Browsing by Subject "Colorectal cancer"
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Item A Multi-Center, Single Arm, Phase Ib study of Pembrolizumab (MK-3475) in Combination with Chemotherapy for Patients with Advanced Colorectal Cancer: HCRN GI14-186(Springer, 2021) Herting, Cameron J.; Farren, Matthew R.; Tong, Yan; Liu, Ziyue; O’Neil, Bert; Bekaii-Saab, Tanios; Noonan, Anne; McQuinn, Christopher; Mace, Thomas A.; Shaib, Walid; Wu, Christina; El-Rayes, Bassel F.; Shahda, Safi; Lesinski, Gregory B.; Biostatistics and Health Data Science, Richard M. Fairbanks School of Public HealthModified FOLFOX6 is an established therapy for patients with metastatic colorectal cancer (mCRC). We conducted a single-arm phase Ib study to address the hypothesis that addition of pembrolizumab to this regimen could safely and effectively improve patient outcomes (NCT02375672). The relationship between immune biomarkers and clinical response were assessed in an exploratory manner. Patients with mCRC received concurrent pembrolizumab and modified FOLFOX6. The study included safety run-in for the first six patients. The primary objective was median progression-free survival (mPFS), with secondary objectives including median overall survival, safety, and exploratory assessment of immune changes. To assess immunological impact, peripheral blood was collected at baseline and during treatment. The levels of soluble factors were measured via bioplex, while a panel of checkpoint molecules and phenotypically defined cell populations were assessed with flow cytometry and correlated with RECIST and mPFS. Due to incidences of grade 3 and grade 4 neutropenia in the safety lead-in, the dose of mFOLFOX6 was reduced in the expansion cohort. Median PFS was 8.8 months and median OS was not reached at data cutoff. Best responses of stable disease, partial response, and complete response were observed in 43.3%, 50.0%, and 6.7% of patients, respectively. Several soluble and cellular immune biomarkers were associated with improved RECIST and mPFS. Immunosuppressive myeloid and T cell subsets that were analyzed were not associated with response. Primary endpoint was not superior to historic control. Biomarkers that were associated with improved response may be informative for future regimens combining chemotherapy with immune checkpoint inhibitors.Item A novel preoperative risk score to optimize patient selection for performing concomitant liver resection with cytoreductive surgery/HIPEC(Wiley, 2021) Lee, Rachel M.; Gamboa, Adriana C.; Turgeon, Michael K.; Zaidi, Mohammad Y.; Kimbrough, Charles; Leiting, Jennifer; Grotz, Travis; Lee, Andrew J.; Fournier, Keith; Powers, Benjamin; Dineen, Sean; Baumgartner, Joel M.; Veerapong, Jula; Mogal, Harveshp; Clarke, Callisia; Wilson, Gregory; Patel, Sameer; Hendrix, Ryan; Lambert, Laura; Pokrzywa, Courtney; Abbott, Daniel E.; LaRocca, Christopher J.; Raoof, Mustafa; Greer, Jonathan; Johnston, Fabian M.; Staley, Charles A.; Cloyd, Jordan M.; Maithel, Shishir K.; Russell, Maria C.; Surgery, School of MedicineBackground: While parenchymal hepatic metastases were previously considered a contraindication to cytoreductive surgery (CRS) and heated intraperitoneal chemotherapy (HIPEC), liver resection (LR) is increasingly performed with CRS/HIPEC. Methods: Patients from the US HIPEC Collaborative (2000-2017) with invasive appendiceal or colorectal adenocarcinoma undergoing primary, curative intent CRS/HIPEC with CC0-1 resection were included. LR was defined as a formal parenchymal resection. Primary endpoints were postoperative complications and overall survival (OS). Results: A total of 658 patients were included. About 83 (15%) underwent LR of colorectal (58%) or invasive appendiceal (42%) metastases. LR patients had more complications (81% vs. 60%; p = .001), greater number of complications (2.3 vs. 1.5; p < .001) per patient and required more reoperations (22% vs. 11%; p = .007) and readmissions (39% vs. 25%; p = .014) than non-LR patients. LR patients had decreased OS (2-year OS 62% vs. 79%, p < .001), even when accounting for peritoneal carcinomatosis index and histology type. Preoperative factors associated with decreased OS on multivariable analysis in LR patients included age < 60 years (HR, 3.61; 95% CI, 1.10-11.81), colorectal histology (HR, 3.84; 95% CI, 1.69-12.65), and multiple liver tumors (HR, 3.45; 95% CI, 1.21-9.85) (all p < .05). When assigning one point for each factor, there was an incremental decrease in 2-year survival as the risk score increased from 0 to 3 (0: 100%; 1: 91%; 2: 58%; 3: 0%). Conclusions: As CRS/HIPEC + LR has become more common, we created a simple risk score to stratify patients considered for CRS/HIPEC + LR. These data aid in striking the balance between an increased perioperative complication profile with the potential for improvement in OS.Item A phase II trial of UGT1A1 genotype-guided FOLFIRI plus bevacizumab as first-line therapy for advanced, unresectable colorectal cancer(Oxford University Press, 2024) Sanoff, Hanna K.; Deal, Allison M.; Patel, Jai; Sorah, Jonathan D.; Gaddy, Jacquelyne; O’Neil, Bert; Turk, Anita; Irvin, William; Boles, Jeremiah; Lee, Michael S.; McRee, Autumn; Wardell, Alexis C.; Weck, Karen E.; Basch, Ethan; Wood, William A.; Innocenti, Federico; Medicine, School of MedicineBackground: FOLFIRI is a standard regimen for metastatic colorectal cancer (mCRC). We hypothesized that a pharmacogenomic-directed strategy where more efficient irinotecan metabolizers (UGT1A1 *1/*1 homozygotes and *1/*28 heterozygotes) receive higher-than-standard irinotecan doses would improve progression-free survival (PFS) compared to non-genotype selected historical controls with acceptable toxicity. Methods: In this phase II multicenter study irinotecan dosing in first-line FOLFIRI and bevacizumab for mCRC was based on UGT1A1 genotype with *1/*1, *1/*28, and *28/*28 patients receiving 310 mg/m2, 260 mg/m2, and 180 mg/m2, respectively. Primary endpoint was PFS. Secondary endpoints were investigator and patient-reported adverse events, and estimation of overall survival (OS). Results: One-hundred patients were enrolled with 91 evaluable for PFS and 83 evaluable for best response. Median PFS was 12.5 months (90% CI 10.9, 15.4), shorter than the anticipated alternative hypothesis of 14 months. PFS by genotype was 12.5 months (90% CI 10.9, 17.4) for *1/*1, 14.6 months (90% CI 11.8, 17.5) for *1/*28, and 6 months (90% CI 2.3, 7.7) for *28/28, respectively. OS was 24.5 months (90% CI 19.1, 30.7) and by genotype was 26.5 (90% CI 19.1, 32.9), 25.9 (90% CI 17.6, 37.7), and 13.4 (90% CI 2.3, 20.5) months for *1/*1, *1/*28, and *28/*28, respectively. G3/4 toxicity was similar between all subgroups, including diarrhea and neutropenia. Conclusions: A pharmacogenomic-directed irinotecan strategy improved PFS in the *1/*1 and *1/*28 genotypes with higher rates of neutropenia and similar rates of diarrhea compared to expected with standard FOLFIRI dosing. However, improvements in response rate and PFS were modest. This strategy should not change standard practice for mCRC patients in the first-line setting.Item The accuracy and completeness for receipt of colorectal cancer care using Veterans Health Administration administrative data.(BMC, 2016) Sherer, Eric A.; Fisher, Deborah A.; Barnd, Jeffrey; Jackson, George L.; Provenzale, Dawn; Haggstrom, David A.; Department of Medicine, IU School of MedicineThe National Comprehensive Cancer Network and the American Society of Clinical Oncology have established guidelines for the treatment and surveillance of colorectal cancer (CRC), respectively. Considering these guidelines, an accurate and efficient method is needed to measure receipt of care.Item ACVR2B antagonism as a countermeasure to multi‐organ perturbations in metastatic colorectal cancer cachexia(Wiley, 2020-12) Huot, Joshua R.; Pin, Fabrizio; Narasimhan, Ashok; Novinger, Leah J.; Keith, Austin S.; Zimmers, Teresa A.; Willis, Monte S.; Bonetto, Andrea; Surgery, School of MedicineBackground: Advanced colorectal cancer (CRC) is often accompanied by the development of liver metastases, as well as cachexia, a multi-organ co-morbidity primarily affecting skeletal (SKM) and cardiac muscles. Activin receptor type 2B (ACVR2B) signalling is known to cause SKM wasting, and its inhibition restores SKM mass and prolongs survival in cancer. Using a recently generated mouse model, here we tested whether ACVR2B blockade could preserve multiple organs, including skeletal and cardiac muscle, in the presence of metastatic CRC. Methods: NSG male mice (8 weeks old) were injected intrasplenically with HCT116 human CRC cells (mHCT116), while sham-operated animals received saline (n = 5-10 per group). Sham and tumour-bearing mice received weekly injections of ACVR2B/Fc, a synthetic peptide inhibitor of ACVR2B. Results: mHCT116 hosts displayed losses in fat mass ( - 79%, P < 0.0001), bone mass ( - 39%, P < 0.05), and SKM mass (quadriceps: - 22%, P < 0.001), in line with reduced muscle cross-sectional area ( - 24%, P < 0.01) and plantarflexion force ( - 28%, P < 0.05). Further, despite only moderately affected heart size, cardiac function was significantly impaired (ejection fraction %: - 16%, P < 0.0001; fractional shortening %: - 25%, P < 0.0001) in the mHCT116 hosts. Conversely, ACVR2B/Fc preserved fat mass ( + 238%, P < 0.001), bone mass ( + 124%, P < 0.0001), SKM mass (quadriceps: + 31%, P < 0.0001), size (cross-sectional area: + 43%, P < 0.0001) and plantarflexion force ( + 28%, P < 0.05) in tumour hosts. Cardiac function was also completely preserved in tumour hosts receiving ACVR2B/Fc (ejection fraction %: + 19%, P < 0.0001), despite no effect on heart size. RNA sequencing analysis of heart muscle revealed rescue of genes related to cardiac development and contraction in tumour hosts treated with ACVR2B/Fc. Conclusions: Our metastatic CRC model recapitulates the multi-systemic derangements of cachexia by displaying loss of fat, bone, and SKM along with decreased muscle strength in mHCT116 hosts. Additionally, with evidence of severe cardiac dysfunction, our data support the development of cardiac cachexia in the occurrence of metastatic CRC. Notably, ACVR2B antagonism preserved adipose tissue, bone, and SKM, whereas muscle and cardiac functions were completely maintained upon treatment. Altogether, our observations implicate ACVR2B signalling in the development of multi-organ perturbations in metastatic CRC and further dictate that ACVR2B represents a promising therapeutic target to preserve body composition and functionality in cancer cachexia.Item Addressing unmet needs for people with cancer cachexia: recommendations from a multistakeholder workshop(Wiley, 2022-04) Garcia, Jose M.; Dunne, Richard F.; Santiago, Kristen; Martin, Lisa; Birnbaum, Morris J.; Crawford, Jeffrey; Hendifar, Andrew E.; Kochanczyk, Martin; Moravek, Cassadie; Piccinin, Doris; Picozzi, Vincent; Roeland, Eric J.; Selig, Wendy K.D.; Zimmers, Teresa A.; Surgery, School of MedicineItem Age and comorbidity association with survival outcomes in metastatic colorectal cancer: CALGB 80405 analysis(Elsevier, 2022) McCleary, Nadine J.; Zhang, Sui; Ma, Chao; Ou, Fang-Shu; Bainter, Tiffany M.; Venook, Alan P.; Niedzwiecki, Donna; Lenz, Heinz-Josef; Innocenti, Federico; O'Neil, Bert H.; Polite, Blase N.; Hochster, Howard S.; Atkins, James N.; Goldberg, Richard M.; Ng, Kimmie; Mayer, Robert J.; Blanke, Charles D.; O'Reilly, Eileen M.; Fuchs, Charles S.; Meyerhardt, Jeffrey A.; Medicine, School of MedicineBackground: Little is known about the interaction of comorbidities and age on survival outcomes in colorectal cancer (mCRC), nor how comorbidities impact treatment tolerance. Methods: We utilized a cohort of 1345 mCRC patients enrolled in CALGB/SWOG 80405, a multicenter phase III trial of fluorouracil/leucovorin + oxaliplatin (FOLFOX) or irinotecan (FOLFIRI) plus bevacizumab, cetuximab or both. Endpoints were overall survival (OS), progression-free survival (PFS), and grade ≥ 3 toxicities assessed using NCI CTCAE v.3.0. Participants completed a questionnaire, including a modified Charlson Comorbidity Index. Adjusted Cox and logistic regression models tested associations of comorbidities and age on the endpoints. Results: In CALGB/SWOG 80405, 1095 (81%) subjects were < 70 years and >70 250 (19%). Presence of ≥1 comorbidity was not significantly associated with either OS (HR 1.10, 95% CI 0.96-1.25) or PFS (HR 1.03, 95% CI 0.91-1.16). Compared to subjects <70 with no comorbidities, OS was non-significantly inferior for ≥70 with no comorbidities (HR 1.21, 95% CI 0.98-1.49) and significantly inferior for ≥70 with at least one comorbidity (HR 1.51, 95% CI 1.22-1.86). There were no significant associations or interactions between age or comorbidity with PFS. Comorbidities were not associated with treatment-related toxicities. Age ≥ 70 was associated with greater risk of grade ≥ 3 toxicities (OR 2.15, 95% CI 1.50-3.09, p < 0.001). Conclusions: Among participants in a clinical trial of combination chemotherapy for mCRC, presence of older age with comorbidities was associated with worse OS but not PFS. The association of age with toxicity suggests additional factors of care should be measured in clinical trials.Item Algorithm Development and Early Performance Evaluation of a Next-Generation Multitarget Stool DNA Screening Test for Colorectal Cancer(Elsevier, 2024-05-17) Imperiale, Thomas F.; Gagrat, Zubin D.; Krockenberger, Martin; Porter, Kyle; Ziegler, Emily; Leduc, Christine M.; Matter, Michael B.; Olson, Marilyn C.; Limburg, Paul J.; Medicine, School of MedicineBackground and aims: The multitarget stool DNA (mt-sDNA) assay is a noninvasive average-risk colorectal cancer (CRC) screening test. A new biomarker panel was developed for a next-generation test to improve specificity while maintaining/increasing sensitivity. We aimed first to establish an algorithm and cutoff for the next-generation mt-sDNA test and then to validate it using archived samples from the pivotal DeeP-C study (NCT01397747) of the first-generation test. Methods: Algorithm development and cross-validation included 3011 samples from 2 specimen collection studies (NCT03821948 and NCT03789162). The algorithm and cutoff were locked before validation. Validation test set samples included 57 CRC, 583 advanced precancerous lesions (APLs), and 7022 samples negative for CRC or APLs from the DeeP-C study, which prospectively enrolled average-risk, asymptomatic adults aged 50-84 years before screening colonoscopy. Next-generation biomarkers included methylated DNA markers ceramide synthase 4 gene, leucine-rich repeat-containing protein 4 gene, serine/threonine-protein phosphatase 2A 56 kDa regulatory subunit gamma isoform gene, and zinc finger DHHC-type containing 1 gene (reference marker), and fecal hemoglobin. Primary validation end points were CRC sensitivity and specificity for the absence of advanced neoplasia. Secondary end points included APL sensitivity and specificity for non-neoplastic findings or negative colonoscopy. Results: Cross-validation and best-fit results from algorithm development closely matched, confirming algorithm reliability and reproducibility. For the test set, next-generation mt-sDNA test sensitivity was 93.0% (95% confidence interval [CI], 83.0%-98.1%) for CRC and 48.4% (95% CI, 44.2%-52.5%) for APLs. Specificity was 88.5% (95% CI, 87.7%-89.2%) for the absence of advanced neoplasia and 90.4% (95% CI, 89.5%-91.2%) for the combination of non-neoplastic findings or negative colonoscopy. Conclusion: Based on archived samples, the next-generation mt-sDNA test demonstrated promising CRC screening performance characteristics that will be further assessed in a prospective clinical validation study (BLUE-C; NCT04144738).Item Altered metabolite levels and correlations in patients with colorectal cancer and polyps detected using seemingly unrelated regression analysis(Springer Nature, 2017-11) Chen, Chen; Gowda, G. A. Nagana; Zhu, Jiangjiang; Deng, Lingli; Gu, Haiwei; Chiorean, E. Gabriela; Zaid, Mohammad Abu; Harrison, Marietta; Zhang, Dabao; Zhang, Min; Raftery, Daniel; Graduate Medical Education, IU School of MedicineIntroduction: Metabolomics technologies enable the identification of putative biomarkers for numerous diseases; however, the influence of confounding factors on metabolite levels poses a major challenge in moving forward with such metabolites for pre-clinical or clinical applications. Objectives: To address this challenge, we analyzed metabolomics data from a colorectal cancer (CRC) study, and used seemingly unrelated regression (SUR) to account for the effects of confounding factors including gender, BMI, age, alcohol use, and smoking. Methods: A SUR model based on 113 serum metabolites quantified using targeted mass spectrometry, identified 20 metabolites that differentiated CRC patients (n = 36), patients with polyp (n = 39), and healthy subjects (n = 83). Models built using different groups of biologically related metabolites achieved improved differentiation and were significant for 26 out of 29 groups. Furthermore, the networks of correlated metabolites constructed for all groups of metabolites using the ParCorA algorithm, before or after application of the SUR model, showed significant alterations for CRC and polyp patients relative to healthy controls. Results: The results showed that demographic covariates, such as gender, BMI, BMI2, and smoking status, exhibit significant confounding effects on metabolite levels, which can be modeled effectively. Conclusion: These results not only provide new insights into addressing the major issue of confounding effects in metabolomics analysis, but also shed light on issues related to establishing reliable biomarkers and the biological connections between them in a complex disease.Item Atractylenolide I enhances responsiveness to immune checkpoint blockade therapy by activating tumor antigen presentation(The American Society for Clinical Investigation, 2021-05-17) Xu, Hanchen; Van der Jeught, Kevin; Zhou, Zhuolong; Zhang, Lu; Yu, Tao; Sun, Yifan; Li, Yujing; Wan, Changlin; So, Ka Man; Liu, Degang; Frieden, Michael; Fang, Yuanzhang; Mosley, Amber L.; He, Xiaoming; Zhang, Xinna; Sandusky, George E.; Liu, Yunlong; Meroueh, Samy O.; Zhang, Chi; Wijeratne, Aruna B.; Huang, Cheng; Ji, Guang; Lu, Xiongbin; Medical and Molecular Genetics, School of MedicineOne of the primary mechanisms of tumor cell immune evasion is the loss of antigenicity, which arises due to lack of immunogenic tumor antigens as well as dysregulation of the antigen processing machinery. In a screen for small-molecule compounds from herbal medicine that potentiate T cell–mediated cytotoxicity, we identified atractylenolide I (ATT-I), which substantially promotes tumor antigen presentation of both human and mouse colorectal cancer (CRC) cells and thereby enhances the cytotoxic response of CD8+ T cells. Cellular thermal shift assay (CETSA) with multiplexed quantitative mass spectrometry identified the proteasome 26S subunit non–ATPase 4 (PSMD4), an essential component of the immunoproteasome complex, as a primary target protein of ATT-I. Binding of ATT-I with PSMD4 augments the antigen-processing activity of immunoproteasome, leading to enhanced MHC-I–mediated antigen presentation on cancer cells. In syngeneic mouse CRC models and human patient–derived CRC organoid models, ATT-I treatment promotes the cytotoxicity of CD8+ T cells and thus profoundly enhances the efficacy of immune checkpoint blockade therapy. Collectively, we show here that targeting the function of immunoproteasome with ATT-I promotes tumor antigen presentation and empowers T cell cytotoxicity, thus elevating the tumor response to immunotherapy.