Browsing by Author "Pascual, Tomas"

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    A Multiparameter Molecular Classifier to Predict Response to Neoadjuvant Lapatinib plus Trastuzumab without Chemotherapy in HER2+ Breast Cancer
    (American Association for Cancer Research, 2023) Veeraraghavan, Jamunarani; Gutierrez, Carolina; De Angelis, Carmine; Davis, Robert; Wang, Tao; Pascual, Tomas; Selenica, Pier; Sanchez, Katherine; Nitta, Hiroaki; Kapadia, Monesh; Pavlick, Anne C.; Galvan, Patricia; Rexer, Brent; Forero-Torres, Andres; Nanda, Rita; Storniolo, Anna M.; Krop, Ian E.; Goetz, Matthew P.; Nangia, Julie R.; Wolff, Antonio C.; Weigelt, Britta; Reis-Filho, Jorge S.; Hilsenbeck, Susan G.; Prat, Aleix; Osborne, C. Kent; Schiff, Rachel; Rimawi, Mothaffar F.; Medicine, School of Medicine
    Purpose: Clinical trials reported 25% to 30% pathologic complete response (pCR) rates in HER2+ patients with breast cancer treated with anti-HER2 therapies without chemotherapy. We hypothesize that a multiparameter classifier can identify patients with HER2-"addicted" tumors who may benefit from a chemotherapy-sparing strategy. Experimental design: Baseline HER2+ breast cancer specimens from the TBCRC023 and PAMELA trials, which included neoadjuvant treatment with lapatinib and trastuzumab, were used. In the case of estrogen receptor-positive (ER+) tumors, endocrine therapy was also administered. HER2 protein and gene amplification (ratio), HER2-enriched (HER2-E), and PIK3CA mutation status were assessed by dual gene protein assay (GPA), research-based PAM50, and targeted DNA-sequencing. GPA cutoffs and classifier of response were constructed in TBCRC023 using a decision tree algorithm, then validated in PAMELA. Results: In TBCRC023, 72 breast cancer specimens had GPA, PAM50, and sequencing data, of which 15 had pCR. Recursive partitioning identified cutoffs of HER2 ratio ≥ 4.6 and %3+ IHC staining ≥ 97.5%. With PAM50 and sequencing data, the model added HER2-E and PIK3CA wild-type (WT). For clinical implementation, the classifier was locked as HER2 ratio ≥ 4.5, %3+ IHC staining ≥ 90%, and PIK3CA-WT and HER2-E, yielding 55% and 94% positive (PPV) and negative (NPV) predictive values, respectively. Independent validation using 44 PAMELA cases with all three biomarkers yielded 47% PPV and 82% NPV. Importantly, our classifier's high NPV signifies its strength in accurately identifying patients who may not be good candidates for treatment deescalation. Conclusions: Our multiparameter classifier differentially identifies patients who may benefit from HER2-targeted therapy alone from those who need chemotherapy and predicts pCR to anti-HER2 therapy alone comparable with chemotherapy plus dual anti-HER2 therapy in unselected patients.
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    Multiomics in primary and metastatic breast tumors from the AURORA US network finds microenvironment and epigenetic drivers of metastasis
    (Springer Nature, 2023) Garcia-Recio, Susana; Hinoue, Toshinori; Wheeler, Gregory L.; Kelly, Benjamin J.; Garrido-Castro, Ana C.; Pascual, Tomas; De Cubas, Aguirre A.; Xia, Youli; Felsheim, Brooke M.; McClure, Marni B.; Rajkovic, Andrei; Karaesmen, Ezgi; Smith, Markia A.; Fan, Cheng; Gonzalez Ericsson, Paula I.; Sanders, Melinda E.; Creighton, Chad J.; Bowen, Jay; Leraas, Kristen; Burns, Robyn T.; Coppens, Sara; Wheless, Amy; Rezk, Salma; Garrett, Amy L.; Parker, Joel S.; Foy, Kelly K.; Shen, Hui; Park, Ben H.; Krop, Ian; Anders, Carey; Gastier-Foster, Julie; Rimawi, Mothaffar F.; Nanda, Rita; Lin, Nancy U.; Isaacs, Claudine; Marcom, P. Kelly; Storniolo, Anna Maria; Couch, Fergus J.; Chandran, Uma; Davis, Michael; Silverstein, Jonathan; Ropelewski, Alexander; Liu, Minetta C.; Hilsenbeck, Susan G.; Norton, Larry; Richardson, Andrea L.; Symmans, W. Fraser; Wolff, Antonio C.; Davidson, Nancy E.; Carey, Lisa A.; Lee, Adrian V.; Balko, Justin M.; Hoadley, Katherine A.; Laird, Peter W.; Mardis, Elaine R.; King, Tari A.; AURORA US Network; Perou, Charles M.; Medicine, School of Medicine
    The AURORA US Metastasis Project was established with the goal to identify molecular features associated with metastasis. We assayed 55 females with metastatic breast cancer (51 primary cancers and 102 metastases) by RNA sequencing, tumor/germline DNA exome and low-pass whole-genome sequencing and global DNA methylation microarrays. Expression subtype changes were observed in ~30% of samples and were coincident with DNA clonality shifts, especially involving HER2. Downregulation of estrogen receptor (ER)-mediated cell-cell adhesion genes through DNA methylation mechanisms was observed in metastases. Microenvironment differences varied according to tumor subtype; the ER+/luminal subtype had lower fibroblast and endothelial content, while triple-negative breast cancer/basal metastases showed a decrease in B and T cells. In 17% of metastases, DNA hypermethylation and/or focal deletions were identified near HLA-A and were associated with reduced expression and lower immune cell infiltrates, especially in brain and liver metastases. These findings could have implications for treating individuals with metastatic breast cancer with immune- and HER2-targeting therapies.