Browsing by Author "Badve, Sunil"
Now showing 1 - 10 of 59
Results Per Page
Sort Options
Item A Gene Signature to Determine Metastatic Behavior in Thymomas(Public Library of Science, 2013-07-24) Gökmen-Polar, Yesim; Cook, Robert W.; Goswami, Chirayu Pankaj; Wilkinson, Jeff; Maetzold, Derek; Stone, John F.; Oelschlager, Kristen M.; Vladislav, Ioan Tudor; Shirar, Kristen L.; Kesler, Kenneth A.; Loehrer, Patrick J.; Badve, Sunil; Medicine, School of MedicinePurpose: Thymoma represents one of the rarest of all malignancies. Stage and completeness of resection have been used to ascertain postoperative therapeutic strategies albeit with limited prognostic accuracy. A molecular classifier would be useful to improve the assessment of metastatic behaviour and optimize patient management. Methods: qRT-PCR assay for 23 genes (19 test and four reference genes) was performed on multi-institutional archival primary thymomas (n = 36). Gene expression levels were used to compute a signature, classifying tumors into classes 1 and 2, corresponding to low or high likelihood for metastases. The signature was validated in an independent multi-institutional cohort of patients (n = 75). Results: A nine-gene signature that can predict metastatic behavior of thymomas was developed and validated. Using radial basis machine modeling in the training set, 5-year and 10-year metastasis-free survival rates were 77% and 26% for predicted low (class 1) and high (class 2) risk of metastasis (P = 0.0047, log-rank), respectively. For the validation set, 5-year metastasis-free survival rates were 97% and 30% for predicted low- and high-risk patients (P = 0.0004, log-rank), respectively. The 5-year metastasis-free survival rates for the validation set were 49% and 41% for Masaoka stages I/II and III/IV (P = 0.0537, log-rank), respectively. In univariate and multivariate Cox models evaluating common prognostic factors for thymoma metastasis, the nine-gene signature was the only independent indicator of metastases (P = 0.036). Conclusion: A nine-gene signature was established and validated which predicts the likelihood of metastasis more accurately than traditional staging. This further underscores the biologic determinants of the clinical course of thymoma and may improve patient management.Item A phase II study of buparlisib in relapsed or refractory thymomas(Frontiers, 2022-10-17) Abu Zaid, Mohammad I.; Radovich, Milan; Althouse, Sandra; Liu, Hao; Spittler, Aaron J.; Solzak, Jeffrey; Badve, Sunil; Loehrer Sr., Patrick J.; Medicine, School of MedicinePurpose To investigate the efficacy and safety of buparlisib, an oral pan-PI3K inhibitor, in relapsed or refractory thymomas. Methods This was a single center, single arm, open label phase II trial of buparlisib in patients with recurrent thymoma who have progressed after at least one prior line of treatment. The primary endpoint was objective response rate (complete response [CR] + partial response [PR]). Secondary endpoints included toxicity; progression free survival (PFS); overall survival (OS); disease control rate (DCR), i.e., the percentage of patients who achieve either PR or CR or stable disease [SD] for at least 4 months. Results Between 10/13/2014 and 1/18/2017, 14 patients with stage IV disease were enrolled. Median age was 58y (23–74). 71% were females and 71% white. All patients had WHO B2 (29%) or B3 (71%) thymoma. Patients received buparlisib for a median of 4.5m (2–33). At a median follow up of 16.6m (2.4–31.3), onr patients (7%) achieved a PR. DCR was 50%. Median PFS was 11.1m (95% CI 2.9 – 18.8). Median OS, updated as of March, 2021 was 22.5m (10.7–31.3). Most common grade 3-4 adverse events related to buparlisib were dyspnea (21%), rash (14%), elevated transaminases (14%), cough (7%), pneumonitis (7%), anxiety (7%), fatigue (7%) and hyperglycemia (7%). Reasons for treatment discontinuation included progression of disease (n= 5), rash (n=4), pulmonary toxicity (n=3), sinusitis (n=1), and disseminated toxoplasmosis plus autoimmune cholangitis (n=1). As of 3/2021, 8 patients have died, 7 due to disease progression and 1 due to central nervous system toxoplasmosis and autoimmune cholangitis. Conclusion Buparlisib showed modest activity in patients with relapsed or refractory thymomas. Further investigation of PI3K pathway targeted therapy in thymoma is warranted. (clinicaltrials.gov ID: NCT02220855). Clinical trial registration clinicaltrials.gov, identifier (NCT02220855)Item A phase II study of buparlisib in relapsed or refractory thymomas(Frontiers Media, 2022-10-18) Abu Zaid, Mohammad I.; Radovich, Milan; Althouse, Sandra; Liu, Hao; Spittler, Aaron J.; Solzak, Jeffrey; Badve, Sunil; Loehrer, Patrick J.; Medicine, School of MedicinePurpose: To investigate the efficacy and safety of buparlisib, an oral pan-PI3K inhibitor, in relapsed or refractory thymomas. Methods: This was a single center, single arm, open label phase II trial of buparlisib in patients with recurrent thymoma who have progressed after at least one prior line of treatment. The primary endpoint was objective response rate (complete response [CR] + partial response [PR]). Secondary endpoints included toxicity; progression free survival (PFS); overall survival (OS); disease control rate (DCR), i.e., the percentage of patients who achieve either PR or CR or stable disease [SD] for at least 4 months. Results: Between 10/13/2014 and 1/18/2017, 14 patients with stage IV disease were enrolled. Median age was 58y (23-74). 71% were females and 71% white. All patients had WHO B2 (29%) or B3 (71%) thymoma. Patients received buparlisib for a median of 4.5m (2-33). At a median follow up of 16.6m (2.4-31.3), onr patients (7%) achieved a PR. DCR was 50%. Median PFS was 11.1m (95% CI 2.9 - 18.8). Median OS, updated as of March, 2021 was 22.5m (10.7-31.3). Most common grade 3-4 adverse events related to buparlisib were dyspnea (21%), rash (14%), elevated transaminases (14%), cough (7%), pneumonitis (7%), anxiety (7%), fatigue (7%) and hyperglycemia (7%). Reasons for treatment discontinuation included progression of disease (n= 5), rash (n=4), pulmonary toxicity (n=3), sinusitis (n=1), and disseminated toxoplasmosis plus autoimmune cholangitis (n=1). As of 3/2021, 8 patients have died, 7 due to disease progression and 1 due to central nervous system toxoplasmosis and autoimmune cholangitis. Conclusion: Buparlisib showed modest activity in patients with relapsed or refractory thymomas. Further investigation of PI3K pathway targeted therapy in thymoma is warranted.Item Adjuvant Durvalumab Following Trimodality Therapy for Locally Advanced Esophageal and Gastroesophageal Junction Adenocarcinoma(Elsevier, 2021) Mamdani, Hirva; Schneider, Bryan; Perkins, Susan M.; Burney, Heather; Kasi, Pashtoon Murtaza; Abushahin, Laith; Birdas, Thomas; Kesler, Kenneth; Watkins, Tracy M.; Badve, Sunil; Jalal, Shadia I.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthBackground: Concurrent chemoradiation (CRT) followed by esophagectomy is a standard of care for resectable locally advanced esophageal and gastroesophageal junction (GEJ) adenocarcinoma. The relapse rate is high among patients who do not achieve a pathologic complete response (pCR) following neoadjuvant CRT. Methods: We conducted a phase II study of durvalumab in patients with locally advanced esophageal and GEJ adenocarcinoma who have undergone preoperative CRT followed by R0 resection with histologic evidence of persistent residual disease in the surgical specimen. Patients received durvalumab 1500 mg IV every four weeks for up to one year. The primary endpoint was 1-year relapse free survival (RFS). Findings: Thirty-seven patients were enrolled. The majority (64∙9%) had pathologically positive lymph nodes. One-year RFS was 73%, and median RFS was 21 months (95% CI, 14-40.4 months). Nineteen (51∙4%) patients had PD-L1 CPS of ≥1% and 7 (18∙9%) had PD-L1 CPS of ≥10%. There was a numerical trend toward superior 1-year RFS among patients with PD-L1 positive disease compared to those with PD-L1 negative disease, using CPS of ≥10% (100% vs 66.7%, p=0.1551) and ≥1% (84.2% vs 61.1%, p=0.1510) cutoffs. The most common treatment related adverse events were fatigue (27%), diarrhea (18.9%), arthralgia (16.2%), nausea (16.2%), pruritus (16.2%), cough (10.8%), and increase in AST/ALT/bilirubin (10.8%). Three (8.1%) patients developed grade 3 immune mediated adverse events, including pneumonitis(1), colitis(1), and hepatitis(1). Interpretation: Adjuvant durvalumab in patients with residual disease in the surgical specimen following trimodality therapy for locally advanced esophageal and GEJ adenocarcinoma led to clinically meaningful improvement in 1-year RFS compared to historical control rate. Higher PD-L1 expression may have a correlation with the efficacy of durvalumab in this setting.Item AKT Alters Genome-Wide Estrogen Receptor α Binding and Impacts Estrogen Signaling in Breast Cancer(American Society for Microbiology, 2008-12) Bhat-Nakshatri, Poornima; Wang, Guohua; Appaiah, Hitesh; Luktuke, Nikhil; Carroll, Jason S.; Geistlinger, Tim R.; Brown, Myles; Badve, Sunil; Liu, Yunlong; Nakshatri, HarikrishnaEstrogen regulates several biological processes through estrogen receptor α (ERα) and ERβ. ERα-estrogen signaling is additionally controlled by extracellular signal activated kinases such as AKT. In this study, we analyzed the effect of AKT on genome-wide ERα binding in MCF-7 breast cancer cells. Parental and AKT-overexpressing cells displayed 4,349 and 4,359 ERα binding sites, respectively, with ∼60% overlap. In both cell types, ∼40% of estrogen-regulated genes associate with ERα binding sites; a similar percentage of estrogen-regulated genes are differentially expressed in two cell types. Based on pathway analysis, these differentially estrogen-regulated genes are linked to transforming growth factor β (TGF-β), NF-κB, and E2F pathways. Consistent with this, the two cell types responded differently to TGF-β treatment: parental cells, but not AKT-overexpressing cells, required estrogen to overcome growth inhibition. Combining the ERα DNA-binding pattern with gene expression data from primary tumors revealed specific effects of AKT on ERα binding and estrogen-regulated expression of genes that define prognostic subgroups and tamoxifen sensitivity of ERα-positive breast cancer. These results suggest a unique role of AKT in modulating estrogen signaling in ERα-positive breast cancers and highlights how extracellular signal activated kinases can change the landscape of transcription factor binding to the genome.Item ANTXR1, a stem cell enriched functional biomarker, connects collagen signaling to cancer stem-like cells and metastasis in breast cancer(American Association for Cancer Research, 2013-09-15) Chen, Daohong; Bhat-Nakshatri, Poornima; Goswami, Chirayu; Badve, Sunil; Nakshatri, HarikrishnaCancer stem-like cells are thought to contribute to tumor recurrence. The anthrax toxin receptor ANTXR1 has been identified as a functional biomarker of normal stem cells and breast cancer stem-like cells. Primary stem cell-enriched basal cells (CD49f+/EpCAM−/Lin−) expressed higher levels of ANTXR1 compared to mature luminal cells. CD49f+/EpCAM−, CD44+/EpCAM−, CD44+/CD24− or ALDEFLUOR-positive subpopulations of breast cancer cells were enriched for ANTXR1 expression. CD44+/CD24−/ANTXR1+ cells displayed enhanced self-renewal as measured by mammosphere assay compared to CD44+/CD24−/ANTXR1− cells. Activation of ANTXR1 by its natural ligand C5A, a fragment of collagen VI α3, increased stem cell self-renewal in mammosphere assays and Wnt signaling including the expression of the Wnt receptor LRP6, phosphorylation of GSK3α/β and elevated expression of Wnt target genes. RNAi-mediated silencing of ANTXR1 enhanced the expression of luminal-enriched genes but diminished Wnt signaling including reduced LRP6 and ZEB1 expression, self-renewal, invasion, tumorigenicity and metastasis. ANTXR1 silencing also reduced the expression of HSPA1A, which is overexpressed in metastatic breast cancer stem cells. Analysis of public databases revealed ANTXR1 amplification in medullary breast carcinoma and overexpression in estrogen receptor-negative breast cancers with the worst outcome. Further, ANTXR1 is among the 10% most overexpressed genes in breast cancer and is co-expressed with collagen VI. Thus, ANTXR1:C5A interactions bridge a network of collagen cleavage and remodeling in the tumor microenvironment, linking it to a stemness signaling network drives metastatic progression.Item Assessment of Ki67 in Breast Cancer: Updated Recommendations From the International Ki67 in Breast Cancer Working Group(Oxford University Press, 2021) Nielsen, Torsten O.; Leung, Samuel C. Y.; Rimm, David L.; Dodson, Andrew; Acs, Balazs; Badve, Sunil; Denkert, Carsten; Ellis, Matthew J.; Fineberg, Susan; Flowers, Margaret; Kreipe, Hans H.; Laenkholm, Anne-Vibeke; Pan, Hongchao; Penault-Llorca, Frédérique M.; Polley, Mei-Yin; Salgado, Roberto; Smith, Ian E.; Sugie, Tomoharu; Bartlett, John M. S.; McShane, Lisa M.; Dowsett, Mitch; Hayes, Daniel F.; Pathology and Laboratory Medicine, School of MedicineKi67 immunohistochemistry (IHC), commonly used as a proliferation marker in breast cancer, has limited value for treatment decisions due to questionable analytical validity. The International Ki67 in Breast Cancer Working Group (IKWG) consensus meeting, held in October 2019, assessed the current evidence for Ki67 IHC analytical validity and clinical utility in breast cancer, including the series of scoring studies the IKWG conducted on centrally stained tissues. Consensus observations and recommendations are: 1) as for estrogen receptor and HER2 testing, preanalytical handling considerations are critical; 2) a standardized visual scoring method has been established and is recommended for adoption; 3) participation in and evaluation of quality assurance and quality control programs is recommended to maintain analytical validity; and 4) the IKWG accepted that Ki67 IHC as a prognostic marker in breast cancer has clinical validity but concluded that clinical utility is evident only for prognosis estimation in anatomically favorable estrogen receptor-positive and HER2-negative patients to identify those who do not need adjuvant chemotherapy. In this T1-2, N0-1 patient group, the IKWG consensus is that Ki67 5% or less, or 30% or more, can be used to estimate prognosis. In conclusion, analytical validity of Ki67 IHC can be reached with careful attention to preanalytical issues and calibrated standardized visual scoring. Currently, clinical utility of Ki67 IHC in breast cancer care remains limited to prognosis assessment in stage I or II breast cancer. Further development of automated scoring might help to overcome some current limitations.Item Association of Circulating Tumor DNA and Circulating Tumor Cells After Neoadjuvant Chemotherapy With Disease Recurrence in Patients With Triple-Negative Breast Cancer: Preplanned Secondary Analysis of the BRE12-158 Randomized Clinical Trial(American Medical Association, 2020-09) Radovich, Milan; Jiang, Guanglong; Hancock, Bradley A.; Chitambar, Christopher; Nanda, Rita; Falkson, Carla; Lynce, Filipa C.; Gallagher, Christopher; Isaacs, Claudine; Blaya, Marcelo; Paplomata, Elisavet; Walling, Radhika; Daily, Karen; Mahtani, Reshma; Thompson, Michael A.; Graham, Robert; Cooper, Maureen E.; Pavlick, Dean C.; Albacker, Lee A.; Gregg, Jeffrey; Solzak, Jeffrey P.; Chen, Yu-Hsiang; Bales, Casey L.; Cantor, Erica; Shen, Fei; Storniolo, Anna Maria V.; Badve, Sunil; Ballinger, Tarah J.; Chang, Chun-Li; Zhong, Yuan; Savran, Cagri; Miller, Kathy D.; Schneider, Bryan P.; Medical and Molecular Genetics, School of MedicineImportance: A significant proportion of patients with early-stage triple-negative breast cancer (TNBC) are treated with neoadjuvant chemotherapy. Sequencing of circulating tumor DNA (ctDNA) after surgery, along with enumeration of circulating tumor cells (CTCs), may be used to detect minimal residual disease and assess which patients may experience disease recurrence. Objective: To determine whether the presence of ctDNA and CTCs after neoadjuvant chemotherapy in patients with early-stage TNBC is independently associated with recurrence and clinical outcomes. Design, setting, and participants: A preplanned secondary analysis was conducted from March 26, 2014, to December 18, 2018, using data from 196 female patients in BRE12-158, a phase 2 multicenter randomized clinical trial that randomized patients with early-stage TNBC who had residual disease after neoadjuvant chemotherapy to receive postneoadjuvant genomically directed therapy vs treatment of physician choice. Patients had blood samples collected for ctDNA and CTCs at time of treatment assignment; ctDNA analysis with survival was performed for 142 patients, and CTC analysis with survival was performed for 123 patients. Median clinical follow-up was 17.2 months (range, 0.3-58.3 months). Interventions: Circulating tumor DNA was sequenced using the FoundationACT or FoundationOneLiquid Assay, and CTCs were enumerated using an epithelial cell adhesion molecule-based, positive-selection microfluidic device. Main outcomes and measures: Primary outcomes were distant disease-free survival (DDFS), disease-free survival (DFS), and overall survival (OS). Results: Among 196 female patients (mean [SD] age, 49.6 [11.1] years), detection of ctDNA was significantly associated with inferior DDFS (median DDFS, 32.5 months vs not reached; hazard ratio [HR], 2.99; 95% CI, 1.38-6.48; P = .006). At 24 months, DDFS probability was 56% for ctDNA-positive patients compared with 81% for ctDNA-negative patients. Detection of ctDNA was similarly associated with inferior DFS (HR, 2.67; 95% CI, 1.28-5.57; P = .009) and inferior OS (HR, 4.16; 95% CI,1.66-10.42; P = .002). The combination of ctDNA and CTCs provided additional information for increased sensitivity and discriminatory capacity. Patients who were ctDNA positive and CTC positive had significantly inferior DDFS compared with those who were ctDNA negative and CTC negative (median DDFS, 32.5 months vs not reached; HR, 5.29; 95% CI, 1.50-18.62; P = .009). At 24 months, DDFS probability was 52% for patients who were ctDNA positive and CTC positive compared with 89% for those who were ctDNA negative and CTC negative. Similar trends were observed for DFS (HR, 3.15; 95% CI, 1.07-9.27; P = .04) and OS (HR, 8.60; 95% CI, 1.78-41.47; P = .007). Conclusions and relevance: In this preplanned secondary analysis of a randomized clinical trial, detection of ctDNA and CTCs in patients with early-stage TNBC after neoadjuvant chemotherapy was independently associated with disease recurrence, which represents an important stratification factor for future postneoadjuvant trials.Item Beta-2 Adrenergic Receptor Gene Expression in HER2-Positive Early-Stage Breast Cancer Patients: A Post-hoc Analysis of the NCCTG-N9831 (Alliance) Trial(Elsevier, 2022) Caparica, Rafael; Ma, Yaohua; De Angelis, Claudia; Richard, François; Desmedt, Christine; Awada, Ahmad; Piccart, Martine; Perez, Edith A.; Moreno-Aspitia, Alvaro; Badve, Sunil; Thompson; de Azambuja, Evandro; Pathology and Laboratory Medicine, School of MedicineBackground: Beta-2 adrenergic receptor (ß2AR) modulates immune activation and may enhance trastuzumab activity. We assessed the impact of ß2AR gene (ADRB2) expression on the outcomes of patients with HER2-positive early-stage breast cancer enrolled on the NCCTG-N9831 trial. Patients and methods: This is a post-hoc analysis of the NCCTG-N9831 trial, which compared chemotherapy (arm A) versus chemotherapy plus trastuzumab (arms B&C) as adjuvant treatment of patients with HER2-positive early-stage breast cancer, with disease-free survival (DFS) as primary endpoint. Gene expression levels retrieved by DASL assay were used to classify patients as ADRB2-high or ADRB2-low. Hazard ratios (HRs) were calculated by a Cox proportional model adjusted for prognostic variables and ADRB2 expression. Correlations between ADRB2 expression and stromal tumor-infiltrating lymphocyte (TIL) levels were assessed with Pearson coefficient. A multivariable Cox regression model with interaction term was performed to assess the interaction between ADRB2 expression and treatment arm; and ADRB2 expression and a 8-gene signature previously shown to predict trastuzumab benefit. Results: Overall, 1,282 patients were included (ADRB2-high [N = 944] / ADRB2-low [N = 338]). A high expression of ADRB2 was associated with a longer DFS (P = .01) in the overall population. The addition of trastuzumab to chemotherapy improved DFS only in patients with ADRB2-high tumors (P < .01). ADRB2 expression was correlated with TIL levels (r = 0.24, P < .001). No association between ADRB2 expression and the 8-gene trastuzumab benefit signature was observed (P = .32). Conclusion: Our findings suggest that a high ADRB2 expression is a favorable prognostic factor and may identify patients with HER2-positive early-stage breast cancer who benefit from adjuvant trastuzumab.Item Breast calcifications following electrical defibrillation: An unusual mammographic appearance(Radiology Case Reports U of Washington, 2010) Westphal, Steven M.; Jani, Manish; Badve, Sunil; Department of Radiology and Imaging Sciences, IU School of MedicineWe present a case of a 57-year-old woman with a past medical history of end-stage renal disease and a recent history of electrical defibrillation who arrived for her annual mammogram with no breast-related complaints. The mammogram showed interval development of unusual clusters of heterogeneous calcifications. The patient underwent stereotactic core-needle biopsy for definitive diagnosis. The pathologic evaluation revealed fibrosis, abnormal adipocytes, and calcifications with no evidence of malignancy. The constellation of findings was consistent with fat necrosis and fibrosis related to tissue damage sustained during the recent defibrillation.