ABCG2 and TOP1 mRNA expression as predictive biomarkers for adjuvant FOLFIRI treatment in stage III colon cancer patients: Results from the PETAAC-3 prospective randomized clinical trial.

591 Background: FOLFIRI as adjuvant treatment in primary colon cancer was previously tested in two pivotal prospective randomized clinical trials (PETACC-3 and CALGB 89803), both of which failed to demonstrate significant beneficial effects when adding irinotecan to 5FU. As a consequence, FOLFIRI is presently not used as adjuvant treatment for colon cancer. Methods: The study included 580 patients with mRNA expression data performed on tumor samples (FFPE) from stage III colon cancer patients enrolled in the PETACC-3 study, which randomized the patients to 5FU plus Leucovorin +/- irinotecan. Primary end-points were disease free survival (DFS) and overall survival (OS). Median ABCG2 and the 75 percentile TOP-1 mRNA expression data were used to allocate the patients into one of two groups: One with high ABCG2 expression (above median) and low TOP-1 expression (below 75 percentile) (n = 167) and another group including all other combinations of these two genes. Kaplan Meier curves and Cox proportional hazards model were used to visualize differences between groups and calculate p-values (log-rank test). Results: The survival statistics showed a significant difference for both RFS (HR: 0.63 (0.44-0.92); p = 0.017) and OS (HR: 0.6 (0.39-0.93); p = 0.021) between the two groups when the patients received FOLFIRI. In contrast, no significant differences were observed between the groups when patients received 5FU and Leucovorin alone (RFS: 0.58; OS: 0.75). Conclusions: We here show that the combination of two independent gene expression abundance with a strong association to irinotecan treatment (high ABCG2 drug efflux pump and low TOP-1, which is the target for irinotecan) identified a group of stage III colon cancer patients who will not benefit from FOLFIRI adjuvant treatment while patients with other combinations of expression of these two genes appear to significantly benefit from adjuvant FOLFIRI treatment. The lack of a similar effect in patients receiving treatment with 5FU and Leucovorin only, points to a predictive value of ABCG2 and TOP-1 measurements.

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ABCG2 and TOP-1 mRNA expression as predictive biomarkers for adjuvant FOLFIRI treatment in stage III colon cancer patients: Results from the PETAAC-3 prospective randomized clinical trial.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.11594 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 11594-11594

Author(s):

Nils Brunner ◽

Jan Stenvang ◽

Eva Budinska ◽

Sune Boris Nygaard

Keyword(s):

Colon Cancer ◽

Mrna Expression ◽

Cancer Patients ◽

Adjuvant Treatment ◽

Stage Iii ◽

Expression Data ◽

P Values ◽

Mrna Expression Data ◽

Stage Iii Colon Cancer ◽

Significant Difference

11594 Background: FOLFIRI as adjuvant treatment in primary colon cancer was previously tested in two pivotal prospective randomized clinical trials (PETACC-3 and CALGB 89803), both of which failed to demonstrate significant beneficial effects when adding irinotecan to 5FU. As a consequence, FOLFIRI is presently not used as adjuvant treatment for colon cancer. Methods: The study included 580 patients with mRNA expression data performed on tumor samples (FFPE) from stage III colon cancer patients enrolled in the PETACC-3 study, which randomized the patients to 5FU plus Leucovorin +/- irinotecan. Primary end-points were recurrence-free survival (RFS) and overall survival (OS). Median ABCG2 and the 75 percentile TOP-1 mRNA expression data were used to allocate the patients into one of two groups: One with high ABCG2 expression (above median) and low TOP-1 expression (below 75 percentile) (n = 167) and another group including all other combinations of these two genes. Kaplan Meier curves and Cox proportional hazards model were used to visualize differences between groups and calculate p-values (log-rank test). Results: The survival statistics showed a significant difference for both RFS (HR: 0.63 (0.44-0.92); p = 0.017) and OS (HR: 0.6 (0.39-0.93); p = 0.021) between the two groups when the patients received FOLFIRI. In contrast, no significant differences were observed between the groups when patients received 5FU and Leucovorin alone (p-values: RFS: 0.58; OS: 0.75). Conclusions: We here show that the combination of two independent gene expression abundance with a strong association to irinotecan treatment (high ABCG2 drug efflux pump and low TOP-1, the latter being the target for irinotecan) identified a group of stage III colon cancer patients who will not benefit from FOLFIRI adjuvant treatment while patients with other combinations of expression of these two genes appear to significantly benefit from adjuvant FOLFIRI treatment. The lack of a similar effect in patients receiving treatment with 5FU and Leucovorin only, points to a predictive value of ABCG2 and TOP-1 measurements.

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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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Retrospective comparison of efficacy and safety of CAPOX and FOLFOX regimens as adjuvant treatment in patients with stage III colon cancer

Journal of International Medical Research ◽

10.1177/0300060519848258 ◽

2019 ◽

Vol 47 (6) ◽

pp. 2507-2515 ◽

Cited By ~ 2

Author(s):

Serkan Degirmencioglu ◽

Ozgur Tanrıverdi ◽

Atike Gokcen Demiray ◽

Hande Senol ◽

Gamze Gokoz Dogu ◽

...

Keyword(s):

Colon Cancer ◽

Overall Survival ◽

Disease Progression ◽

Adjuvant Treatment ◽

Survival Rates ◽

Mortality Rates ◽

Stage Iii ◽

Efficacy And Safety ◽

Stage Iii Colon Cancer ◽

Significant Difference

Objective This study aimed to evaluate the efficacy and safety profile of capecitabine and oxaliplatin (CAPOX) and 5-fluorouracil, leucovorin, and oxaliplatin (FOLFOX) regimens as adjuvant treatment in patients with stage III colon cancer. Methods A total of 243 patients who received CAPOX and FOLFOX chemotherapy between 2014 and 2018 for stage III colon cancer in two centers were retrospectively studied. Among the patients, 106 (43.6%) and 137 (56.4%) were treated using CAPOX and FOLFOX regimens, respectively. Efficacy, treatment-related side effects, and overall survival rates with these two regimens were compared. Results The rate of disease progression was significantly higher in the presence of moderately/poorly differentiated histology, and KRAS and NRAS mutations. An increased number of metastatic lymph nodes and prolonged time from surgery to chemotherapy significantly increased disease progression. Patients who received CAPOX were significantly older than those who received FOLFOX. Disease progression, metastasis, and mortality rates were significantly higher in the FOLFOX arm than in the CAPOX arm. There was no significant difference in the overall survival rate between the two regimens. Conclusion The CAPOX regimen is preferred in older patients. Disease progression, metastasis, and mortality rates are higher with FOLFOX than with CAPOX.

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The prognostic role of PD-L1 expression according to MSI status in stage III colon cancer after curative resection.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.4_suppl.555 ◽

2019 ◽

Vol 37 (4_suppl) ◽

pp. 555-555 ◽

Cited By ~ 1

Author(s):

Sang-Hee Cho ◽

Jun Eul Hwang ◽

Woo Kyun Bae ◽

Ik-Joo Chung

Keyword(s):

Colon Cancer ◽

Cancer Patients ◽

Curative Resection ◽

Stage Iii ◽

Survival Outcomes ◽

Prognostic Role ◽

Stage Iii Colon Cancer ◽

Significant Difference ◽

Resected Stage

555 Background: Tumors expressing PD-L1 can render immune inactivated via triggering of PD-1 receptor on T cells with various pathways. Based on these mechanism, the blockade PD-1/PD-L1 pathway based been used as a therapeutic target for metastatic CRC. In the present study, we evaluated the prognostic role of PD-L1 expression associated with microsatellite status in surgically resected stage III colon cancer patients. Methods: PD-L1 expression was performed by immunohistochemistry from 182 stage III colon cancer patients after curative resection. Using the immunohistochemical stain, percentages of PD-L1 positive tumor cells and staining intensity were evaluated and categorized as ‘strong’ and ‘weak’ positive group. Clinical and histopathologic parameters including of MSI status and survival outcomes were analyzed with IDO expression which stands for the suppressive immune environment. Results: Strong PD-L1 expression was observed in 29% of all patients. PNI and lymphocyte response response were more frequently shown in strong PD-L1 patients. Among these patients, MSI was shown in 23 patients (12%). Although there was no significant difference between MSI and PD-L1 status, strong PD-L1 tended to better OS in MSS colon cancer (P = 0.056). In contrast, strong PD-L1 expression significantly correlated with significantly worse prognosis in disease free survival (P = 0.001) and overall survival (P < 0.001) than weak PD-L1 expression inMSI patients regardless of adjuvant chemotherapy. In MSI patients, the strong IDO expression was tended to be more frequently shown in strong PD-L1 expression patients (36.4%) than weak PD-L1 expression patients (14.3%). Conclusions: The expression of PD-L1 is differently affected on the survival according to the status of microsatellite. There is no significant relationship between the expression of PD-L1 and prognosis in MSS stage III colon cancer patients. However, in MSI colon cancer which has been well known as a highly immunogenic property, strong PD-L1 expression is significantly associated with poor prognosis on survival outcomes reflecting of immunosuppressive microenvironment in curative resected stage III colon cancer patient.

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“Real world” effectiveness of different postoperative adjuvant chemotherapy regimens in stage III colon cancer patients.

Journal of Clinical Oncology ◽

10.1200/jco.2016.34.4_suppl.754 ◽

2016 ◽

Vol 34 (4_suppl) ◽

pp. 754-754

Author(s):

Jy Ming Chiang ◽

Hsin Yuan Hung

Keyword(s):

Colon Cancer ◽

Cancer Patients ◽

Real World ◽

Cox Regression ◽

Univariate Analysis ◽

Oral Chemotherapy ◽

Stage Iii ◽

Stage Iii Colon Cancer ◽

Significant Difference ◽

Better Than

754 Background: In clinical practice, choosing oral chemotherapy or FOLFOX may depend to drug toxicity and patients’ age and comorbidities, in addition to heterogeneous stage III colon cancer. The benefit of oxaliplatin in the real world practice remained further clarified. Methods: 688 stage III colon cancer patients were collected. Treatment outcomes were retrospectively compared based on the type of chemotherapy in terms of OS and DFS. Multivariate Cox-regression modeling was used to adjust for the potential confounders. Results: This study included capecitabine (259 patients), fluorouracil-leucovorin plus oxaliplatin (FOLFOX) (283 patients) and Tegafur-uracil(146 patients). Comparing patients with capecitabine and tegafur regimens, patients receiving FOLFOX were significantly younger (mean age 56.5 yrs v.s. 65,1 yrs and 66,9 yrs ), more poor differentiation (15.9% v.s. 8.1% and 8.2%), deeper tumor invasion (T4 lesion 25.1% v.s. 15.8% and 17.1%), more advanced nodal involvement (N2/3 51.9% v.s. 18.1% and 20.5%) and had less comorbidity (50.2% v.s. 61.4% and 65.1%). Rate of completeness of chemotherapies (88.0% v.s. 87.6% and 81.5%) was no significant difference. Comparing treatment outcome, by univariate analysis, demonstrated significant (p = 0.0258) difference in OS for N2/3 patients but no difference in N1 patiens. However, by balancing confounding factors including co-morbidities, multivariate analysis showed that impact on overall survival in patients receiving capecitabine was statistically significant better than Tegafur (HR = 0.59, p = 0. 03) while no difference comparing with FOLFOX regimen (HR = 0.76, p = 0.3219). However, disease free survival (DFS) was no significantly different for FOLFOX comparing with capecitabine HR 0.97 and Tegafur HR 0.89 by multivariate Cox regression analyses. Conclusions: As post-operative adjuvant setting, oral chemotherapy either Capecitabine or Tegafur-uracil showed similar effectiveness as folfox in terms of DFS while in terms of OS, Capecitabine demonstrated similar effectiveness to folfox but better than Tegafur-urecil.

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