Browsing by Author "Liu, Minetta C."

Now showing 1 - 8 of 8
  • Thumbnail Image
    Item
    Adjuvant Trastuzumab Emtansine Versus Paclitaxel Plus Trastuzumab for Stage I Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer: 5-Year Results and Correlative Analyses From ATEMPT
    (Wolters Kluwer, 2024) Tarantino, Paolo; Tayob, Nabihah; Villacampa, Guillermo; Dang, Chau; Yardley, Denise A.; Isakoff, Steven J.; Valero, Vicente; Faggen, Meredith; Mulvey, Therese; Bose, Ron; Weckstein, Douglas; Wolff, Antonio C.; Reeder-Hayes, Katherine; Rugo, Hope S.; Ramaswamy, Bhuvaneswari; Zuckerman, Dan; Hart, Lowell; Gadi, Vijayakrishna K.; Constantine, Michael; Cheng, Kit; Merrill Garrett, Audrey; Marcom, P. Kelly; Albain, Kathy; DeFusco, Patricia; Tung, Nadine; Ardman, Blair; Nanda, Rita; Jankowitz, Rachel C.; Rimawi, Mothaffar; Abramson, Vandana; Pohlmann, Paula R.; Van Poznak, Catherine; Forero-Torres, Andres; Liu, Minetta C.; Ruddy, Kathryn J.; Waks, Adrienne G.; DeMeo, Michelle; Burstein, Harold J.; Partridge, Ann H.; Dell'Orto, Patrizia; Russo, Leila; Krause, Emma; Newhouse, Daniel J.; Kurt, Busem Binboğa; Mittendorf, Elizabeth A.; Schneider, Bryan; Prat, Aleix; Winer, Eric P.; Krop, Ian E.; Tolaney, Sara M.; Consortium of the TBCRC Translational Investigators; TBCRC Translational Investigators; Medicine, School of Medicine
    Purpose: Long-term outcomes of patients with stage I human epidermal growth factor receptor 2 (HER2)-positive breast cancer receiving adjuvant trastuzumab emtansine (T-DM1) remain undefined, and prognostic predictors represent an unmet need. Methods: In the ATEMPT phase II trial, patients with stage I centrally confirmed HER2-positive breast cancer were randomly assigned 3:1 to adjuvant T-DM1 for 1 year or paclitaxel plus trastuzumab (TH). Coprimary objectives were to compare the incidence of clinically relevant toxicities between arms and to evaluate invasive disease-free survival (iDFS) with T-DM1. Correlative analyses included the HER2DX genomic tool, multiomic evaluations of HER2 heterogeneity, and predictors of thrombocytopenia. Results: After a median follow-up of 5.8 years, 11 iDFS events were observed in the T-DM1 arm, consistent with a 5-year iDFS of 97.0% (95% CI, 95.2 to 98.7). At 5 years, the recurrence-free interval (RFI) was 98.3% (95% CI, 97.0 to 99.7), the overall survival was 97.8% (95% CI, 96.3 to 99.3), and the breast cancer-specific survival was 99.4% (95% CI, 98.6 to 100). Comparable iDFS was observed with T-DM1 irrespective of tumor size, hormone receptor status, centrally determined HER2 immunohistochemical score, and receipt of T-DM1 for more or less than 6 months. Although ATEMPT was not powered for this end point, the 5-year iDFS in the TH arm was 91.1%. Among patients with sufficient tissue for HER2DX testing (n = 187), 5-year outcomes significantly differed according to HER2DX risk score, with better RFI (98.1% v 81.8%, hazard ratio [HR], 0.10, P = .01) and iDFS (96.3% v 81.8%, HR, 0.20, P = .047) among patients with HER2DX low-risk versus high-risk tumors, respectively. Conclusion: Adjuvant T-DM1 for 1 year leads to outstanding long-term outcomes for patients with stage I HER2-positive breast cancer. A high HER2DX risk score predicted a higher risk of recurrence in ATEMPT.
  • Thumbnail Image
    Item
    Automated lesion detection of breast cancer in [18F] FDG PET/CT using a novel AI-Based workflow
    (Frontiers, 2022-11-14) Leal, Jeffrey P.; Rowe, Steven P.; Stearns, Vered; Connolly, Roisin M.; Vaklavas, Christos; Liu, Minetta C.; Storniolo, Anna Maria; Wahl, Richard L.; Pomper, Martin G.; Solnes, Lilja B.; Medicine, School of Medicine
    Applications based on artificial intelligence (AI) and deep learning (DL) are rapidly being developed to assist in the detection and characterization of lesions on medical images. In this study, we developed and examined an image-processing workflow that incorporates both traditional image processing with AI technology and utilizes a standards-based approach for disease identification and quantitation to segment and classify tissue within a whole-body [18F]FDG PET/CT study. Methods One hundred thirty baseline PET/CT studies from two multi-institutional preoperative clinical trials in early-stage breast cancer were semi-automatically segmented using techniques based on PERCIST v1.0 thresholds and the individual segmentations classified as to tissue type by an experienced nuclear medicine physician. These classifications were then used to train a convolutional neural network (CNN) to automatically accomplish the same tasks. Results Our CNN-based workflow demonstrated Sensitivity at detecting disease (either primary lesion or lymphadenopathy) of 0.96 (95% CI [0.9, 1.0], 99% CI [0.87,1.00]), Specificity of 1.00 (95% CI [1.0,1.0], 99% CI [1.0,1.0]), DICE score of 0.94 (95% CI [0.89, 0.99], 99% CI [0.86, 1.00]), and Jaccard score of 0.89 (95% CI [0.80, 0.98], 99% CI [0.74, 1.00]). Conclusion This pilot work has demonstrated the ability of AI-based workflow using DL-CNNs to specifically identify breast cancer tissue as determined by [18F]FDG avidity in a PET/CT study. The high sensitivity and specificity of the network supports the idea that AI can be trained to recognize specific tissue signatures, both normal and disease, in molecular imaging studies using radiopharmaceuticals. Future work will explore the applicability of these techniques to other disease types and alternative radiotracers, as well as explore the accuracy of fully automated and quantitative detection and response assessment.
  • No Thumbnail Available
    Item
    CYP2D6 Activity in Patients with Metastatic Breast Cancer Treated with Single Agent Tamoxifen: Results from ECOG-ACRIN E3108
    (Springer, 2025) Stearns, Vered; ONeill, Anne; Schneider, Bryan P.; Skaar, Todd C.; Liu, Minetta C.; Lohrisch, Caroline; Goetz, Matthew P.; Vallejos, Carlos S.; Sparano, Joseph A.; Villa, Diego; Silverman, Paula; Cheema, Puneet S.; Moore, Dennis F., Jr.; Sledge, George W., Jr.; Medicine, School of Medicine
    Purpose: In tamoxifen-treated individuals, reduced-function genetic variants in the CYP2D6 gene or inhibition of the enzyme result in low circulating endoxifen concentrations. We assessed the impact of reduced CYP2D6 activity and circulating endoxifen concentrations on breast cancer outcomes. Patients and methods: Patients with locally advanced or stage IV hormone receptor-positive breast cancer were enrolled in this single arm phase II trial and received open label tamoxifen 20 mg PO daily. The primary objective was to assess CYP2D6 poor metabolizer (PM) vs intermediate and normal metabolizer status (IM + NM) with progression-free survival (PFS). CYP2D6 phenotype was determined from whole blood samples (Roche Amplichip), and secondary endpoint evaluated endoxifen concentrations determined from 3 month post registration plasma samples (Quest Diagnostics). Results: From September 2010 to June 2013, 113 of planned 204 patients were registered to the trial and began protocol treatment. Accrual to the trial closed early due to lower-than-expected rate of CYP2D6 poor metabolizers. Median age was 62, 86% (97/113) were white, 33% (30/113) Hispanic, 83% (92/113) postmenopausal. Samples were evaluable for CYP2D6 in 75% (85/113) of patients (2/85 PM, 27/85 IM, and 56/85 NM). Median PFS for PM and IM + NM was 12.9 months and 6.9 months, respectively. Median PFS was 11.1 and 13.8 months respectively for patients with low (≤ 15.5) and high (> 15.5) endoxifen concentrations (ng/ml). Conclusion: We did not observe significant associations between CYP2D6 metabolizer status or endoxifen with PFS. Small sample sizes and barriers to adequate samples in this trial prohibited determination of relationship between these markers and PFS.
  • Thumbnail Image
    Item
    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.
  • Thumbnail Image
    Item
    Significance of Circulating Tumor Cells in metastatic triple negative breast cancer patients within a randomized, phase II trial: TBCRC 019
    (American Association for Cancer Research, 2015-06) Paoletti, Costanza; Li, Yufeng; Muñiz, Maria C.; Kidwell, Kelley M.; Aung, Kimberly; Thomas, Dafydd G.; Brown, Martha E.; Abramson, Vandana G.; Irvin, William J., Jr.; Lin, Nancy U.; Liu, Minetta C.; Nanda, Rita; Nangia, Julie R.; Storniolo, Anna M.; Traina, Tiffany A.; Vaklavas, Christos; Van Poznak, Catherine H.; Wolff, Antonio C.; Forero-Torres, Andres; Hayes, Daniel F.; Department of Medicine, IU School of Medicine
    Purpose: Circulating tumor cells (CTC) are prognostic in metastatic breast cancer (MBC). We tested whether EpCAM-based capture system (CellSearch) is effective in patients with triple-negative (TN) MBC, and whether CTC apoptosis and clustering enhances the prognostic role of CTC. Experimental Design: CTC enumeration and apoptosis were determined using the CXC CellSearch kit at baseline and days 15 and 29 in blood drawn from TN MBC patients who participated in a prospective randomized phase II trial of nanoparticle albumin-bound paclitaxel (nab-paclitaxel) with or without tigatuzumab. Association between levels of CTC and patient outcomes was assessed using logistic regression, Kaplan–Meier curves, and Cox proportional hazards modeling. Results: Nineteen of 52 (36.5%), 14 of 52 (26.9%), and 13 of 49 (26.5%) patients who were evaluable had elevated CTC (≥5 CTC/7.5 mL whole blood) at baseline and at days 15 and 29, respectively. Patients with elevated versus not elevated CTC at each time point had worse progression-free survival (PFS; P = 0.005, 0.0003, 0.0002, respectively). The odds of clinical benefit response for those who had elevated versus low CTC at baseline and days 15 and 29 were 0.25 (95% CI: 0.08–0.84; P = 0.024), 0.19 (95% CI: 0.05–0.17; P = 0.014), and 0.06 (95% CI: 0.01–0.33; P = 0.001), respectively. There was no apparent prognostic effect comparing CTC apoptosis versus non-apoptosis. Presence of CTC cluster at day 15 and day 29 was associated with shorter PFS. Conclusions: CTC were detected using CellSearch assay in approximately one-third of TN MBC patients. Elevated CTC at baseline and days 15 and 29 were prognostic, and reductions in CTC levels reflected response.
  • Thumbnail Image
    Item
    TBCRC 018: phase II study of iniparib in combination with irinotecan to treat progressive triple negative breast cancer brain metastases
    (Springer, 2014) Anders, Carey; Deal, Allison M.; Abramson, Vandana; Liu, Minetta C.; Storniolo, Anna M.; Carpenter, John T.; Puhalla, Shannon; Nanda, Rita; Melhem-Bertrandt, Amal; Lin, Nancy U.; Marcom, P. Kelly; Van Poznak, Catherine; Stearns, Vered; Melisko, Michelle; Smith, J. Keith; Karginova, Olga; Parker, Joel; Berg, Jonathan; Winer, Eric P.; Peterman, Amy; Prat, Aleix; Perou, Charles M.; Wolff, Antonio C.; Carey, Lisa A.; Medicine, School of Medicine
    Nearly half of patients with advanced triple negative breast cancer (TNBC) develop brain metastases (BM) and most will also have uncontrolled extracranial disease. This study evaluated the safety and efficacy of iniparib, a small molecule anti-cancer agent that alters reactive oxygen species tumor metabolism and penetrates the blood brain barrier, with the topoisomerase I inhibitor irinotecan in patients with TNBC-BM. Eligible patients had TNBC with new or progressive BM and received irinotecan and iniparib every 3 weeks. Time to progression (TTP) was the primary end point; secondary endpoints were response rate (RR), clinical benefit rate (CBR), overall survival (OS), toxicity, and health-related quality of life. Correlative endpoints included molecular subtyping and gene expression studies on pre-treatment archival tissues, and determination of germline BRCA1/2 status. Thirty-seven patients began treatment; 34 were evaluable for efficacy. Five of 24 patients were known to carry a BRCA germline mutation (4 BRCA1, 1 BRCA2). Median TTP was 2.14 months and median OS was 7.8 months. Intracranial RR was 12 %, while intracranial CBR was 27 %. Treatment was well-tolerated; the most common grade 3/4 adverse events were neutropenia and fatigue. Grade 3/4 diarrhea was rare (3 %). Intrinsic subtyping revealed 19 of 21 tumors (79 %) were basal-like, and intracranial response was associated with high expression of proliferation-related genes. This study suggests a modest benefit of irinotecan plus iniparib in progressive TNBC-BM. More importantly, this trial design is feasible and lays the foundation for additional studies for this treatment-refractory disease.
  • Thumbnail Image
    Item
    TBCRC 019: A phase II trial of nanoparticle albumin-bound paclitaxel with or without the anti-death receptor 5 monoclonal antibody tigatuzumab in patients with triple negative breast cancer
    (2015-06) Forero-Torres, Andres; Varley, Katherine E.; Abramson, Vandana Gupta; Li, Yufeng; Vaklavas, Christos; Lin, Nancy U.; Liu, Minetta C.; Rugo, Hope S.; Nanda, Rita; Storniolo, Anna Maria; Traina, Tiffany A.; Patil, Sujata; Van Poznak, Catherine H.; Nangia, Julie R.; Irvin, William Johnson, Jr.; Krontiras, Helen; De Los Santos, Jennifer F.; Haluska, Paul; Grizzle, William; Meyers, Richard M.; Wolff, Antonio C.; Department of Medicine, IU School of Medicine
    Purpose: Tigatuzumab (TIG), an agonistic anti-DR5 antibody, triggers apoptosis in DR5+ human tumor cells without crosslinking. TIG has strong in vitro/in vivo activity against basal-like breast cancer cells enhanced by chemotherapy agents. This study evaluates activity of TIG and chemotherapy in patients with metastatic triple-negative breast cancer (TNBC). Experimental Design: Randomized 2:1 phase II trial of albumin-bound paclitaxel (nab-PAC) ± TIG in patients with TNBC stratified by prior chemotherapy. Patients received nab-PAC weekly × 3 ± TIG every other week, every 28 days. Primary objective was within-arm objective response rate (ORR). Secondary objectives were safety, progression-free survival (PFS), clinical benefit, and TIG immunogenicity. Metastatic research biopsies were required. Results: Among 64 patients (60 treated; TIG/nab-PAC n = 39 and nab-PAC n = 21), there were 3 complete remissions (CR), 8 partial remissions (PR; 1 almost CR), 11 stable diseases (SD), and 17 progressive diseases (PD) in the TIG/nab-PAC arm (ORR, 28%), and no CRs, 8 PRs, 4 SDs, and 9 PDs in the nab-PAC arm (ORR, 38%). There was a numerical increase in CRs and several patients had prolonged PFS (1,025+, 781, 672, 460, 334) in the TIG/nab-PAC arm. Grade 3 toxicities were 28% and 29%, respectively, with no grade 4–5. Exploratory analysis suggests an association of ROCK1 gene pathway activation with efficacy in the TIG/nab-PAC arm. Conclusions: ORR and PFS were similar in both. Preclinical activity of TIG in basal-like breast cancer and prolonged PFS in few patients in the combination arm support further investigation of anti-DR5 agents. ROCK pathway activation merits further evaluation.
  • Thumbnail Image
    Item
    Updated Results of TBCRC026: Phase II Trial Correlating Standardized Uptake Value With Pathological Complete Response to Pertuzumab and Trastuzumab in Breast Cancer
    (American Society of Clinical Oncology, 2021) Connolly, Roisin M.; Leal, Jeffrey P.; Solnes, Lilja; Huang, Chiung-Yu; Carpenter, Ashley; Gaffney, Katy; Abramson, Vandana; Carey, Lisa A.; Liu, Minetta C.; Rimawi, Mothaffar; Specht, Jennifer; Storniolo, Anna Maria; Valero, Vicente; Vaklavas, Christos; Krop, Ian E.; Winer, Eric P.; Camp, Melissa; Miller, Robert S.; Wolff, Antonio C.; Cimino-Mathews, Ashley; Park, Ben H.; Wahl, Richard L.; Stearns, Vered; Medicine, School of Medicine
    Purpose: Predictive biomarkers to identify patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer who may benefit from targeted therapy alone are required. We hypothesized that early measurements of tumor maximum standardized uptake value corrected for lean body mass (SULmax) on 18F-labeled fluorodeoxyglucose positron emission tomography-computed tomography (PET-CT) would predict pathologic complete response (pCR) to pertuzumab and trastuzumab (PT). Patients and methods: Patients with stage II or III, estrogen receptor-negative, HER2-positive breast cancer received four cycles of neoadjuvant PT. 18F-labeled fluorodeoxyglucose positron emission tomography-computed tomography was performed at baseline and 15 days after PT initiation (C1D15). Eighty evaluable patients were required to test the null hypothesis that the area under the curve of percent change in SULmax by C1D15 predicting pCR is ≤ 0.65, with a one-sided type I error rate of 10%. Results: Eighty-eight women were enrolled (83 evaluable), and 85% (75 of 88) completed all four cycles of PT. pCR after PT alone was 22%. Receiver operator characteristic analysis of percent change in SULmax by C1D15 yielded an area under the curve of 0.72 (80% CI, 0.64 to 0.80; one-sided P = .12), which did not reject the null hypothesis. However, between patients who obtained pCR and who did not, a significant difference in median percent reduction in SULmax by C1D15 was observed (63.8% v 41.8%; P = .004) and SULmax reduction ≥ 40% was more prevalent (83% v 52%; P = .03; positive predictive value, 31%). Participants not obtaining a 40% reduction in SULmax by C1D15 were unlikely to obtain pCR (negative predictive value, 91%). Conclusion: Although the primary objective was not met, early changes in SULmax predict response to PT in estrogen receptor-negative and HER2-positive breast cancer. Once optimized, this quantitative imaging strategy may facilitate tailoring of therapy in this setting.