Publications by authors named "Christina Wu"

127 Publications

Impact of Tumor Side on Clinical Outcomes in Stage II and III Colon Cancer With Known Microsatellite Instability Status.

Front Oncol 2021 30;11:592351. Epub 2021 Mar 30.

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, United States.

Background: Tumor sidedness as a prognostic factor in advanced stage colon cancer (CC) is well established. The impact of tumor sidedness on the clinical outcomes of stage II and III CC has not been well studied.

Methods: The National Cancer Database (NCDB) was utilized to identify patients with pathological stage II and III primary adenocarcinoma of the colon from 2010 to 2015 using ICD-O-3 morphology and topography codes: 8140-47, 8210-11, 8220-21, 8260-63, 8480-81, 8490 and C18.0, 18.2,18.3, 18.5,18.6, 18.7. Univariate (UVA) and multivariable (MVA) survival analyses and Kaplan-Meier Curves with Log-rank test were utilized to compare overall survival (OS) based on tumor location and treatment received.

Results: A total of 35,071 patients with stage II (n = 17,629) and III (n = 17,442) CC were identified. 51.3% female; 81.5% Caucasian; median age 66 (range, 18-90). Majority of stage II and III tumors were right sided, 61.2% (n = 10,794) and 56.0% (n = 9,763). Microsatellite instability high (MSI-H) was more common in stage II compared to III, 23.3% (n = 4,115) 18.2% (n = 3,171) (p < 0.0001). In stage II MSI-H CC right was more common than left, 78.3% (n = 3223) 21.7% (n = 892). There was no significant difference in survival between stage II MSI-H left right (5-year OS 76.2 74.7%, p = 0.1578). Stage II MSS CC right was more common than left, 56.0% (n = 7571) 44.0% (n = 5943), and survival was better in the left right (5-year OS 73.2 70.8%, p = 0.0029). Stage III MSI-H CC was more common in the right than in the left, 75.6% (n = 2,397) vs 24.4% (n = 774) and survival was better in the left (5-year OS 62.5 56.5%, p = 0.0026). Stage III MSS CC was more common in the right than in the left, 51.6% (n = 7,366) 48.4% (n = 6,905), and survival was better in the left right (5-year OS 67.0 54.4%, p < 0.001).

Conclusion: Survival was better in left sided tumors compared to right in stage II MSS, stage III MSS, and stage III MSI-H CC.
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http://dx.doi.org/10.3389/fonc.2021.592351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8042136PMC
March 2021

Safety and Efficacy of 7 Days on/7 Days off Versus 14 Days on/7 Days off Schedules of Capecitabine in Patients with Metastatic Colorectal Cancer: A Retrospective Review.

Clin Colorectal Cancer 2021 Mar 16. Epub 2021 Mar 16.

Department of Hematology/Medical Oncology, Winship Cancer Institute, Emory Healthcare, Atlanta, GA.

Introduction/background: The administration schedule of capecitabine for the treatment of metastatic colorectal cancer (mCRC) in clinical trials has been 14 days of drug with 7 days off in a 21 day cycle (14/7). In an effort to improve tolerability, an alternative every other week treatment (7/7) is often administered. The purpose of this study was to determine the safety and efficacy of administering 7/7 compared with 14/7 capecitabine dosing.

Materials And Methods: In this retrospective study, mCRC patients received capecitabine on a 7/7 or 14/7 schedule. The primary objective was to determine the tolerability of the respective dosing schedules, defined according to frequency of dose reductions and treatment delays. Secondary objectives included comparisons of objective response rate (ORR), progression-free survival (PFS), overall survival (OS), and safety of dosing strategies.

Results: Of 175 included patients, 73 (41.7%) received the capecitabine 7/7 schedule and 102 (58.3%) received the 14/7 schedule. There was a statistically significant difference between the 7/7 and 14/7 groups with regard to dose reductions (4% vs. 29%; P < .001) and treatment delays (22% vs. 43%; P = .004). The incidence of any adverse effects (45% vs. 72%; P < .001) and specifically, palmar-plantar erythrodysesthesia (18% vs. 45%; P < .001), were significantly higher in the 14/7 group. No significant difference was seen with regard to ORR, PFS, or OS.

Conclusion: Patients with mCRC who received the 7/7 schedule had significantly fewer dose reductions and treatment delays compared with patients who received the 14/7 schedule. Although no difference in efficacy outcomes were observed, prospective studies are needed to confirm these findings.
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http://dx.doi.org/10.1016/j.clcc.2020.12.002DOI Listing
March 2021

Mismatch Repair (MMR) Gene Alteration and BRAF V600E Mutation Are Potential Predictive Biomarkers of Immune Checkpoint Inhibitors in MMR-Deficient Colorectal Cancer.

Oncologist 2021 Feb 25. Epub 2021 Feb 25.

Emory University School of Medicine, Winship Cancer Institute, Atlanta, Georgia, USA.

Background: Immune checkpoint inhibitor (ICI) therapy is highly effective in metastatic mismatch repair-deficient (MMR-D) colorectal cancer (CRC). In this study, we evaluated molecular and clinical predictors of ICI response in MMR-D CRC.

Materials And Methods: Patient databases at four cancer institutions were queried. The Fisher exact test was performed to test the association of clinical and molecular markers. The Kaplan-Meier method was used to estimate progression-free survival (PFS) and compared by the log-rank test. Twelve- and 24-month PFS rates were compared by the Z test.

Results: A total of 60 patients with CRC with MMR-D/microsatellite instability-high who previously received ICIs were identified. Patients with liver metastasis had a lower overall response rate as compared with other sites of metastasis (36.4% vs. 68.7%; p = .081). Patients with MLH1/PMS2 loss had worse 1-year and 2-year PFS rates compared with patients with MSH2/MSH6 loss (84.2% vs. 57.8% and 78.2% vs. 54.2%, respectively; p < .001). There were improved 1-year and 2-year PFS rates in patients with wild-type BRAF when compared with patients with BRAF V600E mutation (73.3% vs. 40%, and 73.3% vs. 26.7%; respectively; p < .001). Patients aged >65 had significantly worse PFS rates as compared with patients aged ≤65 (p < .001).

Conclusion: BRAF V600E mutation, MLH1 and/or PMS2 loss, as well as age >65 years and liver metastasis, may be predictive of duration of ICI response in patients with MMR-D CRC. Larger cohorts are needed to confirm our findings.

Implications For Practice: The results of this study reveal clinically important biomarkers that potentially predict immune checkpoint inhibitor response in patients with mismatch repair-deficient colorectal cancer.
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http://dx.doi.org/10.1002/onco.13741DOI Listing
February 2021

Impact of high-risk features for stage II adenocarcinoma of the appendix.

Cancer Treat Res Commun 2021 Feb 4;27:100329. Epub 2021 Feb 4.

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.

Background: Clinico-pathological high-risk features are frequently utilized in adjuvant chemotherapy (AC) decisions in stage II colorectal cancer and their utility in stage II appendiceal adenocarcinoma (AA) is not established. The aim of this study is to determine the impact of high-risk features in clinical outcomes and whether high risk features are predictive of AC benefit in stage II AA.

Methods: Patients with pathological stage II AA between 2010 and 2015 were identified from the National Cancer Database (NCDB) using ICD-O-3 morphology and topography codes: 8140, 8480 and C18.1. High risk stage II AA was defined as having at least one of the following clinicopathological features: T4 tumor, <12 lymph nodes examined, poorly differentiated histology, positive margins, or lymphovascular invasion. Patients with none of these features were defined as low-risk.

Results: A total of 1040 patients with pathological stage II AA were identified. 51.0% males, 84.5% Caucasian; median age 61 (range, 19-90). 46.4% were determined to have high-risk stage II AA. High-risk status was associated with worse OS compared to low-risk in univariate (HR 1.55; 95% CI 1.18-2.02; p = 0.001) and multivariable analyses (HR 1.36; 95% CI 1.03-1.79; p = 0.028). High-risk stage II AA patients had significantly worse 5-year OS compared to low-risk patients (67.1% vs. 74.5%, p = 0.0013). AC was administered in 34.4% (n = 166) of high-risk patients and in 36.5% (n = 203) of low-risk patients. Among high-risk patients, AC was not associated with better OS in univariate (HR 0.86; 95% CI 0.59-1.26; p = 0.448) and multivariable analyses (HR 1.35; 95% CI 0.90-2.04; p = 0.151) compared to no AC. Similarly, among low-risk patients, AC was not associated with better OS in univariate (HR 0.92; 95% CI 0.60-1.39; p = 0.679) and multivariable analyses (HR 1.27; 95% CI 0.81-2.02; p = 0.299) compared to no AC. For high-risk patients, 5-year OS was 68.3% in patients that received AC vs. 66.5% in patients that did not (p = 0.722). For low-risk patients, 5-year OS was 74.0% in patients that received AC vs. 76.3% in patients that did not (p = 0.813).

Conclusion: High-risk stage II AA patients had significantly worse 5-year OS compared to low-risk patients. AC did not improve survival regardless of high-risk features in stage II AA in this retrospective study. A prospective randomized clinical trial would be required to determine the impact of high-risk features on AC in stage II AA.
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http://dx.doi.org/10.1016/j.ctarc.2021.100329DOI Listing
February 2021

Intranasal ketorolac, diagnosis, and desensitization for aspirin-exacerbated respiratory disease.

Ann Allergy Asthma Immunol 2021 Jan 19. Epub 2021 Jan 19.

Department of Medicine, University of California San Diego, La Jolla, California. Electronic address:

Background: Intranasal ketorolac has been proposed as a diagnostic test for aspirin-exacerbated respiratory disease (AERD) and a faster, safer, and reliable addition to facilitating aspirin (ASA) desensitization.

Objective: We conducted the first prospective study to dissect the impact of intranasal ketorolac incorporation during ASA desensitization vs standard oral protocols in concert with evaluating its diagnostic use for AERD.

Methods: Patients with AERD were enrolled in a prospective open-label observational study between November 2006 and August 2013. Participants selected either one of the following desensitization protocols: intranasal ketorolac 1 day before oral ASA (group 1, combined) or ketorolac challenge with greater than 2 weeks elapsing until oral ASA (group 2, washout). All patients were on a leukotriene-modifying drug (montelukast) for at least 1 week before the challenge.

Results: A total of 20 patients were enrolled: 13 in group 1 and 7 in group 2. No significant differences were seen for baseline symptom scores or forced expiratory volume in 1 second. Group 1 exhibited significant increases for the threshold dose of ASA (P = .009), the likelihood of having silent ASA desensitization (P = .01), and decreased reaction severity to oral ASA (P = .04). There were no significant differences in reaction forced expiratory volume in 1 second, the incidence of extrapulmonary symptoms, limited nasoocular reactions, rescue treatment requirements, or time to symptom resolution. There was 100% concordance between reactions to intranasal ketorolac and oral ASA for group 2, supporting its use as a diagnostic test for AERD.

Conclusion: Intranasal ketorolac is a useful diagnostic test and adjunct within the combined ketorolac/ASA protocol to achieve effective, efficient, and perhaps safer desensitization to ASA for patients with AERD.
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http://dx.doi.org/10.1016/j.anai.2021.01.011DOI Listing
January 2021

Is adjuvant chemotherapy beneficial for stage II-III goblet cell carcinoid/goblet cell adenocarcinoma of the appendix?

Surg Oncol 2021 Mar 10;36:120-129. Epub 2020 Dec 10.

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA. Electronic address:

Background: Goblet cell carcinoma (GCC), formerly known as goblet cell carcinoid, of the appendix constitutes less than 14% of all primary appendiceal neoplasms. Surgical resection is the main treatment and the role of adjuvant chemotherapy (AC) is not established. This study aims to evaluate the impact of AC in stage II-III appendiceal GCC.

Methods: Patients with pathological stage II and III GCC who underwent surgical resection between 2006 and 2015 were identified from the National Cancer Database (NCDB) using ICD-O-3 morphology and topography codes: 8243/3 (goblet cell carcinoid) and C18.1. Patients treated with neoadjuvant systemic and/or radiation therapy and adjuvant radiation were excluded. Univariate and multivariable analyses were conducted, and Kaplan-Meier Curves were used to compare overall survival (OS) based on treatment received with Log-rank test.

Results: A total of 619 patients were identified. 54.4% males and 89.0% Caucasian; median age 56 (range, 23-90) years. Distribution across pathological stages II-III was 82.7% (N = 512) and 17.3% (N = 107) respectively. AC was administered in 9.4% (N = 48) of stage II and 47.7% (N = 51) of stage III patients. For stage II patients, AC was not associated with better OS in univariate (HR 0.32; 95% CI 0.04-2.34; p = 0.261) or multivariable analyses (HR 0.29; 95% CI 0.04-2.12; p = 0.221). By contrast, in stage III patients, AC was associated with better OS in univariate (HR 0.35; 95% CI 0.17-0.71; p = 0.004) and multivariable analyses (HR 0.25; 95% CI 0.07-0.88; p = 0.031). In the entire cohort 5-year OS for patients that received AC was 85.5% (74.0%, 92.1%) versus 82.7% (77.5%, 86.8%) (p = 0.801) with no AC. For stage II patients, 5-year OS was 96.9% with AC vs. 89.1% with no AC (p = 0.236). For stage III patients, 5-year OS was 77.1% with AC vs. 42.8% with no AC (p = 0.003).

Conclusion: AC was associated with improved OS in patients with pathological stage III GCC of the appendix, but not with pathological stage II.
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http://dx.doi.org/10.1016/j.suronc.2020.12.003DOI Listing
March 2021

Impact of Sarcopenia, BMI, and Inflammatory Biomarkers on Survival in Advanced Hepatocellular Carcinoma Treated With Anti-PD-1 Antibody.

Am J Clin Oncol 2021 02;44(2):74-81

Department of Hematology and Medical Oncology, Winship Cancer Institute.

Background: Sarcopenia and inflammation are independently associated with worse survival in cancer patients. This study aims to determine the impact of sarcopenia, body mass index (BMI), and inflammatory biomarkers on survival in advanced hepatocellular carcinoma (HCC) patients treated with anti-PD-1 antibody-based immunotherapy.

Methods: A retrospective review of advanced HCC patients treated with immunotherapy at Winship Cancer Institute between 2015 and 2019 was performed. Baseline computed tomography and magnetic resonance images were collected at mid-L3 level, assessed for skeletal muscle density using SliceOmatic (TomoVision, version 5.0) and converted to skeletal muscle index (SMI) by dividing it by height (m2). Sex-specific sarcopenia was defined by the median value of SMI. The optimal cut for continuous inflammation biomarker was determined by bias-adjusted log-rank test. Overall survival (OS) was set as primary outcome and Cox proportional hazard model was used for association with survival.

Results: A total of 57 patients were included; 77.2% male, 52.6% Caucasian, 58.5% Eastern Cooperative Oncology Group performance status 0-1, 80.7% Child Pugh A. Treatment was second line and beyond in 71.9% of patients. The median follow-up time was 6 months. Sarcopenia cut-off for males and females was SMI of 43 and 39, respectively. 49.1% of patients had sarcopenia. Median OS was 5 versus 14.3 months in sarcopenic versus nonsarcopenic patients (Log-rank P=0.054). Median OS was 5 and 17.5 months in patients with BMI <25 and BMI ≥25, respectively (Log-rank P=0.034). Median OS was 3.6 and 14.3 months for patients with neutrophil-to-lymphocyte ratio (NLR) ≥5.15 versus NLR <5.15 (Log-rank P<0.001). In multivariable Cox regression model, higher baseline NLR was associated with worse OS (hazard ratio [HR]: 4.17, 95% confidence interval [CI]: 1.52-11.39, P=0.005). Sex-specific sarcopenia showed a trend of worse OS (HR: 1.71, 95% CI: 0.73-4.00, P=0.215) but was not statistically significant. BMI<25 was associated with worse OS (HR: 2.28, 95% CI: 0.92-5.65, P=0.076). In the association with progression free survival, neither baseline BMI nor sex-specific sarcopenia showed statistical significance.

Conclusion: After controlling for baseline Child Pugh score and NLR, sex-specific sarcopenia does not predict OS. Baseline BMI and NLR together may predict OS in advanced HCC patients treated with anti-PD-1 antibody.
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http://dx.doi.org/10.1097/COC.0000000000000787DOI Listing
February 2021

Selective activation of FZD7 promotes mesendodermal differentiation of human pluripotent stem cells.

Elife 2020 12 17;9. Epub 2020 Dec 17.

Department of Cellular & Molecular Medicine, University of California San Diego, San Diego, United States.

WNT proteins are secreted symmetry breaking signals that interact with cell surface receptors of the FZD family to regulate a multitude of developmental processes. Studying selectivity between WNTs and FZDs has been hampered by the paucity of purified WNT proteins and by their apparent non-selective interactions with the FZD receptors. Here, we describe an engineered protein, called F7L6, comprised of antibody-derived single-chain variable fragments, that selectively binds to human FZD7 and the co-receptor LRP6. F7L6 potently activates WNT/β-catenin signaling in a manner similar to Wnt3a. In contrast to Wnt3a, F7L6 engages only FZD7 and none of the other FZD proteins. Treatment of human pluripotent stem (hPS) cells with F7L6 initiates transcriptional programs similar to those observed during primitive streak formation and subsequent gastrulation in the mammalian embryo. This demonstrates that selective engagement and activation of FZD7 signaling is sufficient to promote mesendodermal differentiation of hPS cells.
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http://dx.doi.org/10.7554/eLife.63060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7759383PMC
December 2020

Perioperative therapy in metastatic colorectal cancer: Pattern of use and survival outcomes.

J Surg Oncol 2021 Feb 30;123(2):596-605. Epub 2020 Oct 30.

Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

Background: Multimodality therapy of metastatic colorectal cancer (mCRC) is currently considered the standard of care. The aim of this study was to evaluate the impact of perioperative therapy on surgical resection in mCRC.

Methods: The National Cancer Database was analyzed for affected patients between 2004 and 2013. Univariate and multivariate analyses were done to identify factors associated with patient outcomes. Kaplan-Meier analysis and Cox proportional hazards models were used for the association between patient characteristics and survival.

Results: About 61,940 patients with mCRC were identified. Mean age = 63.4 years (SD ± 14). About 69% had a colon primary and 32% had only one metastatic site. Only 49% of those who underwent surgery for both primary and metastatic sites received postoperative chemotherapy (p < .001). Negative prognostic factors included no chemotherapy received (hazard ratio [HR], 2.32; 2.27-2.37; p < .001), more than three metastatic sites (HR, 2.28; 2.09-2.48; p < .001), year of diagnosis between 2004 and 2008 (HR, 1.71; 1.15-1.20; p < .001) and colon tumor location with right worse than left-sided (HR, 1.21; 1.19-1.24; p < .001). Five-year overall survival for resection of the primary and metastatic site (28.2%) was higher than for no surgical treatment (4.7%).

Conclusion: Perioperative therapy was associated with improved survival, following resection of metastatic sites or primary tumor.
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http://dx.doi.org/10.1002/jso.26278DOI Listing
February 2021

Retrospective study evaluating the safety of administering pegfilgrastim on the final day of 5-fluorouracil continuous intravenous infusion.

J Oncol Pharm Pract 2020 Aug 6:1078155220945771. Epub 2020 Aug 6.

Emory Winship Cancer Institute, Emory University, Atlanta, GA, USA.

Background: Pegfilgrastim, a long-acting granulocyte-colony-stimulating factor used to prevent neutropenia, is not indicated for administration within 24 h of completion of chemotherapy. The safety of administering pegfilgrastim in gastrointestinal cancer chemotherapy regimens containing continuous intravenous infusion of 5-fluorouracil (5-FUCI) on the day of completion of 5-fluorouracil has not been adequately studied.

Methods: An institutional review board-approved retrospective analysis of patients with a gastrointestinal malignancy receiving pegfilgrastim on the final day of 5-FUCI was conducted. The primary end point was to determine the incidence of grade 3 and grade 4 neutropenia and febrile neutropenia when pegfilgrastim was administered on the final day of 5-FUCI. The secondary endpoint was to determine rate of dose reductions and treatment delays.

Results: A total of 300 patients were reviewed from January 2010 to May 2017. The most common cancers were colorectal (25%) and pancreatic (60%), with 77% of patients having late stage disease. The risk of a patient developing grade 3 neutropenia was 0.010 (95% CI 0.002-0.029) and grade 4 neutropenia was 0.007 (95% CI 0.001-0.024). The risk of febrile neutropenia was 0.007 (95% CI 0.001-0.024). The risks of treatment delay and treatment reduction were 0.013 (95% CI 0.004-0.034) and 0.010 (95% CI 0.002-0.029), respectively.

Conclusion: The low risk of grade 3 and grade 4 neutropenia, febrile neutropenia, as well as dose delays and/or reduction suggests that pegfilgrastim can be administered on the final day of 5-FUCI. Limitations of this study were that it was retrospective in nature and was conducted at a single institution.
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http://dx.doi.org/10.1177/1078155220945771DOI Listing
August 2020

Phase 1 safety and pharmacodynamic study of lenalidomide combined with everolimus in patients with advanced solid malignancies with efficacy signal in adenoid cystic carcinoma.

Br J Cancer 2020 10 24;123(8):1228-1234. Epub 2020 Jul 24.

Department of Hematology and Medical Oncology, Emory University, Atlanta, GA, USA.

Background: Purpose: The combination of a mammalian target of rapamycin inhibitor and lenalidomide showed enhanced preclinical cytotoxicity. We conducted a phase 1 study in advanced solid tumour patients to assess safety, efficacy and pharmacodynamic (PD) outcomes.

Methods: We employed a 3+3 dose escalation design to establish the safety and recommended phase 2 doses (RP2D) of daily everolimus and lenalidomide in patients with advanced solid tumours. The starting doses were 5 and 10 mg, respectively, with planned escalation to maximum single-agent doses of 10 and 25 mg in the absence of dose-limiting toxicity. PD endpoints of lymphocyte subsets and immune cytokines were assessed in peripheral blood using multiparameter flow cytometry and LUMINEX assay. Efficacy was evaluated by cross-sectional imaging after every two cycles of treatment.

Results: The study enrolled 44 patients, median age of 58 years and 28 males (63.6%). The RP2D was established as 10 and 25 mg daily continuously for everolimus and lenalidomide. Common (>5%) grade ≥3 adverse events included rash (19%), neutropenia (19%), hypokalaemia (11%) and fatigue (9%). Best efficacy outcomes in 36 evaluable patients were partial response in 5 (13.8%), stable disease in 24 (55.8%) and progressive disease in 7 (19.4%) patients. PD assessment revealed significant association of cytokine levels (interleukin-2 (IL2), IL21 and IL17), baseline activated and total CD8+ lymphocytes and change in B cell lymphocytes and activated NK cells with clinical benefit.

Conclusions: The study demonstrated the safety of everolimus and lenalidomide with promising efficacy signal in thyroid and adenoid cystic cancers.

Clinical Trial Registration: NCT01218555.
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http://dx.doi.org/10.1038/s41416-020-0988-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7553949PMC
October 2020

Survival outcome of adjuvant chemotherapy in deficient mismatch repair stage III colon cancer.

Cancer 2020 Sep 22;126(18):4136-4147. Epub 2020 Jul 22.

Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.

Background: The prognostic impact of DNA mismatch repair (MMR) status remains controversial in patients with stage III colon cancer who are treated with adjuvant chemotherapy (AC). The aim of this study was to evaluate the survival outcome of AC in deficient mismatch repair (dMMR)/microsatellite instable (MSI) stage III CC.

Methods: Patients with pathological stage III CC between 2010 and 2013 were identified from the National Cancer Database using International Classification of Diseases for Oncology (3rd Edition) morphology and topography codes 8140, 8480, and C18.0-18.8. Patients with pathologic stage T3N2, T4N1, or T4N were considered high risk; patients with stage T3N1 were considered low risk. Univariate and multivariable analyses were conducted, and Kaplan-Meier analysis and Cox proportional hazards models were used to identify the association between AC and overall survival (OS).

Results: A total of 9226 patients with pathological stage III CC were identified, of which 2384 (25.8%) were MSI-high (MSI-H) and met the inclusion criteria of the final analysis. MSI-low (MSI-L) patients (n = 6842) were excluded. There was a preponderance of women (55.0% [n = 1311]), and 76.6% (n = 1825) of patients were non-Hispanic white. The median age was 65 years (range, 19-90 years). The primary sites were the cecum (29.7% [n = 707]), ascending colon (26.0% [n = 620]), sigmoid colon (17.2% [n = 410]), and transverse colon (10.8% [n = 257]). The most common tumor grade was moderately differentiated (n = 50.4% [1202]), followed by poorly differentiated (34.1% [n = 813]) and well differentiated (5.1% [n = 121]). High-risk pathologic stage III CC (T4N1, TxN2) constituted 51.0% (n = 1215) of the study population. High-risk stage III was associated with worse OS compared with low-risk stage III on univariate (P < .001) analysis and displayed a similar trend on multivariable analysis, without a statistically significant difference. Multiagent AC was associated with improved OS compared with no treatment on univariate (P < .001) and multivariable (P < .001) analysis. When stratified by risk status, multiagent AC was associated with improved OS compared with no treatment for high-risk (P < .001) and low-risk (P < .001) stage III disease.

Conclusion: Adjuvant chemotherapy is associated with better OS in stage III dMMR/MSI-H CC. An enhanced benefit was shown for high-risk stage III disease.
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http://dx.doi.org/10.1002/cncr.33049DOI Listing
September 2020

Radiation as a Single-Modality Treatment in Localized Pancreatic Cancer.

Pancreas 2020 07;49(6):822-829

From the Department of Hematology and Oncology, Winship Cancer Institute.

Objectives: Locally advanced pancreatic cancer (LAPC) is managed with multimodality therapy. We aim to evaluate the outcome of single-modality radiation therapy for LAPC.

Methods: Locally advanced pancreatic cancer patients were identified between 2004 and 2013 using the National Cancer Database excluding patients who received chemotherapy or surgery.

Results: A total of 6590 patients were included. The mean age was 73.5 (range, 28-90) years, 83.2% were white, and 54.4% were female. Tumors of 4 cm or greater (>T3 stage) accounted for 52.7%. The median radiation dose was 39.6 Gy. Stereotactic body radiation (SBRT) delivered to 64 patients and external-beam/intensity modulated radiotherapy in 416 patients. Radiation therapy was associated with improved overall survival (OS) compared with no treatment in univariate and multivariable analyses. The medians OS for patients who received SBRT, external-beam/intensity modulated radiotherapy, or no radiation were 8.6, 6.7, and 3.4 months, respectively (P < 0.001). There is a significant difference in 12-month OS for the SBRT cohort (31.9%; 95% confidence interval [CI], 20.9%-43.5%) compared with patients who received no radiation (15.1%; 95% CI, 14.2%-16.0%), and on multivariable analysis (hazard ratio, 0.50; 95% CI, 0.38-0.65; P < 0.001).

Conclusions: The current study suggests potential benefit for radiation therapy alone in comparison with no treatment in LAPC.
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http://dx.doi.org/10.1097/MPA.0000000000001584DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8011591PMC
July 2020

Blood-based next-generation sequencing analysis of neuroendocrine neoplasms.

Oncotarget 2020 May 12;11(19):1749-1757. Epub 2020 May 12.

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, USA.

Neuroendocrine neoplasms (NENs) are a heterogeneous group of neoplasms that span from well-differentiated neuroendocrine tumors (NETs) to highly aggressive neoplasms classified as neuroendocrine carcinomas (NECs). The genomic landscape of NENs has not been well studied. The aim of this study is to confirm the feasibility of next generation sequencing (NGS) testing circulating tumor DNA (ctDNA) in patients with NENs and characterize common alterations in the genomic landscape. Of the 320 NEN patients, 182 (57%) were male with a median age of 63 years (range: 8-93) years. Tumor type included pancreatic NET ( 165, 52%), gastrointestinal NEC ( 52, 16%), large cell lung NEC ( 21, 7%), nasopharyngeal NEC ( 16, 5%) and NEC/NET not otherwise specified ( 64, 20%). ctDNA NGS testing was performed on 338 plasma samples; 14 patients had testing performed twice and 2 patients had testing performed three times. Genomic alterations were defined in 280 (87.5%) samples with a total of 1,012 alterations identified after excluding variants of uncertain significance (VUSs) and synonymous mutations. Of the 280 samples with alterations, associated genes were most commonly altered ( 145, 52%), followed by ( 61, 22%), ( 33, 12%), ( 30, 11%), ( 28, 10%), ( 28, 10%), ( 28, 10%), ( 22, 8%), ( 19, 7%), ( 19, 7%), ( 19, 7%), ( 19, 7%), ( 19, 7%), ( 16, 6%) and ( 14, 5%). Evaluation of ctDNA was feasible among individuals with NEN. Liquid biopsies are non-invasive methods that can provide personalized options for targeted therapies in NEN patients. Molecular alterations in 338 plasma samples from 320 patients with NEN were evaluated using clinical-grade NGS of ctDNA (Guardant360) across multiple institutions. The test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes.
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http://dx.doi.org/10.18632/oncotarget.27588DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7233805PMC
May 2020

Provider Recommendations for Phase I Clinical Trials Within a Shared Decision-Making Model in Phase I Cancer Clinical Trial Discussions.

JCO Oncol Pract 2020 09 19;16(9):e859-e867. Epub 2020 May 19.

Winship Cancer Institute, Atlanta, GA.

Purpose: Debate continues over whether explicit recommendations for a clinical trial should be included as an element of shared decision making within oncology. We aimed to determine if and how providers make explicit recommendations in the setting of phase I cancer clinical trials.

Methods: Twenty-three patient/provider conversations about phase I trials were analyzed to determine how recommendations are made and how the conversations align with a shared decision-making framework. In addition, 19 providers (9 of whose patient encounters were observed) were interviewed about the factors they consider when deciding whether to recommend a phase I trial.

Results: We found that providers are comprehensive in the factors they consider when recommending clinical trials. The two most frequently stated factors were performance status (89%) and patient preferences (84%). Providers made explicit recommendations in 19 conversations (83%), with 12 of those being for a phase I trial (12 [63%] of 19). They made these recommendations in a manner consistent with a shared decision-making model; 18 (95%) of the 19 conversations during which a recommendation was made included all steps, or all but 1 step, of shared decision making, as did 11 of the 12 conversations during which a phase I trial was recommended. In 7 (58%) of these later conversations, providers also emphasized the importance of the patient's opinion.

Conclusion: We suggest that providers not hesitate to make explicit recommendations for phase I clinical trials, because they are able to do so in a manner consistent with shared decision making. With further research, these results can be applied to other clinical trial settings.
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http://dx.doi.org/10.1200/JOP.19.00772DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489480PMC
September 2020

Napabucasin (BBI 608), a potent chemoradiosensitizer in rectal cancer.

Cancer 2020 Jul 8;126(14):3360-3371. Epub 2020 May 8.

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

Background: The induction of reactive oxygen species (ROS) represents a viable strategy for enhancing the activity of radiotherapy. The authors hypothesized that napabucasin would increase ROS via its ability to inhibit NAD(P)H:quinone oxidoreductase 1 and potentiate the response to chemoradiotherapy in rectal cancer via distinct mechanisms.

Method: Proliferation studies, colony formation assays, and ROS levels were measured in HCT116 and HT29 cell lines treated with napabucasin, chemoradiation, or their combination. DNA damage (pγH2AX), activation of STAT, and downstream angiogenesis were evaluated in both untreated and treated cell lines. Finally, the effects of napabucasin, chemoradiotherapy, and their combination were assessed in vivo with subcutaneous mouse xenograft models.

Results: Napabucasin significantly potentiated the growth inhibition of chemoradiation in both cell lines. Napabucasin increased ROS generation. Inhibition of ROS by N-acetylcysteine decreased the growth inhibitory effect of napabucasin alone and in combination with chemoradiotherapy. Napabucasin significantly increased pγH2AX in comparison with chemoradiotherapy alone. Napabucasin reduced the levels of pSTAT3 and VEGF and inhibited angiogenesis through an ROS-mediated effect. Napabucasin significantly potentiated the inhibition of growth and blood vessel formation by chemoradiotherapy in mouse xenografts.

Conclusion: Napabucasin is a radiosensitizer with a novel mechanism of action: increasing ROS production and inhibiting angiogenesis. Clinical trials testing the addition of napabucasin to chemoradiotherapy in rectal cancer are needed.
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http://dx.doi.org/10.1002/cncr.32954DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7380507PMC
July 2020

Synthetic and immunological studies on the OCT4 immunodominant motif antigen-based anti-cancer vaccine.

Cancer Biol Med 2020 02;17(1):132-141

Department of Physiology, School of Basic Medical Sciences, Shenzhen University Health Sciences Center, Shenzhen University, Shenzhen 518060, China.

Cancer stem cell is one of the important causes of tumorigenesis as well as a drug target in the treatment of malignant tumor. However, at present, there is no immune vaccine targeting these cells. Octamer-binding transcription factor 4 (OCT4), a marker of embryonic stem cells and germ cells, often highly expresses in the early stages of tumorigenesis and is therefore a good candidate for cancer vaccine development. To identify the optimal carrier and adjuvant combination, we chemically synthesized and linked three different OCT4 epitope antigens to a carrier protein, keyhole limpet hemocyanin (KLH), combined with Toll-like receptor 9 agonist (TLR9). Immunization with OCT4-3 + TLR9 produced the strongest immune response in mice. In prevention assays, significant tumor growth inhibition was achieved in BABL/c mice treated with OCT4-3 + TLR9 ( < 0.01). Importantly, the results showed that cytotoxic T lymphocyte activity and the inhibition of tumor growth were enhanced in mice immunized with OCT4-3 combined with TLR9. Meanwhile, multiple cytokines [such as interferon (IFN)-γ ( < 0.05), interleukin (IL)-12 ( < 0.05), IL-2 ( < 0.01), and IL-6 ( < 0.05)] promoting cellular immune responses were shown to be greatly enhanced in mice immunized with OCT4-3 + TLR9. Moreover, we considered safety considerations in terms of the composition of the vaccines to help facilitate the development of effective next-generation vaccines. Collectively, these experiments demonstrated that combination therapy with TLR9 agonist induced a tumor-specific adaptive immune response, leading to the suppression of primary tumor growth in testis embryonic carcinoma.
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http://dx.doi.org/10.20892/j.issn.2095-3941.2019.0224DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7142840PMC
February 2020

Phase I Trial of Trametinib with Neoadjuvant Chemoradiation in Patients with Locally Advanced Rectal Cancer.

Clin Cancer Res 2020 07 6;26(13):3117-3125. Epub 2020 Apr 6.

Moffitt Cancer Center, Tampa, Florida.

Purpose: The RAS/RAF/MEK/ERK signaling pathway is critical to the development of colorectal cancers, and , , and mutations foster resistance to radiation. We performed a phase I trial to determine the safety of trametinib, a potent MEK1/2 inhibitor, with 5-fluorouracil (5-FU) chemoradiation therapy (CRT) in patients with locally advanced rectal cancer (LARC).

Patients And Methods: Patients with stage II/III rectal cancer were enrolled on a phase I study with 3+3 study design, with an expansion cohort of 9 patients at the MTD. Following a 5-day trametinib lead-in, with pre- and posttreatment tumor biopsies, patients received trametinib and CRT, surgery, and adjuvant chemotherapy. Trametinib was given orally daily at 3 dose levels: 0.5 mg, 1 mg, and 2 mg. CRT consisted of infusional 5-FU 225 mg/m/day and radiation dose of 28 daily fractions of 1.8 Gy (total 50.4 Gy). The primary endpoint was to identify the MTD and recommended phase II dose. IHC staining for phosphorylated ERK (pERK) and genomic profiling was performed on the tumor samples.

Results: Patients were enrolled to all dose levels, and 18 patients were evaluable for toxicities and responses. Treatment was well tolerated, and there was one dose-limiting toxicity of diarrhea, which was attributed to CRT rather than trametinib. At the 2 mg dose level, 25% had pathologic complete response. IHC staining confirmed dose-dependent decrease in pERK with increasing trametinib doses.

Conclusions: The combination of trametinib with 5-FU CRT is safe and well tolerated, and may warrant additional study in a phase II trial, perhaps in a -mutant selected population.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-4193DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7334091PMC
July 2020

Receipt of Adjuvant Chemotherapy in Stage II Colon Cancer and Overall Survival: A National Cancer Database Study.

J Surg Res 2020 08 31;252:69-79. Epub 2020 Mar 31.

Division of Colorectal Surgery, Department of Surgery, Emory University School of Medicine, Atlanta, Georgia. Electronic address:

Background: There are variations in the use of adjuvant chemotherapy (AC) in stage II colon cancer (CRC). We sought to determine which patients received chemotherapy, what factors were associated with receipt of AC, and how this impacted overall survival.

Methods: Using the National Cancer Database, patients with stage II CRC who underwent surgical resection were selected; patients who received radiation or neoadjuvant chemotherapy were excluded. High-risk features (HRFs) were defined as pathological tumor stage IV, positive surgical margins, and perineural or lymphovascular invasion. Multivariable and subgroup analysis with eight subgroups stratified in the presence of HRFs, age, and the Charlson-Deyo score was performed.

Results: Of 77,739 patients identified with stage II CRC, 18.3% received AC. Younger, healthier patients with HRFs had the highest chemotherapy receipt rate (46.7%), whereas patients without HRFs, ≥ 75 y, and with the Charlson-Deyo score of 2+ had the lowest rate (2.1%). Community cancer centers were more likely to initiate AC (odds ratio = 1.24 P < 0.01) especially among healthy HRF-negative patients and younger patients. No significant racial differences in AC use were observed. AC was associated with improved overall survival in subgroups with HRFs (hazard ratio [HR]: 0.81 P < 0.001; HR: 0.75 P < 0.001; HR: 0.65 P = 0.03; HR: 0.55, P < 0.001) but not in patients without HRFs.

Conclusions: AC receipt rates differed depending on patient age and type of institution delivering care. AC was associated with survival benefits only in patients with HRFs regardless of age. These findings are clinically relevant to inform appropriate use of AC in stage II CRC.
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http://dx.doi.org/10.1016/j.jss.2020.02.016DOI Listing
August 2020

Combined Effect of Sarcopenia and Systemic Inflammation on Survival in Patients with Advanced Stage Cancer Treated with Immunotherapy.

Oncologist 2020 03 5;25(3):e528-e535. Epub 2019 Dec 5.

Department of Urology, Emory University School of Medicine, Atlanta, Georgia, USA.

Background: Sarcopenia and inflammation have been associated with poor survival in patients with cancer. We explored the combined effects of these variables on survival in patients with cancer treated with immunotherapy.

Methods: We performed a retrospective review of 90 patients enrolled on immunotherapy-based phase I clinical trials at Emory University from 2009 to 2017. Baseline neutrophil-to-lymphocyte ratio, monocyte-to-lymphocyte ratio, and platelet-to-lymphocyte ratio (PLR) were used as surrogates of inflammation. The skeletal muscle index (SMI) was derived from the skeletal muscle density calculated from baseline abdominal computed tomography images. Optimal cutoffs for continuous inflammation biomarkers and SMI were determined by bias-adjusted log-rank test. A four-level risk stratification was used to create low-risk (PLR <242 and nonsarcopenic), intermediate-risk (PLR <242 and sarcopenic), high-risk (PLR ≥242 and nonsarcopenic), and very-high-risk (PLR ≥242 and sarcopenic) groups with subsequent association with survival.

Results: Most patients (59%) were male, and the most common cancers were melanoma (33%) and gastrointestinal (22%). Very high-risk, high-risk, and intermediate-risk patients had significantly shorter overall survival (hazard ratio [HR], 8.46; 95% confidence interval [CI], 2.65-27.01; p < .001; HR, 5.32; CI, 1.96-14.43; p = .001; and HR, 4.01; CI, 1.66-9.68; p = .002, respectively) and progression-free survival (HR, 12.29; CI, 5.15-29.32; p < .001; HR, 3.51; CI, 1.37-9.02; p = .009; and HR, 2.14; CI, 1.12-4.10; p = .022, respectively) compared with low-risk patients.

Conclusion: Baseline sarcopenia and elevated inflammatory biomarkers may have a combined effect on decreasing survival in immunotherapy-treated patients in phase I trials. These data may be immediately applicable for medical oncologists for the risk stratification of patients beginning immunotherapeutic agents.

Implications For Practice: Sarcopenia and inflammation have been associated with poor survival in patients with cancer, but it is unclear how to apply this information to patient care. The authors created a risk-stratification system that combined sarcopenia and platelet-to-lymphocyte ratio as a marker of systemic inflammation. The presence of sarcopenia and systemic inflammation decreased progression-free survival and overall survival in our cohort of 90 patients who received immunotherapy in phase I clinical trials. The data presented in this study may be immediately applicable for medical oncologists as a way to risk-stratify patients who are beginning treatment with immunotherapy.
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http://dx.doi.org/10.1634/theoncologist.2019-0751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7066707PMC
March 2020

Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer Living With HIV: A Perspective on Recent Progress and Future Needs.

JCO Oncol Pract 2020 06 11;16(6):319-325. Epub 2020 Mar 11.

Emory University School of Medicine, Winship Cancer Institute, Atlanta, GA.

Recent studies have identified durable responses with the use of immune checkpoint inhibitors in patients with mismatch repair-deficient (MMR-D)/microsatellite instability-high (MSI-H) metastatic colorectal cancer (CRC). The dramatic improvement in clinical outcomes led to the US Food and Drug Administration approval of pembrolizumab, nivolumab, and nivolumab in combination with ipilimumab in metastatic patients with MSI-H/MMR-D CRC who previously experienced progression on cytotoxic therapies. In the clinical trials investigating these agents, HIV-seropositive patients were not included and therefore the clinical efficacy of these agents in patients with metastatic MSI-H/MMR-D CRC living with HIV is unclear. On the basis of growing evidence, immune checkpoint blockade therapies seem to be a safe approach in patients with well-controlled HIV infection. Research on immunotherapeutic approaches in patients living with HIV and cancer is an area of unmet medical need that can be addressed by clinical trial designs that are inclusive of patients with well-controlled seropositive HIV and trials that specifically evaluate immune therapies in patients living with HIV.
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http://dx.doi.org/10.1200/JOP.19.00754DOI Listing
June 2020

Young Adults With Pancreatic Cancer: National Trends in Treatment and Outcomes.

Pancreas 2020 03;49(3):341-354

From the Department of Hematology and Oncology, Winship Cancer Institute.

Objectives: The treatment and outcomes of patients younger than 50 years (young adults [YAs]) with pancreatic cancer are largely unknown. We evaluated the presentation, treatment, and outcomes of these patients.

Methods: The National Cancer Database was analyzed. Univariate and multivariate Cox proportional hazards models were performed to identify variables associated with overall survival.

Results: A total of 124,442 patients with pancreatic cancer were identified, with 9657 between 18 and 50 years of age. Mean age was 45.4 years (standard deviation, 4.6 years). About 30.9% of YA patients and 25% of patients older than 50 years underwent resection of the primary tumor. Survival advantage was seen for patients 18 to 39 years (hazard ratio, 1.14; 95% confidence interval, 1.07-1.23; P < 0.001). This age advantage was similar across all the racial groups. Overall, YAs treated between 2009 and 2013 had higher survival rates compared with 2004 to 2008 (hazard ratio, 0.85; 95% confidence interval, 0.81-0.89; P < 0.001). This survival improvement was highest in American Indians and Asian/Pacific Islanders (16.6% vs 6.5%), African Americans (10.6% vs 8.5%), and Hispanics (14.5% vs 12.6%).

Conclusions: Survival of YAs with pancreatic cancer patients is superior to older patients and has improved over time, especially in minority populations.
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http://dx.doi.org/10.1097/MPA.0000000000001502DOI Listing
March 2020

Establishment and Analysis of Three-Dimensional (3D) Organoids Derived from Patient Prostate Cancer Bone Metastasis Specimens and their Xenografts.

J Vis Exp 2020 02 3(156). Epub 2020 Feb 3.

Department of Urology, University of California, San Diego; Moores Cancer Center, University of California, San Diego;

Three-dimensional (3D) culture of organoids from tumor specimens of human patients and patient-derived xenograft (PDX) models of prostate cancer, referred to as patient-derived organoids (PDO), are an invaluable resource for studying the mechanism of tumorigenesis and metastasis of prostate cancer. Their main advantage is that they maintain the distinctive genomic and functional heterogeneity of the original tissue compared to conventional cell lines that do not. Furthermore, 3D cultures of PDO can be used to predict the effects of drug treatment on individual patients and are a step towards personalized medicine. Despite these advantages, few groups routinely use this method in part because of the extensive optimization of PDO culture conditions that may be required for different patient samples. We previously demonstrated that our prostate cancer bone metastasis PDX model, PCSD1, recapitulated the resistance of the donor patient's bone metastasis to anti-androgen therapy. We used PCSD1 3D organoids to characterize further the mechanisms of anti-androgen resistance. Following an overview of currently published studies of PDX and PDO models, we describe a step-by-step protocol for 3D culture of PDO using domed or floating basement membrane (e.g., Matrigel) spheres in optimized culture conditions. In vivo stitch imaging and cell processing for histology are also described. This protocol can be further optimized for other applications including western blot, co-culture, etc. and can be used to explore characteristics of 3D cultured PDO pertaining to drug resistance, tumorigenesis, metastasis and therapeutics.
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http://dx.doi.org/10.3791/60367DOI Listing
February 2020

A Phase I Study of Safety, Pharmacokinetics, and Pharmacodynamics of Concurrent Everolimus and Buparlisib Treatment in Advanced Solid Tumors.

Clin Cancer Res 2020 06 31;26(11):2497-2505. Epub 2020 Jan 31.

Department of Hematology & Medical Oncology, Emory University, Atlanta, Georgia.

Purpose: Concurrent inhibition of mTOR and PI3K led to improved efficacy in preclinical models and provided the rationale for this phase I study of everolimus and buparlisib (BKM120) in patients with advanced solid tumor.

Patients And Methods: We used the Bayesian Escalation with Overdose Control design to test escalating doses of everolimus (5 or 10 mg) and buparlisib (20, 40, 60, 80, and 100 mg) in eligible patients. Pharmacokinetic assessment was conducted using blood samples collected on cycle 1, days 8 and 15. Pharmacodynamic impact on mTOR/PI3K pathway modulation evaluated in paired skin biopsies collected at baseline and end of cycle 1.

Results: We enrolled 43 patients, median age of 63 (range, 39-78) years; 25 (58.1%) females, 35 (81.4%) Caucasians, and 8 (18.6%) Blacks. The most frequent toxicities were hyperglycemia, diarrhea, nausea, fatigue, and aspartate aminotransferase elevation. Dose-limiting toxicities observed in 7 patients were fatigue (3), hyperglycemia (2), mucositis (1), acute kidney injury (1), and urinary tract infection (1). The recommended phase II dose (RP2D) for the combination was established as everolimus (5 mg) and buparlisib (60 mg). The best response in 27 evaluable patients was progressive disease and stable disease in 3 (11%) and 24 (89%), respectively. The median progression-free survival and overall survival were 2.7 (1.8-4.2) and 9 (6.4-13.2) months. Steady-state pharmacokinetic analysis showed dose-normalized maximum concentrations and AUC values for everolimus and buparlisib in combination to be comparable with single-agent pharmacokinetic.

Conclusions: The combination of everolimus and buparlisib is safe and well-tolerated at the RP2D of 5 and 60 mg on a continuous daily schedule.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-2697DOI Listing
June 2020

Immune-Related Adverse Events and Immune Checkpoint Inhibitor Efficacy in Patients with Gastrointestinal Cancer with Food and Drug Administration-Approved Indications for Immunotherapy.

Oncologist 2020 08 14;25(8):669-679. Epub 2020 Jan 14.

Division of Hematology and Oncology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee, USA.

Introduction: Immune-related adverse event (IRAE) onset may represent a clinical biomarker for anti-programmed cell death protein 1 (PD-1) antibody response based on emerging evidence from patients with various advanced malignancies. This phenomenon has not been previously reported in a multidisease cohort of patients with gastrointestinal (GI) cancer with Food and Drug Administration (FDA)-approved indications to receive immune checkpoint inhibitor therapy.

Materials And Methods: The study was a multicenter retrospective cohort analysis of 76 patients with GI cancer who had received anti-PD-1 antibodies for FDA-approved indications. The primary and secondary outcomes of the study were progression-free survival (PFS) and overall survival (OS) in patients based upon IRAE presence, respectively. PFS and OS were estimated by the Kaplan-Meier method; a Cox proportional-hazards model adjusted for IRAE onset, patient age, and enrolling institution was used to analyze outcomes.

Results: Median PFS and OS were prolonged in patients who experienced IRAEs compared with those who did not experience them (PFS: not reached [NR] vs. 3.9 months [hazard ratio (HR) 0.13, 95% confidence interval (CI) 0.05-0.3, p < .001]; OS: NR vs. 7.4 months [HR 0.11, 95% CI 0.03-0.36, p < .001]). Among patients who experienced IRAEs, there were no significant differences in PFS and OS by either initial IRAE severity, management, or time to onset.

Conclusion: Patients with gastrointestinal cancer who experienced IRAEs while on anti-PD-1 antibodies demonstrated significant improvements in PFS and OS compared with their counterparts who did not develop IRAEs. Although these findings add to results from studies in other tumor types, larger prospective studies are needed prior to clinical adoption of IRAE onset as a biomarker for immune checkpoint inhibitor response.

Implications For Practice: Predictive clinical biomarkers for immune checkpoint inhibitor response have been understudied in the field of immuno-oncology. Immune-related adverse event onset appears to be one such biomarker. Across tumor types, immune-related adverse event onset has been associated with response to anti-programmed cell death protein 1 (PD-1) antibodies. The results of this study demonstrate this for the first time in patients with gastrointestinal cancer receiving anti-PD-1 antibodies. Before immune-related adverse event onset can be adopted clinically as a predictive biomarker for immune checkpoint inhibitor response, however, larger prospective studies are needed to better understand the nuances between immune-related adverse event characteristics (severity, site, management, timing of onset) and immune checkpoint inhibitor effectiveness.
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http://dx.doi.org/10.1634/theoncologist.2019-0637DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7418359PMC
August 2020

Blood-Based Next-Generation Sequencing Analysis of Appendiceal Cancers.

Oncologist 2020 05 29;25(5):414-421. Epub 2019 Nov 29.

Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia, USA.

Background: Appendiceal cancers (ACs) are rare. The genomic landscape of ACs has not been well studied. The aim of this study was to confirm the feasibility of next-generation sequencing (NGS) using circulating tumor DNA (ctDNA) in ACs and characterize common genomic alterations.

Materials And Methods: Molecular alterations in 372 plasma samples from 303 patients with AC using clinical-grade NGS of ctDNA (Guardant360) across multiple institutions were evaluated. Test detects single nucleotide variants in 54-73 genes, copy number amplifications, fusions, and indels in selected genes.

Results: A total of 303 patients with AC were evaluated, of which 169 (56%) were female. Median age was 56.8 (25-83) years. ctDNA NGS testing was performed on 372 plasma samples; 48 patients had testing performed twice, 9 patients had testing performed three times, and 1 patient had testing performed four times. Genomic alterations were defined in 207 (n = 207/372, 55.6%) samples, and 288 alterations were identified excluding variants of uncertain significance and synonymous mutations. Alterations were identified in at least one sample from 184 patients; TP53-associated genes (n = 71, 38.6%), KRAS (n = 33, 17.9%), APC (n = 14, 7.6%), EGFR (n = 12, 6.5%), BRAF (n = 11, 5.9%), NF1 (n = 10, 5.4%), MYC (n = 9, 4.9%), GNAS (n = 8, 4.3%), MET (n = 6, 3.3%), PIK3CA (n = 5, 2.7%), and ATM (n = 5, 2.7%). Other low-frequency but clinically relevant genomic alterations were as follows: AR (n = 4, 2.2%), TERT (n = 4, 2.2%), ERBB2 (n = 4, 2.2%), SMAD4 (n = 3, 1.6%), CDK4 (n = 2, 1.1%), NRAS (n = 2, 1.1%), FGFR1 (n = 2, 1.1%), FGFR2 (n = 2, 1.1%), PTEN (n = 2, 1.1%), RB1 (n = 2, 1.1%), and CDK6, CDKN2A, BRCA1, BRCA2, JAK2, IDH2, MAPK, NTRK1, CDH1, ARID1A, and PDGFRA (n = 1, 0.5%).

Conclusion: Evaluation of ctDNA is feasible among patients with AC. The frequency of genomic alterations is similar to that previously reported in tissue NGS. Liquid biopsies are not invasive and can provide personalized options for targeted therapies in patients with AC.

Implications For Practice: The complexity of appendiceal cancer and its unique genomic characteristics suggest that customized combination therapy may be required for many patients. Theoretically, as more oncogenic pathways are discovered and more targeted therapies are approved, customized treatment based on the patient's unique molecular profile will lead to personalized care and improve patient outcomes. Liquid biopsies are noninvasive, cost-effective, and promising methods that provide patients with access to personalized treatment.
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http://dx.doi.org/10.1634/theoncologist.2019-0558DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7216457PMC
May 2020

Clinicopathological features and survival outcomes of rare histologic variants of gallbladder cancer.

J Surg Oncol 2019 Nov 28. Epub 2019 Nov 28.

Department of Hematology and Medical Oncology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia.

Background: Adenocarcinoma (AC) is the most common histological type in gallbladder carcinoma (GBC). Squamous cell carcinoma (SCC), adenosquamous carcinoma (ASC), and papillary carcinoma (PC) are rare histologic variants of GBC.

Methods: Patients with AC, SCC, ASC, and PC of the gallbladder between 2004 and 2013 were identified from the National Cancer Database. Univariate and multivariate analyses were performed, and Kaplan-Meier curves were used to compare overall survival (OS) based on histological subtype.

Results: A total of 5956 patients ≥18 years of age were included in the final analysis. Most patients (n = 5398; 90.6%) had AC compared with variant histologies. PC (n = 227; 3.8%) was the most common variant, followed by ASC (n = 216; 3.6%) and SCC (n = 115; 1.9%); 70.3% were female and 78.9% Caucasian. The median age was 70 (range, 25-90) years. Surgical resection was performed in 77.7% of AC, 53.0% of SCC, 88.9% of ASC, and 96.9% of PC (P < .001). Systemic therapy after surgery was administered in 25.1% of AC, 18.3% of SCC, 35.7% of ASC, and 19.4% of PC (P = .001). In multivariate analysis, multiagent chemotherapy was associated with improved OS in all histologies except for SCC and PC (p < .001), and adjuvant systemic therapy was associated with improved OS in ASC and AC (P < .001).

Conclusion: Survival differs between the gallbladder variants. Except for SCC, GBC variants underwent surgical resection more often than AC. Adjuvant systemic therapy was associated with improved OS in ASC and AC.
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http://dx.doi.org/10.1002/jso.25781DOI Listing
November 2019

In-hospital 30-day mortality for older patients with pancreatic cancer undergoing pancreaticoduodenectomy.

J Geriatr Oncol 2020 05 6;11(4):660-667. Epub 2019 Nov 6.

Department of Hematology and Oncology, Winship Cancer Institute, Emory University, Atlanta, Georgia.

Objective: Surgical resection remains the only potentially curative therapy for pancreatic ductal adenocarcinoma (PDAC). There is paucity of literature about morbidity and mortality in older patients with PDAC undergoing pancreaticoduodenectomy. This retrospective analysis evaluates the in-hospital 30-day mortality of this population utilizing the Nationwide Inpatient Sample (NIS) database.

Subjects And Methods: All US patients hospitalized for pancreaticoduodenectomy (Whipple procedure) were included. Data was obtained from the NIS provided by the Agency for Healthcare Research and Quality. Pancreaticoduodenectomy diagnoses were identified using Clinical Classifications Software codes based on ICD-9 between 2007 and 2010. Univariable and multivariable analyses were performed using the logistic model, weighted chi-square test, and generalized linear model.

Results: A total of 6149 patient discharges for pancreaticoduodenectomy were identified. Mean age was 64.9 years (SD ± 12.3); 21% of patients were ≥ 76 years of age. Majority were White (N = 5257, 77.9%) with a male:female ratio of 1. Patients aged 76 and older (OR: 1.76; 1.36-2.28; p < .001), Hispanics (OR: 1.40; 0.92-2.13; p = .12), and high comorbidity score (OR: 5.70; 3.44-9.46; p < .001) were found to be associated with a higher risk of 30-day in-hospital mortality. In the multivariable analysis, advanced age (>76) remained a significant predictor of longer in-hospital length of stay (OR: 1.09; 1.04-1.14; p < .001) and 30-day in-hospital mortality (OR 1.46; 1.07-2.00; p = .016). The 30-day in-hospital mortality rate for all patients across all years was 3.24%, for patients >76 years 4.11% and for patients <76 years 2.77%. Patients who underwent surgery at teaching hospitals (OR: 0.61; 0.42-0.88; p = .008) had a lower risk of 30-day in-hospital mortality compared to non-teaching hospitals.

Conclusion: In-hospital 30 day mortality was higher in selected older patients with PDAC undergoing pancreaticoduodenectomy. Mortality was lower at high volume and teaching centers. Further stringent selection criteria are needed to decrease mortality in the older population.
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http://dx.doi.org/10.1016/j.jgo.2019.10.012DOI Listing
May 2020

Adiposity may predict survival in patients with advanced stage cancer treated with immunotherapy in phase 1 clinical trials.

Cancer 2020 02 24;126(3):575-582. Epub 2019 Oct 24.

Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.

Background: Body mass index (BMI) is used to define obesity, but it is an imperfect measure of body composition. In the current study, the authors explored the association between types of fat and survival in patients treated with immunotherapy.

Methods: A retrospective analysis of 90 patients who were treated with immunotherapy on phase 1 clinical trials at the Winship Cancer Institute in Atlanta, Georgia, from 2009 through 2017 was performed. Overall survival (OS) and progression-free survival (PFS) were used to measure clinical outcomes. Baseline BMI and radiographic images at the middle of the third lumbar vertebrae were obtained. Fat densities were calculated and converted to indices (subcutaneous fat index [SFI], intermuscular fat index [IFI], and visceral fat index [VFI]) after dividing by height in meters squared. Risk groups were created using recursive partitioning and the regression trees method for SFI and IFI, which were selected by stepwise variable selection among all fat-related variables. The Cox proportional hazards model and Kaplan-Meier method were used for the association with OS and PFS.

Results: The majority of patients (59%) were male and diagnosed with melanoma (33%) or gastrointestinal cancers (22%). The median BMI was 27.4 kg/m , the median SFI was 62.78, the median IFI was 4.06, and the median VFI was 40.53. Low-risk patients (those with an SFI ≥73) had a significantly longer OS (hazard ratio, 0.20; 95% CI, 0.09-0.46 [P < .001]) and PFS (hazard ratio, 0.38; 95% CI, 0.20-0.72 [P = .003]) compared with patients at intermediate risk (those with an SFI <73 and IFI <3.4) and poor risk (those with an SFI <73 and IFI ≥3.4). The Uno concordance statistics were found to be higher for fat risk groups than BMI in predicting OS (0.603 vs 0.574; P = .581) and PFS (0.602 vs 0.586; P = .71).

Conclusions: Increased BMI, increased SFI, and decreased IFI may be associated with prolonged survival in patients with cancer who are treated with immunotherapy. Further studies are needed to elucidate the effect of adiposity on the host immune response to immunotherapy.
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http://dx.doi.org/10.1002/cncr.32576DOI Listing
February 2020