Browsing by Author "Abramson, Vandana G."

Now showing 1 - 5 of 5
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    Epithelial Expressed B7-H4 Drives Differential Immunotherapy Response in Murine and Human Breast Cancer
    (American Association for Cancer Research, 2024) Wescott, Elizabeth C.; Sun, Xiaopeng; Gonzalez-Ericsson, Paula; Hanna, Ann; Taylor, Brandie C.; Sanchez, Violeta; Bronzini, Juliana; Opalenik, Susan R.; Sanders, Melinda E.; Wulfkuhle, Julia; Gallagher, Rosa I.; Gomez, Henry; Isaacs, Claudine; Bharti, Vijaya; Wilson, John T.; Ballinger, Tarah J.; Santa-Maria, Cesar A.; Shah, Payal D.; Dees, Elizabeth C.; Lehmann, Brian D.; Abramson, Vandana G.; Hirst, Gillian L.; Brown Swigart, Lamorna; van ˈt Veer, Laura J.; Esserman, Laura J.; Petricoin, Emanuel F.; Pietenpol, Jennifer A.; Balko, Justin M.; Medicine, School of Medicine
    Combinations of immune checkpoint inhibitors (ICI, including anti-PD-1/PD-L1) and chemotherapy have been FDA approved for metastatic and early-stage triple-negative breast cancer (TNBC), but most patients do not benefit. B7-H4 is a B7 family ligand with proposed immunosuppressive functions being explored as a cancer immunotherapy target and may be associated with anti-PD-L1 resistance. However, little is known about its regulation and effect on immune cell function in breast cancers. We assessed murine and human breast cancer cells to identify regulation mechanisms of B7-H4 in vitro. We used an immunocompetent anti-PD-L1-sensitive orthotopic mammary cancer model and induced ectopic expression of B7-H4. We assessed therapy response and transcriptional changes at baseline and under treatment with anti-PD-L1. We observed B7-H4 was highly associated with epithelial cell status and transcription factors and found to be regulated by PI3K activity. EMT6 tumors with cell-surface B7-H4 expression were more resistant to immunotherapy. In addition, tumor-infiltrating immune cells had reduced immune activation signaling based on transcriptomic analysis. Paradoxically, in human breast cancer, B7-H4 expression was associated with survival benefit for patients with metastatic TNBC treated with carboplatin plus anti-PD-L1 and was associated with no change in response or survival for patients with early breast cancer receiving chemotherapy plus anti-PD-1. While B7-H4 induces tumor resistance to anti-PD-L1 in murine models, there are alternative mechanisms of signaling and function in human cancers. In addition, the strong correlation of B7-H4 to epithelial cell markers suggests a potential regulatory mechanism of B7-H4 independent of PD-L1. Significance: This translational study confirms the association of B7-H4 expression with a cold immune microenvironment in breast cancer and offers preclinical studies demonstrating a potential role for B7-H4 in suppressing response to checkpoint therapy. However, analysis of two clinical trials with checkpoint inhibitors in the early and metastatic settings argue against B7-H4 as being a mechanism of clinical resistance to checkpoints, with clear implications for its candidacy as a therapeutic target.
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    Identifying homologous recombination deficiency in breast cancer: genomic instability score distributions differ among breast cancer subtypes
    (Springer, 2023) Lenz, Lauren; Neff, Chris; Solimeno, Cara; Cogan, Elizabeth S.; Abramson, Vandana G.; Boughey, Judy C.; Falkson, Carla; Goetz, Matthew P.; Ford, James M.; Gradishar, William J.; Jankowitz, Rachel C.; Kaklamani, Virginia G.; Marcom, P. Kelly; Richardson, Andrea L.; Storniolo, Anna Maria; Tung, Nadine M.; Vinayak, Shaveta; Hodgson, Darren R.; Lai, Zhongwu; Dearden, Simon; Hennessy, Bryan T.; Mayer, Erica L.; Mills, Gordon B.; Slavin, Thomas P.; Gutin, Alexander; Connolly, Roisin M.; Telli, Melinda L.; Stearns, Vered; Lanchbury, Jerry S.; Timms, Kirsten M.; Medicine, School of Medicine
    Purpose: A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of BRCA1/2-deficient estrogen receptor-positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of BRCA1/2-deficient ovarian cancer. Methods: Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic BRCA1/2 mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes. Results: A total of 560 ovarian cancer, 805 ER + BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of BRCA1/2-deficient samples was shifted lower for ER + BC (p = 0.015), but not TNBC (p = 0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of ≥ 42 and ≥ 33 were significant predictors of response to platinum therapy. Conclusions: This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER + BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy.
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    NKG2A Is a Therapeutic Vulnerability in Immunotherapy Resistant MHC-I Heterogeneous Triple-Negative Breast Cancer
    (American Association for Cancer Research, 2024) Taylor, Brandie C.; Sun, Xiaopeng; Gonzalez-Ericsson, Paula I.; Sanchez, Violeta; Sanders, Melinda E.; Wescott, Elizabeth C.; Opalenik, Susan R.; Hanna, Ann; Chou, Shu-Ting; Van Kaer, Luc; Gomez, Henry; Isaacs, Claudine; Ballinger, Tarah J.; Santa-Maria, Cesar A.; Shah, Payal D.; Dees, Elizabeth C.; Lehmann, Brian D.; Abramson, Vandana G.; Pietenpol, Jennifer A.; Balko, Justin M.; Medicine, School of Medicine
    Despite the success of immune checkpoint inhibition (ICI) in treating cancer, patients with triple-negative breast cancer (TNBC) often develop resistance to therapy, and the underlying mechanisms are unclear. MHC-I expression is essential for antigen presentation and T-cell-directed immunotherapy responses. This study demonstrates that TNBC patients display intratumor heterogeneity in regional MHC-I expression. In murine models, loss of MHC-I negates antitumor immunity and ICI response, whereas intratumor MHC-I heterogeneity leads to increased infiltration of natural killer (NK) cells in an IFNγ-dependent manner. Using spatial technologies, MHC-I heterogeneity is associated with clinical resistance to anti-programmed death (PD) L1 therapy and increased NK:T-cell ratios in human breast tumors. MHC-I heterogeneous tumors require NKG2A to suppress NK-cell function. Combining anti-NKG2A and anti-PD-L1 therapies restores complete response in heterogeneous MHC-I murine models, dependent on the presence of activated, tumor-infiltrating NK and CD8+ T cells. These results suggest that similar strategies may enhance patient benefit in clinical trials. Significance: Clinical resistance to immunotherapy is common in breast cancer, and many patients will likely require combination therapy to maximize immunotherapeutic benefit. This study demonstrates that heterogeneous MHC-I expression drives resistance to anti-PD-L1 therapy and exposes NKG2A on NK cells as a target to overcome resistance.
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    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.
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    Subcutaneous vs Intravenous Trastuzumab/Pertuzumab: A Time and Motion Substudy of a Phase II Trial of Adjuvant Trastuzumab/Pertuzumab for Stage I HER2+ Breast Cancer (ADEPT trial)
    (Wolters Kluwer, 2025) Waks, Adrienne G.; Chen, Emily L.; Graham, Noah; Frey, Anna Mae; Almeida, Kenneth; Attaya, Victoria; Ryding, Cari; Abbass, Ibrahim; Fung, Anita; Sussell, Jesse; Cortazar, Patricia; Harvey, Caroline; Leth, Denise; Faggen, Meredith; Sinclair, Natalie; Walsh, Jeanna; Tung, Nadine; Sinclair, Sarah; Lo, Steve; Yardley, Denise; Valero, Vicente; Meisel, Jane; Ballinger, Tarah J.; Adams, Sylvia; Carey, Lisa A.; Rauch, Julia K.; Abramson, Vandana G.; Williams, Nicole O.; Chen, Wendy Y.; Leone, Jose P.; Schumer, Susan T.; Tayob, Nabihah; Tolaney, Sara M.; Medicine, School of Medicine
    Purpose: The time required for in-clinic drug administration can substantially affect breast cancer patients' quality of life. Subcutaneous (SC) drug administration, as opposed to intravenous (IV), may reduce this time commitment. This study sought to estimate the difference in time burden between IV and SC administration of trastuzumab and pertuzumab (HP). Methods: We prospectively enrolled a subcohort of patients participating in the ADEPT trial (ClinicalTrials.gov identifier: NCT04569747, investigating adjuvant HP plus endocrine therapy for stage I human epidermal growth factor receptor 2-positive breast cancer) to this single-arm crossover time and motion substudy. Patients received two cycles of IV HP followed by two cycles of SC HP. During each cycle, time points in drug preparation and administration were captured. The primary end point was total patient time in the treatment chair. Additional end points included total patient treatment experience time and total pharmacy workflow time. A sample size of 22 patients was estimated to provide 90.7% power with two-sided alpha .05 to detect a difference of 70 minutes in the primary end point by treatment arm (IV v SC). Results: Twenty-two patients were enrolled. The mean total patient time in the treatment chair was 61.8 minutes shorter with SC versus IV HP (22.5 v 84.3 minutes; P < .0001). The mean total patient treatment experience time (incorporating time spent waiting for treatment initiation and time spent in the treatment chair) was 81.8 minutes shorter for SC administration (96 v 177.8 minutes; P < .0001). The pharmacy workflow time was 78.2 minutes shorter for SC versus IV formulation (41 v 119.2 minutes; P < .0001). Conclusion: SC administration of HP shortened patient time burden by approximately 1 hour. SC drug administration can facilitate faster workflows for health care professionals and improve patients' breast cancer treatment experience.