The impact of colorectal cancer screening on incidence and stage IV disease in the Netherlands.

3531 Background: Population-based screening for colorectal cancer (CRC) aims to decrease incidence and mortality due to precancerous polyp removal, early detection and early treatment of CRC. In the Netherlands, phased introduction of a biennial fecal immunochemical hemoglobin test started in 2014 for individuals aged 55-75. This evaluation of the national data focuses on the initial effect of CRC screening on incidence and stage distribution and the impact on stage IV disease. Methods: All CRC patients diagnosed in the Netherlands between 2009 and 2018 were selected from the Netherlands Cancer Registry (NCR). Patients were linked to the Dutch national pathology registry (PALGA) to identify screen-detected tumors. Results: The NCR identified 137,717 CRC patients between 2009 and 2018. The incidence within screening age (55-75 yr) of all CRC stages showed an initial peak after introduction of screening in 2014, followed by a continuous decrease for all stages. CRC incidence outside the screening age did not show these explicit changes between 2009 and 2018. In 2018, the incidence of stage IV CRC within screening age was lower than the level at the start of the screening program. Stage distribution within screening age shifted towards earlier stages in the screening period (2014-2018) compared to the period before screening (2009-2012) (stage I: 31% vs. 18%, stage II: 22% vs. 26%, stage III: 29% vs. 31%, Stage IV: 18% vs. 25%, respectively). In the period 2014-2018 and within screening age, the ratio of screen-detected and symptom-detected tumors was highest in stage I (47%:53%) and lowest in stage IV (9%:91%). Screen-detected compared to symptom-detected stage IV patients diagnosed in the period 2014-2018 and within screening age had more frequently single organ metastases (74.5% vs 57.4%, p < 0.001), higher resection rate of the primary tumor (57.5% vs. 41.3%; p < 0.001) and higher local treatment rate of metastases (40.0% vs. 23.4% p < 0.001). The median overall survival of screen-detected stage IV patients was significantly longer than that of symptom-detected stage IV patients (31.0 months (95% CI: 27.7 – 34.3) vs. 15.0 months (95% CI: 14.5 – 15.5), p < 0.001). Conclusions: The initial results of the introduction of CRC screening in the Netherlands showed a favorable trend on CRC incidence and stage distribution. Screen-detected patients with stage IV disease had less extensive disease, resulting in better treatment options and improved survival.

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The impact of the COVID-19 pandemic on stage at diagnosis of breast and colorectal cancers.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.6501 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 6501-6501

Author(s):

Jade Zhou ◽

Shelly Kane ◽

Celia Ramsey ◽

Melody Ann Akhondzadeh ◽

Ananya Banerjee ◽

...

Keyword(s):

Breast Cancer ◽

Colorectal Cancer ◽

Cancer Screening ◽

Late Stage ◽

Stage Iv ◽

Stage I ◽

Screening Programs ◽

Stage Distribution ◽

Number Of Patients ◽

The Impact

6501 Background: Effective cancer screening leads to a substantial increase in the detection of earlier stages of cancer, while decreasing the incidence of later stage cancer diagnoses. Timely screening programs are critical in reducing cancer-related mortality in both breast and colorectal cancer by detecting tumors at an early, curable stage. The COVID-19 pandemic resulted in the postponement or cancellation of many screening procedures, due to both patient fears of exposures within the healthcare system as well as the cancellation of some elective procedures. We sought to identify how the COVID-19 pandemic has impacted the incidence of early and late stage breast and colorectal cancer diagnoses at our institution. Methods: We examined staging for all patients presenting to UCSD at first presentation for a new diagnosis of malignancy or second opinion in 2019 and 2020. Treating clinicians determined the stage at presentation for all patients using an AJCC staging module (8th edition) in the electronic medical record (Epic). We compared stage distribution at presentation in 2019 vs 2020, both for cancers overall and for colorectal and breast cancer, because these cancers are frequently detected by screening. Results: Total numbers of new patient visits for malignancy were similar in 2019 and 2020 (1894 vs 1915 pts), and stage distribution for all cancer patients was similar (stage I 32% in 2019 vs 29% in 2020; stage IV 26% in both 2019 and 2020). For patients with breast cancer, we saw a lower number of patients presenting with stage I disease (64% in 2019 vs 51% in 2020) and a higher number presenting with stage IV (2% vs 6%). Similar findings were seen in colorectal cancer (stage I: 22% vs 16%; stage IV: 6% vs 18%). Conclusions: Since the COVID-19 pandemic, there has been an increase in incidence of late stage presentation of colorectal and breast cancer, corresponding with a decrease in early stage presentation of these cancers at our institution. Cancer screening is integral to cancer prevention and control, specifically in colorectal and breast cancers which are often detected by screening, and the disruption of screening services has had a significant impact on our patients. We plan to continue following these numbers closely, and will present data from the first half of 2021 as it becomes available.

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Impact of BRAF mutations on prognosis and immunotherapy response in microsatellite instability/mismatch repair deficient metastatic colorectal cancer: A systematic review and meta-analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.3557 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 3557-3557

Author(s):

Robin Park ◽

Laércio Lopes da Silva ◽

Sunggon Lee ◽

Anwaar Saeed

Keyword(s):

Colorectal Cancer ◽

Systematic Review ◽

Braf Mutation ◽

Meta Analysis ◽

Stage Iv ◽

Stage I ◽

Prognostic Impact ◽

Braf Mutations ◽

Mutation Status ◽

The Impact

3557 Background: Mismatch repair deficient/microsatellite instability high (dMMR/MSI-H) colorectal cancer (CRC) defines a molecular subtype with distinct clinicopathologic characteristics including an excellent response to immunotherapy. Although BRAF mutations are established as a negative prognostic marker in CRC, whether they retain their negative prognostic impact in or alter the response to immunotherapy in dMMR/MSI-H CRC remains unknown. Herein, we present a systematic review and meta-analysis of the impact of BRAF mutations on the overall survival (OS) and immune checkpoint inhibitor (ICI) response in dMMR/MSI-H CRC. Methods: Studies published from inception to 26 January 2021 were searched in PubMed, Embase, and major conference proceedings (AACR, ASCO, and ESMO). Eligible studies included the following: 1) observational studies reporting outcomes based on BRAF mutation status in dMMR/MSI-H CRC patients and 2) experimental studies of ICI reporting outcomes based on BRAF mutation status in dMMR/MSI-H CRC patients. A summary hazard ratio (HR) was calculated for OS in BRAF mutated ( BRAFmut) vs. BRAF wild type ( BRAFwt) patients (pts) with the random effects meta-analysis (REM). A summary odds ratio (OR) was calculated for objective response rate (ORR) in BRAFmut vs. BRAFwt pts treated with ICI with the REM. Results: Database search conducted according to PRISMA guidelines found 4221 studies in total. Initial screening identified 30 studies and after full-text review, 9 studies (N = 4158 pts) were included for the meta-analysis of prognosis (analysis A) and 3 studies (N = 178 pts) were included for the meta-analysis of ICI response (analysis B). The outcome measures are summarized in the table below. Analysis A showed that in stage I-IV dMMR/MSI-H CRC pts, BRAFmut was associated with worse OS than BRAFwt (HR 1.57, 1.23-1.99). The heterogeneity was low (I2 = 21%). Subgroup analysis showed no significant difference in the prognostic impact of BRAF mutation status between stage IV only and stage I-IV CRC pts. Analysis B showed no difference in ORR (OR 1.04, 0.48-2.25) between BRAFmut vs. BRAFwt dMMR/MSI-H pts who received ICI. The heterogeneity was low (I2 = 0%). Conclusions: BRAF mutations retain their negative prognostic impact in dMMR/MSI-H stage I-IV and stage IV CRC but are not associated with differential ICI response. Limitations include the following: analysis A was based on retrospective studies; also, the impact of BRAF status on the survival outcome of ICI could not be assessed due to limited number of studies.[Table: see text]

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Is Colorectal Cancer Screening Appropriate in Nigeria?

Journal of Global Oncology ◽

10.1200/jgo.19.00035 ◽

2019 ◽

pp. 1-10

Author(s):

Gregory C. Knapp ◽

Olusegun I. Alatise ◽

Olalekan O. Olasehinde ◽

Ademola Adeyeye ◽

Omobolaji O. Ayandipo ◽

...

Keyword(s):

Colorectal Cancer ◽

Parasitic Infection ◽

Molecular Profile ◽

Future Research ◽

Middle Income ◽

Crc Screening ◽

Middle Income Countries ◽

Incidence And Mortality ◽

Prospective Trials ◽

The Impact

PURPOSE The global burden of colorectal cancer (CRC) will continue to increase for the foreseeable future, largely driven by increasing incidence and mortality in low- and middle-income countries (LMICs) such as Nigeria. METHODS We used the Wilson-Jungner framework (1968) to review the literature relevant to CRC screening in Nigeria and propose areas for future research and investment. RESULTS Screening is effective when the condition sought is both important and treatable within the system under evaluation. The incidence of CRC is likely increasing, although the exact burden of disease in Nigeria remains poorly understood and access to definitive diagnosis and treatment has not been systematically quantified. In high-income countries (HICs), CRC screening builds on a well-known natural history. In Nigeria, a higher proportion of CRC seems to demonstrate microsatellite instability, which is dissimilar to the molecular profile in HICs. Prospective trials, tissue banking, and next-generation sequencing should be leveraged to better understand these potential differences and the implications for screening. Fecal immunochemical test for hemoglobin (FIT) is recommended for LMICs that are considering CRC screening. However, FIT has not been validated in Nigeria, and questions about the impact of high ambient temperature, endemic parasitic infection, and feasibility remain unanswered. Prospective trials are needed to validate the efficacy of stool-based screening, and these trials should consider concomitant ova and parasite testing. CONCLUSION Using the Wilson-Jungner framework, additional work is needed before organized CRC screening will be effective in Nigeria. These deficits can be addressed without missing the window to mitigate the increasing burden of CRC in the medium to long term.

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The impact of socioeconomic status (SES) on stage of cancer at time of diagnosis: A population-based study in Ontario, Canada

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.6505 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 6505-6505

Author(s):

C. M. Booth ◽

G. Li ◽

W. J. Mackillop

Keyword(s):

Overall Survival ◽

Cox Model ◽

Stage Iv ◽

Stage I ◽

Absolute Difference ◽

Stage At Diagnosis ◽

Stage Iv Disease ◽

Incident Cases ◽

The Impact ◽

Universal Health

6505 Background: Lower SES is known to be associated with worsened cancer survival. Here we evaluate the impact of SES on stage of cancer at diagnosis in Ontario which has universal health insurance. Methods: All incident cases of breast, colon, rectal, non-small cell lung, cervical and larynx cancer diagnosed in Ontario 2003–2005 were identified using the Ontario Cancer Registry. Stage information is only captured routinely for patients seen at Ontario's 8 Regional Cancer Centers (RCCs). This represents approximately 68% of the population and forms the basis for all analyses. Using a best stage grouping approach, cases were assigned stage based on pathologic TNM if available and clinical TNM otherwise. The population of Ontario was divided into quintiles based on community median household income reported in the 2001 Canadian census. Using postal code at time of diagnosis cases were assigned to quintiles (Q); Q1 represents the communities where the poorest 20% of the Ontario population resided. Comparisons between Q1 and Q2–5 were made using the chi-square test. A Cox model was used to evaluate overall survival, SES, stage, and age. Results: Stage at diagnosis was available for 19,239/23,254 (83%) of cases seen at RCCs. Among cases with breast cancer, those in Q1 were less likely to have stage I disease (43 vs 47%, p = 0.004) and more likely to have stage IV disease (5 vs 4%, 0.008) than Q2–5. With lung cancer, cases in Q1 were more likely to have stage I disease compared to Q2–5 (16 vs 13%, p = 0.015). Distribution of stage I and stage IV disease did not differ by SES across other individual diseases. However, for all 6 cancers combined, cases in Q1 were less likely than Q2–5 to have stage I disease (27 vs 30%, p = 0.001) and more likely to have stage IV disease (21 vs 18%, p < 0.0001). We found significant gradients in 3-year overall survival across Q1-Q5 for breast (5% absolute difference in survival, p < 0.001), colon (4%, p = 0.049), and cervical (18%, p = 0.031) cancers. Adjustment for stage and age only slightly diminished these survival gradients. Conclusions: Despite universal health care, SES remains associated with survival among patients with cancer in Ontario. These data suggest that the difference in outcome is only partially explained by differences in stage at diagnosis. No significant financial relationships to disclose.

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The impact of prostate cancer on overall cancer stage migration over time.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.2_suppl.35 ◽

2016 ◽

Vol 34 (2_suppl) ◽

pp. 35-35

Author(s):

Jay P. Ciezki ◽

Chandana A. Reddy ◽

Eric A. Klein

Keyword(s):

Stage Iv ◽

Stage I ◽

Stage Migration ◽

Cancer Stage ◽

Subsequent Increase ◽

Female Breast ◽

Stage Iv Disease ◽

Changes Over Time ◽

The Impact ◽

Over Time

35 Background: To define cancer stage migration according to year of diagnosis and type of cancer diagnosis. Methods: Cancer stage, site, and year of diagnosis information were retrieved from an academic radiation oncology center's database. The Jonckheere-Terpstra test was used to assess changes over time. Results: From 2005 to 2014, 12,807 newly diagnosed patients (pts) were seen. The distribution of pts by stage was 2% stage 0, 17% stage I, 33% stage II, 16% stage III, and 32% stage IV. The pattern of stage distribution significantly changed over time as seen in the table (p = 0.0016). For 4 of the 5 most commonly seen cancers, (female breast, lung, esophagus, head and neck, and prostate (CaP)) over time fewer late stage cancers were diagnosed or had no change in stage. The only exception was CaP, the largest number of pts (26.5% of total). In 2005, 10.76% of new CaP cases presented with stage IV disease, dipped to 4.6% in 2011, and rose to 8.47% in 2014 (p < 0.0001). The changes in stage I definition accounted for the increase seen in stage I disease, but could not account for the dip and subsequent increase in stage IV disease. Conclusions: The presentation of cancer by stage has changed over time, and it was predominately driven by CaP. The changes seen in stage IV CaP incidence in which it fell and then rose over the study period suggests that global practice changes may be present. An increased preference for active surveillance, recommendations against PSA screening, and increasing insurance deductibles may have favored a delay in treating/diagnosing CaP pts in the recent past. [Table: see text]

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An improved method for detection of methylated circulating tumor DNA in colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.e15120 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. e15120-e15120 ◽

Cited By ~ 1

Author(s):

Nicky Boulter ◽

Gregor Tevz ◽

Betty Yu ◽

Michelle Chan ◽

David Murray ◽

...

Keyword(s):

Colorectal Cancer ◽

Stage Iv ◽

Circulating Tumor Dna ◽

Qpcr Assay ◽

Stage I ◽

Stage Ii ◽

Detection Methods ◽

Assay Sensitivity ◽

Crc Screening ◽

Tumor Dna

e15120 Background: Assays detecting methylated circulating tumor DNA (ctDNA) hold promise for colorectal cancer (CRC) screening, but there is a need to develop more accurate assays for early stages. In this study, we examined modifications to COLVERA (an IKZF1 and BCAT1 methylation marker qPCR assay) that added a third biomarker (IRF4) as well as introducing double stranded detection. Methods: Bisulfite converted DNA extracted from plasma collected from subjects undergoing diagnosis for CRC was assayed using either a double-stranded (ds) specific multiplexed qPCR for BCAT1 and IKZF1 detection (Assay 1) and/or a single-stranded (ss) specific BCAT1/IRF4, ds-specific IKZF1 multiplexed qPCR (Assay 2). The unmodified COLVERA test (Clinical Genomics) was used for comparison. Detection of any marker was considered positive. Results: Assay 1 performance evaluated against COLVERA on bisulfite converted DNA from 1453 samples showed an improved sensitivity for CRC detection (93/134 (69.4%) vs 79/134 (59.0%) COLVERA, p = 0.02), but specificity was suboptimal (no neoplasia: 861/1023 (84.2%) vs 946/1023 (92.5%) COLVERA, p < 0.0001). The decrease in specificity resulted primarily from modifications in the BCAT1 assay component (1023 no neoplasia: 60 positive with ss- BCAT1 vs 146 positive with ds- BCAT1, p < 0.0001). Thus, a novel configuration, Assay 2 (ss- BCAT1, ss- IRF4 and ds- IKZF1) was compared to Assay 1 using 189 previously untested specimens. Assay 2 showed a notable improvement in specificity (99/104 (95.2%) vs 93/104 (89.4%) Assay 1; p = 0.0351). Both assays exhibited comparable sensitivities for CRC (41/49 (83.7%) vs 39/49 (79.6%), Assay 1, p = 0.3633). Assay 2 was positive in: adenomas, 9/36 (25.0%); Stage I, 3/7 (42.9%); Stage II, 17/19 (89.5%); Stage III, 6/6 (100%); Stage IV, 7/7 (100%) and 8/10 (80%) unstaged CRCs. Prior COLVERA sensitivity estimates were 9% adenoma, 41% Stage I and 76% Stage II. Conclusions: Targeting both of the non-complementary bisulfite converted strands of selective regions of interest markedly improve ctDNA assay sensitivity for cancer including early lesions while achieving good specificity. Prospective evaluation in a true CRC screening population is now underway. Clinical trial information: 12611000318987.

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Immunomagnetic Enrichment and Detection of Micrometastases in Colorectal Cancer: Correlation With Established Clinical Parameters

Journal of Clinical Oncology ◽

10.1200/jco.2002.02.152 ◽

2002 ◽

Vol 20 (21) ◽

pp. 4338-4343 ◽

Cited By ~ 21

Author(s):

Martin R. Weihrauch ◽

Edmund Skibowski ◽

Thomas C. Koslowsky ◽

Wilfried Voiss ◽

Daniel Re ◽

...

Keyword(s):

Colorectal Cancer ◽

Bone Marrow ◽

Cancer Patients ◽

Stage Iv ◽

Stage I ◽

Clinical Parameters ◽

Uicc Stage ◽

Detection Rates ◽

Stage Iv Disease ◽

Colorectal Cancer Patients

PURPOSE: Micrometastatic disease in bone marrow is of prognostic significance in colorectal cancer patients. However, detection rates of standard immunocytology are relatively low. We used magnetic activated cell sorting (MACS), a highly sensitive method, to increase detection rates and correlated the presence of cytokeratin (CK)-expressing cells with clinical parameters. PATIENTS AND METHODS: Bone marrow was obtained from 51 consecutive patients with newly diagnosed colorectal adenocarcinoma who underwent primary surgery and 18 control subjects. International Union Against Cancer (UICC) stage I disease was diagnosed in 11 patients, stage II disease was diagnosed in 14 patients, stage III disease was diagnosed in 12 patients, and stage IV disease was diagnosed in 14 patients. CK-positive cells were enriched and stained with magnetically labeled CAM 5.2 antibodies directed to CK 7 and 8. RESULTS: CK-positive cells were found in 33 (65%) patients and were absent in 18 (35%). Four of 11 (36%) patients with UICC stage I disease, nine of 14 (64%) with stage II diease, eight of 12 (67%) with stage III disease, and 12 of 14 (86%) with stage IV disease were CK-positive. Epithelial cells were more frequently found in pT3/4 (72%) than in pT1/2 (36%) tumors (P = .026), but there was no difference for lymph node status. CK-positive patients had a higher chance for elevated carcinoembryonic antigen (85% v 15%, P = NS) and CA 19-9 levels (92% v 8%, P = .019). There were no significant differences in CA 72-4, sex, age, tumor grading, or tumor localization regarding the presence of CK-positive cells. All control subjects were CK-negative. CONCLUSION: In searching for micrometastases in colorectal cancer patients, we have achieved high detection rates by using MACS. The presence of these cells correlated significantly with tumor stage, tumor extension, and the tumor marker CA 19-9.

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Estimating the impact of differential adherence on the comparative effectiveness of stool-based colorectal cancer screening using the CRC-AIM microsimulation model

PLoS ONE ◽

10.1371/journal.pone.0244431 ◽

2020 ◽

Vol 15 (12) ◽

pp. e0244431

Author(s):

Andrew Piscitello ◽

Leila Saoud ◽

A. Mark Fendrick ◽

Bijan J. Borah ◽

Kristen Hassmiller Lich ◽

...

Keyword(s):

Colorectal Cancer ◽

Real World ◽

Base Case ◽

Fecal Occult Blood ◽

Microsimulation Model ◽

Crc Screening ◽

Life Years ◽

Incidence And Mortality ◽

Screening Strategies ◽

The Impact

Background Real-world adherence to colorectal cancer (CRC) screening strategies is imperfect. The CRC-AIM microsimulation model was used to estimate the impact of imperfect adherence on the relative benefits and burdens of guideline-endorsed, stool-based screening strategies. Methods Predicted outcomes of multi-target stool DNA (mt-sDNA), fecal immunochemical tests (FIT), and high-sensitivity guaiac-based fecal occult blood tests (HSgFOBT) were simulated for 40-year-olds free of diagnosed CRC. For robustness, imperfect adherence was incorporated in multiple ways and with extensive sensitivity analysis. Analysis 1 assumed adherence from 0%-100%, in 10% increments. Analysis 2 longitudinally applied real-world first-round differential adherence rates (base-case imperfect rates = 40% annual FIT vs 34% annual HSgFOBT vs 70% triennial mt-sDNA). Analysis 3 randomly assigned individuals to receive 1, 5, or 9 lifetime (9 = 100% adherence) mt-sDNA tests and 1, 5, or 9 to 26 (26 = 100% adherence) FIT tests. Outcomes are reported per 1000 individuals compared with no screening. Results Each screening strategy decreased CRC incidence and mortality versus no screening. In individuals screened between ages 50–75 and adherence ranging from 10%a-100%, the life-years gained (LYG) for triennial mt-sDNA ranged from 133.1–300.0, for annual FIT from 96.3–318.1, and for annual HSgFOBT from 99.8–320.6. At base-case imperfect adherence rates, mt-sDNA resulted in 19.1% more LYG versus FIT, 25.4% more LYG versus HSgFOBT, and generally had preferable efficiency ratios while offering the most LYG. Completion of at least 21 FIT tests is needed to reach approximately the same LYG achieved with 9 mt-sDNA tests. Conclusions Adherence assumptions affect the conclusions of CRC screening microsimulations that are used to inform CRC screening guidelines. LYG from FIT and HSgFOBT are more sensitive to changes in adherence assumptions than mt-sDNA because they require more tests be completed for equivalent benefit. At imperfect adherence rates, mt-sDNA provides more LYG than FIT or HSgFOBT at an acceptable tradeoff in screening burden.

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A metagene of NRF2 expression is a prognostic biomarker in all stage colorectal cancer

10.1101/690974 ◽

2019 ◽

Cited By ~ 1

Author(s):

Séan M. O’Cathail ◽

Chieh-Hsi Wu ◽

Annabelle Lewis ◽

Chris Holmes ◽

Maria A Hawkins ◽

...

Keyword(s):

Colorectal Cancer ◽

Poor Prognosis ◽

Prognostic Biomarker ◽

Molecular Taxonomy ◽

Disease Free Survival ◽

Stage Iv ◽

Stage I ◽

Braf V600e ◽

Stage Iv Disease ◽

Nrf2 Expression

ABSTRACTObjectiveNrf2 overexpression confers poor prognosis in some cancers but its role in colorectal cancer (CRC) is unknown. Due to its role as a transcription factor we hypothesise a metagene of NRF2 regulated genes could act as a prognostic biomarker in CRC.DesignUsing known NRF2 regulated genes, we defined an NRF2 metagene to represent the pathway expression using principal component analysis and Cox proportional hazard models. The NRF2 metagene was validated in four independent datasets, including the recently profiled MRC FOCUS randomised controlled trial.Results36 genes comprised the final prognostic metagene in the training set. 1,360 patients were included in the validation analyses. High NRF2 metagene expression is associated with worse disease free survival (DFS) and overall survival (OS) outcomes in stage I/II/III disease and worse OS in stage IV disease. In multivariate analyses, NRF2 expression remained significant when adjusted for known prognostic factors of adjuvant chemotherapy and stage in stage I/II/III disease, as well as BRAF V600E mutation and sidedness in stage IV disease. NRF2 metagene expression exhibits variation within each of the Consensus Molecular Subtypes (CMS) but high expression is particularly enriched in CMS 4.ConclusionWe demonstrate in a large scale analysis that NRF2 expression is a novel biomarker of poor prognosis across all stages of colorectal cancer. Higher expression observed in CMS 4 further refines the molecular taxonomy of colorectal cancer.

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Nrf2 metagene as a prognostic biomarker across all stages of colorectal cancer (CRC).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.557 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 557-557

Author(s):

Sean Micheal O'Cathail ◽

Chieh-Hsi Wu ◽

Annabelle Lewis ◽

Tim Maughan ◽

Maria A Hawkins

Keyword(s):

Colorectal Cancer ◽

Transcription Factor ◽

Prognostic Biomarker ◽

Stage Iv ◽

Stage I ◽

Braf V600e ◽

Candidate Gene Approach ◽

Metastatic Focus ◽

Stage Iv Disease ◽

Nrf2 Expression

557 Background: Keap1/Nrf2 is an important intracellular canonical stress response pathway, with Nrf2 acting as a potent transcription factor. Lung cancer is known to acquire constitutive activation of the pathway thus promoting survival, resisting chemo-radiation and dysregulating metabolism. Mechanisms of pathway activation include methylation of KEAP1, somatic mutation and direct activation by KRAS, BRAF and MYC. Its role in CRC is unknown. Due to its role as a transcription factor, activated in many ways, we hypothesise a metagene of Nrf2 regulated genes would act as a prognostic biomarker in CRC. Methods: Using a candidate gene approach and publicly available data (GSE17536), we derived and trained a 36 gene metagene to aggregate Nrf2 pathway expression, using principal component analysis and cox proportional hazard models. GSE14333 was used for validation in stage I/II/III CRC. The first line metastatic FOCUS trial was used for validation in Stage IV disease. Results: 601 patients are included in the validation analysis. Nrf2 metagene expression is associated with worse DFS outcomes in stage I/II/III disease in Cox PH model comparisons (LRT, p = 0.00175) and worse OS in stage IV disease (LRT, p = 0.00574). On multivariate analysis, Nrf2 expression remained significant when adjusted for known prognostic factors of adjuvant chemotherapy and Duke’s stage in stage I/II/III disease (ANOVA, p = 0.03), BRAF V600E and sidedness in stage IV disease (ANOVA, p = 0.00255). Using the median cut point, high expression has a HR 2.36 (C.I 1.27-4.38) in stage I/II/III disease and HR 1.39 (C.I 1.12-1.72) in metastatic disease. Conclusions: Nrf2 expression is a novel, robust prognostic biomarker of poor prognosis across all stages of colorectal cancer. Greater understanding of its mechanistic role could lead to targeted strategies to improve outcomes in CRC. [Table: see text]

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