Polymorphisms of genes encoding for regulatory proteins in the coagulation cascade to predict outcome for stage II and III colon cancer.

227 Background: In cancer patients, an activated coagulation cascade might promote tumor cell dissemination. There are preliminary data suggesting that fibrinogen in combination with platelets can build a meshwork that entraps cancer cells enabling them to escape from immunosurveillance. We therefore hypothesize that variations in genes encoding for regulatory proteins within the coagulation pathway may predict outcome in patients with stage II and III colon cancer. Methods: The impact of three functional single nucleotide polymorphisms (SNPs) within the FGB, SERPINC1 and ITGA2B genes on time to recurrence and overall survival was evaluated in 209 patients with stage II and III colon cancer. Genomic DNA was isolated from formalin-fixed paraffin embedded tissue and the SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics were as follows: median age = 70y (19-91); female/male ratio = 42.8% / 57.2%; 111 patients had stage II, and 98 stage III colon cancer. The FGB rs4220 SNP showed significant association with recurrence rate in the overall population. Patients harboring any A allele had a higher 3-years recurrence rate compared to those with a G/G genotype (28% vs 17%) in both univariate (HR 1.83, 95% confidence interval (CI) 0.99-3.36, p = 0.048) and multivariate analyses (HR 1.94, 95% CI 1.05-3.57, p = 0.034). This trend was most evident among pts with stage II and especially the subgroup of high-risk stage II colon cancer. Again, A allele carriers had a higher 3-years recurrence rate compared to those having a G/G genotype (24% vs 10% and 44% vs 15% respectively) in both univariate (HR 3.32, 95% CI 1.26-8.74, p = 0.010 and HR 5.34, 95% CI 1.38-20.68, p = 0.006) and multivariate analyses (HR 3.34, 95% CI 1.27-8.78, p = 0.015 and HR 5.44, 95% CI 1.40-21.15, p = 0.015). Conclusions: Here, we demonstrate that the FGB polymorphism rs4220 might serve as a prognostic biomarker in stage II colon cancer. Assessment of FGB rs4220 might help us to identify those stage II colon cancer patients who will derive the most benefit from adjuvant chemotherapy.

Download Full-text

Association of genetic variations within the PD-L2 immune checkpoint gene with outcome in stage II and III colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.626 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 626-626

Author(s):

Martin D. Berger ◽

Inti Zlobec ◽

Dongyun Yang ◽

Shu Cao ◽

Yu Sunakawa ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Patients ◽

Recurrence Rate ◽

Immune Checkpoint ◽

Multivariate Analyses ◽

Stage Ii ◽

Stage Iii ◽

Immune Checkpoints ◽

High Recurrence Rate ◽

The Impact

626 Background: Immune checkpoints can either inhibit or stimulate T-cell responses and therefore play a key role in maintaining an equilibrium between self tolerance and autoimmunity. Targeting immune checkpoint molecules can result in increased antitumor immunity by stimulation of the immune system. We hypothesize, that variations in genes encoding for both inhibitory or stimulatory immune checkpoint proteins may predict outcome in stage II and III colon cancer patients. Methods: The impact of 6 functional single nucleotide polymorphisms (SNPs) within the PD1, PD-L1, PD-L2, TIM3, OX40 and CD27 genes on time to recurrence was evaluated in 201 patients with stage II and III colon cancer. Genomic DNA was extracted from formalin-fixed paraffin embedded tissue and the SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics were as follows: female/male ratio = 42.8% / 57.2%; median age = 70y (19-91); median follow-up = 43months. The PD-L2 rs16923189 SNP showed significant association with recurrence rate. Patients with a G/G genotype had a higher 3-years recurrence rate compared to those harboring any A allele (41% vs 19%) in both univariate (HR 2.68, 95% Confidence interval (CI) 1.28-5.61, p = 0.006) and multivariate analyses (HR 3.13, 95% CI 1.42-6.28, p = 0.003). The high recurrence rate was most evident among patients with stage III and left-sided tumors carrying the G/G genotype (53% vs 24% and 65% vs 18%) in both univariate (HR 2.87, 95% CI 1.24-6.66, p = 0.009 and HR 5.28, 95% CI 2.24-12.44, p < 0.0001) and multivariate analyses (HR 4.32, 95% CI 1.76-9.91, p = 0.001 and HR 5.20, 95% CI 2.02-12.75, p = 0.001). Conclusions: Our results provide the first evidence, that polymorphisms within the PD-L2 gene might serve as prognostic markers in patients with stage II and III colon cancer. Interestingly, the prognostic effect is most significant among patients with stage III and left-sided colon cancers. Targeting PD-L2 might be a promising approach to further optimize treatment options and to improve outcome of colon cancer patients in the adjuvant setting.

Download Full-text

Effect of Oncotype DX colon cancer test results on treatment recommendations in patients with stage II colon cancer: Preliminary results.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.4_suppl.398 ◽

2012 ◽

Vol 30 (4_suppl) ◽

pp. 398-398

Author(s):

Thomas H. Cartwright ◽

Calvin Chao ◽

Margarita Lopatin ◽

Tanya GK Bentley ◽

Michael Samuel Broder ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Patients ◽

Adjuvant Treatment ◽

Recurrence Score ◽

Treatment Recommendations ◽

Oncotype Dx ◽

Stage Ii ◽

Medical Oncologists ◽

Stage Ii Colon Cancer ◽

The Impact

398 Background: The Oncotype DX Colon Cancer Recurrence Score (RS) has been clinically validated as an independent predictor of individual recurrence risk in stage II colon cancer patients following surgery. As a result, physicians have been ordering the Oncotype DX assay for stage II colon cancer patients since January 2010, yet no data exist on the assay’s impact on adjuvant treatment planning in practice. We performed a survey to characterize the impact of the assay on adjuvant treatment recommendations in stage II colon cancer. Methods: U.S. medical oncologists (N=277) who ordered Oncotype DX for ≥3 patients with stage II colon cancer were contacted and asked to complete a web-based survey regarding the single most recent stage II colon cancer patient for whom the assay was ordered. The survey was developed through cognitive interviews with four medical oncologists, and the protocol was institutional review board approved. Results: As a planned preliminary analysis, we analyzed surveys from 92 eligible physicians. Physicians were more often in community (85%) than academic or other practices, and had a median of 14.5 years (range, 2-40) of practice experience. The median patient age was 62 years (range, 34–81). 84% of patients had T3 disease. Patients had ≤8, 9-11 and ≥12 nodes examined 2%, 14% and 84% of the time and 36% had comorbidities. Of the 60 patients tested for MMR/MSI, 9 (15%) were MMR-D or MSI-high and 37 (62%) were MMR-P or MSI-low; 14 (23%) unknown. Median RS was 20 (range, 1-77). Before obtaining the RS, chemotherapy was planned in 38 (41%) patients, observation in 35 (38%), and there was no recommendation in 19 (21%). For the 73 patients with pre-assay recommendations, recommended treatment changed after obtaining the RS for 23 patients (32%), including changes from chemotherapy to observation and vice-versa. Conclusions: These preliminary findings indicate that for stage II colon cancer patients, treatment recommendations were changed by RS results approximately one-third of the time. Final results will be reported to include accrual through December 2011.

Download Full-text

The Impact of Delayed Chemotherapy on Its Completion and Survival Outcomes in Stage II Colon Cancer Patients

PLoS ONE ◽

10.1371/journal.pone.0107993 ◽

2014 ◽

Vol 9 (9) ◽

pp. e107993 ◽

Cited By ~ 6

Author(s):

Fang Xu ◽

Alfred A. Rimm ◽

Pingfu Fu ◽

Smitha S. Krishnamurthi ◽

Gregory S. Cooper

Keyword(s):

Colon Cancer ◽

Cancer Patients ◽

Stage Ii ◽

Survival Outcomes ◽

Stage Ii Colon Cancer ◽

The Impact

Download Full-text

Prospective Multicenter Study of the Impact of Oncotype DX Colon Cancer Assay Results on Treatment Recommendations in Stage II Colon Cancer Patients

The Oncologist ◽

10.1634/theoncologist.2013-0401 ◽

2014 ◽

Vol 19 (5) ◽

pp. 492-497 ◽

Cited By ~ 34

Author(s):

Geetika Srivastava ◽

Lindsay A. Renfro ◽

Robert J. Behrens ◽

Margarita Lopatin ◽

Calvin Chao ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Patients ◽

Multicenter Study ◽

Treatment Recommendations ◽

Oncotype Dx ◽

Stage Ii ◽

Prospective Multicenter Study ◽

Stage Ii Colon Cancer ◽

The Impact

Download Full-text

Impact of adjuvant chemotherapy on recurrence risk in stage II colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.533 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 533-533

Author(s):

Taiwo Adesoye ◽

Chung-Yuan Hu ◽

Amanda Cuddy ◽

Amanda B. Francescatti ◽

Jessica R. Schumacher ◽

...

Keyword(s):

Colon Cancer ◽

Overall Survival ◽

High Risk ◽

Adjuvant Chemotherapy ◽

Recurrence Rate ◽

Recurrence Risk ◽

Stage Ii ◽

Stage Iii ◽

Stage Ii Colon Cancer ◽

The Impact

533 Background: Although clinical guidelines recommend consideration of adjuvant chemotherapy in high-risk stage II colon cancer, the impact on recurrence risk and cancer related survival is unclear. Furthermore, among Medicare patients, adjuvant chemotherapy was not associated with improved survival. We examine the effect of adjuvant chemotherapy on recurrence risk and overall survival in a diverse cohort. Methods: 6,095 patients who underwent surgery for stage II-III colon cancer (2006-2007) were randomly selected from facilities reporting to the National Cancer Data Base for additional abstraction of tumor information, 5 year recurrence and survival. Death or second cancer within 6 months were excluded. Patients were classified as high or low risk using standard pathologic factors. Multivariate Cox regression with propensity score weighting was performed to compare recurrence risk and overall survival. Results: Of 3,423 patients with stage II colon cancer, 26.9% (n = 883) received chemotherapy compared to 76.2% (n = 1,839) of stage III patients. Among stage II patients, 47.8% (n = 1,636) had at least one high risk feature and 30.8% (n = 481) of these received chemotherapy. Five year recurrence rate in stage II patients was 13% (n = 392), greater in high risk compared to non-high risk patients (13.3% vs 9.3% p < 0.0001) and 24.4% (n = 874) in stage III patients. Chemotherapy did not improve recurrence risk in stage II patients regardless of risk status (High risk: hazard ratio [HR] 1.37; 95% CI 0.96 - 1.97; Non-high risk: HR 1.39; 95% CI 0.91 - 2.11). Chemotherapy was associated with a significant improvement in recurrence risk in stage III patients (HR 0.79; 95% CI 0.63 - 0.96). However, chemotherapy was associated with improved overall survival in both high (HR 0.69; 95% CI 0.51 - 0.92) and non-high risk stage II patients (HR 0.76; 95% CI 0.55 - 1.04), and also in stage III patients (HR 0.47; 95% CI 0.41 - 0.54). Conclusions: Adjuvant chemotherapy was not associated with a lower recurrence rate among stage II colon cancer patients. The observed survival benefit associated with chemotherapy is likely attributable to non-oncologic factors such as patient selection. Decision-making regarding chemotherapy use in this cohort should be carefully approached.

Download Full-text

Effect of the 12-gene colon cancer assay results on treatment recommendations in patients with stage II colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.3626 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 3626-3626

Author(s):

Thomas H. Cartwright ◽

Calvin Chao ◽

Margarita Lopatin ◽

Tanya G. Bentley ◽

Michael S. Broder ◽

...

Keyword(s):

Colon Cancer ◽

Cancer Patients ◽

Adjuvant Treatment ◽

Treatment Recommendations ◽

Oncotype Dx ◽

Stage Ii ◽

Treatment Intensity ◽

Medical Oncologists ◽

Stage Ii Colon Cancer ◽

The Impact

3626 Background: The Oncotype DX Colon Cancer Recurrence Score (RS) has been clinically validated as an independent predictor of individual recurrence risk in stage II colon cancer patients following surgery. As a result, physicians have been ordering the Oncotype DX assay for stage II colon cancer patients since January 2010, yet no data exist on the assay’s impact on adjuvant treatment planning in clinical practice. We performed a survey to characterize the impact of the assay on adjuvant treatment recommendations in stage II colon cancer. Methods: U.S. medical oncologists (n=346) who ordered Oncotype DX for ≥3 patients with stage II colon cancer were contacted and asked to complete a web-based survey regarding the single most recent stage II colon cancer patient for whom the assay was ordered. The survey was developed through cognitive interviews with four medical oncologists, and the protocol was institutional review board approved. Results: We analyzed survey results from 116 eligible physicians. Physicians were more often in community (86%) than academic or other practices, and had a median of 14.5 years (range, 2-40) of practice experience. The median patient age was 62 years (range, 32–85). Most patients (81%) had T3 disease. Patients had ≤8, 9-11 and ≥12 nodes examined 3%, 13% and 84% of the time and 38% had comorbidities. Of the 76 patients tested for MMR/MSI, 13 (17%) were MMR-D or MSI-H and 46 (61%) were MMR-P or MSI-L; 17 (22%) unknown. Median RS was 20 (range, 1-77). Before obtaining the RS, chemotherapy was planned in 52 (45%) patients, observation in 40 (34%), and there was no recommendation in 24 (21%). For the 92 patients with pre-assay recommendations, recommended treatment changed after obtaining the RS for 27 patients (29%). Treatment intensity decreased for 18 (67%) and increased for 9 (33%) of 27 changed recommendations. A significant trend of decreasing treatment intensity with lower RS values was observed (p=.0035). Conclusions: These findings indicate that for stage II colon cancer patients, treatment recommendations were changed by RS results in 29% of patients. Use of the Oncotype DX assay may lead to reductions in treatment intensity, contributing to the assay’s cost effectiveness.

Download Full-text

Recurrence risk factors and outcome stratification in stage II colon cancer patients: A subanalysis of the SACURA trial.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.3611 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 3611-3611

Author(s):

Megumi Ishiguro ◽

Eiji Nakatani ◽

Hideki Ueno ◽

Toshiaki Ishikawa ◽

Hiroyuki Uetake ◽

...

Keyword(s):

Risk Factors ◽

Colon Cancer ◽

Risk Factor ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Recurrence Rate ◽

Clinicopathological Characteristics ◽

Stage Ii ◽

Risk Factors For Recurrence ◽

Stage Ii Colon Cancer

3611 Background: Efficacy of adjuvant chemotherapy for stage II colon cancer is still controversial. We conducted the SACURA trial, a phase III study which evaluated the superiority of 1-year adjuvant treatment with oral tegafur-uracil (UFT) to surgery alone in stage II colon cancer. However, survival benefit of 1-year UFT to surgery alone was not demonstrated (ASCO2016 abst#3617). We herein aimed to identify risk factors for recurrence in the stage II patients “without adjuvant chemotherapy”, and to stratify the prognosis by using these factors. Methods: Among a total of 982 patients without adjuvant chemotherapy enrolled to the SACURA trial, we extracted the factors correlated to recurrence using a univariate and multivariate Cox proportional hazard model. 943 and 935 patients in the surgery alone group and UFT group were divided to subgroups according to the number of risk factors, and the recurrence rate in each subgroup was evaluated. Results: Among the conventional clinicopathological characteristics, the multivariate analysis identified pT4, elevated CEA, and examined lymph nodes less than 12 as significant risk factors for recurrence. The rate of patients with 0, 1, 2, and 3 risk factors were 45.0%, 42.4%, 11.5%, and 1.1%, respectively. The recurrence rate for each subgroup was shown in the table: the recurrence rate increased with number of risk factors, while 10.2% of patients without any risk factors developed recurrence. Difference in the recurrence rate between the treatment groups was significant in patients without risk factor, marginal in patients with 1 risk factor, and none in patients with >1 factors. Conclusions: pT4, elevated CEA, and examined lymph nodes less than 12 were identified as risk factors for recurrence in stage II colon cancer patients. The recurrence rate was divided by the number of these risk factors, but we could not extract the very-low risk group in whom adjuvant therapy is unnecessary. Induction of novel risk factors other than conventional clinicopathological characteristics is recommended. Clinical trial information: NCT00392899. [Table: see text]

Download Full-text

Association of genetic variations within the T-cell costimulatory LIGHT gene with outcome in stage II and III colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.2633 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 2633-2633

Author(s):

Martin D. Berger ◽

Shu Cao ◽

Inti Zlobec ◽

Yuji Miyamoto ◽

Mitsukuni Suenaga ◽

...

Keyword(s):

Colon Cancer ◽

Overall Survival ◽

T Cell ◽

Cancer Patients ◽

Recurrence Rate ◽

T Cell Activation ◽

Cell Activation ◽

Multivariate Analyses ◽

Stage Ii ◽

Stage Iii Colon Cancer

2633 Background: T-cell activation plays a key role in maintaining an effective host immunity and antitumor control. Targeting costimulatory immune checkpoint proteins can lead to increased antitumor immunity. We hypothesize, that variations in genes encoding for T-cell activation molecules may predict outcome in stage II and III colon cancer patients. Methods: The impact of 4 functional single nucleotide polymorphisms (SNPs) within the LIGHT, ICOS, CD80 and GITR genes on time to recurrence and overall survival was evaluated in 209 patients with stage II and III colon cancer. Genomic DNA was extracted from formalin-fixed paraffin embedded tissue and the SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics were as follows: median age = 70y (19-91); female/male ratio = 41.6% / 58.4%; 111 patients had stage II, and 98 stage III colon cancer. The LIGHT rs3760746 SNP showed significant association with recurrence rate in the overall population. Patients harboring any G allele had a lower 3-years recurrence rate compared to those with a A/A genotype (16% vs 30%) in both univariate (HR 0.53, 95% Confidence intervall (CI) 0.29-0.96, p = 0.033) and multivariate analyses (HR 0.52, 95% CI 0.29-0.95, p = 0.034). This trend was most evident among patients with stage III colon cancer. Here again, G allele carriers had both a lower 3-years recurrence and a longer 5-years overall survival rate compared to those having a A/A genotype (21% vs 40% and 77% vs 43%) in both univariate (HR 0.42, 95% CI 0.19-0.90, p = 0.021 and HR 0.51, 95% CI 0.25-1.03, p = 0.046) and multivariate analyses (HR 0.43, 95% CI 0.20-0.93, p = 0.033 and HR 0.30, 95% CI 0.14-0.65, p = 0.002). Conclusions: Our results provide the first evidence that polymorphisms within the T-cell costimulatory LIGHT gene might serve as prognostic markers in patients with stage II and III colon cancer. Targeting LIGHT might be a promising approach to further optimize treatment options and to improve outcome of colon cancer patients in the adjuvant setting.

Download Full-text

Association of chemotherapy with survival in stage II colon cancer patients who received radical surgery: a retrospective cohort study

BMC Cancer ◽

10.1186/s12885-021-08057-3 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Zhihao Lv ◽

Yuqi Liang ◽

Huaxi Liu ◽

Delong Mo

Keyword(s):

Colon Cancer ◽

Overall Survival ◽

Cancer Patients ◽

Prediction Models ◽

Radical Surgery ◽

Survival Rates ◽

Stage Ii ◽

Survival Prediction ◽

Stage Ii Colon Cancer ◽

Overall Survival Rates

Abstract Background It remains controversial whether patients with Stage II colon cancer would benefit from chemotherapy after radical surgery. This study aims to assess the real effectiveness of chemotherapy in patients with stage II colon cancer undergoing radical surgery and to construct survival prediction models to predict the survival benefits of chemotherapy. Methods Data for stage II colon cancer patients with radical surgery were retrieved from the Surveillance, Epidemiology, and End Results (SEER) database. Propensity score matching (1:1) was performed according to receive or not receive chemotherapy. Competitive risk regression models were used to assess colon cancer cause-specific death (CSD) and non-colon cancer cause-specific death (NCSD). Survival prediction nomograms were constructed to predict overall survival (OS) and colon cancer cause-specific survival (CSS). The predictive abilities of the constructed models were evaluated by the concordance indexes (C-indexes) and calibration curves. Results A total of 25,110 patients were identified, 21.7% received chemotherapy, and 78.3% were without chemotherapy. A total of 10,916 patients were extracted after propensity score matching. The estimated 3-year overall survival rates of chemotherapy were 0.7% higher than non- chemotherapy. The estimated 5-year and 10-year overall survival rates of non-chemotherapy were 1.3 and 2.1% higher than chemotherapy, respectively. Survival prediction models showed good discrimination (the C-indexes between 0.582 and 0.757) and excellent calibration. Conclusions Chemotherapy improves the short-term (43 months) survival benefit of stage II colon cancer patients who received radical surgery. Survival prediction models can be used to predict OS and CSS of patients receiving chemotherapy as well as OS and CSS of patients not receiving chemotherapy and to make individualized treatment recommendations for stage II colon cancer patients who received radical surgery.

Download Full-text