- Browse by Author
Browsing by Author "Abramson, Vandana G."
Now showing 1 - 3 of 3
Results Per Page
Sort Options
Item 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 MedicinePurpose: 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.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.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 MedicinePurpose: 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.