Journal Article
. 2019 May;11().
doi: 10.2147/CMAR.S196662.

A novel LARCassigner3 classification predicts outcomes in patients with locally advanced rectal cancer treated with neoadjuvant chemoradiotherapy: a retrospective training and validation analysis

Jing Zhang 1 Lijun Shen 1 Yun Deng 1 Xiaoyang Sun 1 Yaqi Wang 1 Ye Yao 1 Hui Zhang 1 Wei Zou 1 Zhiyuan Zhang 1 Juefeng Wan 1 Lifeng Yang 1 Ji Zhu 1 Zhen Zhang 1 
  • PMID: 31123421
  •     56 References


Purpose: To build and validate a predictive model of outcome for patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy. Materials and methods: We developed a LARCassigner3 classifier based on tumor and paired normal tissues of patients treated with neoadjuvant chemoradiation and surgery from January 2007 to December 2012 in Fudan University Shanghai Cancer Center. Excluding 23 pairs of tissues failed in the RNA quality test, rested 197 patients were divided into discovery (n=98) and validation (n=99) cohorts randomly. Median follow-up time was 58 months. We used the Kaplan-Meier method to estimate disease-free survival (DFS), overall survival (OS), local recurrent, and distant metastatic rate We constructed a multivariate Cox model to identify the variables independently associated with progression-free and OS. Results: We identified three classifier genes related to relevant colorectal cancer features (CXCL9, SFRP2, and CD44) that formed the LARCassigner3 classifier assay. In the discovery set, the median DFS was 48.1 months (95% confidence interval (CI) 47.3-49.5) in the low-risk group and 23.4 months (95% CI 22.1-24.8) in the high-risk group (p=0.0134); the median OS was 39.2 months (95% CI 38.4-40.3) in the high-risk group and 19.1 months (95% CI 18.3-20.7) in the low-risk group (p=0.0134); 5-year distant metastasis was 13.9% (95% CI 9.0-21.3) in the low-risk group and 49.8% (95% CI 38.7-60.9) in the high-risk group (p=0.0072). Additionally, the different responses to neoadjuvant chemoradiotherapy and the LARCassigner3 low-risk and high-risk groups was statistically significant (p=0.004) in the discovery cohort. Similar results were obtained in the internal evaluation cohort. Conclusions: Patients with LARCassigner3 low-risk tumors were associated with a good prognosis. The clinical utility of using LARCassigner3 subtyping for the identification of patients for neoadjuvant chemoradiotherapy requires validation in dependent clinical trial cohorts.

Keywords: locally advanced rectal cancer; neoadjuvant chemoradiotherapy; prognostic marker.

Expression of CD44 in Apc and Tcf mutant mice implies regulation by the WNT pathway.
V J Wielenga, R Smits, +5 authors, S T Pals.
Am J Pathol, 1999 Feb 23; 154(2). PMID: 10027409    Free PMC article.
Highly Cited.
MIG (CXCL9) chemokine gene therapy combines with antibody-cytokine fusion protein to suppress growth and dissemination of murine colon carcinoma.
J M Ruehlmann, R Xiang, +5 authors, R A Reisfeld.
Cancer Res, 2001 Dec 04; 61(23). PMID: 11731434
Chemokines in cancer.
M J Frederick, G L Clayman.
Expert Rev Mol Med, 2003 Oct 31; 3(19). PMID: 14585143
Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes.
Kenji Kawada, Masahiro Sonoshita, +7 authors, Makoto Mark Taketo.
Cancer Res, 2004 Jun 03; 64(11). PMID: 15173015
STRAP is a strong predictive marker of adjuvant chemotherapy benefit in colorectal cancer.
Martin Buess, Luigi Terracciano, +6 authors, Christoph Rochlitz.
Neoplasia, 2005 Feb 22; 6(6). PMID: 15720808    Free PMC article.
Effectiveness of gene expression profiling for response prediction of rectal adenocarcinomas to preoperative chemoradiotherapy.
B Michael Ghadimi, Marian Grade, +8 authors, Thomas Ried.
J Clin Oncol, 2005 Mar 19; 23(9). PMID: 15774776    Free PMC article.
Long-term oncologic outcome following preoperative combined modality therapy and total mesorectal excision of locally advanced rectal cancer.
Jose G Guillem, David B Chessin, +9 authors, W Douglas Wong.
Ann Surg, 2005 Apr 26; 241(5). PMID: 15849519    Free PMC article.
Improved therapeutic effectiveness by combining recombinant CXC chemokine ligand 10 with Cisplatin in solid tumors.
Gang Li, Ling Tian, +14 authors, Yu-Quan Wei.
Clin Cancer Res, 2005 Jun 03; 11(11). PMID: 15930360
Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results--EORTC 22921.
Jean-François Bosset, Gilles Calais, +7 authors, Laurence Collette.
J Clin Oncol, 2005 Jul 13; 23(24). PMID: 16009958
Highly Cited.
The Wnt antagonist sFRP1 is downregulated in premalignant large bowel adenomas.
G M Caldwell, C E Jones, +4 authors, D G Morton.
Br J Cancer, 2006 Mar 09; 94(6). PMID: 16523202    Free PMC article.
Prediction of sensitivity of rectal cancer cells in response to preoperative radiotherapy by DNA microarray analysis of gene expression profiles.
Toshiaki Watanabe, Yasuhiro Komuro, +8 authors, Hirokazu Nagawa.
Cancer Res, 2006 Apr 06; 66(7). PMID: 16585155
Combination of MIG (CXCL9) chemokine gene therapy with low-dose cisplatin improves therapeutic efficacy against murine carcinoma.
R Zhang, L Tian, +13 authors, Y-Q Wei.
Gene Ther, 2006 May 05; 13(17). PMID: 16672984
Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.
Soonmyung Paik, Gong Tang, +11 authors, Norman Wolmark.
J Clin Oncol, 2006 May 25; 24(23). PMID: 16720680
Highly Cited.
Chemotherapy with preoperative radiotherapy in rectal cancer.
Jean-François Bosset, Laurence Collette, +8 authors, EORTC Radiotherapy Group Trial 22921.
N Engl J Med, 2006 Sep 15; 355(11). PMID: 16971718
Highly Cited.
The multifaceted roles of chemokines in malignancy.
A Ben-Baruch.
Cancer Metastasis Rev, 2006 Oct 04; 25(3). PMID: 17016763
Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair.
Maria Mirotsou, Zhongyan Zhang, +6 authors, Victor Dzau.
Proc Natl Acad Sci U S A, 2007 Jan 26; 104(5). PMID: 17251350    Free PMC article.
Highly Cited.
Epigenetic alterations of the Wnt/beta-catenin pathway in human disease.
Oscar Aguilera, Alberto Muñoz, Manel Esteller, Mario F Fraga.
Endocr Metab Immune Disord Drug Targets, 2007 Mar 10; 7(1). PMID: 17346200
Role of RHAMM within the hierarchy of well-established prognostic factors in colorectal cancer.
I Zlobec, L Terracciano, +4 authors, A Lugli.
Gut, 2008 Apr 26; 57(10). PMID: 18436576
Meta-analysis of gene expression profiles in breast cancer: toward a unified understanding of breast cancer subtyping and prognosis signatures.
Pratyaksha Wirapati, Christos Sotiriou, +10 authors, Mauro Delorenzi.
Breast Cancer Res, 2008 Jul 30; 10(4). PMID: 18662380    Free PMC article.
Highly Cited.
Promoter hypermethylation of the SFRP2 gene is a high-frequent alteration and tumor-specific epigenetic marker in human breast cancer.
Jürgen Veeck, Erik Noetzel, +4 authors, Edgar Dahl.
Mol Cancer, 2008 Nov 08; 7. PMID: 18990230    Free PMC article.
CXCL10 expression and prognostic significance in stage II and III colorectal cancer.
Zheng Jiang, Ye Xu, Sanjun Cai.
Mol Biol Rep, 2009 Oct 13; 37(6). PMID: 19821051
Biomolecular network reconstruction identifies T-cell homing factors associated with survival in colorectal cancer.
Bernhard Mlecnik, Marie Tosolini, +10 authors, Jérôme Galon.
Gastroenterology, 2009 Nov 17; 138(4). PMID: 19909745
Highly Cited.
Suppression of human CD4+ T cell activation by 3,4-dimethoxycinnamonyl-anthranilic acid (tranilast) is mediated by CXCL9 and CXCL10.
Anne Hertenstein, Theresa Schumacher, +5 authors, Michael Platten.
Biochem Pharmacol, 2011 Jun 28; 82(6). PMID: 21703247
Wait-and-see policy for clinical complete responders after chemoradiation for rectal cancer.
Monique Maas, Regina G H Beets-Tan, +10 authors, Geerard L Beets.
J Clin Oncol, 2011 Nov 10; 29(35). PMID: 22067400
Highly Cited.
Partial pathologic response and nodal status as most significant prognostic factors for advanced rectal cancer treated with preoperative chemoradiotherapy.
Marianne Huebner, Bruce G Wolff, +2 authors, David W Larson.
World J Surg, 2012 Jan 25; 36(3). PMID: 22270980
Preoperative versus postoperative chemoradiotherapy for locally advanced rectal cancer: results of the German CAO/ARO/AIO-94 randomized phase III trial after a median follow-up of 11 years.
Rolf Sauer, Torsten Liersch, +10 authors, Claus Rödel.
J Clin Oncol, 2012 Apr 25; 30(16). PMID: 22529255
Highly Cited.
FAK, CD44v6, c-Met and EGFR in colorectal cancer parameters: tumour progression, metastasis, patient survival and receptor crosstalk.
Alexandros Garouniatis, Adamantia Zizi-Sermpetzoglou, +3 authors, Athanasios G Papavassiliou.
Int J Colorectal Dis, 2012 Jun 27; 28(1). PMID: 22733437
Cost-effectiveness of the 21-gene recurrence score assay in the context of multifactorial decision making to guide chemotherapy for early-stage breast cancer.
Shelby D Reed, Michaela A Dinan, Kevin A Schulman, Gary H Lyman.
Genet Med, 2012 Sep 15; 15(3). PMID: 22975761    Free PMC article.
Clinical significance of CD44 variants expression in colorectal cancer.
Xiao-Dong Li, Mei Ji, +2 authors, Chang-Ping Wu.
Tumori, 2013 Apr 04; 99(1). PMID: 23549006
A colorectal cancer classification system that associates cellular phenotype and responses to therapy.
Anguraj Sadanandam, Costas A Lyssiotis, +13 authors, Douglas Hanahan.
Nat Med, 2013 Apr 16; 19(5). PMID: 23584089    Free PMC article.
Highly Cited.
Poor-prognosis colon cancer is defined by a molecularly distinct subtype and develops from serrated precursor lesions.
Felipe De Sousa E Melo, Xin Wang, +15 authors, Louis Vermeulen.
Nat Med, 2013 Apr 16; 19(5). PMID: 23584090
Highly Cited.
Colorectal cancer intrinsic subtypes predict chemotherapy benefit, deficient mismatch repair and epithelial-to-mesenchymal transition.
Paul Roepman, Andreas Schlicker, +14 authors, Iris M Simon.
Int J Cancer, 2013 Jul 16; 134(3). PMID: 23852808    Free PMC article.
Highly Cited.
CD44v6 is a marker of constitutive and reprogrammed cancer stem cells driving colon cancer metastasis.
Matilde Todaro, Miriam Gaggianesi, +11 authors, Giorgio Stassi.
Cell Stem Cell, 2014 Mar 13; 14(3). PMID: 24607406
Highly Cited.
Tumor regression grading after preoperative chemoradiotherapy for locally advanced rectal carcinoma revisited: updated results of the CAO/ARO/AIO-94 trial.
Emmanouil Fokas, Torsten Liersch, +11 authors, Claus Rödel.
J Clin Oncol, 2014 Apr 23; 32(15). PMID: 24752056
Highly Cited.
CD44v6 expression in patients with stage II or stage III sporadic colorectal cancer is superior to CD44 expression for predicting progression.
L H Zhao, Q L Lin, +3 authors, H Y Yan.
Int J Clin Exp Pathol, 2015 Mar 11; 8(1). PMID: 25755763    Free PMC article.
Combined detection of plasma GATA5 and SFRP2 methylation is a valid noninvasive biomarker for colorectal cancer and adenomas.
Xie Zhang, Yu-Fei Song, +5 authors, Zhi-Gang Huang.
World J Gastroenterol, 2015 Mar 12; 21(9). PMID: 25759530    Free PMC article.
The consensus molecular subtypes of colorectal cancer.
Justin Guinney, Rodrigo Dienstmann, +37 authors, Sabine Tejpar.
Nat Med, 2015 Oct 13; 21(11). PMID: 26457759    Free PMC article.
Highly Cited.
Challenging the Cancer Molecular Stratification Dogma: Intratumoral Heterogeneity Undermines Consensus Molecular Subtypes and Potential Diagnostic Value in Colorectal Cancer.
Philip D Dunne, Darragh G McArt, +16 authors, Sandra Van Schaeybroeck.
Clin Cancer Res, 2016 May 07; 22(16). PMID: 27151745
Highly Cited.
Clinical Outcome From Oxaliplatin Treatment in Stage II/III Colon Cancer According to Intrinsic Subtypes: Secondary Analysis of NSABP C-07/NRG Oncology Randomized Clinical Trial.
Nan Song, Katherine L Pogue-Geile, +9 authors, Soonmyung Paik.
JAMA Oncol, 2016 Jun 09; 2(9). PMID: 27270348    Free PMC article.
Practical and Robust Identification of Molecular Subtypes in Colorectal Cancer by Immunohistochemistry.
Anne Trinh, Kari Trumpi, +16 authors, Louis Vermeulen.
Clin Cancer Res, 2016 Jul 28; 23(2). PMID: 27459899
Highly Cited.
KRAS, BRAF oncogene mutations and tissue specific promoter hypermethylation of tumor suppressor SFRP2, DAPK1, MGMT, HIC1 and p16 genes in colorectal cancer patients.
Binnur Bagci, Musa Sari, +3 authors, Gokhan Bagci.
Cancer Biomark, 2016 Aug 20; 17(2). PMID: 27540971
CD44: More than a mere stem cell marker.
I Morath, T N Hartmann, V Orian-Rousseau.
Int J Biochem Cell Biol, 2016 Sep 20; 81(Pt A). PMID: 27640754
Biomarker-Based Scoring System for Prediction of Tumor Response After Preoperative Chemoradiotherapy in Rectal Cancer by Reverse Transcriptase Polymerase Chain Reaction Analysis.
Hyuk Hur, Inna Tulina, +5 authors, Nam Kyu Kim.
Dis Colon Rectum, 2016 Nov 09; 59(12). PMID: 27824703
Selective analysis of cancer-cell intrinsic transcriptional traits defines novel clinically relevant subtypes of colorectal cancer.
Claudio Isella, Francesco Brundu, +13 authors, Andrea Bertotti.
Nat Commun, 2017 Jun 01; 8. PMID: 28561063    Free PMC article.
Highly Cited.
Organ preservation for rectal cancer (GRECCAR 2): a prospective, randomised, open-label, multicentre, phase 3 trial.
Eric Rullier, Philippe Rouanet, +17 authors, Adélaïde Doussau.
Lancet, 2017 Jun 12; 390(10093). PMID: 28601342
Highly Cited.
Neoadjuvant chemotherapy affects molecular classification of colorectal tumors.
K Trumpi, I Ubink, +10 authors, O Kranenburg.
Oncogenesis, 2017 Jul 12; 6(7). PMID: 28692036    Free PMC article.
KRAS Mutation and Consensus Molecular Subtypes 2 and 3 Are Independently Associated with Reduced Immune Infiltration and Reactivity in Colorectal Cancer.
Neeraj Lal, Brian S White, +7 authors, Gary W Middleton.
Clin Cancer Res, 2017 Oct 25; 24(1). PMID: 29061646    Free PMC article.
Colorectal Cancer Consensus Molecular Subtypes Translated to Preclinical Models Uncover Potentially Targetable Cancer Cell Dependencies.
Anita Sveen, Jarle Bruun, +14 authors, Ragnhild A Lothe.
Clin Cancer Res, 2017 Dec 16; 24(4). PMID: 29242316
Immunological landscape of consensus clusters in colorectal cancer.
Pawel Karpinski, Joanna Rossowska, Maria Malgorzata Sasiadek.
Oncotarget, 2017 Dec 30; 8(62). PMID: 29285252    Free PMC article.
Chemoprevention of colorectal cancer by black raspberry anthocyanins involved the modulation of gut microbiota and SFRP2 demethylation.
Lili Chen, Bowen Jiang, +5 authors, Xiuli Bi.
Carcinogenesis, 2018 Jan 24; 39(3). PMID: 29361151
The role of chemotherapy in localized and locally advanced rectal cancer: A systematic revision.
Susana Roselló, Federica Papaccio, +2 authors, Andrés Cervantes.
Cancer Treat Rev, 2018 Feb 07; 63. PMID: 29407455
Systematic Review.
Prospective patient stratification into robust cancer-cell intrinsic subtypes from colorectal cancer biopsies.
Matthew Alderdice, Susan D Richman, +12 authors, Philip D Dunne.
J Pathol, 2018 Feb 08; 245(1). PMID: 29412457    Free PMC article.
Pattern and Management of Recurrence of Mid-Low Rectal Cancer After Neoadjuvant Intensity-Modulated Radiotherapy: Single-Center Results of 687 Cases.
Ai-Wen Wu, Yong Cai, +4 authors, Jia-Fu Ji.
Clin Colorectal Cancer, 2018 Mar 12; 17(2). PMID: 29525524
Contemporary management of locally advanced rectal cancer: Resolving issues, controversies and shifting paradigms.
Aeris Jane D Nacion, Youn Young Park, Nam Kyu Kim.
Chin J Cancer Res, 2018 Mar 17; 30(1). PMID: 29545727    Free PMC article.
Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer.
Joseph A Sparano, Robert J Gray, +27 authors, George W Sledge.
N Engl J Med, 2018 Jun 05; 379(2). PMID: 29860917    Free PMC article.
Highly Cited.
CD44 is a RAS/STAT5-regulated invasion receptor that triggers disease expansion in advanced mastocytosis.
Niklas Mueller, Daniel Wicklein, +17 authors, Peter Valent.
Blood, 2018 Jul 19; 132(18). PMID: 30018080    Free PMC article.