Early-stage Colon Cancer Research Articles

Changes in the Proportion of Patients Presenting With Early Stage Colon Cancer Over Time Among Medicaid Expansion and Nonexpansion States: A Cross-sectional Study.

The 2010 Patient Protection and Affordable Care Act mandated preventive screening coverage and provided support to participating states for Medicaid coverage. The association of Medicaid expansion with colon cancer stage at diagnosis is unknown. This study aimed to determine whether the proportion of patients diagnosed with early stage colon cancer changed over time within states that expanded Medicaid compared with nonexpansion states. This is a cross-sectional cohort study. This study evaluated multicenter registry data from the National Cancer Database (2006-2016). There were 25,462 uninsured or Medicaid-insured patients with newly diagnosed colon cancer who resided in 2014 Medicaid expansion or nonexpansion states. This study assessed the annual proportion of patients with early stage (I-II) versus late stage (III-IV) colon cancer. A total of 10,289 patients were identified in expansion states and 15,173 patients in nonexpansion states. Cohorts were similar in age (median 55 years) and sex (46.7% female). A greater proportion of patients in nonexpansion states were Black (33.4% vs 24.0%) and resided in a zip code with median income <$38,000 (39.7% vs 28.2%) and lower educational status (37.4% vs 28.1%). In 2006, the proportions of patients with early stage colon cancer in expansion and nonexpansion cohorts were similar (33.2% vs 32.5%). The proportion of patients with early stage colon cancer within nonexpansion states declined by 0.8% per year after 2014, whereas the proportion within expansion states increased by 0.9% per year after 2014 ( p < 0.05). By 2016, the absolute difference in the propensity-adjusted proportion of early stage colon cancer was 8.8% (39.7% vs 30.9%, p < 0.001). National Cancer Database data are obtained only from Commission on Cancer-accredited sites and are not population based. After Medicaid expansion in 2014, the proportion of patients diagnosed and treated at Commission on Cancer-accredited facilities with early stage colon cancer increased within expansion states and decreased in nonexpansion states. Increase in insurance coverage may have facilitated earlier diagnosis among patients in expansion states. See Video Abstract at http://links.lww.com/DCR/B804 . ANTECEDENTES:La Ley del Cuidado de Salud a Bajo Precio del 2010 ordenó la cobertura de exámenes preventivos y brindó apoyo a los estados participantes para la cobertura de Medicaid. Se desconoce la asociación de la expansión de Medicaid con el estadio del cáncer de colon en el momento del diagnóstico.OBJETIVO:Determinar si la proporción de pacientes diagnosticados con cáncer de colon en estadio temprano cambió con el tiempo dentro de los estados que expandieron Medicaid en comparación con los estados sin expansión.DISEÑO:Estudio de cohorte transversal.ENTORNO CLINICO:Datos de registro multicéntrico de la Base de datos nacional de cáncer (2006-2016).PACIENTES:Había 25,462 pacientes sin seguro o asegurados por Medicaid con cáncer de colon recién diagnosticado. Exposición: Residencia en estados de expansión o no expansión de Medicaid en el 2014.PRINCIPALES MEDIDAS DE RESULTADO:Proporción anual de pacientes con cáncer de colon en estadio temprano (I-II) versus tardío (III-IV).RESULTADOS:Se identificaron un total de 10.289 pacientes en estados de expansión y 15.173 pacientes en estados de no expansión. Las cohortes fueron similares en edad (mediana de 55 años) y sexo (46,7% mujeres). Una mayor proporción de pacientes en estados sin expansión eran de raza negra (33,4% vs 24,0%) y residían en un código postal con ingresos medios <$38 000 (39,7% vs 28,2%) y un nivel educativo más bajo (37,4% vs 28,1%). En el 2006, las proporciones de pacientes con cáncer de colon en estadio temprano en cohortes en expansión y sin expansión fueron similares (33,2% vs 32,5%). La proporción de pacientes con estadio temprano dentro de los estados sin expansión disminuyó en un 0,8% por año después del 2014, mientras que la proporción dentro de los estados de expansión aumentó en un 0,9% por año después del 2014 (p <0,05). Para el 2016, la diferencia absoluta en la proporción ajustada por propensión de cáncer de colon en estadio temprano fue de 8.8% (39.7% vs 30.9%, p <0.001).LIMITACIONES:Los datos de la Base de datos nacional de cáncer se obtienen únicamente de los sitios acreditados por la Comisión de cáncer y no se basan en la población.CONCLUSIONES:Después de la expansión de Medicaid en el 2014, la proporción de pacientes diagnosticados y tratados en instalaciones acreditadas por la Comisión de Cáncer en pacientes con cáncer de colon en estadio temprano aumentó dentro de los estados de expansión y disminuyó en los estados de no expansión. El aumento de la cobertura del seguro puede haber facilitado un diagnóstico más temprano entre los pacientes en estados de expansión. Consulte Video Resumen en http://links.lww.com/DCR/B804 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

Colorectal Cancer in Biopsy-defined Celiac Disease Seen over 30 Years: Rare, Even in Elderly Adults

Some malignant disorders, including colorectal cancer (CRC), may be reduced in celiac disease. In this study, 154 older adults, including elderly adults over age 60 years, were seen over 30 years. All patients were biopsy-defined and treated with a gluten-free diet. A single elderly female had an early stage colon cancer in the cecum but a persistent iron deficiency anemia led to later detection of biopsy-defined celiac disease and a gluten-free diet mucosal response. This study indicates that colon cancer is rare in biopsy-defined celiac disease. In this study, there were no gastric, pancreatic or hepato-biliary tract cancers seen. Genetic and environmental dietary factors may play a role, however, the rarity of colorectal cancer in other celiac-associated colonic diseases (eg., collagenous or lymphocytic colitis) suggests that an immune-mediated protective effect may occur.

Recent Updates on Mechanisms of Resistance to 5-Fluorouracil and Reversal Strategies in Colon Cancer Treatment.

Simple SummaryAcquired resistance to chemotherapy by cancer cells is the predominant factor in chemotherapy failure, which ultimately leads to disease progression and death. Recent studies have presented compelling evidence of the various mechanisms and pathways through which cancer cells have developed resistance to drugs. This review summarises the mechanisms pertaining to 5-FU resistance and discusses ongoing efforts to prevent chemotherapy resistance in cancer cells and to re-sensitise them to cancer drugs.5-Fluorouracil (5-FU) plus leucovorin (LV) remain as the mainstay standard adjuvant chemotherapy treatment for early stage colon cancer, and the preferred first-line option for metastatic colon cancer patients in combination with oxaliplatin in FOLFOX, or irinotecan in FOLFIRI regimens. Despite treatment success to a certain extent, the incidence of chemotherapy failure attributed to chemotherapy resistance is still reported in many patients. This resistance, which can be defined by tumor tolerance against chemotherapy, either intrinsic or acquired, is primarily driven by the dysregulation of various components in distinct pathways. In recent years, it has been established that the incidence of 5-FU resistance, akin to multidrug resistance, can be attributed to the alterations in drug transport, evasion of apoptosis, changes in the cell cycle and DNA-damage repair machinery, regulation of autophagy, epithelial-to-mesenchymal transition, cancer stem cell involvement, tumor microenvironment interactions, miRNA dysregulations, epigenetic alterations, as well as redox imbalances. Certain resistance mechanisms that are 5-FU-specific have also been ascertained to include the upregulation of thymidylate synthase, dihydropyrimidine dehydrogenase, methylenetetrahydrofolate reductase, and the downregulation of thymidine phosphorylase. Indeed, the successful modulation of these mechanisms have been the game plan of numerous studies that had employed small molecule inhibitors, plant-based small molecules, and non-coding RNA regulators to effectively reverse 5-FU resistance in colon cancer cells. It is hoped that these studies would provide fundamental knowledge to further our understanding prior developing novel drugs in the near future that would synergistically work with 5-FU to potentiate its antitumor effects and improve the patient’s overall survival.

Abstract 28: Prognostic value of baseline and early changes of circulating cell-free (cf)DNA in the neoadjuvant setting of early stage colon cancer (CC)

Abstract Introduction Circulating tumour (ct)DNA is an indicator of minimal residual disease and negative prognostic factor in stage II-III CC treated with surgery +/- adjuvant chemotherapy. No study, however, has ever analysed the prognostic value of this biomarker in CC patients (pts) treated with neoadjuvant chemotherapy. We sought to evaluate the prognostic value of baseline and early, on-treatment changes of cfDNA and ctDNA in stage II-III CC pts who were treated with one cycle of neoadjuvant FOLFOX chemotherapy followed by surgery +/- adjuvant FOLFOX chemotherapy in the PePiTA trial. Methods PePITA was a multicentre, single-arm, prospective phase II trial aiming to test in vivo tumour chemosensitivity as assessd by metabolic response using 18F-FDG PET/CT scan of early stage CC and to evaluate its association with survival outcome (NCT00994864). Plasma samples were prospectively collected at baseline and 2 weeks (ie, after one cycle of neoadjuvant FOLFOX chemotherapy). cfDNA was isolated with the QIAmp circulating nucleic acid kit (Qiagen), and quantified with the Qubit fluorometer (Life-Technologies). cfDNA samples were bisulfite converted using the EZ DNA Methylation-Gold™ Kit (Zymo Research), with NPY and WIF1 being selected as universal methylation markers for ctDNA and analysed with digital droplet (dd)PCR technology. Data from ddPCR were processed with the QuantaSoft V1.6 software (BioRad). The primary outcome measure was 3-year disease-free survival (DFS). Receiver operating characteristics curve analyses, Kaplan-Meier method, cox proportional hazards models and log-rank tests were used. Statistical analyses were carried out with the SPSS for MacOS version 25.0 (SPSS Inc). Results 80 pts were included (ypStage I-II 56%, ypStage III 44%). After a median follow-up of 52.5 months, 3-year DFS was 80% (95%CI 71.2-90.8) and 5-year OS 84% (95%CI 75.2-94.9). Pts with high (≥1.2 ng/µl) baseline cfDNA level had worse 3-year DFS (48% vs 80%; HR 2.72, 95%CI 1.02-7.25; p=0.036) and 5-year OS (71% vs 90%; HR 5.36, 95%CI 1.14-25.28; p=0.017) than those with low baseline cfDNA level. In a multivariable analysis (including sex, ypStage and CEA), baseline cfDNA was the only factor showing a trend towards statistical significance (HR DFS 2.6, 95%CI 0.96-7.01; p=0.059; HR OS 4.65, 95%CI 0.97-22.32; p=0.055). Early changes of cfDNA (Δ ≥11%) after one cycle of neoadjuvant FOLFOX chemotherapy failed to predict survival (HR DFS 1.08, 95%CI 0.42-2.81; p=0.873; HR OS 0.68, 95%CI 0.19-2.39; p=0.543). ctDNA analyses are ongoing and will be presented at the meeting. Conclusions For the first time, we have shown that baseline cfDNA may predict survival outcome in early stage CC pts treated with neoadjuvant chemotherapy. Pending confirmation in larger series, testing for cfDNA at baseline could help select high-risk pts who may benefit from neoadjuvant, FOXTROT-like, treatment strategies. Citation Format: Giacomo Bregni, Elena Trevisi, Chiara Senti, Andrea Pretta, Caroline Vandeputte, Pashalina Kehagias, Elena Acedo Reina, Amélie Deleporte, Paraskevas Gkolfakis, Jean-Luc Van Laethem, Philippe Vergauwe, Marc Van den Eynde, Guido Deboever, Jos Janssens, Gauthier Demolin, Stephane Holbrechts, Marylene Clausse, Thierry De Grez, Marc Peeters, Lionel D'Hondt, Karen Geboes, Tatiana Besse-Hammer, Alexis Buggenhout, Françoise Rothé, Patrick Flamen, Alain Hendlisz, Francesco Sclafani. Prognostic value of baseline and early changes of circulating cell-free (cf)DNA in the neoadjuvant setting of early stage colon cancer (CC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 28.

Abstract 1069: Determining the effect of bazedoxifene in combination with chemotherapy on colon cancer cells

Abstract Inflammatory cytokines, such as interleukin-6 (IL-6) and IL-11, activate the signal transducer and activator of transcription 3 (STAT3), which drives the gene transcription of cellular processes attributed as hallmarks of cancer. High levels of these cytokines, in combination with driver mutations, facilitate tumour growth and progression in preclinical models of colon cancer. Previous studies in our laboratory identified bazedoxifene (BZA), currently approved for the treatment of osteoporosis, as a small molecule inhibitor of GP130 (the receptor common to the IL-6 family of cytokines), selectively suppressing IL-6 and IL-11 signalling to reduce colon and gastric cancer growth in vivo (Thilakasiri et al. EMBO Mol Med 2019). The aim of this study is to determine the key cellular mechanisms influenced by GP130 inhibition to mediate anti-tumour effects in colon cancer cells. Additionally, we assessed the combined effects of BZA with standard of care chemotherapy drugs on cell proliferation and apoptosis. Using LIM2405 and HT29 colon cancer cells, the combined effect of BZA, fluorouracil and oxaliplatin on inducing apoptosis in LIM2405 and HT29 colon cancer cells was analysed using flow cytometry and confirmed using Western blotting and DIC microscopy. The effects of BZA was further analysed on HT29 xenograft growth and metastasis in vivo. Levels of STAT3 activation in response to IL-11/STAT3 signalling was characterised by Western blotting. Our results demonstrated that combination treatment with BZA, fluorouracil and oxaliplatin significantly increased apoptosis in LIM2405 cells and BZA significantly induced apoptosis in HT29 cells. Our data showed that BZA inhibited GP130-dependent STAT3 activity in the human colon cancer cell line LIM2405 and HT29. BZA treatment sensitized cells to chemotherapy leading to increased apoptosis. BZA treatment also reduced both primary tumour and metastatic burden in vivo demonstrating that gp130 mediated STAT3 inhibition is an attractive target for the treatment of early stage and advanced stage colon cancer. Citation Format: Rhynelle S. Dmello, Pathum Thilakasiri, Belinda Duscio, Ivan Poon, Matthias Ernst, Ashwini Chand. Determining the effect of bazedoxifene in combination with chemotherapy on colon cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1069.

Hospitalizations among early-stage colon cancer patients receiving adjuvant chemotherapy: a real-world study.

ObjectiveTo assess the patterns of hospitalizations among early-stage colon cancer patients receiving adjuvant chemotherapy and to identify high-risk groups that may benefit from more careful monitoring in a real-world, population-based context.MethodsThis is a population-based study using linked administrative databases from the province of Alberta, Canada. Any events of hospitalization among patients with non-metastatic colon cancer undergoing upfront surgery followed by adjuvant chemotherapy were reviewed. Multivariable logistic regression analysis was used to examine factors associated with risk of hospitalization, and the impact of hospitalization on overall survival was assessed through Kaplan–Meier estimates and Multivariable Cox regression analysis.ResultsA total of 2257 patients were considered eligible and were included in the current analysis, including 483 patients (21.4%) who were hospitalized within 6 months of the start of adjuvant chemotherapy, and 1774 patients (78.6%) who were not. The following factors were associated with a higher hospitalization risk: older age (OR: 1.02; 95% CI 1.01–1.03), higher comorbidity (OR: 1.48; 95% CI 1.31–1.67), women (OR for men versus women: 0.79; 95% CI 0.64–0.98), living in the North zone (OR for Edmonton zone versus North zone: 0.60; 95% CI 0.42–0.87), and CAPOX chemotherapy (OR for CAPOX versus FOLFOX: 1.50; 95% CI 1.12–2.00). Patients with a history of hospitalization during adjuvant chemotherapy had a worse overall survival compared to patients who were not hospitalized (P < 0.001).ConclusionIn this study, one out of five colon cancer patients were hospitalized during adjuvant chemotherapy. Older individuals, women, those with higher comorbidity, and those receiving adjuvant CAPOX were more likely to be hospitalized.Supplementary informationThe online version contains supplementary material available at 10.1007/s00384-021-03952-4.

Prognostic value of baseline and early changes of circulating-free (cf) and circulating tumor (ct) DNA in the neoadjuvant (NA) setting of early stage colon cancer (CC).

3600 Background: ctDNA is an indicator of minimal residual disease and negative prognostic factor in stage II-III CC treated with surgery +/- adjuvant chemotherapy (CT). No study, however, has ever analysed the prognostic value of this biomarker in CC patients (pts) treated with NACT. We sought to evaluate the prognostic value of baseline and early changes of cf/ctDNA in stage II-III CC pts who were treated with one cycle of NA FOLFOX CT followed by surgery +/- adjuvant FOLFOX CT in the PePiTA trial. Methods: PePiTA was a multicentre, single-arm, prospective phase II trial testing in vivo tumour chemosensitivity of early stage CC (as assessed by 18F-FDG PET/CT-based metabolic response to one cycle of NA FOLFOX) and its association with long-term outcome (NCT00994864). Plasma samples were prospectively collected at baseline, 2 weeks after one cycle of NA FOLFOX CT, and before surgery. NPY and WIF1 were selected as universal methylation markers for ctDNA and analysed with digital droplet (dd)PCR technology. Data from ddPCR were processed with the QuantaSoft v1.6 software (Bio-Rad). Survival outcome measures were 5-year disease-free survival (DFS) and 6-year overall survival (OS). ROC curve analyses, Kaplan-Meier method, cox proportional hazards models and log-rank tests were used. Statistical analyses were carried out with SPSS v25.0 (SPSS Inc.). Results: 80 pts were included (44 ypStage I-II and 36 ypStage III). After a median follow-up of 52.5 months, 5-year DFS and 6-year OS were 68% (95%CI 52-84) and 84% (95%CI 74-94), respectively. Pts with high (≥1600 ng/ml) baseline cfDNA had worse 6-year OS (HR 6.45, 95%CI 1.61-25.84; p = 0.008). Early changes of cfDNA after one cycle of NA FOLFOX CT failed to predict survival (HR DFS 0.96, 95%CI 0.38-2.43; p = 0.92; HR OS 0.62, 95%CI 0.16-2.50; p = 0.50). At baseline, 25 out of 60 (42%) ctDNA-assessable patients were positive. Detectable ctDNA at baseline (HR DFS 2.06, 95%CI 0.65-6.49; p = 0.22; HR OS 3.11, 95%CI 0.57-16.99; p = 0.19) or at any timepoint before surgery (HR DFS 1.65, 95%CI 0.54-5.04; p = 0.38; HR OS 2.80, 95%CI 0.54-14.44; p = 0.22) was not significantly associated with survival. A trend toward a significant association between ctDNA increase at surgery and 5-year DFS was found (HR 3.66, 95%CI 0.81-16.44; p = 0.09). Data on the correlation between early changes of cf/ctDNA and 18F-FDG PET/CT-based metabolic response will be presented at the meeting. Conclusions: For the first time, we have shown that baseline cfDNA may predict survival outcome in early stage CC pts treated with NACT. Pending confirmation in larger series, testing for cfDNA at baseline could help select high-risk pts who may benefit from FOxTROT-like, NACT treatment strategies. While analysis of ctDNA in this setting did not appear useful to predict prognosis, these results might be secondary to the small sample size.

Type of 5-fluorouracil and risk of cardiovascular events in early-stage colon cancer.

e15596 Background: Older patients with colorectal cancer are at increased risk of developing cardiovascular (CV) disease. 5-FU-based chemotherapy was found to increase CV morbidity; however, whether CV risks differ among different fluorouracil types, including infusional 5-FU, capecitabine, and tegafur-uracil (UFT), remains unclear. We aimed to assess the association between CV morbidities, including myocardial infarction and heart failure, and different 5-FU types in patients with colorectal cancer. Methods: We evaluated patients from Taiwan Cancer Registry linked with national health insurance research database with stage I to III colorectal cancer between January 1, 2004, and December 31, 2014. A multivariate Cox proportional model with age as the time scale was conducted for comparison. UFT alone was set as the control group. Results: In the cohort of 29176 patients (median [interquartile range] age, 65 [43-79] years), 2241 (7.6%) received UFT, 25181 (86.3%) received infusional 5-FU or capecitabine, 1754 (6%) received mixed. Overall, 290 patients were diagnosed with myocardial infarction (1.78 per 1000 person-years) during a median (interquartile range) follow-up of 5.5 years. Compared with those received UFT, those using infusional 5-FU or capecitabine showed no increased risk of myocardial infarction (weighted hazard ratio [HR], 0.84; 95% CI, 0.57-1.24). There were 376 patients diagnosed with heart failure, corresponding to 2.3 per 1000 person-years. The risks of heart failure between the UFT group and infusional 5-FU/capecitabine were similar (weighted HR, 0.9; 95% CI, 0.62-1.31). Conclusions: In this study, we did not observe any increased CV risk using infusional 5-FU or capecitabine compared with UFT alone use.

Effect of hyperlipidemia in patients with a history of colon cancer.

e15603 Background: The most common cancer of the digestive system is colorectal cancer. 5-year survival rate of early-stage colon cancer is &gt; 90% whereas it is only 10% for patients with distant metastases. Recent studies have shown that lipids influence a tumor’s metastatic capabilities. High fat diet has also been linked with colon cancer. In this study, we try to understand the effect of hyperlipidemia in patients with a history of colon cancer. Methods: This is a retrospective study examining data from the National Inpatient Sample (NIS) Database of the year 2018. We identified patients with any history of Colon cancer using their specific ICD-10 codes. Additionally, we queried for ICD10 codes for hyperlipidemia. Primary outcome was inpatient mortality. Secondary outcome was hospital length of stay and total charge. Utilizing STATA MP 16.1 we performed multivariate logistic regression analysis. Various comorbidities including previous history of coronary artery disease, peripheral artery disease, stroke, smoking, diabetes, hypertension and chemotherapy were incorporated into the analysis. Additionally, hospital demographics were included in the analysis as well including race, hospital bed size teaching status, location, region, insurance and patient income. Data was considered statistically significant if p-value was &lt; 0.05. Results: The total number of patients included in this study were 34,792. They were all adults age &gt; 18 years. Approximately 49% were females. Mean age was 67 years and average hospital length of stay was 6.5 days. After running multivariable analysis for inpatient mortality, we noted that patients with hyperlipidemia had lower odds of mortality (Odds Ratio (OR) 0.64, 95% Confidence Intervals (CI) 0.56 – 0.73). Higher odds of mortality were seen in patients with coronary artery disease (OR 1.23, 95% CI 1.05 – 1.44). Among racial distributions, Blacks had higher odds of mortality when compared with White (OR 1.3, 95% CI 1.1 – 1.5). Hispanics had lower odds of inpatient mortality compared to Whites (OR 0.8, 95% CI 0.6 – 0.9). The odds of mortality were higher with increasing age (OR 1.025, 95% CI 1.02 – 1.031) and lower among females (0.82, 95% CI 0.73 – 0.91). Among secondary outcomes, hyperlipidemia did not affect the hospital length of stay or cost. Several factors increased the hospital length of stay which included any history of coronary artery disease, peripheral artery disease, or diabetes. In addition, patients admitted over the weekend had a higher length of stay. Conclusions: In this study, we find that hyperlipidemia is associated with lower mortality in patients with colon cancer. This could be possible because patients with hyperlipidemia are on statin therapy. This indirectly could point to a potential benefit of statins in colon cancer. Hyperlipidemia does not affect hospital length of stay or cost.

Suboptimal Completion Rates, Adverse Events, Costs, Resource Utilization, and Cost Impact of Noncompletion in Oral Adjuvant Capecitabine–Based Chemotherapy in Patients With Early-Stage Colon Cancer

BackgroundSuboptimal completion of chemotherapy, which may involve reduced patient adherence, remains a serious issue and leads to reduced treatment efficacy. This study assessed the completion rates, risk factors for noncompletion, and cost impact for noncompletion in patients on capecitabine monotherapy (Cape) or capecitabine with oxaliplatin (CAPOX) for the adjuvant treatment of early-stage colon cancer. MethodsPatients with a diagnosis of early-stage colon cancer between April 2013 and March 2017 were retrospectively identified. Treatment completion was evaluated. Multivariate logistic regressions analyses were used to assess the baseline factors associated with noncompletion. Adverse events, costs, healthcare resource utilization, and cost impact for noncompletion were investigated. ResultsA total of 673 patients met the eligibility criteria, of which 382 (57%) were treated with Cape and 291 (43%) with CAPOX. The overall completion rate for adjuvant therapy was 40% (Cape 46%; CAPOX 33%). Noncompletion was associated with CAPOX treatment and higher healthcare costs within 6 months prior to chemotherapy. The 6-month unadjusted total healthcare costs were $44,444 for Cape and $71,247 for CAPOX. The nonchemotherapy costs were 41% higher for noncompleters than completers in both treatment groups (P = .002). ConclusionsThe real-world completion rates for adjuvant capecitabine–based chemotherapy in early-stage colon cancer patients are low. Noncompletion of therapy is associated with higher baseline healthcare costs. The nonchemotherapy costs are significantly higher in noncompleters than completers, highlighting the financial burden of managing adverse events and preexisting comorbidities, which may lead to early discontinuation of therapy. Effective strategies to optimize completion of oral chemotherapy may consider adherence monitoring.

SOX9 is associated with advanced T-stages of clinical stage II colon cancer in young Mexican patients.

Colorectal cancer (CRC) is one of the most common malignancies worldwide and includes colon cancer (CC) and rectal cancer (RC). Regarding CC, the development of novel molecular biomarkers for the accurate diagnosis and prognosis, as well as the identification of novel targets for therapeutic intervention, are urgently needed. SRY-related high-mobility group box 9 (SOX9), a transcription factor, is involved in development, and has been associated with the progression of human cancer. However, its underlying clinical and functional effects in CRC have not been fully understood. Therefore, the present study aimed to evaluate the clinical and functional relevance of SOX9 expression in CC. The expression of SOX9 in tumor tissues was evaluated in 97 biopsies from Mexican patients with CC with early-stage I and II disease by immunohistochemistry (IHC). In addition, SOX9 silencing in the HCT116 cell line was performed using specific small interfering RNAs, while downregulation efficiency was verified by reverse transcription-quantitative PCR and immunofluorescence. Spheroid-formation assay was carried out using ultra-low attachment plates. The IHC results showed that SOX9 was upregulated in patients with stage II (91%) and advanced T3 stage (67%) CC. Interestingly, higher SOX9 expression was associated with clinical stage, tumor size and tumor location. Furthermore, increased SOX9 expression was found in relapsed cases with local tumors; however, it was not associated with increased survival probability. Additionally, functional analysis indicated that SOX9 silencing significantly attenuated the sphere-formation capability of HCT116 cells. The present study was the first to evaluate the expression levels of SOX9 in Mexican patients diagnosed with early-stage CC. The aforementioned findings indicated that high SOX9 expression could play an important role in tumorigenesis and be associated with advanced T-stages of clinical-stage II patients, but not with relapse-free survival.

Effect of sidedness on survival among patients with early-stage colon cancer: a SEER-based propensity score matching analysis

BackgroundMost previous studies compared survival between left-sided and right-sided colon cancer without adjustment for clinicopathological parameters. We investigated the effect of sidedness on survival among patients with early-stage colon cancer, using a propensity score matching method.MethodsThe 18 registry custom data within the SEER database were used to identify patients who were diagnosed with colon cancer between 2010 and 2014. A propensity score matching analysis was performed using the nearest neighbor method. Survival was estimated using the Kaplan–Meier method. A Cox proportional hazards model was applied to determine the prognostic factors.ResultsIn the unmatched cohort, 25,094 (35.72%) patients were diagnosed with left-sided colon cancer and 45,156 (64.28%) with right-sided colon cancer. After propensity score matching, each cohort included 5118 patients, and the clinicopathological characteristics were well balanced. In the unmatched cohort, left-sided colon cancer had superior all-cause (χ2=315, P<0.01) and cancer-specific (χ2=43, P<0.01) survival than right-sided tumors. However, in the matched cohort, no difference was observed for all-cause (χ2=0.7, P=0.4) and cancer-specific (χ2=0, P=0.96) survival between left and right colon cancer. The Cox model did not indicate sidedness as a prognostic factor. In the subgroup analysis, stage II right-sided colon cancer had a better survival outcome, while stage III left-sided tumors had a better survival outcome.ConclusionsAfter adjusting for clinicopathological characteristics in this study, sidedness showed no impact on survival in early-stage colon cancer. However, sidedness was associated with prognostic differences in stages II and III early-stage colon cancer.

PD-L1 as a Prognostic Factor in Early-Stage Colon Carcinoma within the Immunohistochemical Molecular Subtype Classification.

Simple SummaryColorectal cancer (CRC) is a very heterogeneous disease. Efforts to characterize and search for biomarkers for these patients are currently ongoing in the hope of establishing a more targeted therapeutic approach. The role of PD-1 ligand (PD-L1) expression as a biomarker has not yet been fully elucidated. The Consensus Molecular Subtype classification has been delineated, but although already acknowledged in the most recent international guidelines, it has yet to be implemented in clinical practice. We investigate PD-L1 expression as a biomarker of prognosis in the early-stage setting and integrate it with the Consensus Molecular Subtype (CMS), in an effort to differentiate those patients with a worse prognosis who could potentially benefit from an early, more aggressive treatment. Our results suggest PD-L1 as an independent prognostic factor in early stage setting when assessed by immunohistochemistry. Additionally, PD-L1 expression appears to be a viable biomarker to differentiate patients in the CMS (CMS2/CMS3) who lack a clear prognosis.Background. There is a patent need to better characterize early-stage colorectal cancer (CRC) patients. PD-1 ligand (PD-L1) expression has been proposed as a prognostic factor but yields mixed results in different settings. The Consensus Molecular Subtype (CMS) classification has yet to be integrated into clinical practice. We sought to evaluate the prognostic value of PD-L1 expression overall and within CMS in early-stage colon cancer patients, in the hope of assisting treatment choice in this setting. Methods. Tissue-microarrays were constructed from tumor samples of 162 stage II/III CRC patients. They underwent automatic immunohistochemical staining for PD-L1 and the proposed CMS panel. Primary endpoints were overall survival (OS) and disease-free survival (DFS). Results. PD-L1 expression was significantly and independently associated with better prognosis (HR = 0.46 (0.26–0.82), p = 0.009) and was mostly seen in immune cells of the tumor-related stroma. CMS4 five-folds the risk of mortalitycompared with CMS1 (HR = 5.58 (1.36, 22.0), p = 0.034). In the subgroup CMS2/CMS3 analysis, PD-L1 expression significantly differentiated individuals with better OS (p = 0.004) and DFS (p < 0.001). Conclusions. Our study suggests that PD-L1 expression is an independent prognostic factor in patients with stage II/III colon cancer. Additionally, it successfully differentiates patients with better prognosis in the CMS2/CMS3 group and may prove significant for the clinical relevance of the CMS classification.

Systemic Inflammatory Biomarkers as Surrogate Markers for Stage in Colon Cancer.

This study aimed to investigate whether the systemic inflammatory parameters currently in use in staging the disease can be used as biomarker tests operated colon cancer patients. Neutrophil, lymphocyte, monocyte, platelet, neutrophil/lymphocyte ratio (NLR), lymphocyte/monocyte ratio (LMR), platelet/lymphocyte ratio (PLR), neutrophil/monocyte ratio (NMR), CRP, albumin, lymphocyte/CRP ratio, CRP/albumin ratio, and neutrophil/albumin ratio as systemic inflammatory biomarkers and prognostic nutritional index (PNI) were evaluated. This retrospective study included 592 patients. Patients with colon cancer in the cohort were divided into 2 subgroups: Tumor, nodes, metastases (TNM) stage 0, TNM stage 1, and TNM stage 2; early stage (n: 332) and TNM stage 3 and TNM stage 4; late stage (n: 260) colon cancer patients. LDH (P < .001), NLR (P < .001), PLR (P < .05), CRP/albumin (P < .01), and neutrophil/albumin (P < .01) were significantly higher, while monocyte count (P < .05) and PNI (P < .01) were found to be significantly lower in late stage colon cancer patients than in early stage colon cancer patients. Moderate negative correlation was found between the PNI and the neutrophil/albumin ratio in late stage colon cancer patients (r: -.568, P < .001). Our data suggest that high serum LDH, NLR, PLR, CRP/albumin, and neutrophil/albumin may be useful predictive markers for advanced stage in colon cancer. According to the receiver operating characteristic analysis results, CRP/albumin ratio can be used to discriminate early from late stage. Preoperative low monocyte count and PNI are associated with postoperative staging patients with colon cancer.

Gene-Microbiome Co-expression Networks in Colon Cancer.

It is known that cancer onset and development arise from complex, multi-factorial phenomena spanning from the molecular, functional, micro-environmental, and cellular up to the tissular and organismal levels. Important advances have been made in the systematic analysis of the molecular (mostly genomic and transcriptomic) within large studies of high throughput data such as The Cancer Genome Atlas collaboration. However, the role of the microbiome in the induction of biological changes needed to reach these pathological states remains to be explored, largely because of scarce experimental data. In recent work a non-standard bioinformatics strategy was used to indirectly quantify microbial abundance from TCGA RNA-seq data, allowing the evaluation of the microbiome in well-characterized cancer patients, thus opening the way to studies incorporating the molecular and microbiome dimensions altogether. In this work, we used such recently described approaches for the quantification of microbial species alongside with gene expression. With this, we will reconstruct bipartite networks linking microbial abundance and gene expression in the context of colon cancer, by resorting to network reconstruction based on measures from information theory. The rationale is that microbial communities may induce biological changes important for the cancerous state. We analyzed changes in microbiome-gene interactions in the context of early (stages I and II) and late (stages III and IV) colon cancer, studied changes in network descriptors, and identify key discriminating features for early and late stage colon cancer. We found that early stage bipartite network is associated with the establishment of structural features in the tumor cells, whereas late stage is related to more advance signaling and metabolic features. This functional divergence thus arise as a consequence of changes in the organization of the corresponding gene-microorganism co-expression networks.

Low levels of BRCA1 protein expression predict a worse prognosis in stage I-II colon cancer.

BRCA1 and BRCA2 have been well studied for their roles in tumorigeneis, plus cancer diagnosis and treatment, but their prognostic value in colon cancer, especially for early-stage cancer, has not been fully illuminated. This study examined the expression levels of BRCA1 and BRCA2 proteins in sporadic colon cancer cases and investigated their value in prognosis. The expression levels of BRCA1 and BRCA2 in 275 colon cancer patients who underwent radical surgeries were assayed by immunohistochemical staining in dissected tumor samples. Also, its correlation with clinicopathological characteristics, disease-free survival, and overall survival was investigated. Tumors with low expression levels of BRCA1, BRCA2, and both were 19.6%, 17.8%, and 6.5%, respectively. The levels of BRCA1/2 expression were not associated with clinicopathological parameters (gender, age, histological differentiation, and tumor node metastasis stage). Patients with low-levels of BRCA1 protein in their tumors demonstrated a lower chance of 5-year disease-free survival (55.6% vs. 69.7%, P=0.046), which was more obvious in the patients with stage I-II tumors without chemotherapy (52.6% vs. 82.6%, P=0.006). Neither BRCA1 nor BRCA2 affected overall survival in this cohort. Multivariate analysis revealed that pathologic stage and the level of BRCA1 protein were independent factors of long-term disease-free survival. This study highlights BRCA1 as an independent prognosticator of early-stage colon cancer.

In vivo sentinel lymph node identification using fluorescent tracer imaging in colon cancer: A systematic review and meta-analysis.

The use of fluorescence might improve the performance of the sentinel lymph node procedure in patients with colon cancer. This systematic review was conducted to gain insight in the performance and applicability of the sentinel lymph node procedure using fluorescence. A systematic literature search was performed. Databases were searched for prospective studies concerning sentinel node identification using fluorescence in colon cancer. Detection rate, accuracy rate and sensitivity of the sentinel lymph node procedure were calculated for early stage (T1-T2) and more invasive (T3-T4) tumours. Analyses of five included studies showed for respectively T3-T4 and T1-T2 tumours a detection rate of 90 % and 91 %, an accuracy rate of 77 % and 98 %, and a sensitivity of 30 % and 80 %. The sentinel lymph node procedure using fluorescence in early stage (T1-T2) colon cancer seems to be promising. Larger cohorts are necessary to confirm these results.

Model-based effectiveness and cost-effectiveness of risk-based selection strategies for adjuvant chemotherapy in Dutch stage II colon cancer patients.

Background:We aimed to evaluate the cost-effectiveness of risk-based strategies to improve the selection of surgically treated stage II colon cancer (CC) patients for adjuvant chemotherapy.Methods:Using the ‘Personalized Adjuvant TreaTment in EaRly stage coloN cancer’ (PATTERN) model, we evaluated five selection strategies: (1) no chemotherapy, (2) Dutch guideline recommendations assuming observed adherence, (3) Dutch guideline recommendations assuming perfect adherence, (4) biomarker mutation OR pT4 stage strategy in which patients with MSS status combined with a pT4 stage or a mutation in BRAF and/or KRAS receive chemotherapy assuming perfect adherence and (5) biomarker mutation AND pT4 stage strategy in which patients with MSS status combined with a pT4 stage tumor and a BRAF and/or KRAS mutation receive chemotherapy assuming perfect adherence. Outcomes were number of CC deaths per 1000 patients and total discounted costs and quality-adjusted life-years (QALYs) per patient (pp). Analyses were conducted from a societal perspective. The robustness of model predictions was assessed in sensitivity analyses.Results:The reference strategy, that is, no adjuvant chemotherapy, resulted in 139 CC deaths in a cohort of 1000 patients, 8.077 QALYs pp and total costs of €22,032 pp. Strategies 2–5 were more effective (range 8.094–8.217 QALYs pp and range 118–136 CC deaths per 1000 patients) and more costly (range €22,404–€25,102 pp). Given a threshold of €50,000/QALY, the optimal use of resources would be to treat patients with either the full adherence strategy and biomarker mutation OR pT4 stage strategy.Conclusion:Selection of stage II CC patients for chemotherapy can be improved by either including biomarker status in the selection strategy or by improving adherence to the Dutch guideline recommendations.

Prognostic and Predictive Cross-Roads of Microsatellite Instability and Immune Response to Colon Cancer.

Understanding molecular features of colon cancer has shed light on its pathogenesis and progression. Over time, some of these features acquired clinical dignity and were incorporated in decision making. Namely, microsatellite instability (MSI) due to mismatch repair of defects, which primarily was adopted for the diagnosis of Lynch syndrome, became recognized as the biomarker of a different disease type, showing a less aggressive behavior. MSI tumors harbor high amounts of tumor infiltrating lymphocytes (TILs) due to their peculiar load in neoantigens. However, microsatellite stable colon cancer may also show high amounts of TILs, and this feature is as well associated with better outcomes. High TIL loads are in general associated with a favorable prognosis, especially in stage II colon cancer, and therein identifies a patient subset with the lowest probability of relapse. With respect to post-surgical adjuvant treatment, particularly in stage III, TILs predictive ability seems to weaken along with the progression of the disease, being less evident in high risk patients. Moving from cohort studies to the analysis of a series from clinical trials contributed to increase the robustness of TILs as a biomarker. The employment of high TIL densities as an indicator of good prognosis in early-stage colon cancers is strongly advisable, while in late-stage colon cancers the employment as an indicator of good responsiveness to post-surgical therapy requires refinement. It remains to be clarified whether TILs could help in identifying those patients with node-positive cancers to whom adjuvant treatment could be spared, at least in low-risk groups as defined by the TNM staging system.

Delaying definitive resection in early stage (I/II) colon cancer appears safe up to 6 weeks

BackgroundThe objective of this study was to determine if there is an impact of surgical delay on 5-year overall survival (OS) from early stage colon cancer, and if so, to define how long surgery can safely be postponed. MethodsUsing the NCDB, we compared early (14–30 days) and delayed surgery (31–90 days) in patients with Stage I/II colon cancer. Outcomes included OS at five years and odds of death. ResultsDelayed resection conferred a decreased 5-year OS of 73.0% (95% CI, 72.6–73.4), compared to early resection 78.3% (95% CI, 77.9–78.8). When time to surgery was divided into one-week intervals, there was no difference in the odds of death with delay up to 35–41 days (6 weeks), but odds of death increased by 9% per week thereafter. ConclusionsThese data support that definitive resection for early stage colon cancer may be safely delayed up to 6 weeks.