Evaluation of a 55-gene classifier as a prognostic biomarker for adjuvant chemotherapy in stage III colon cancer patients

Abstract Background Adjuvant chemotherapy reduces the risk of recurrence of stage III colon cancer (CC). However, more effective prognostic and predictive biomarkers are needed for better treatment stratification of affected patients. Here, we constructed a 55-gene classifier (55GC) and investigated its utility for classifying patients with stage III CC. Methods We retrospectively identified patients aged 20–79 years, with stage III CC, who received adjuvant chemotherapy with or without oxaliplatin, between the years 2009 and 2012. Results Among 938 eligible patients, 203 and 201 patients who received adjuvant chemotherapy with and without oxaliplatin, respectively, were selected by propensity score matching. Of these, 95 patients from each group were analyzed, and their 5-year relapse-free survival (RFS) rates with and without oxaliplatin were 73.7 and 77.1%, respectively. The hazard ratios for 5-year RFS following adjuvant chemotherapy (fluoropyrimidine), with and without oxaliplatin, were 1.241 (95% CI, 0.465–3.308; P = 0.67) and 0.791 (95% CI, 0.329–1.901; P = 0.60), respectively. Stratification using the 55GC revealed that 52 (27.3%), 78 (41.1%), and 60 (31.6%) patients had microsatellite instability (MSI)-like, chromosomal instability (CIN)-like, and stromal subtypes, respectively. The 5-year RFS rates were 84.3 and 72.0% in patients treated with and without oxaliplatin, respectively, for the MSI-like subtype (HR, 0.495; 95% CI, 0.145–1.692; P = 0.25). No differences in RFS rates were noted in the CIN-like or stromal subtypes. Stratification by cancer sidedness for each subtype showed improved RFS only in patients with left-sided primary cancer treated with oxaliplatin for the MSI-like subtype (P = 0.007). The 5-year RFS rates of the MSI-like subtype in left-sided cancer patients were 100 and 53.9% with and without oxaliplatin, respectively. Conclusions Subclassification using 55GC and tumor sidedness revealed increased RFS in patients within the MSI-like subtype with stage III left-sided CC treated with fluoropyrimidine and oxaliplatin compared to those treated without oxaliplatin. However, the predictive power of 55GC subtyping alone did not reach statistical significance in this cohort, warranting larger prospective studies. Trial registration The study protocol was registered in the University Hospital Medical Education Network (UMIN) clinical trial registry (UMIN study ID: 000023879).

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Evaluation of A 55-Gene Classifier As A Prognostic Biomarker for Adjuvant Chemotherapy in Stage III Colon Cancer Patients

10.21203/rs.3.rs-579197/v1 ◽

2021 ◽

Author(s):

Eiji Oki ◽

Eiji Shinto ◽

Mototsugu Shimokawa ◽

Shigeki Yamaguchi ◽

Megumi Ishiguro ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Statistical Significance ◽

Predictive Biomarkers ◽

Recurrence Risk ◽

University Hospital ◽

Stage Iii ◽

Clinical Trial Registry ◽

Stage Iii Colon Cancer ◽

Education Network

Abstract Background Adjuvant chemotherapy reduces the recurrence risk in stage III colon cancer (CC). However, better prognostic and predictive biomarkers are required to stratify patients for treatment. We constructed a 55-gene classifier (55GC) and investigated its utility for classifying patients with stage III CC. Methods We retrospectively identified patients with stage III CC aged 20–79 years who received adjuvant chemotherapy with or without oxaliplatin during 2009–2012. Results Among 938 eligible patients, 203 and 201 patients who received adjuvant chemotherapy with and without oxaliplatin, respectively, were selected by propensity-score matching. Of these, 95 patients from each group were analyzed and their 5-year relapse-free survival (RFS) rates with and without oxaliplatin were 73.7% and 77.1%, respectively. The hazard ratios for 5-year RFS for adjuvant chemotherapy (fluoropyrimidine), with or without oxaliplatin, were 1.241 (95% CI, 0.465–3.308; P = 0.67) and 0.791 (95% CI, 0.329–1.901; P = 0.60), respectively. Stratification using the 55GC revealed that 52 (27.3%), 78 (41.1%), and 60 (31.6%) patients had microsatellite instability (MSI)-like, chromosomal instability (CIN)-like, and stromal subtypes, respectively. The 5-year RFS rates were 84.3% and 72.0% in patients treated with and without oxaliplatin, respectively, for the MSI-like subtype (HR, 0.495; 95% CI, 0.145–1.692; P = 0.25). No RFS rate differences were noted in CIN-like or stromal subtypes. Stratification by cancer sidedness for each subtype showed improved RFS only in left-sided primary cancer treated with oxaliplatin for the MSI-like subtype (P = 0.007). The 5-year RFS rates for the MSI-like subtype in left-sided cancer were 100% and 53.9% with and without oxaliplatin, respectively. Conclusions Subclassification using 55GC and tumor sidedness revealed increased RFS of patients within the MSI-like subtype with stage III left-sided CC treated with fluoropyrimidine with oxaliplatin relative to those treated without oxaliplatin. However, the predictive power of 55GC subtyping alone did not reach statistical significance in this cohort, warranting larger prospective studies. Trial registration: The study protocol was registered in the University Hospital Medical Education Network (UMIN) clinical trial registry (UMIN study ID 000023879).

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An Explorative Analysis of ABCG2/TOP-1 mRNA Expression as a Biomarker Test for FOLFIRI Treatment in Stage III Colon Cancer Patients: Results from Retrospective Analyses of the PETACC-3 Trial

Cancers ◽

10.3390/cancers12040977 ◽

2020 ◽

Vol 12 (4) ◽

pp. 977 ◽

Cited By ~ 3

Author(s):

Jan Stenvang ◽

Eva Budinská ◽

Eric van Cutsem ◽

Fred Bosman ◽

Vlad Popovici ◽

...

Keyword(s):

Colon Cancer ◽

Mrna Expression ◽

Cancer Patients ◽

Proportional Hazards ◽

Statistical Significance ◽

Predictive Biomarkers ◽

Cox Proportional Hazards ◽

Stage Iii ◽

End Points ◽

Stage Iii Colon Cancer

Biomarker-guided treatment for patients with colon cancer is needed. We tested ABCG2 and topoisomerase 1 (TOP1) mRNA expression as predictive biomarkers for irinotecan benefit in the PETACC-3 patient cohort. The present study included 580 patients with mRNA expression data from Stage III colon cancer samples from the PETACC-3 study, which randomized the patients to Fluorouracil/leucovorin (5FUL) +/− irinotecan. The primary end-points were recurrence free survival (RFS) and overall survival (OS). Patients were divided into one group with high ABCG2 expression (above median) and low TOP-1 expression (below 75 percentile) (“resistant”) (n = 216) and another group including all other combinations of these two genes (“sensitive”) (n = 364). The rationale for the cut-offs were based on the distribution of expression levels in the PETACC-3 Stage II set of patients, where ABCG2 was unimodal and TOP1 was bimodal with a high expression level mode in the top quarter of the patients. Cox proportional hazards regression was used to estimate the hazard ratios and the association between variables and end-points and log-rank tests to assess the statistical significance of differences in survival between groups. Kaplan-Meier estimates of the survival functions were used for visualization and estimation of survival rates at specific time points. Significant differences were found for both RFS (Hazard ratio (HR): 0.63 (0.44–0.92); p = 0.016) and OS (HR: 0.60 (0.39–0.93); p = 0.02) between the two biomarker groups when the patients received FOLFIRI (5FUL+irinotecan). Considering only the Microsatellite Stable (MSS) and Microsatellite Instability-Low (MSI-L) patients (n = 470), the differences were even more pronounced. In contrast, no significant differences were observed between the groups when patients received 5FUL alone. This study shows that the combination of ABCG2 and TOP1 gene expression significantly divided the Stage III colon cancer patients into two groups regarding benefit from adjuvant treatment with FOLFIRI but not 5FUL.

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ERCC1, defective mismatch repair status as predictive biomarkers of survival for stage III colon cancer patients receiving oxaliplatin-based adjuvant chemotherapy

British Journal of Cancer ◽

10.1038/bjc.2013.83 ◽

2013 ◽

Vol 108 (6) ◽

pp. 1238-1244 ◽

Cited By ~ 32

Author(s):

P Li ◽

Y J Fang ◽

F Li ◽

Q J Ou ◽

G Chen ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Mismatch Repair ◽

Predictive Biomarkers ◽

Stage Iii ◽

Stage Iii Colon Cancer ◽

Mismatch Repair Status ◽

Defective Mismatch Repair

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Intensity of adjuvant chemotherapy regimens and grade III–V toxicities among elderly stage III colon cancer patients

European Journal of Cancer ◽

10.1016/j.ejca.2016.03.074 ◽

2016 ◽

Vol 61 ◽

pp. 1-10 ◽

Cited By ~ 7

Author(s):

F.N. van Erning ◽

L.G.E.M. Razenberg ◽

V.E.P.P. Lemmens ◽

G.J. Creemers ◽

J.F.M. Pruijt ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Stage Iii ◽

Stage Iii Colon Cancer ◽

Grade Iii

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Abstract B56: Racial disparities in the receipt of adjuvant chemotherapy among stage III colon cancer patients

10.1158/1538-7755.disp14-b56 ◽

2015 ◽

Author(s):

Caitlin C. Murphy ◽

Linda C. Harlan ◽

Joan L. Warren ◽

Ann M. Geiger

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Racial Disparities ◽

Cancer Patients ◽

Stage Iii ◽

Stage Iii Colon Cancer

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Prognostic impact of preoperative albumin to globulin ratio in curative colon cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.647 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 647-647

Author(s):

Yuji Toiyama ◽

Hiroyuki Fujikawa ◽

Yasuhiro Inoue ◽

Hiroki Imaoka ◽

Masato Okigami ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Poor Prognosis ◽

Early Recurrence ◽

Stage I ◽

Stage Iii ◽

Prognostic Impact ◽

Stage Iii Colon Cancer ◽

Albumin To Globulin Ratio

647 Background: Albumin to globulin ratio (AGR) has been reported to predict long term mortality in patients with several cancers. However, prognostic impact of preoperative AGR in colon cancer patients with curative intent has not yet been fully addressed. Therefore, we, for the first time, investigated the association between AGR and clinico-pathological findings including overall survival (OS) and disease free survival (DFS) in stage I-III colon cancer patients. Methods: Clinicopathological findings including preoperative laboratory data (carcinoembryonic antigen [CEA] and AGR) from 251 curative colon cancer patients were assessed as indicators of early recurrence and poor prognosis in this retrospective study. AGR was calculated as [AGR = albumin/ (total protein - albumin)]. The cut-off value of AGR was 1.32 in current study. Results: Several clinicopathological categories related with tumor progression such as lymph node metastasis, T4 tumor, large tumor size, undifferentiated tumor, venous and lymphatic invasion, and high CEA were significantly associated with low AGR level. The patients with low AGR were significantly poorer OS (P = 0.001) and DFS (P = 0.003) than those with high AGR, respectively. In addition, multivariate analyses demonstrated that low AGR was independently associated with early recurrence (HR = 2.87, P = 0.007) and poor prognosis (HR = 2.56, P = 0.008), respectively. On the other hand, sub analysis of survival curves revealed that stage III colon cancer patients with low AGR were significantly poorer OS (P = 0.007) and DFS (P = 0.02) than those with high AGR, respectively. Furthermore, significantly poorer OS and DFS were also shown in stage I-II colon cancer patients with low AGR, respectively (OS: P = 0.02, DFS: P = 0.01). Conclusions: Preoperative AGR was an independent predictor of early recurrence and poor prognosis in curative colon cancer patients. AGR may represent a simple, potentially useful predictive biomarker for selecting stage I-II colon cancer patients who might need adjuvant chemotherapy. Furthermore, AGR may select candidates who are better to introduce more intensive adjuvant chemotherapy after curative operation in stage III colon cancer patients.

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Prognosis of microsatellite instability and/or mismatch repair deficiency stage III colon cancer patients after disease recurrence: Results of an accent meta-analysis of seven studies.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.3525 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 3525-3525 ◽

Cited By ~ 1

Author(s):

Julien Taieb ◽

Levi Pederson ◽

Qian Shi ◽

Steven R Alberts ◽

Norman Wolmark ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Patients ◽

Mismatch Repair ◽

Statistical Significance ◽

Multivariable Analysis ◽

Disease Recurrence ◽

Stage Iii ◽

Wild Type ◽

Poor Prognostic Factor ◽

Stage Iii Colon Cancer

3525 Background: Microsatellite instable/deficient mismatch repair (MSI) metastatic colorectal cancers have been reported to be of poor prognosis. The interaction between MSI and BRAFV600E mutation complicates the picture. Methods: Patients with resected stage III CC from 7 studies with disease recurrence and data available for MSI and BRAFV600E status were analyzed. The primary endpoint was survival after recurrence (SAR) to assess the prognostic roles of MSI and BRAFV600E, respectively. Associations of markers with SAR were analyzed using Cox proportional hazards models adjusted for clinicopathologic features (data collected 12/1998 to 11/2009). Results: Among 2630 patients with cancer recurrence (1491 men [56.7%], mean age, 58.5 [19-85] years), multivariable analysis revealed that patients with MSI tumors (n = 220) had significantly better SAR (adjusted hazard ratio [aHR], 0.82; 95% CI, 0.69-0.98; P = .029) than patients with microsatellite stable /proficient MMR (MSS) tumors (n = 1766). This was also observed when looking at patients treated by the standard FOLFOX adjuvant regimen only (aHR, 0.76; 0.58-1.00; P = .048). Same trends were observed when looking at MSI/dMMR patients outcome in BRAFV600E wild-type (aHR, 0.84; P = .10) and mutant (aHR, 0.88; P = .43) subgroups separately, without reaching statistical significance. As previously described poor SAR was observed in BRAFV600E mutants vs wild type patients (n = 244; aHR, 2.06; 95% CI, 1.73-2.46; P < .0001) and this was also true in BRAFV600E mutants MSI/dMMR patients (n = 77, aHR, 2.65 ; 95% CI, 1.67-4.21; p < .0001). Other factors associated with a poor SAR were : olderage, male gender, T4/N2, proximal primary tumor location, poorly differentiated adenocarcinoma, and early recurrence (by 1y increase). Conclusions: In stage III colon cancer patients recurring after adjuvant chemotherapy and before the era of immuno-oncologic agents, MSI/dMMR was associated with a better survival compared to MSS. BRAFV600E mutation seems to be a poor prognostic factor for both MSI/dMMR and MSS/pMMR patients.

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