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  • American Association for Cancer Research (AACR)  (7)
  • Varadhachary, Gauri R.  (7)
  • 1
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 23 ( 2018-12-01), p. 5883-5894
    Abstract: Pancreatic ductal adenocarcinoma (PDAC) is a heterogeneous disease with variable presentations and natural histories of disease. We hypothesized that different morphologic characteristics of PDAC tumors on diagnostic computed tomography (CT) scans would reflect their underlying biology. Experimental Design: We developed a quantitative method to categorize the PDAC morphology on pretherapy CT scans from multiple datasets of patients with resectable and metastatic disease and correlated these patterns with clinical/pathologic measurements. We modeled macroscopic lesion growth computationally to test the effects of stroma on morphologic patterns, hypothesizing that the balance of proliferation and local migration rates of the cancer cells would determine tumor morphology. Results: In localized and metastatic PDAC, quantifying the change in enhancement on CT scans at the interface between tumor and parenchyma (delta) demonstrated that patients with conspicuous (high-delta) tumors had significantly less stroma, higher likelihood of multiple common pathway mutations, more mesenchymal features, higher likelihood of early distant metastasis, and shorter survival times compared with those with inconspicuous (low-delta) tumors. Pathologic measurements of stromal and mesenchymal features of the tumors supported the mathematical model's underlying theory for PDAC growth. Conclusions: At baseline diagnosis, a visually striking and quantifiable CT imaging feature reflects the molecular and pathological heterogeneity of PDAC, and may be used to stratify patients into distinct subtypes. Moreover, growth patterns of PDAC may be described using physical principles, enabling new insights into diagnosis and treatment of this deadly disease.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 2
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 2599-2599
    Abstract: Background: Prognostic and therapeutic stratification of pancreatic ductal adenocarcinoma (PDAC) patients remains elusive due to a lack of effective biomarkers, and a predilection towards metastatic disease. Peripheral blood-based liquid biopsies for tumor markers has emerged as a potential minimally invasive strategy for tumor monitoring. We have implemented a liquid biopsy assay utilizing DNA derived from vesicles known as exosomes (exoDNA) and circulating tumor DNA (ctDNA) in the metastatic setting to determine the potential utility of these liquid biopsy compartments in tumor management. Methods: A total of 318 plasma samples from 123 metastatic pancreatic patients were prospectively collected. ExoDNA and ctDNA were then extracted from matched plasma samples. Digital PCR, was used to identify codon 12/13 KRAS gene mutations. We assessed clinical endpoints in relation to progression free survival (PFS) and overall survival (OS) using univariate and multivariate analyses. In a metastatic PDAC patient, six serial liquid biopsies and seven tissue biopsies taken throughout disease progression underwent whole genome sequencing for detection of copy number events. Results: Detection rates of KRAS mutations in exoDNA and ctDNA at baseline treatment naïve staus were 61.0% and 52.9%, respectively. On multivariate COX regression analysis, exoDNA KRAS mutant allelic fraction (MAF) ≥ 5% was a significant predictor of poorer PFS (HR 2.28, 95% CI 1.18-4.40, P=0.014) and OS (HR 3.46, 95% CI 1.40-8.50, P=0.007) in metastatic patients. Among 34 patients, liquid biopsy tumor monitoring was performed across 127 serial blood draws during a median followup time of 11.1 months. The presence of an exoDNA MAF peak ≥ 1% during tumor monitoring was significantly correlated to radiological progression (p=0.0003). Specifically, detection of an exoDNA MAF peak ≥ 1% preceded radiological progression by a median of 50 days compared to a median of 0 days for CA19-9 (p=0.03). CtDNA did not emerge as a significant predictor of survival outcomes in our cohort. In a patient with multiple longitudinal liquid biopsies, comprehensive genomic profiling of exoDNA further demonstrated our ability to capture additional mutational events as they emerged during therapy and correlated to progression including amplifications in ERBB2 and MYC and deletions in CDKN2A and SMAD4. Conclusions: Liquid biopsies in PDAC provide direct evidence of those patients likely to experience poorer outcomes allowing for more effective therapeutic stratification. Liquid biopsies also demonstrate utility in characterization of putative emerging driver events during disease progression. Citation Format: Vincent Bernard, Dong U. Kim, F. Anthony San Lucas, Jonathan Castillo, Kelvin Allenson, Feven C. Mulu, Bret M. Stephens, Jonathan Huang, Eugene Koay, Cullen M. Taniguchi, Milind Javle, Robert A. Wolff, Matthew H. Katz, Gauri R. Varadhachary, Hector A. Alvarez, Anirban Maitra. Circulating nucleic acids as biomarkers of prognosis and chemorefractory status in metastatic pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2599.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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  • 3
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 24_Supplement ( 2019-12-15), p. B36-B36
    Abstract: Background: More than half of patients (pts) with pancreatic cancer (PC) initially present with unresectable, locally advanced disease (LAPC). Data on management of these pts after systemic chemotherapy are scarce. Many clinicians utilize a strategy of induction chemotherapy followed by consolidative concurrent chemoradiation (CRT) for pts not progressing on initial chemotherapy. How to manage pts after CRT is controversial. We sought to evaluate the role of maintenance chemotherapy (MCT) after CRT in pts with LAPC. Methods: We retrospectively analyzed LAPC pts treated with CRT at MD Anderson from 2005-2018. Pts who were taken for curative-intent surgery were excluded. Primary and secondary outcomes were median progression-free survival (mPFS) and median overall survival (mOS), respectively, as measured from the start date of CRT. Data were also obtained on pt demographics, response, and duration of induction chemotherapy as well as MCT regimens. Results: We included 165 pts with LAPC treated with CRT in our analysis. Median age was 66 (range 39 – 84), and 97 (59%) pts were male. Median follow-up was 12.9 months. The median duration from initiation of induction chemotherapy to start of CRT was 4.4 months. Most pts (84%) received 1 line of induction chemotherapy prior to CRT. Ten pts (6%) did not receive induction chemotherapy and 17 pts (10%) received at least 2 lines prior to CRT. All but 9 pts (94%) developed disease progression (PD) after CRT, and 49 pts (33%) had PD within 3 months of CRT. On univariate analysis, PD on the induction chemotherapy regimen immediately prior to CRT was associated with shortened PFS (HR 2.46, p & lt; 0.001) and OS (HR 2.96, p & lt; 0.001) after CRT. Most pts (78%) did not receive MCT after CRT. 69% of pts who received MCT were male, compared to 56% of those who did not receive MCT. The percentages of pts who had PD on the chemotherapy regimen immediately prior to CRT in the MCT and no-MCT groups were 9% and 12%, respectively. Sixteen pts who received MCT were treated with either gemcitabine alone or a gemcitabine-containing regimen, while 14 pts received capecitabine monotherapy. On univariate analysis, the use of MCT after CRT was associated with prolonged mPFS (9.0 vs. 4.2 months, p = 0.01), but was not associated with an increase in mOS (15.5 vs. 12.5 months, p = 0.14). On multivariable analysis controlling for race, radiation dose, age, and whether there was progression on the chemotherapy regimen prior to CRT, the use of MCT was significantly associated with both prolonged PFS (HR 0.45, p & lt; 0.001) and OS (HR 0.66, p = 0.047). Conclusions: In this single-institution retrospective analysis of 165 pts with LAPC treated with CRT, treatment with post-CRT MCT was associated with a significant improvement in both PFS and OS as measured from the start date of CRT. Based on these results, MCT may be an appropriate option for pts with LAPC who have not progressed following consolidative CRT, and a prospective trial should be performed to better address this knowledge gap. Citation Format: Jonathan D. Mizrahi, Shalini Moningi, Graciela M. Nogueras-Gonzalez, Robert A. Wolff, Milind M. Javle, Gauri R. Varadhachary, Linus Ho, David R. Fogelman, Kanwal P. Raghav, Michael J. Overman, Christopher H. Crane, Joseph M. Herman, Albert C. Koong, Eugene J. Koay, Jane E. Rogers, Shubham Pant. Maintenance chemotherapy after chemoradiation in patients with locally advanced pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B36.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 4
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 26, No. 6 ( 2020-03-15), p. 1385-1394
    Abstract: Family history of BRCA-related tumors may correlate with response to chemotherapy and overall survival (OS) in pancreatic cancer. The frequency of germline mutations has been reported in patients predominantly under the age of 60 or with strong family history. We examine the incidence of deleterious germline mutations and compare the chemotherapy responses and OS in an unselected group of patients with metastatic pancreatic cancer. Experimental Design: Patients with metastatic pancreatic cancer, who were seen at a single cancer center between 2010 and 2016, were included. Germline DNA was sequenced using a 263-gene panel to identify novel mutations (N = 133 MD Anderson cohort, N = 127 TCGA cohort). Chemotherapy response and OS were determined by review of medical records. Results: Deleterious germline mutations were identified in 26 of 133 patients (19.5%). Patients with DNA damage repair (DDR) gene mutations (ATM, BRCA1/2, CDKN2A, CHEK2, ERCC4, PALB2, n = 15) had an improved OS as compared with patients without (16.8 vs. 9.1 months, P = 0.03). Conversely, patients with other deleterious mutations had a trend toward worse OS. However, survival in the latter group was longer (P = NS) in those mutants initially treated with gemcitabine/nab-paclitaxel. A family history of multiple breast, ovarian, and pancreatic cancers was associated with DDR gene mutations and better survival. Conclusions: We have identified novel germline mutations that are prognostic for survival in patients with pancreatic cancer. We observe improved survival in patients with DDR gene mutations and worsened survival in patients with deleterious mutations in non-DDR genes.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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  • 5
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 24_Supplement ( 2019-12-15), p. B35-B35
    Abstract: Background: Objective responses to first-line systemic chemotherapy in patients (pts) with metastatic pancreatic cancer (mPC) are seen in less than one third of cases. While disease stabilization is achievable for a significant percentage, many of these pts will have radiographic evidence of disease progression (PD) on their first restaging imaging. With patients’ short life expectancy in the metastatic setting, limited systemic treatment options, and significant toxicities associated with multidrug chemotherapy, it is crucial for clinicians to be prudent when deciding whom and when to treat. The purpose of our study was to evaluate outcomes of pts who progressed on their first restaging imaging while on first-line therapy. Methods: We retrospectively analyzed mPC pts treated at MD Anderson since 2011 whose first restaging imaging on first-line therapy demonstrated PD. Data collected included patient demographics, choice of first-line therapy, and whether they received second-line therapy. Primary outcome was overall survival (OS) from date of metastatic diagnosis to death or last follow-up. Results: A total of 121 pts were included in the analysis. Seventy-two received second-line therapy, and 49 did not pursue second-line therapy. The median ages for pts who did and did not receive second-line therapy were 61 and 67, respectively (p=0.001). More pts had a poor Eastern Cooperative Oncology Group (ECOG) performance status (ECOG 2-3) at the time of initial diagnosis in the non-second-line therapy group (31% vs. 6.9%, p=0.003). Forty-two pts (34.7%) received combination 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) first-line, while 72 pts (59.5%) received gemcitabine + nab-paclitaxel (GnP). Thirty-four pts (80%) who received FOLFIRINOX first-line did proceed with second-line therapy, and 29 pts (40%) who received GnP proceeded with second-line therapy. Median OS for those receiving second-line therapy was 8.28 months compared to 2.73 months for those not receiving second-line therapy (p & lt;0.001). Conclusions: Although likely biased due to better performance status and younger age, our mPC pts who progressed rapidly on first-line therapy showed an OS benefit if they received second-line therapy. These results suggest that pts maintaining a good performance status after immediate progression on first-line therapy should be offered second-line therapy. Citation Format: Jonathan D. Mizrahi, Jane E. Rogers, Graciela M. Nogueras-Gonzalez, Robert A. Wolff, Gauri R. Varadhachary, Milind M. Javle, Rachna T. Shroff, Linus Ho, David R. Fogelman, Kanwal P. Raghav, Michael J. Overman, Shubham Pant. Outcomes of patients with metastatic pancreatic cancer who progress on first restaging imaging [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr B35.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
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    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
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  • 6
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 70, No. 8_Supplement ( 2010-04-15), p. 2760-2760
    Abstract: BACKGROUND: MK-0646 binds to IGF-1R and blocks its interaction with the IGF-I/ II ligands, enhances gemcitabine (G)-induced apoptosis and inhibits the MEK/ Erk and the PI3-kinase/ Akt signaling pathways which are important in cellular proliferation, survival and drug resistance in pancreatic cancer. Receptor cross-talk between IGF-1R and EGFR and enhanced IGF-1R-induced activation of the PI3-kinase/ Akt pathways mediate resistance to anti-EGFR agents such as E. The combination of IGF-1R and EGFR antagonists has demonstrated synergy in preclinical pancreatic cancer models. METHODS: Patients with stage IV, previously untreated pancreatic cancer, ECOG performance status (PS) 0-1, adequate hematologic and organ function were enrolled. MK-0646 was escalated in two dose levels using 3+3 statistical design. Uncontrolled hyperglycemia or cardio-respiratory conditions were exclusions. Blood was collected at study entry for IGF-1 and IGFBP-3 levels. Arm A: G 1000 mg/m2 over 100 min, weekly x 3, MK-0646 over 60 min: 5 or 10 mg/kg, weekly x 4; Arm B: G 1000 mg/m2 over 100 min, weekly x 3, MK-0646 over 60 min: 5 or 10 mg/kg, weekly x 4 + E 100 mg daily. Cycles were repeated q 4 weeks. Radiologic responses were measured with RECIST (study radiologist PB). Study endpoints: maximal tolerated dose, progression-free survival, response rate, toxicity and overall survival. RESULTS: 22 pts enrolled, 15 males, 2 prior Whipple, 20 PS 1, 2 PS 0. Median of 2 cycles (range 1-8) administered as of 9/09. Hematologic toxicity was common: grade 3 or 4 neutropenia (n=9) or thrombocytopenia (n=6). Other grade 3 toxicities: hyperglycemia (n=2), fatigue (n=2), ALT (n=3). Dose limiting toxicity reached in Arm B at dose level 2 (MK-0646 at 10 mg/kg + E + G): febrile neutropenia (n=1), hepatic transaminitis (n=1). Radiologic responses: 5 PR (including 1 hepatic CR), 7 PD, 8 SD, 1 not evaluated, 1 not treated. TTP range (based on 12 pts) was 4 to & gt;36 weeks. Ranges for: IGF-1 levels, 28-280 ng/mL; IGFBP-3 levels, 900-4000 ng/mL. The range of IGF-1 to IGFBP-3 ratios for patients with PR and SD was .027-.036 versus a range of .034-.058 for patients with PD. CONCLUSION: MK-0646 is tolerable in a dose of 10 mg/kg with G 1000 mg/m2 and at 5 mg/kg with G 1000 mg/m2 and E 100 mg. Promising anti-tumor activity was noted. A randomized phase II study will be conducted with the control arm of G+E. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2760.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2010
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  • 7
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 78, No. 13_Supplement ( 2018-07-01), p. 1547-1547
    Abstract: Background: Pancreatic duct adenocarcinoma (PDAC) is an aggressive cancer with poor prognosis. Epithelial to mesenchymal transition (EMT) plays an important role in the progression, metastasis and chemoresistance of PDAC. However the expression of EMT markers and their clinical significance in PDAC patients who received neoadjuvant therapy are not clear. Methods: One hundred and twenty cases were included in this study. All patients received neoadjuvant chemoradiation therapy and underwent surgical resection at our institution from 1999 to 2007. Expressions of EMT markers, including Zeb-1, E-cadherin, vimentin and N-cadherin, were evaluated by immunohistochemistry using tissue microarrays. The staining for Zeb-1 was categorized as positive (≥10% nuclear staining in tumor cells) and negative ( & lt;10% nuclear staining in tumor cells); the staining for E-cadherin was categorized as low (negative or & lt;50% membranous staining) or high (≥50% membranous staining); the staining for vimentin and N-cadherin was categorized negative ( & lt;10% cytoplasmic staining) or positive (≥10% cytoplasmic staining). The expression results were correlated with clinicopathologic parameters and survival. All the statistical analyses were carried out with the SPSS software. Results: Among 120 cases, 45 (37.5%) were positive for Zeb-1, 25 (20.8 %) were E-cadherin-low, 14 (11.7%) were positive for vimentin, and 2 (1.7%) were positive for N-cadherin. There was negative correlation between the expression of E-cadherin and vimentin (p=0.03). E-cadherin-low and positive vimentin expression correlated with poor differentiation (p=0.02 and p=0.004, respectively). However, no correlations between the EMT markers with other clinical pathologic parameters were found (p & gt;0.05). The median overall survival (OS) and disease-free survival (DFS) were 35.3 ± 2.8 months and 15.9 ± 3.6 months, respectively, in vimentin-negative group compared to 16.1 ± 1.1 months (p=0.03) and 7.0 ± 1.1 months (p=0.02), respectively, in vimentin-positive group. There were no correlation between the expression of Zeb-1, E-cadherin or N-cadherin and survival (P & gt;0.05). In multivariate analysis, expression of vimentin was an independent predictor of shorter OS [HR (95% CI): 2.57 (1.34-4.93), p=0.004] and DFS [HR (95% CI): 2.80 (1.45-5.43), p=0.002] . Conclusion: Our results show that EMT markers are frequently expressed in treated PDAC. Expression of vimentin is a prognostic biomarker for both OS and DFS in patients with PDAC who received neoadjuvent therapy and surgery. Citation Format: Minhua Wang, Jeannelyn S. Estrella, Matthew H. Katz, Asif Rashid, Jeffrey E. Lee, Anirban Maitra, Robert A. Wolff, Gauri R. Varadhachary, Huamin Wang. Expression of epithelial-to-mesenchymal transition markers (EMT) in treated pancreatic duct adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1547.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    RVK:
    RVK:
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
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