the phase III trial CALGB 40601 identifies predictors of response to trastuzumab-based neoadjuvant chemotherapy in HER2-positive breast cancer

Purpose: Response to a complex trastuzumab-based regimen is affected by multiple features of the tumor and its microenvironment. Developing a predictive algorithm is key to optimizing HER2-targeting therapy. Experimental Design: We analyzed 137 pretreatment tumors with mRNA-seq and DNA exome sequencing from CALGB 40601, a neoadjuvant phase III trial of paclitaxel plus trastuzumab with or without lapatinib in stage II to III HER2-positive breast cancer. We adopted an Elastic Net regularized regression approach that controls for covarying features within high-dimensional data. First, we applied 517 known gene expression signatures to develop an Elastic Net model to predict pCR, which we validated on 143 samples from four independent trials. Next, we performed integrative analyses incorporating clinicopathologic information with somatic mutation status, DNA copy number alterations (CNA), and gene signatures. Results: The Elastic Net model using only gene signatures predicted pCR in the validation sets (AUC ¼ 0.76). Integrative analyses showed that models containing gene signatures, clinical features, and DNA information were better pCR predictors than models containing a single data type. Frequently selected variables from the multiplatform models included amplifications of chromosome 6p, TP53 mutation, HER2-enriched subtype, and immune signatures. Variables predicting resistance included Luminal/ERþ features. Conclusions: Models using RNA only, as well as integrated RNA and DNA models, can predict pCR with improved accuracy over clinical variables. Somatic DNA alterations (mutation, CNAs), tumor molecular subtype (HER2E, Luminal), and the microenvironment (immune cells) were independent predictors of response to trastuzumab and paclitaxel-based regimens. This highlights the complexity of predicting response in HER2-positive breast cancer

Serial Analysis of Circulating Tumor Cells in Metastatic Breast Cancer Receiving First-Line Chemotherapy

BACKGROUND: We examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy. METHODS: Serial CTC data from 469 patients (2202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs, combined CTC status at baseline to the end of cycle 1, and tCTC. Akaike information criterion was used to select the model that best predicted PFS and OS. RESULTS: Latent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (56.9% ), low (23.7%), intermediate (14.5%), or high (4.9%). Patients with low, intermediate, and high tCTC patterns had statistically significant inferior PFS and OS compared with those with undetectable CTCs (P < .001). Akaike Information Criterion indicated that the tCTC model best predicted PFS and OS compared with baseline CTCs and combined CTC status at baseline to the end of cycle 1 models. Validation studies in an independent cohort of 1856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model. CONCLUSIONS: We identified 4 novel prognostic groups in MBC based on similarities in tCTC patterns during chemotherapy. Prognostic groups included patients with very poor outcome (intermediate + high CTCs, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be used for fine-tuning of CTC-based risk stratification strategies to guide future prospective clinical trials in MBC

Aspectos biológicos e pesqueiros de Paralonchurus brasiliensis Steindachner, (Pisces, Sciaenidae), na Armação do Itapocoroy, Penha, Santa Catarina, Brasil Biological and fishing aspects of Paralonchurus brasiliensis Steindachner, (Pisces, Sciaenidae), in the Armação do Itapocoroy, Penha, Santa Catarina, Brazil

Apesar da abundância de Paralonchurus brasiliensis (Steindachner, 1875) na ictiofauna acompanhante do camarão sete-barbas, apresenta baixo valor comercial sendo freqüentemente descartada. Esse trabalho tem como objetivo apresentar informações básicas sobre a biologia e pesca de P. brasiliensis na Armação do Itapocoroy, Penha, Santa Catarina. As coletas foram realizadas mensalmente durante o período de agosto 1996 a julho 2003, em três áreas tradicionais de atuação da pesca artesanal. A espécie apresentou crescimento alométrico positivo, com uma razão sexual de 1:2,1 entre machos e fêmeas, e tamanho de primeira maturação em 14,8 cm e 15,0 cm. P. brasiliensis apresentou amplo espectro trófico composto por 27 itens, sendo que, a partir da primavera ocorreu um incremento gradual na ingestão de alimento até o verão, seguido de queda abrupta no outono e de pequena recuperação no inverno. Apesar das flutuações sazonais ao longo dos sete anos, essa espécie ocupou a segunda posição em número e biomassa entre as integrantes da ictiofauna acompanhante.<br>Due to abundance of P. brasiliensis (Steindachner, 1875) in ictiofauna of the sea-bob-shrimp's bycatch, it presents low commercial value and frequently being discarded. This work aims to present basic information on biology and fisheries of P. brasiliensis in the Armação do Itapocoroy, Penha, Santa Catarina. The collections were carried out monthly during the period of August 1996 to July 2003, in three traditional areas of performance of artisan fisheries. The species presented positive alometric growth, with a sexual ratio of 1:2,1 between males and females, and the size of first maturation in 14,8 cm and 15,0 cm. P. brasiliensis presented a great trophy specter composed by 27 items, being that, from the spring a gradual increment in the food ingestion occurred until the summer, followed of abrupt fall in the autumn and small recovery in the winter. Despite of the seasonal fluctuations during the seven years, this species occupied the second position in number and biomass among the integrant of ictiofauna bycatch