Prospective Multicenter Study on the Prognostic and Predictive Impact of Tumor Budding in Stage II Colon Cancer: Results From the SACURA Trial

Hideki Ueno, Megumi Ishiguro, Eiji Nakatani, Toshiaki Ishikawa, Hiroyuki Uetake, Chu Matsuda, Yoshihiko Nakamoto, Masanori Kotake, Kiyotaka Kurachi, Tomohisa Egawa, Keigo Yasumasa, Kohei Murata, Osamu Ikawa, Seiichi Shinji, Kenta Murotani, Shigeyuki Matsui, Satoshi Teramukai, Naohiro Tomita, Kenichi Sugihara, SACURA Study Group, Hideki Ueno, Megumi Ishiguro, Eiji Nakatani, Toshiaki Ishikawa, Hiroyuki Uetake, Chu Matsuda, Yoshihiko Nakamoto, Masanori Kotake, Kiyotaka Kurachi, Tomohisa Egawa, Keigo Yasumasa, Kohei Murata, Osamu Ikawa, Seiichi Shinji, Kenta Murotani, Shigeyuki Matsui, Satoshi Teramukai, Naohiro Tomita, Kenichi Sugihara, SACURA Study Group

Abstract

Purpose: The International Union Against Cancer highlighted tumor budding as a tumor-related prognostic factor. International assessment criteria for tumor budding were recently defined by the 2016 International Tumor Budding Consensus Conference (ITBCC2016). This study aimed to clarify the prognostic and predictive values of tumor budding in a randomized controlled trial evaluating the superiority of adjuvant chemotherapy with oral tegafur-uracil over surgery alone for stage II colon cancer (SACURA trial; ClinicalTrials.gov identifier: NCT00392899).

Patients and methods: Between 2006 and 2010, we enrolled 991 patients from 123 institutions with stage II colon cancer. Tumor budding was diagnosed by central review on the basis of the criteria adopted in the ITBCC2016. We prospectively recorded all clinical and pathologic data, including the budding grade, and performed prognostic analyses after 5 years of completing the patients' registration.

Results: Of 991 tumors, 376, 331, and 284 were classified as BD1, BD2, and BD3, respectively; the 5-year relapse-free survival (RFS) rate was 90.9%, 85.1%, and 74.4%, respectively (P < .001), and ranged widely in T4 tumors (86.6% to 53.3%). The budding grade significantly correlated with recurrence in the liver, lungs, lymph nodes, and peritoneum (P < .001 to .01). Multivariable analysis revealed that budding and T stage exerted an independent impact on RFS, and on the basis of the Harrell concordance index, these two factors substantially contributed to the improvement of the Cox model for predicting RFS. Both the BD2 and BD3 groups demonstrated greater improvement in the 5-year recurrence rate in the adjuvant chemotherapy group than the surgery-alone group by approximately 5%, but the difference was statistically nonsignificant.

Conclusion: Tumor budding grade on the basis of the ITBCC2016 criteria should be routinely evaluated in pathologic practice and could improve the benefit of adjuvant chemotherapy for stage II colon cancer.

Figures

FIG 1.
FIG 1.
Kaplan-Meier estimates of the relapse-free survival (RFS) rate in patients with colon cancer according to grade of tumor budding.
FIG 2.
FIG 2.
Comparison of time to recurrence between the surgery-alone group and the chemotherapy group in patients with (A) BD1, (B) BD2, and (C) BD3 tumors. The 5-year recurrence rates (95% CI) for the surgery-alone and tegafur-uracil (UFT) group were 6.8% (4.0% to 11.4%) and 6.5% (3.6% to 11.5%) in BD1, 10.3% (6.5% to 16.0%) and 14.8% (10.1% to 21.5%) in BD2, and 21.0% (15.0% to 29.0%) and 26.4% (20.1% to 34.4%) in BD3, respectively. Log-rank test: BD1, P = .8124; BD2, P = .1889; BD3, P = .2954.
FIG A1.
FIG A1.
CONSORT diagram. Numbers in brackets indicate the number of patients in the translational study for new histopathologic factors. UFT, tegafur-uracil.

References

    1. Watanabe T, Muro K, Ajioka Y, et al. Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2016 for the treatment of colorectal cancer. Int J Clin Oncol. 2018;23:1–34.
    1. Lugli A, Kirsch R, Ajioka Y, et al. Recommendations for reporting tumor budding in colorectal cancer based on the International Tumor Budding Consensus Conference (ITBCC) 2016. Mod Pathol. 2017;30:1299–1311.
    1. Union for International Cancer Control . : TNM Classification of Malignant Tumours (ed 8). West Sussex, United Kingdom, John Wiley & Sons, 2017.
    1. Matsuda C, Ishiguro M, Teramukai S, et al. A randomised-controlled trial of 1-year adjuvant chemotherapy with oral tegafur-uracil versus surgery alone in stage II colon cancer: SACURA trial. Eur J Cancer. 2018;96:54–63.
    1. Ishiguro M, Mochizuki H, Tomita N, et al. Study protocol of the SACURA trial: A randomized phase III trial of efficacy and safety of UFT as adjuvant chemotherapy for stage II colon cancer. BMC Cancer. 2012;12:281.
    1. De Smedt L, Palmans S, Andel D, et al. Expression profiling of budding cells in colorectal cancer reveals an EMT-like phenotype and molecular subtype switching. Br J Cancer. 2017;116:58–65.
    1. Zlobec I, Lugli A. Tumour budding in colorectal cancer: Molecular rationale for clinical translation. Nat Rev Cancer. 2018;18:203–204.
    1. Yang AD, Fan F, Camp ER, et al. Chronic oxaliplatin resistance induces epithelial-to-mesenchymal transition in colorectal cancer cell lines. Clin Cancer Res. 2006;12:4147–4153.
    1. Thiery JP, Acloque H, Huang RY, et al. Epithelial-mesenchymal transitions in development and disease. Cell. 2009;139:871–890.
    1. Japanese Society for Cancer of the Colon and Rectum: Japanese Classification of Colorectal Carcinoma (ed 2). Tokyo, Japan, Kanehara & Co, 2009.
    1. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology, colon cancer version 3. 2018. .
    1. Labianca R, Nordlinger B, Beretta GD, et al. Early colon cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013;24(suppl 6):vi64–vi72.
    1. Harrell FE, Jr, Lee KL, Mark DB. Multivariable prognostic models: Issues in developing models, evaluating assumptions and adequacy, and measuring and reducing errors. Stat Med. 1996;15:361–387.
    1. Morodomi T, Isomoto H, Shirouzu K, et al. An index for estimating the probability of lymph node metastasis in rectal cancers. Lymph node metastasis and the histopathology of actively invasive regions of cancer. Cancer. 1989;63:539–543.
    1. Hase K, Shatney C, Johnson D, et al. Prognostic value of tumor “budding” in patients with colorectal cancer. Dis Colon Rectum. 1993;36:627–635.
    1. Ueno H, Murphy J, Jass JR, et al. Tumour ‘budding’ as an index to estimate the potential of aggressiveness in rectal cancer. Histopathology. 2002;40:127–132.
    1. Mitrovic B, Schaeffer DF, Riddell RH, et al. Tumor budding in colorectal carcinoma: Time to take notice. Mod Pathol. 2012;25:1315–1325.
    1. Jass JR, Barker M, Fraser L, et al. APC mutation and tumour budding in colorectal cancer. J Clin Pathol. 2003;56:69–73.
    1. Nakamura T, Mitomi H, Kanazawa H, et al. Tumor budding as an index to identify high-risk patients with stage II colon cancer. Dis Colon Rectum. 2008;51:568–572.
    1. Wang LM, Kevans D, Mulcahy H, et al. Tumor budding is a strong and reproducible prognostic marker in T3N0 colorectal cancer. Am J Surg Pathol. 2009;33:134–141.
    1. Ueno H, Mochizuki H, Hashiguchi Y, et al. Risk factors for an adverse outcome in early invasive colorectal carcinoma. Gastroenterology. 2004;127:385–394.
    1. Shinto E, Mochizuki H, Ueno H, et al. A novel classification of tumour budding in colorectal cancer based on the presence of cytoplasmic pseudo-fragments around budding foci. Histopathology. 2005;47:25–31.
    1. Prall F, Nizze H, Barten M. Tumour budding as prognostic factor in stage I/II colorectal carcinoma. Histopathology. 2005;47:17–24.
    1. Lugli A, Karamitopoulou E, Panayiotides I, et al. CD8+ lymphocytes/ tumour-budding index: An independent prognostic factor representing a ‘pro-/anti-tumour’ approach to tumour host interaction in colorectal cancer. Br J Cancer. 2009;101:1382–1392.
    1. Karamitopoulou E, Zlobec I, Kölzer V, et al. Proposal for a 10-high-power-fields scoring method for the assessment of tumor budding in colorectal cancer. Mod Pathol. 2013;26:295–301.
    1. Puppa G, Senore C, Sheahan K, et al. Diagnostic reproducibility of tumour budding in colorectal cancer: A multicentre, multinational study using virtual microscopy. Histopathology. 2012;61:562–575.
    1. Zlobec I, Hädrich M, Dawson H, et al. Intratumoural budding (ITB) in preoperative biopsies predicts the presence of lymph node and distant metastases in colon and rectal cancer patients. Br J Cancer. 2014;110:1008–1013.
    1. Tanaka M, Hashiguchi Y, Ueno H, et al. Tumor budding at the invasive margin can predict patients at high risk of recurrence after curative surgery for stage II, T3 colon cancer. Dis Colon Rectum. 2003;46:1054–1059.
    1. Okuyama T, Nakamura T, Yamaguchi M. Budding is useful to select high-risk patients in stage II well-differentiated or moderately differentiated colon adenocarcinoma. Dis Colon Rectum. 2003;46:1400–1406.
    1. Betge J, Kornprat P, Pollheimer MJ, et al. Tumor budding is an independent predictor of outcome in AJCC/UICC stage II colorectal cancer. Ann Surg Oncol. 2012;19:3706–3712.
    1. Lai Y-H, Wu L-C, Li P-S, et al. Tumour budding is a reproducible index for risk stratification of patients with stage II colon cancer. Colorectal Dis. 2014;16:259–264.
    1. Horcic M, Koelzer VH, Karamitopoulou E, et al. Tumor budding score based on 10 high-power fields is a promising basis for a standardized prognostic scoring system in stage II colorectal cancer. Hum Pathol. 2013;44:697–705.
    1. Venook AP, Niedzwiecki D, Lopatin M, et al. Biologic determinants of tumor recurrence in stage II colon cancer: Validation study of the 12-gene recurrence score in cancer and leukemia group B (CALGB) 9581. J Clin Oncol. 2013;31:1775–1781.
    1. Mitrovic B, Handley K, Assarzadegan N, et al. Prognostic and predictive value of tumour budding in stage II colorectal carcinoma. J Clin Oncol. 2015;33(suppl; abstr 3605))

Source: PubMed

Patrocinadores y Colaboradores

Condiciones médicas

Intervenciones de drogas

3
Suscribir