Fotios Loupakis^1,7, Roberto Moretto^1,7, Giuseppe Aprile², Marta Muntoni¹, Chiara Cremolini¹, Donatella Iacono², Mariaelena Casagrande², Laura Ferrari², Lisa Salvatore¹, Marta Schirripa¹, Daniele Rossini¹, Giovanna De Maglio³, Gianpiero Fasola², Lorenzo Calvetti⁴, Sara Pilotto⁴, Luisa Carbognin⁴, Gabriella Fontanini⁵, Giampaolo Tortora⁴, Alfredo Falcone¹, Isabella Sperduti⁶ and Emilio Bria⁴

¹Oncologia Medica 2 Universitaria, Dipartimento di Ricerca Traslazionale e delle Nuove Tecnologie in Medicina e Chirurgia, Azienda Ospedaliero-Universitaria Pisana, Via Roma 67, 56126 Pisa, Italy
²Dipartimento di Oncologia, Azienda Ospedaliero-Universitaria ‘Santa Maria della Misericordia’, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy
³Dipartimento di Medicina di Laboratorio, Azienda Ospedaliero-Universitaria ‘Santa Maria della Misericordia’, Piazzale Santa Maria della Misericordia 15, 33100 Udine, Italy
⁴Dipartimento di Medicina, Oncologia Medica, University of Verona, Azienda Ospedaliera Universitaria Integrata, Piazzale Aristide Stefani 1, 37126 Verona, Italy
⁵Divisione di Patologia, Dipartimento di Chirurgia, University of Pisa, Via Roma 67, 56126 Pisa, Italy
⁶Direzione Scientifica, Biostatistics, Regina Elena National Cancer Institute, Via Elio Chianesi 53, 00144 Rome, Italy

Abstract:

background:
In metastatic colorectal cancer (mCRC), BRAFV600E mutation has been variously associated to specific clinico-pathological features.

methods:
Two large retrospective series of mCRC patients from two Italian Institutions were used as training-set (TS) and validation-set (VS) for developing a nomogram predictive of BRAFV600E status. The model was internally and externally validated.

results:
In the TS, data from 596 mCRC patients were gathered (RAS wild-type (wt) 281 (47.1%); BRAFV600E mutated 54 (9.1%)); RAS and BRAFV600E mutations were mutually exclusive. In the RAS-wt population, right-sided primary (odds ratio (OR): 7.80, 95% confidence interval (CI) 3.05–19.92), female gender (OR: 2.90, 95% CI 1.14–7.37) and mucinous histology (OR: 4.95, 95% CI 1.90–12.90) were independent predictors of BRAFV600E mutation, with high replication at internal validation (100%, 93% and 98%, respectively). A predictive nomogram was calculated: patients with the highest score (right-sided primary, female and mucinous) had a 81% chance to bear a BRAFV600E-mutant tumour; accuracy measures: AUC=0.812, SE:0.034, sensitivity:81.2%; specificity:72.1%. In the VS (508 pts, RAS wt: 262 (51.6%), BRAFV600E mutated: 49 (9.6%)), right-sided primary, female gender and mucinous histology were confirmed as independent predictors of BRAFV600E mutation with high accuracy.

conclusions:
Three simple and easy-to-collect characteristics define a useful nomogram for predicting BRAF status in mCRC with high specificity and sensitivity.

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