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Intra-tumoral stroma has become increasingly important in understanding tumor biology, tumor progression and clinical outcome. The amount itself, quantified as the tumor-stroma ratio (TSR), has proven to be prognostic in stage I-III colon cancer. Also, alterations in stromal organization have been found to provide prognostic and predictive information in certain cancers. Here, we evaluated the predictive value of stromal organization in high-risk stage II and III colon cancer with respect to adjuvant bevacizumab and chemotherapy.
In a post-hoc analysis, stromal organization was microscopically determined in hematoxylin and eosin-stained primary tumor tissue samples of 1226 patients enrolled in the AVANT trial.
We found that patients with tumors with a disorganized stroma showed different survival rates after the addition of bevacizumab compared to standard oxaliplatin-based chemotherapy regimens. However, overall this difference was not significant with a HR of 0.94 (95% CI 0.57–1.55; p = 0.80) for disease-free survival (DFS) and 1.01 (95% CI 0.51–1.99; p = 0.99) for overall survival (OS). Subgroup analysis, however, revealed that stromal organization combined with TSR allowed the identification of stroma-high patients with absolute cumulative survival benefits up to 15% when bevacizumab was added to oxaliplatin-based chemotherapy regimens.
In high-risk stage II and stage III colon cancer, we found that subgroup analysis of the combined parameters stromal organization and TSR allows for the identification of patients with absolute cumulative DFS and OS benefits of up to 15%, when adding bevacizumab to the currently recommended oxaliplatin-based chemotherapy. Stromal organization itself does, however, not serve as an independent prognostic or predictive parameter.
C.J. Allegra, G. Yothers, M.J. O'Connell, S. Sharif, N.J. Petrelli, L.H. Colangelo, J.N. Atkins, T.E. Seay, L. Fehrenbacher, R.M. Goldberg, S. O'Reilly, L. Chu, C.A. Azar, S. Lopa, N. Wolmark, Phase III trial assessing bevacizumab in stages II and III carcinoma of the colon: results of NSABP protocol C-08. J. Clin. Oncol. 29, 11–16 (2011) CrossRef
C.J. Allegra, G. Yothers, M.J. O'Connell, S. Sharif, N.J. Petrelli, S.H. Lopa, N. Wolmark, Bevacizumab in stage II-III colon cancer: 5-year update of the National Surgical Adjuvant Breast and Bowel Project C-08 trial. J. Clin. Oncol. 31, 359–364 (2013) CrossRef
A. de Gramont, E. Van Cutsem, H.J. Schmoll, J. Tabernero, S. Clarke, M.J. Moore, D. Cunningham, T.H. Cartwright, J.R. Hecht, F. Rivera, S.A. Im, G. Bodoky, R. Salazar, F. Maindrault-Goebel, E. Shacham-Shmueli, E. Bajetta, M. Makrutzki, A. Shang, T. Andre, P.M. Hoff, Bevacizumab plus oxaliplatin-based chemotherapy as adjuvant treatment for colon cancer (AVANT): a phase 3 randomised controlled trial. Lancet Oncol. 13, 1225–1233 (2012) CrossRef
R.S. Kerr, S. Love, E. Segelov, E. Johnstone, B. Falcon, P. Hewett, A. Weaver, D. Church, C. Scudder, S. Pearson, P. Julier, F. Pezzella, I. Tomlinson, E. Domingo, D.J. Kerr, Adjuvant capecitabine plus bevacizumab versus capecitabine alone in patients with colorectal cancer (QUASAR 2): an open-label, randomised phase 3 trial. Lancet Oncol. 17, 1543–1557 (2016) CrossRef
L.B. Saltz, S. Clarke, E. Diaz-Rubio, W. Scheithauer, A. Figer, R. Wong, S. Koski, M. Lichinitser, T.S. Yang, F. Rivera, F. Couture, F. Sirzen, J. Cassidy, Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J. Clin. Oncol. 26, 2013–2019 (2008) CrossRef
E. Van Cutsem, A. Cervantes, R. Adam, A. Sobrero, J.H. Van Krieken, D. Aderka, E. Aranda Aguilar, A. Bardelli, A. Benson, G. Bodoky, F. Ciardiello, A. D'Hoore, E. Diaz-Rubio, J.Y. Douillard, M. Ducreux, A. Falcone, A. Grothey, T. Gruenberger, K. Haustermans, V. Heinemann, P. Hoff, C.H. Kohne, R. Labianca, P. Laurent-Puig, B. Ma, T. Maughan, K. Muro, N. Normanno, P. Osterlund, W.J. Oyen, D. Papamichael, G. Pentheroudakis, P. Pfeiffer, T.J. Price, C. Punt, J. Ricke, A. Roth, R. Salazar, W. Scheithauer, H.J. Schmoll, J. Tabernero, J. Taieb, S. Tejpar, H. Wasan, T. Yoshino, A. Zaanan, D. Arnold, ESMO consensus guidelines for the management of patients with metastatic colorectal cancer. Ann. Oncol. 27, 1386–1422 (2016) CrossRef
K. Pietras, A. Ostman, Hallmarks of cancer: interactions with the tumor stroma. Exp. Cell Res. 316, 1324–1331 (2010) CrossRef
D. Hanahan, L.M. Coussens, Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell 21, 309–322 (2012) CrossRef
L.A. Liotta, E.C. Kohn, The microenvironment of the tumour-host interface. Nature 411, 375–379 (2001) CrossRef
A. Huijbers, R.A. Tollenaar, G.W. v Pelt, E.C. Zeestraten, S. Dutton, C.C. McConkey, E. Domingo, V.T. Smit, R. Midgley, B.F. Warren, E.C. Johnstone, D.J. Kerr, W.E. Mesker, The proportion of tumor-stroma as a strong prognosticator for stage II and III colon cancer patients: validation in the VICTOR trial. Ann. Oncol. 24, 179–185 (2013) CrossRef
W.E. Mesker, J.M. Junggeburt, K. Szuhai, P. de Heer, H. Morreau, H.J. Tanke, R.A. Tollenaar, The carcinoma-stromal ratio of colon carcinoma is an independent factor for survival compared to lymph node status and tumor stage. Cell. Oncol. 29, 387–398 (2007)
W.E. Mesker, G.J. Liefers, J.M. Junggeburt, G.W. van Pelt, P. Alberici, P.J. Kuppen, N.F. Miranda, K.A. van Leeuwen, H. Morreau, K. Szuhai, R.A. Tollenaar, H.J. Tanke, Presence of a high amount of stroma and downregulation of SMAD4 predict for worse survival for stage I-II colon cancer patients. Cell. Oncol. 31, 169–178 (2009)
J.H. Park, C.H. Richards, D.C. McMillan, P.G. Horgan, C.S. Roxburgh, The relationship between tumour stroma percentage, the tumour microenvironment and survival in patients with primary operable colorectal cancer. Ann. Oncol. 25, 644–651 (2014) CrossRef
N.P. West, M. Dattani, P. McShane, G. Hutchins, J. Grabsch, W. Mueller, D. Treanor, P. Quirke, H. Grabsch, The proportion of tumour cells is an independent predictor for survival in colorectal cancer patients. Br. J. Cancer 102, 1519–1523 (2010) CrossRef
A. Huijbers, G.W. van Pelt, R.S. Kerr, E.C. Johnstone, R. Tollenaar, D.J. Kerr, W.E. Mesker, The value of additional bevacizumab in patients with high-risk stroma-high colon cancer. A study within the QUASAR2 trial, an open-label randomized phase 3 trial. J. Surg. Oncol. 117, 1043–1048 (2018) CrossRef
S.M. Zunder, G.W. van Pelt, H.J. Gelderblom, C. Mancao, H. Putter, R.A. Tollenaar, W.E. Mesker, Predictive potential of tumour-stroma ratio on benefit from adjuvant bevacizumab in high-risk stage II and stage III colon cancer. Br. J. Cancer 119, 164–169 (2018) CrossRef
P.P. Provenzano, K.W. Eliceiri, J.M. Campbell, D.R. Inman, J.G. White, P.J. Keely, Collagen reorganization at the tumor-stromal interface facilitates local invasion. BMC Med. 4, 38 (2006) CrossRef
H. Ueno, A.M. Jones, K.H. Wilkinson, J.R. Jass, I.C. Talbot, Histological categorisation of fibrotic cancer stroma in advanced rectal cancer. Gut 53, 581–586 (2004) CrossRef
Z.H. Zhou, C.D. Ji, H.L. Xiao, H.B. Zhao, Y.H. Cui, X.W. Bian, Reorganized collagen in the tumor microenvironment of gastric cancer and its association with prognosis. J. Cancer 8, 1466–1476 (2017) CrossRef
T.J. Dekker, A. Charehbili, V.T. Smit, P. ten Dijke, E.M. Kranenbarg, C.J. van de Velde, J.W. Nortier, R.A. Tollenaar, W.E. Mesker, J.R. Kroep, Disorganised stroma determined on pre-treatment breast cancer biopsies is associated with poor response to neoadjuvant chemotherapy: results from the NEOZOTAC trial. Mol. Oncol. 9, 1120–1128 (2015) CrossRef
C.J. Hanley, F. Noble, M. Ward, M. Bullock, C. Drifka, M. Mellone, A. Manousopoulou, H.E. Johnston, A. Hayden, S. Thirdborough, Y. Liu, D.M. Smith, T. Mellows, W.J. Kao, S.D. Garbis, A. Mirnezami, T.J. Underwood, K.W. Eliceiri, G.J. Thomas, A subset of myofibroblastic cancer-associated fibroblasts regulate collagen fiber elongation, which is prognostic in multiple cancers. Oncotarget 7, 6159–6174 (2016) CrossRef
C.R. Drifka, A.G. Loeffler, K. Mathewson, A. Keikhosravi, J.C. Eickhoff, Y. Liu, S.M. Weber, W.J. Kao, K.W. Eliceiri, Highly aligned stromal collagen is a negative prognostic factor following pancreatic ductal adenocarcinoma resection. Oncotarget 7, 76197–76213 (2016) CrossRef
M.W. Conklin, J.C. Eickhoff, K.M. Riching, C.A. Pehlke, K.W. Eliceiri, P.P. Provenzano, A. Friedl, P.J. Keely, Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am. J. Pathol. 178, 1221–1232 (2011) CrossRef
M.W. Conklin, R.E. Gangnon, B.L. Sprague, L. van Germert, J.M. Hampton, K.W. Eliceiri, J.S. Bredfeldt, Y. Liu, N. Surachaicharn, P.A. Newcomb, A. Friedl, P. Keely, A. Trentham-Dietz, Collagen alignment as a predictor of recurrence after ductal carcinoma in situ. Cancer Epidemiol. Biomarkers Prev. 27(2), 138–145 (2018)
- Stromal organization as predictive biomarker for the treatment of colon cancer with adjuvant bevacizumab; a post-hoc analysis of the AVANT trial
Priscilla van der Wilk
- Springer Netherlands
The official journal of the International Society for Cellular Oncology
Print ISSN: 2211-3428
Elektronische ISSN: 2211-3436