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Browsing by Author "Santa-Maria, Cesar A."
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Item Association of Variants in Candidate Genes with Lipid Profiles in Women with Early Breast Cancer on Adjuvant Aromatase Inhibitor Therapy(American Association for Cancer Research, 2016-03-15) Santa-Maria, Cesar A.; Blackford, Amanda; Nguyen, Anne T.; Skaar, Todd C.; Philips, Santosh; Oesterreich, Steffi; Rae, James M.; Desta, Zeruesenay; Robarge, Jason; Henry, Norah Lynn; Storniolo, Anna M.; Hayes, Daniel F.; Blumenthal, Roger S.; Ouyang, Pamela; Post, Wendy S.; Flockhart, David A.; Stearns, Vered; Medicine, School of MedicinePurpose: Aromatase inhibitors can exert unfavorable effects on lipid profiles; however, previous studies have reported inconsistent results. We describe the association of single-nucleotide polymorphisms (SNP) in candidate genes with lipid profiles in women treated with adjuvant aromatase inhibitors. Experimental design: We conducted a prospective observational study to test the associations between SNPs in candidate genes in estrogen signaling and aromatase inhibitor metabolism pathways with fasting lipid profiles during the first 3 months of aromatase inhibitor therapy in postmenopausal women with early breast cancer randomized to adjuvant letrozole or exemestane. We performed genetic association analysis and multivariable linear regressions using dominant, recessive, and additive models. Results: A total of 303 women had complete genetic and lipid data and were evaluable for analysis. In letrozole-treated patients, SNPs in CYP19A1, including rs4646, rs10046, rs700518, rs749292, rs2289106, rs3759811, and rs4775936 were significantly associated with decreases in triglycerides by 20.2 mg/dL and 39.3 mg/dL (P < 0.00053), respectively, and with variable changes in high-density lipoprotein (HDL-C) from decreases by 4.2 mg/dL to increases by 9.8 mg/dL (P < 0.00053). Conclusions: Variants in CYP19A1 are associated with decreases in triglycerides and variable changes in HDL-C in postmenopausal women on adjuvant aromatase inhibitors. Future studies are needed to validate these findings, and to identify breast cancer survivors who are at higher risk for cardiovascular disease with aromatase inhibitor therapy.Item 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 MedicineCombinations 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.Item Landmark trials in the medical oncology management of metastatic breast cancer(Elsevier, 2021) Lu, Pei; Santa-Maria, Cesar A.; Ballinger, Tarah J.; Sheng, Jennifer Y.; Medicine, School of MedicineSignificant advances in the management of metastatic breast cancer (MBC) have guided more personalized treatment according to disease biology and led to improved survival outcomes and quality of life for patients. In this review, we discuss landmark clinical trials in medical oncology that have shaped the current standard of care for MBC. Combinations of endocrine therapy with cyclin-dependent kinase 4/6 inhibitors have led to substantial improvements in overall survival, thus becoming standard first-line treatment for patients with HR-positive MBC. Inhibition of the PI3K and mTOR pathway is another promising strategy to overcome resistance to endocrine therapy. HER2-targeted therapies have also evolved with the addition of pertuzumab to trastuzumab plus a taxane demonstrating remarkable overall survival advantage in patient with HER2-positive MBC. In second or later line therapies, novel anti-HER2 antibody-drug conjugates and TKIs have durable antitumor activity, survival benefit, and encouraging efficacy in the subgroup of patients with brain metastases. Triple negative breast cancer remains the most challenging subtype due to lack of druggable targets. Immunotherapy for patients with PDL-1 expression on tumor infiltrating immune cells and poly (ADP-ribose) polymerase inhibitors for those with germline BRCA1/2 mutations are the latest approved targeted strategies in this population. Numerous obstacles still exist in treating MBC, especially for patients whose disease develops resistance to available agents. Future research is eagerly awaited to address the optimal sequence or combination of therapies and to identify better biomarkers to guide precision medicine.Item 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 MedicineDespite 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.