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

Community structure and feeding ecology of mesopelagic fishes in the slope waters of King-George Island (South Shetland Islands, Antarctica)

The role of mesopelagic fishes in the Southern Ocean ecosystem and more particular their trophic effect on the standing stock of mesozooplankton is at present poorly understood. To get a deeper insight in the Antarctic mid-water ecosystem the mesopelagic fish community of the King George Island slope (South Shetland Islands) was sampled with a pelagic trawl in 1996. The community structure was analysed and the feeding ecology was studied of the five most abundant species. A total of 18 mesopelagic fish species in 10 families was identified. Of these, the Myctophidae was the most important family by species number (9 species), individual number (98.5% of all individuals)and fish wet weight (87.3% of the total weight). The assemblage was numerically dominated by four myctophids (Electrona antarctica, Gymnoscopelus braueri, Gymnoscopelus nicholsi,Protomyctophum bolini) and one gempilyd (Paradiplospinus gracilis). Multivariate statisticalanalysis of the mesopelagic fish data reveals two major groups of stations according to the sampleddepth: a shallow group of stations (295â450 m depth) and a deeper group of stations (440â825 mdepth). The change in relative abundance of mesopelagic fish species at 440â450 m coincides withthe presence of warmer and denser Circumpolar Deep Water at and below these depths. Deeperstations were characterized by a higher density and increased diversity of mesopelagic fish species.The community patterns identified correlated well with the vertical depth distribution of the mostabundant species. Dietary analysis reveals that myctophids are mostly zooplanktivorous, while thegempilyd P. gracilis is classified as a piscivorous predator. The small P. bolini feed mainly oncopepods of the species Metridia gerlachei, while the most important prey item of the largermyctophids E. antarctica, G. braueri, and G. nicholsi were various species of euphausiids.Investigation of feeding chronology showed that G. nicholsi and P. bolini were feeding day andnight. Daily ration estimates for myctophid species ranged from 0.28% to 3.3% of dry body weight(0.5â5.94% of wet body weight). Krill (Euphausia superba) were the most important food of E.antarctica and G. nicholsi, accounting for 53.1% and 58.3% of the total food weight, respectively.The annual removal from the krill stock by both species was estimated to amount to 11.1â26.7% inthe South Shetland Islands region. This estimate emphasizes the important role of mesopelagic fish inthe Antarctic ecosystem as a prevalent consumer of krill