Bcl-xL as a poor prognostic biomarker and predictor of response to adjuvant chemotherapy specifically in BRAF-mutant stage II and III colon cancer

AbstractBackgroundBRAF mutation occurs in 8-15% of colon cancers (CC), and is associated with poor prognosis in metastatic disease. Compared to wild-type BRAF (BRAFWT) disease, stage II/III CC patients with BRAF mutant (BRAFMT) tumors have shorter overall survival after relapse; however, time-to-relapse is not significantly different. The aim of this investigation was to identify, and validate, novel predictors of relapse of stage II/III BRAFMT CC.Patients and methodsWe used gene expression data from a cohort of 460 patients (GSE39582) to perform a supervised classification analysis based on risk-of-relapse within BRAFMT stage II/III CC, to identify transcriptomic biomarkers associated with prognosis within this genotype. These findings were validated using immunohistochemistry in an independent population-based cohort of Stage II/III CC (n=691), applying Cox proportional hazards analysis to determine associations with survival.ResultsHigh gene expression levels of Bcl-xL, a key regulator of apoptosis, were associated with increased risk of relapse, specifically in BRAFMT tumors (HR=8.3, 95% CI 1.7-41.7), but not KRASMT/BRAFWT or KRASWT/BRAFWT tumors. High Bcl-xL protein expression in BRAFMT, untreated, stage II/III CC was confirmed to be associated with an increased risk of death in an independent cohort (HR=12.13, 95% CI 2.49-59.13). Additionally, BRAFMT tumors with high levels of Bcl-xL protein expression appeared to benefit from adjuvant chemotherapy (P for interaction =0.006), indicating the potential predictive value of Bcl-xL expression in this setting.ConclusionsThese findings provide evidence that Bcl-xL gene and/or protein expression identifies a poor prognostic subgroup of BRAFMT stage II/III CC patients, who may benefit from adjuvant chemotherapy.Key MessageUsing a combination of computational biology discovery and immunohistochemistry validation in independent patient cohorts, we show that high expression of the apoptosis regulator Bcl-xL is associated with disease relapse specifically within BRAF mutant stage II/III colon cancer.This data could enable tailored disease management to reduce relapse rates in the most aggressive subtype.

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Time to adjuvant chemotherapy in CEA-positive colon cancer: An NCDB analysis.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.603 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 603-603

Author(s):

Yang Zhang ◽

Sarah J Aurit ◽

Mohan Satish ◽

Eugene Chau ◽

Peter T. Silberstein

Keyword(s):

Colon Cancer ◽

Overall Survival ◽

Adjuvant Chemotherapy ◽

Adjuvant Therapy ◽

Optimal Timing ◽

Metastatic Colon Cancer ◽

Risk Of Death ◽

Increased Risk ◽

Serum Carcinoembryonic Antigen ◽

Test Result

603 Background: It is well accepted that positive serum carcinoembryonic antigen (CEA) levels are associated with inferior survival in patients with advanced non-metastatic colon cancer; however, it is not fully elucidated whether this prognostic factor can inform clinical decisions, specifically for the optimal timing of adjuvant chemotherapy after definitive surgical treatment. This study was aimed to determine the relationship between onset of adjuvant chemotherapy and rate of survival in stage III colon cancer patients who tested CEA-positive, and thus, potentially identifying the optimal timing to increase survivorship. Methods: We identified 19,180 patients from the NCDB with TNM pathologic stage IIIB and IIIC adenocarcinoma of the colon who also had a recorded CEA test result and whom had received adjuvant chemotherapy. We examined unadjusted overall survival based on CEA status with the Kaplan-Meier method. A multivariable Cox regression model was estimated to determine the association of CEA status and overall survival after controlling for site, stage, days from surgery to chemotherapy, demographic background, and facility characteristics. All analyses were conducted with SAS version 9.4 (SAS Institute Inc., Cary, NC) with a statistical threshold of p < 0.05. Results: Based on the log-rank χ2 test, a positive CEA test result was significantly associated with worse survival. We adjusted for patient and facility level characteristics, and found a 49.7% increased risk of death for a patient with a positive CEA result (95% CI: 41.7% to 58.2%). We found a median number of 43 days from definitive surgery to initiation of chemotherapy; after adjusting for all other variables, we found for every ten-day delay in receiving adjuvant therapy after definitive surgical intervention, there was a 1.6% increased risk of death (95% CI: 1.0 to 2.2%). Conclusions: In this cohort of patients who tested CEA-positive, delays in receiving adjuvant chemotherapy had a negative linear association on survival. Adjuvant therapy should be considered as soon as patient’s clinical condition permits.

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VEGF and VEGFR1 gene expression levels and tumor recurrence in adjuvant colon cancer

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.4040 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 4040-4040 ◽

Cited By ~ 2

Author(s):

Y. Ning ◽

G. Lurje ◽

K. Danenberg ◽

J. Cooc ◽

D. Yang ◽

...

Keyword(s):

Gene Expression ◽

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Tumor Recurrence ◽

Stage Ii ◽

Tissue Samples ◽

Expression Levels ◽

Stage Iii Colon Cancer ◽

Gene Expression Levels

4040 Background: Tumor recurrence after curative resection is still a major problem in the management of adjuvant colon cancer, with recurrence rate approximately 30–40%. Identifying molecular markers for tumor recurrence is critical for successfully selecting patients who are more likely to benefit from adjuvant chemotherapy. Our group previously showed that angiogenesis gene polymorphisms (VEGF and IL-8) may associated with tumor recurrence in adjuvant colon cancer (Lurje Ann Oncol, 2008). Here we tested the hypothesis whether gene expression levels of angiogenesis pathway (COX-2, EGFR, VEGF, VEGFR1, VEGFR2 and IL-8) could also predict the risk of tumor recurrence in stage II and III colon cancer patients treated with adjuvant chemotherapy. Methods: Tissue samples from 140 adjuvant colon cancer patients (69 females and 71 males with a median age of 59 years; range=28–86) were available for gene expression assays. These tissue samples were obtained at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC) and LAC+USC medical center between 1999 and 2006. Sixty-three patients had stage II and 77 had stage III colon cancer. The median follow-up was 5.4 years (range=2.0–16.8). 51 of 140 patients (36.4%) developed tumor recurrence with a 5-year probability of 0.28 ± 0.06 for stage II and 0.40 ± 0.06 for stage III colon cancer patients. mRNA was extracted from laser-capture-microdissected tumor tissue. After cDNA was prepared by reverse transcription, quantitation of the candidate genes and an internal reference gene (ß-actin) was performed using a fluorescence-based real-time detection method (TaqMan). Results: We found VEGF and VEGFR1 gene expression levels independently significantly associated with time to tumor recurrence in adjuvant colon cancer patients. Patients with lower VEGF gene expression and lower VEGFR1 gene expression levels had significantly longer time to tumor recurrence compared to those with higher VEGF and higher VEGFR1 gene expression levels (p<0.05, log-rank test). Conclusions: VEGF and VEGFR1 gene expression levels may predict tumor recurrence risk in adjuvant colon cancer patients. Our exploratory data warrant future confirmatory trial. [Table: see text]

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Gene-expression signature of tumor recurrence in patients with stage II and III colon cancer treated with 5′fluoruracil-based adjuvant chemotherapy

International Journal of Cancer ◽

10.1002/ijc.27747 ◽

2012 ◽

Vol 132 (5) ◽

pp. 1090-1097 ◽

Cited By ~ 16

Author(s):

María Dolores Giráldez ◽

Juan José Lozano ◽

Míriam Cuatrecasas ◽

Virginia Alonso-Espinaco ◽

Joan Maurel ◽

...

Keyword(s):

Gene Expression ◽

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Tumor Recurrence ◽

Gene Expression Signature ◽

Stage Ii ◽

Expression Signature

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Loss of LKB1 Protein Expression Correlates with Increased Risk of Recurrence and Death in Patients with Resected, Stage II or III Colon Cancer

Cancer Research and Treatment ◽

10.4143/crt.2019.008 ◽

2019 ◽

Vol 51 (4) ◽

pp. 1518-1526 ◽

Cited By ~ 3

Author(s):

Maria Sfakianaki ◽

Chara Papadaki ◽

Maria Tzardi ◽

Maria Trypaki ◽

Sardar Alam ◽

...

Keyword(s):

Colon Cancer ◽

Protein Expression ◽

Stage Ii ◽

Risk Of Recurrence ◽

Increased Risk ◽

Resected Stage

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Survival benefits of adjuvant chemotherapy in high-grade stage II and III colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.e14529 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. e14529-e14529

Author(s):

Walter Tsang ◽

Argyrios Ziogas ◽

Chaitali Singh Nangia ◽

Jason A. Zell

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Multivariate Analyses ◽

Large Population ◽

Stage Ii ◽

Stage Iii ◽

Low Grade ◽

High Grade ◽

Increased Risk

e14529 Background: High-grade (HG; poorly differentiated and undifferentiated) colon carcinoma has an increased risk of recurrence after surgical resection compared to low-grade tumors. However, the benefits of adjuvant chemotherapy (AC) in this patient population remain unclear. Using a large population-based database, we examined survival outcomes of HG stage II/III colon cancer patients treated with or without AC. Methods: Stage II/III adult colon cancer patients with HG tumors who have undergone resection were identified in the California Cancer Registry from 1989 to 2006, with follow-up through 2009. Estimates of Colorectal Cancer Specific Survival (CRC-SS) were generated using Kaplan-Meier methods. CRC-SS multivariate analyses were performed using Cox proportional-hazard regression models adjusted for age, gender, race/ethnicity, histology, tumor site, chemotherapy, time period of diagnosis (1989-1994, 1995-2000, 2001-2006) and socioeconomic status. Results: Significant CRC-SS improvements were observed in stage III patients treated with AC (n=3,793) versus no AC (n=2,582) in univariate (Table) and multivariate analyses (HR=0.89, 95% CI 0.82-0.96). In contrast, among stage II patients treated with AC (n=1,232) vs. no AC (n=3,470), no differences were observed in univariate analyses (Table); furthermore, an increased risk of CRC-specific mortality was observed in multivariate analyses (HR=1.23, 95% CI 1.06-1.44). Conclusions: In high-grade colon cancer, despite significant survival benefits of adjuvant chemotherapy to stage III patients, adjuvant chemotherapy was independently associated with increased mortality in stage II patients. These findings invoke new questions about the utility of adjuvant chemotherapy among patients with high-grade stage II colon cancer. [Table: see text]

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Adjuvant colon cancer care quality, risk, value, and level one data and guideline compliance among the elderly privately insured in southeastern USA.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.30_suppl.249 ◽

2014 ◽

Vol 32 (30_suppl) ◽

pp. 249-249 ◽

Cited By ~ 1

Author(s):

William J. Hrushesky ◽

Anmol Baranwal ◽

Dinah Faith Q. Huff ◽

William S. Shimp ◽

Avinash Mamgain ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Older Persons ◽

Performance Status ◽

Stage Ii ◽

Phase Iii ◽

Disease Stage ◽

Nccn Guidelines ◽

Time Period

249 Background: Oxaliplatin-containing regimens are among the most efficacious adjuvant treatments for locally-advanced colon cancer, although significant toxicity can occur. Because of relevant level I data, the NCCN revised its guidelines in 2012, recommending omission of oxaliplatin from combination adjuvant chemotherapy regimens for older patients (>70yo) with colon cancer. We examined prescribing behavior of oncologists between 2009 and 2014 to evaluate how rapidly NCCN guidelines were adopted into practice. Methods: This is a retrospective observational study of chemotherapy request data from more than 2,000 community oncologists in the southeastern United States. We examined 57 consecutive months of chemotherapy requests for stage II and III colon cancer patients 70 years and older, based on three epochs. During the middle epoch, one phase III trial evaluating oxaliplatin-containing regimens as adjuvant chemotherapy (NSABP C-07), and a revised 2012 NCCN guidelines, each supported omission of oxaliplatin from adjuvant chemotherapy regimens for older persons with colon cancer. Multivariate analyses evaluated associations among patient characteristics (age, gender, and performance status), disease stage, and time-period, with the odds of receiving oxaliplatin-containing regimens as adjuvant chemotherapy. Results: Among 266 persons with stage II or III colon cancer 70 years of age and older, over the six-year span, most adjuvant chemotherapy requests (184/266, 69.2%) contained oxaliplatin. Older age, male gender, and poor performance status were associated with significantly lower odds of receiving oxaliplatin-containing adjuvant chemotherapy regimens (p<0.05), while time period (epoch) was not significantly associated with temporal changes in patterns of use. Conclusions: Use of oxaliplatin containing adjuvant chemotherapy regimens among older persons with colon cancer did not decrease following publication of phase III clinical trial data and revised NCCN guidelines recommending against oxaliplatin use in this setting. Focused quality improvement initiatives for this population of cancer patients may be helpful.

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Association of Mixed Lineage Kinase Domain-Like Protein Expression With Prognosis in Patients With Colon Cancer

Technology in Cancer Research & Treatment ◽

10.1177/1533034616655909 ◽

2016 ◽

Vol 16 (4) ◽

pp. 428-434 ◽

Cited By ~ 14

Author(s):

Xian Li ◽

Jing Guo ◽

Ai-Ping Ding ◽

Wei-Wei Qi ◽

Pei-Hua Zhang ◽

...

Keyword(s):

Colon Cancer ◽

Overall Survival ◽

Adjuvant Chemotherapy ◽

Protein Expression ◽

Kinase Domain ◽

Stage Ii ◽

Recurrence Free Survival ◽

Free Survival ◽

Mixed Lineage Kinase ◽

Low Expression

Background: The mixed lineage kinase domain-like protein has recently been identified as a key downstream component of tumor necrosis factor–induced necroptosis, which is an important pathway of cancer cell death. The goal of the current study is to explore the expression of mixed lineage kinase domain-like protein in colon cancer tissues and evaluate the prognostic value in patients with colon cancer. Methods: We collected normal and cancer colon tissues from 135 patients diagnosed with colon cancer after radical operation during July 2007 to April 2009 at The Affiliated Hospital of Qingdao University. Immunohistochemistry analysis was scored using an established scoring system. Kaplan-Meier survival curves were generated for recurrence-free survival and overall survival for all patients and 2 subsets of patients. The relationship between mixed lineage kinase domain-like protein expression and prognosis parameter (recurrence-free survival, overall survival) was analyzed by univariate and multivariate Cox regression analyses. Results: The median age of all patients was 67 years and 56.3% were male. Low expression of mixed lineage kinase domain-like protein was associated with decreased overall survival (78.6 vs 81.2 months; P = .011) in all patients. In the subset of 79 patients who received adjuvant chemotherapy, low expression of mixed lineage kinase domain-like protein was associated with decreased recurrence-free survival (60.4 vs 72.8 months; P = .032) and decreased overall survival (66.3 vs 72.9 months; P = .005). Low expression of mixed lineage kinase domain-like protein was associated with decreased overall survival (74.9 vs 79.8 months; P = .006) and recurrence-free survival (69.6 vs 78.8 months; P = .005) among patients with Tumor Node Metastasis (TNM) stage II colon cancer. Conclusions: Low expression of mixed lineage kinase domain-like protein was associated with decreased overall survival in all patient-group with resected colon cancer. It is associated with decreased recurrence-free survival and overall survival in the subset of patients who receive adjuvant chemotherapy and patients who were TNM stage II. Mixed lineage kinase domain-like protein may provide important prognostic information in patients with colon cancer.

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