The online version of this article (https://doi.org/10.1186/s12885-017-3955-4) contains supplementary material, which is available to authorized users.
In metastatic colorectal cancer (mCRC), the localization of the primary tumour has been shown to be of prognostic as well as predictive relevance.
With the aim to investigate clinical and molecular disease characteristics with respect to sidedness in a real-world cohort, we analyzed 161 mCRC patients included in the KRAS Registry of the Arbeitsgemeinschaft Medikamentöse Tumortherapie (AGMT) between January 2006 and October 2013.
Right-sided mCRC displayed a worse median overall survival (OS) in comparison to left-sided disease (18.1 months [95%-CI: 14.3–40.7] versus 32.3 months [95%-CI: 25.5–38.6]; HR: 1.63 [95%-CI: 1.13–2.84]; p = 0.013). The choice of the biological agent in front-line therapy had a statistically significant impact on median OS in patients with right-sided tumours (anti-epidermal growth factor receptor (EGFR): 10.6 months [95%-CI: 5.2-NA]; anti-vascular endothelial growth factor (VEGF): 26.2 months [95%-CI: 17.9-NA]; HR: 2.69 [95%-CI: 1.30–12.28]; p = 0.015) but not in patients with left-sided tumours (anti-EGFR: 37.0 months [95%-CI: 20.2–56.6]; anti-VEGF: 32.3 months [95%-CI: 23.6–41.1]; HR: 0.97 [95%-CI: 0.56–1.66]; p = 0.905). When evaluating molecular characteristics of tumour samples, we found a clinically meaningful trend towards an inferior OS in TP53 mutant mCRC treated with anti-EGFR based therapy compared to anti-VEGF based therapy (17.1 months [95%-CI: 8.7-NA] versus 38.3 months [95%-CI: 23.6–48.0], HR = 1.95 [95%-CI: 0.95–5.88]; p = 0.066), which was not significantly dependent on sidedness. This was not the case in patients with TP53 wild-type tumours. Therefore we evaluated the combined impact of sidedness and TP53 mutation status in the anti-EGFR treated cohort and patients with left-sided/TP53 wild-type mCRC showed the longest median OS (38.9 months) of all groups (right-sided/TP53 mutant: 12.1 months; right-sided/TP53 wild-type: 8.9 months; left-sided/TP53 mutant: 18.4 months; p = 0.020).
TP53 mutation and right-sidedness are associated with shorter OS in patients treated with anti-EGFR based therapy but not with anti-VEGF based therapy. The confirmation of the predictive value of TP53 mutation status in a larger cohort is warranted.
Additional file 1: Table S1. Primers and probes used for molecular analyses of tumour samples. (DOC 38 kb)12885_2017_3955_MOESM1_ESM.doc
Howlader N, Noone AM, Krapcho M, Miller D, Bishop K, Altekruse SF, Kosary CL, Yu M, Ruhl J, Tatalovic Z, et al. Seer cancer statistics review, 1975-2013. National Cancer Institute. 2015;
Missiaglia E, Jacobs B, D'Ario G, Di Narzo AF, Soneson C, Budinska E, Popovici V, Vecchione L, Gerster S, Yan P, et al. Distal and proximal colon cancers differ in terms of molecular, pathological, and clinical features. Annals of oncology : official journal of the European Society for Medical Oncology. 2014;25(10):1995–2001. CrossRef
Lee GH, Malietzis G, Askari A, Bernardo D, Al-Hassi HO, Clark SK. Is right-sided colon cancer different to left-sided colorectal cancer? - a systematic review. European journal of surgical oncology : the journal of the European Society of Surgical Oncology and the British Association of Surgical Oncology. 2015;41(3):300–8. CrossRef
Tejpar S, Stintzing S, Ciardiello F, Tabernero J, Van Cutsem E, Beier F, Esser R, Lenz HJ, Heinemann V. Prognostic and predictive relevance of primary tumor location in patients with RAS wild-type metastatic colorectal cancer: retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA oncology. 2016;
Venook A, Niedzwiecki D, Innocenti F, Fruth B, Greene C, O'Neil BH, Shaw J, Atikins J, Horvath LE, Polite B et al: Impact of primary tumor location on overall survival and progression free survival in patients with metastatic colorectal cancer: analysis of CALGB/SWOG 80405 (Alliance). J Clin Oncol 34; suppl 4S: abstr 493 2016.
Barault L, Veyrie N, Jooste V, Lecorre D, Chapusot C, Ferraz JM, Lievre A, Cortet M, Bouvier AM, Rat P, et al. Mutations in the RAS-MAPK, PI(3)K (phosphatidylinositol-3-OH kinase) signaling network correlate with poor survival in a population-based series of colon cancers. Int J Cancer. 2008;122(10):2255–9. CrossRefPubMed
Lenz H-J, Ou F-S, Venook AP, Hochster HS, Niedzwiecki D, Goldberg RM, Mayer RJ, Bertagnolli MM, Blanke CD, Zemla T, et al. Impact of consensus molecular subtyping (CMS) on overall survival (OS) and progression free survival (PFS) in patients (pts) with metastatic colorectal cancer (mCRC): Analysis of CALGB/SWOG 80405 (Alliance). Journal of Clinical Oncology. 2017;35(15_suppl):3511–1.
Boeckx N, Toler A, Op de Beeck K, Kafatos G, Deschoolmeester V, Rolfo C, Lowe K, Van Camp G, Demonty G, Peeters M: Primary tumor sidedness impacts on prognosis and treatment outcome: results from three randomized studies of panitumumab plus chemotherapy versus chemotherapy or chemotherapy plus bevacizumab in 1st and 2nd line RAS/BRAF WT mCRC. Ann Oncol (2016) 27 (suppl 6): doi: 10.1093/annonc/mdw36337.
Oden-Gangloff A, Di Fiore F, Bibeau F, Lamy A, Bougeard G, Charbonnier F, Blanchard F, Tougeron D, Ychou M, Boissiere F, et al. TP53 mutations predict disease control in metastatic colorectal cancer treated with cetuximab-based chemotherapy. Br J Cancer. 2009;100(8):1330–5. CrossRefPubMedPubMedCentral
Di Fiore F, Lamy A, Blanchard F, Oden-Gangloff A, Sesboüé R, Sabourin JC, Frebourg T, Michel P, Laurent-Puig P: TP53 mutations in irinotecan-refractory KRAS wt-BRAF wt metastatic colorectal cancer patients treated with cetuximab-based chemotherapy. J Clin Oncol 29: 2011 (suppl 4; abstr 426).
Di Bartolomeo M, Pietrantonio F, Perrone F, Dotti KF, Lampis A, Bertan C, Beretta E, Rimassa L, Carbone C, Biondani P, et al. Lack of KRAS, NRAS, BRAF and TP53 mutations improves outcome of elderly metastatic colorectal cancer patients treated with cetuximab, oxaliplatin and UFT. Target Oncol. 2014;9(2):155–62. CrossRefPubMed
Ciardiello F, Normanno N, Maiello E, Martinelli E, Troiani T, Pisconti S, Giuliani F, Barone C, Carteni G, Rachiglio AM, et al. Clinical activity of FOLFIRI plus cetuximab according to extended gene mutation status by next-generation sequencing: findings from the CAPRI-GOIM trial. Annals of oncology: official journal of the European Society for Med Oncol. 2014;25(9):1756–61. CrossRef
Khan SA, Zeng Z, Shia J, Paty PB: EGFR gene amplification and KRAS mutation predict response to combination targeted therapy in metastatic colorectal cancer. Pathology oncology research: POR 2016.
Kasper S, Meiler J, Knipp H, Höhler T, Reimer P, Steinmetz HT, Berger W, Linden G, Ting S, Markus P et al: Cetuximab biweekly (q2w) plus mFOLFOX6 as 1st line therapy in patients (pts) with KRAS wild-type (wt) (exon 2) metastatic colorectal cancer. Annals of Oncology (2016) 27 (6): 149–206 101093/annonc/mdw370.
Sclafani F, Gonzalez D, Cunningham D, Hulkki Wilson S, Peckitt C, Tabernero J, Glimelius B, Cervantes A, Dewdney A, Wotherspoon A, et al. TP53 mutational status and cetuximab benefit in rectal cancer: 5-year results of the EXPERT-C trial. J Natl Cancer Inst. 2014;106(7)
Folprecht G, Beer P, Salazar R, Roth A, Aust D, Salgado R, Laurent-Puig P, Tabernero J, Arnold D, Stein A et al: Frequency of potentially actionable genetic alterations in EORTC SPECTAcolor. Annals of Oncology (2016) 27 (6): 149–206 doi: 10.1093/annonc/mdw370.
- Sidedness and TP53 mutations impact OS in anti-EGFR but not anti-VEGF treated mCRC - an analysis of the KRAS registry of the AGMT (Arbeitsgemeinschaft Medikamentöse Tumortherapie)
- BioMed Central
Neu im Fachgebiet Onkologie
e.Med Kampagnen-Visual, Mail Icon II