Genomic profiling of stage II and III colon cancers reveals APC mutations to be associated with survival in stage III colon cancer patients

4004 Background: Despite recent advances in the treatment of metastatic colorectal cancer, tailoring adjuvant treatment of stage II and III colon cancer patients remains controversial. Identifying a reliable panel of prognostic and predictive markers for tumor recurrence is critical in selecting an individualized and tailored chemotherapy. Tumor angiogenesis plays an important role in tumor development, progression and metastasis. In this retrospective study, we tested whether a specific pattern of 40 functionally significant polymorphisms in 37 genes involved in angiogenesis and tumor microenvironment will predict the risk of tumor recurrence in stage II and III colon cancer patients treated with adjuvant chemotherapy. Methods: Between 1999 and 2006 blood specimens from 140 patients (69 females and 71 males with a median age of 59 years; range=28–86) were obtained at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC). 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. Genomic DNA was extracted from peripheral blood and genotypes were determined using PCR based RFLP. Results: Polymorphisms in VEGF (C936T; p=0.009, log-rank) and VEGFR2 (+4422 AC- repeat; p=0.04, log-rank and +1416 T/A; p=0.0009, log-rank) were associated with risk of tumor recurrence in stage III colon cancer patients (n=77). VEGFR2 AC-repeat polymorphisms were additionally associated with risk of recurrence in Stage II colon cancer patients (n=63, p=0.02, log-rank). Conclusion: VEGF C936T and VEGFR2 (+4422 AC-repeat and +1416 T/A) polymorphisms may help to identify Stage II and III colon cancer patients who are at increased risk for developing tumor recurrence. Angiogenesis seems to play a crucial role in tumor recurrence, thus targeting VEGF and VEGFR2 may be of clinical benefit for stage II and stage III colon cancer patients. Large prospective trials are needed to validate these preliminary data. No significant financial relationships to disclose.

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Whole exome sequencing identifies novel prognostic biomarker in colon cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15098 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15098-e15098

Author(s):

Yinchen Shen ◽

Xiaohong Han ◽

Zheng Wang ◽

Dongge Liu ◽

Yongkun Sun ◽

...

Keyword(s):

Colon Cancer ◽

Exome Sequencing ◽

Whole Exome Sequencing ◽

Prognostic Biomarker ◽

Stage Ii ◽

Stage Iii ◽

Stage Iii Colon Cancer ◽

Novel Gene ◽

Colon Cancers ◽

Whole Exome

e15098 Background: The incidence and mortality of cancer have been increasing in China, of which colorectal cancer (CRC) is ranking the fifth and among the leading cause of cancer-related deaths .Prognostic biomarker for colon cancer treated with standard adjuvant chemotherapy was rare and inconsistent, as gene mutations accumulation contribute to the carcinogenesis, available biomarkers may emerge by genome investigation. Methods: Whole exome sequencing was performed in 13 stage III colon cancers to identify gene alternations in patients with different outcomes, followed by 350 stage II-III colon cancers samples, of which clinicopathological characteristics and survival information were collected simultaneously to evaluate the clinical relevance in this cohort for evaluation of novel gene biomarkers. Results: Eight genes (CD97, ZNF568, WARS2, IL6R, APPL2, C9orf117, ANKRD32, ZNF443) were identified as differently expressed between two groups of good (DFS > 60 months) and poor (DFS < 25 month) separated according to treatment outcomes. ZNF443 was detected in 81.7% (286/350) samples, and ZNF443 (CA) was more common in male compared with female (56.0% vs 40.8%, P = 0.011).ZNF443 (CA) distribution differed related to different N stage, only stage N0 shared a higher frequency over 50% (P = 0.026).ANKRD32 was detected in 212 (93.8%) tumors, and ANKRD32 (CA) appeared more in left sites (included left colon and sigmoid colon, 61.1% vs 41.9%, P = 0.006). Moreover, ANKRD32 (CA) was significantly associated with superior disease-free survival (DFS) in stage III colon cancer patients (P = 0.044, HR 0.49, 95% CI0.24-0.98).Tumor nodal stage appeared as independent prognostic factor for DFS and over-all survival (OS) in stage II-III colon cancer (P < 0.05), and low tumor differentiation indicated a worse OS for colon cancers. While no other significant association was obtained between genes and survival in present study. Conclusions: Whole exome sequencing was efficient in discovering novel gene biomarkers in clinical evaluation. ANKRD32 was independently prognostic for DFS in stage III colon cancer.

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Three- versus six-month adjuvant FOLFOX or CAPOX for high-risk stage II and stage III colon cancer patients: the efficacy results of Hellenic Oncology Research Group (HORG) participation to the International Duration Evaluation of Adjuvant Chemotherapy (IDEA) project

Annals of Oncology ◽

10.1093/annonc/mdz193 ◽

2019 ◽

Vol 30 (8) ◽

pp. 1304-1310 ◽

Cited By ~ 6

Author(s):

J. Souglakos ◽

I. Boukovinas ◽

S. Kakolyris ◽

S. Xynogalos ◽

N. Ziras ◽

...

Keyword(s):

Colon Cancer ◽

High Risk ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Research Group ◽

Stage Ii ◽

Stage Iii ◽

Stage Iii Colon Cancer ◽

Oncology Research

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Germline variants and clinical outcomes of high-risk stage II and stage III colon cancer patients treated with oxaliplatin and fluoropyrimidines adjuvant chemotherapy: a pharmacogenetic ancillary study to TOSCA trial

Annals of Oncology ◽

10.1093/annonc/mdx422.002 ◽

2017 ◽

Vol 28 ◽

pp. vi3-vi4

Author(s):

A. Ruzzo ◽

F. Galli ◽

E. Rulli ◽

S. Lonardi ◽

...

Keyword(s):

Colon Cancer ◽

High Risk ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Clinical Outcomes ◽

Stage Ii ◽

Stage Iii ◽

Germline Variants ◽

Stage Iii Colon Cancer ◽

Ancillary Study

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Early survival outcomes in stage I-III operated colon cancer patients from a low prevalence, lower-middle income country: The Indian experience.

Journal of Clinical Oncology ◽

10.1200/jco.2018.36.4_suppl.857 ◽

2018 ◽

Vol 36 (4_suppl) ◽

pp. 857-857

Author(s):

Rushabh Kiran Kothari ◽

Vikas S. Ostwal ◽

Anant Ramaswamy ◽

Tara Chand Gupta ◽

Sandeep Kumar Bairwa ◽

...

Keyword(s):

Colon Cancer ◽

Adjuvant Chemotherapy ◽

Cancer Patients ◽

Stage I ◽

Stage Ii ◽

Stage Iii ◽

Survival Outcomes ◽

Middle Income ◽

Colon Cancers ◽

Low Prevalence

857 Background: Data regarding survival and outcomes in operated colon cancer patients from a lower-middle income and low prevalence nation like India is scarce. Methods: Patients who underwent curative resection for non-metastatic, non-rectal colon cancer from January 2013 to December 2016 were retrospectively analyzed from a prospectively maintained database for baseline demographics, disease characteristics, adjuvant chemotherapy, recurrence free survival (RFS) and overall survival (OS). RFS and OS were calculated by Kaplan Meier method. Results: 505 patients underwent resection in the pre-defined time-period. Median age of the patients was 53 years (range: 17 – 87) and 339 patients (67.3%) were male. Patients with stage I, stage II and stage III disease were 43(8.6%), 233(46.1%) and 217(42.9%), respectively, while 12 patients(2.4%) were not adequately staged, though non-metastatic. Right sided colon cancers were more prevalent as compared to left sided (56% vs. 44%) and 41 patients (8%) had signet ring adenocarcinoma on cytomorphology. Median number of nodes retrieved during surgery was 22 nodes(range:1-96 ). Adjuvant chemotherapy was planned for 406 patients (80.4%), with the common regimens used being capecitabine-oxaliplatin, capecitabine , 5-fluorouracil – oxaliplatin and 5-fluorouracil in 280 (55.2%), 80 (16%), 34 (7%) and 6 patients (1.2%), respectively. Planned adjuvant chemotherapy was completed in 334 patients(82.3%; n = 406) with 27 patients (6%) required dose reduction. 35 patients (7%) required permanent cessation of adjuvant treatment due to chemotherapy related toxicity. With a median follow up of 21.8 months (range: 0-56),estimated 3 year RFS for the entire cohort was 86.2% and estimated median OS was 95.2%. Estimated RFS in stage I, Stage II, stage III patients were 90.3%, 89.5% and 78% respectively (p-0.006). Conclusions: Early survival outcomes with Stage I-III colon cancers in a low prevalence country like India appears to be comparable or potentially superior to outcomes published from high prevalence countries. Adjuvant chemotherapy in Stage II and Stage III colon cancers in a real world scenario in India appears to be well tolerated.

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Cancer Stem Cell Gene Variants in CD44 Predict Outcome in Stage II and Stage III Colon Cancer Patients

Anticancer Research ◽

10.21873/anticanres.11545 ◽

2017 ◽

Vol 37 (4) ◽

pp. 2011-2018 ◽

Cited By ~ 5

Keyword(s):

Colon Cancer ◽

Stem Cell ◽

Cancer Stem Cell ◽

Cancer Patients ◽

Stage Ii ◽

Stage Iii ◽

Gene Variants ◽

Stage Iii Colon Cancer ◽

Cell Gene ◽

Stem Cell Gene

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A prospective pharmacogenetic study of thymidylate synthase (TS) polymorphisms in high risk stage II or stage III colon cancer patients treated with 5-fluorouracil (5-FU) and leucovorin (LV)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.13018 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 13018-13018

Author(s):

K. E. Mulder ◽

C. A. Butts ◽

A. Scarfe ◽

H. Au ◽

S. Koski ◽

...

Keyword(s):

Colon Cancer ◽

High Risk ◽

Cancer Patients ◽

Binding Sites ◽

Retrospective Studies ◽

Stage Ii ◽

Stage Iii ◽

Pharmacogenetic Study ◽

Stage Iii Colon Cancer ◽

E Box

13018 Background: Retrospective studies suggest TS polymorphisms predict toxicity from TS inhibitors as well as therapeutic response. The TS promoter has a variable number of tandem repeats (VNTR) polymorphism containing putative E-box binding sites that bind upstream stimulatory factor (USF) -1 and -2. One E-box binding site exists in TSER*2 and 2 binding sites exist in TSER*3. A single nucleotide polymorphism (SNP) at position 12 (G→C) in TSER*3’s 2nd repeat abolishes binding of USF-1/2. Combined effects of VNTR and SNP means individuals may have 2, 3 or 4 enhancer regions. We hypothesized that decreased enhancer numbers predicts for patients at risk for grade ≥3 mucositis, diarrhea, neutropenia, and overall toxicity and performed a prospective pharmacogenetic study of TS polymorphisms in adjuvant colon cancer patients treated with 5-FU/LV. Methods: High risk Stage II or Stage III colon cancer patients treated with 5FU/LV (425 mg/m2/ 20 mg/m2) daily for 5 days every 4 weeks had blood drawn for genotyping prior to starting therapy. Patients were assessed for toxicity using NCI CTC 2.0 in cycle 1. Three year disease-free survival will also be assessed. Results: 103 patients were enrolled and genotyped with 95 evaluable for toxicity. Patient characteristics: median age 61yrs (36–79): M 52%/F 48%; Stage III 77%, Stage II 23%. Frequency of genotypes containing 2 enhancers (TSER*2/ TSER*2, TSER*2 / TSER*3C, TSER*3C/ TSER*3C), 3 enhancers (TSER*2/ TSER*3G, TSER*3C/ TSER*3G) and 4 enhancers (TSER*3G/ TSER*3G) was 0.64, 0.31, and 0.05 respectively. No significant difference was seen in overall toxicity, mucositis, diarrhea and neutropenia based on TS polymorphism genotypes. Frequency of recurrence in 2 enhancer patients was 13% versus 26% in 3/4 enhancer patients but this did not reach statistical significance (p = 0.16). Conclusions: This prospective study does not confirm previously published retrospective studies suggesting that TS VNTR and SNP predict toxicity from TS inhibitors in patients treated with 5-fluorouracil for colon cancer. There is a trend for prediction of recurrence which requires further follow-up. No significant financial relationships to disclose.

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