Prognostic value of specific KRAS mutations in patients with colorectal peritoneal metastases

M Tonello; D Baratti; P Sammartino; A Di Giorgio; M Robella; C Sassaroli; M Framarini; M Valle; A Macrì; L Graziosi; F Coccolini; P V Lippolis; R Gelmini; M Deraco; D Biacchi; M Aulicino; M Vaira; S De Franciscis; F D'Acapito; F Carboni; E Milone; A Donini; P Fugazzola; P Faviana; L Sorrentino; E Pizzolato; C Cenzi; P Del Bianco; A Sommariva

doi:10.1016/j.esmoop.2024.102976

Prognostic value of specific KRAS mutations in patients with colorectal peritoneal metastases

ESMO Open. 2024 Apr;9(4):102976. doi: 10.1016/j.esmoop.2024.102976. Epub 2024 Apr 12.

Authors

M Tonello¹, D Baratti², P Sammartino³, A Di Giorgio⁴, M Robella⁵, C Sassaroli⁶, M Framarini⁷, M Valle⁸, A Macrì⁹, L Graziosi¹⁰, F Coccolini¹¹, P V Lippolis¹², R Gelmini¹³, M Deraco², D Biacchi³, M Aulicino⁴, M Vaira⁵, S De Franciscis¹⁴, F D'Acapito⁷, F Carboni⁸, E Milone⁹, A Donini¹⁰, P Fugazzola¹⁵, P Faviana¹⁶, L Sorrentino¹³, E Pizzolato¹, C Cenzi¹⁷, P Del Bianco¹⁷, A Sommariva¹⁸

Affiliations

¹ Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, Padua.
² Peritoneal Surface Malignancy Unit, Department of Surgery, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan.
³ Cytoreductive Surgery and HIPEC Unit, Department of Surgery 'Pietro Valdoni', Sapienza University of Rome, Rome.
⁴ Surgical Unit of Peritoneum and Retroperitoneum, Fondazione Policlinico Universitario A. Gemelli, Rome.
⁵ Surgical Oncology Unit, Candiolo Cancer Institute, FPO-IRCCS, Candiolo, Turin.
⁶ Integrated Medical Surgical Research in Peritoneal Surface Malignancy, Abdominal Oncology Department, Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione Pascale IRCCS, Naples.
⁷ General and Oncologic Department of Surgery, Morgagni-Pierantoni Hospital, AUSL Romagna, Forlì.
⁸ Peritoneal Tumours Unit, IRCCS, Regina Elena Cancer Institute, Rome.
⁹ Peritoneal and Retroperitonel Surgical Unit-University Hospital 'G. Martino' Messina.
¹⁰ General and Emergency Surgery Department, University of Perugia, Santa Maria Della Misericordia Hospital, Perugia.
¹¹ General Emergency and Trauma Surgery, Bufalini Hospital, Cesena; General Emergency and Trauma Surgery, Pisa University Hospital, Pisa.
¹² General and Peritoneal Surgery, Department of Surgery, Hospital University Pisa (AOUP), Pisa.
¹³ General and Oncological Surgery Unit, AOU of Modena University of Modena and Reggio Emilia.
¹⁴ Colorectal Surgical Oncology, Abdominal Oncology Department, Istituto Nazionale per lo Studio e la Cura dei Tumori Fondazione Pascale IRCCS, Naples.
¹⁵ General surgery, Fondazione IRCCS Policlinico San Matteo, Pavia.
¹⁶ Department of Surgical, Medical, Molecular Pathology and Critical Area, University of Pisa, Pisa.
¹⁷ Clinical Research Unit, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy.
¹⁸ Unit of Surgical Oncology of the Esophagus and Digestive Tract, Veneto Institute of Oncology IOV-IRCCS, Padua. Electronic address: antonio.sommariva@iov.veneto.it.

Abstract

Background: There is little evidence on KRAS mutational profiles in colorectal cancer (CRC) peritoneal metastases (PM). This study aims to determine the prevalence of specific KRAS mutations and their prognostic value in a homogeneous cohort of patients with isolated CRC PM treated with cytoreductive surgery and hyperthermic intraperitoneal chemotherapy.

Materials and methods: Data were collected from 13 Italian centers, gathered in a collaborative group of the Italian Society of Surgical Oncology. KRAS mutation subtypes have been correlated with clinical and pathological characteristics and survival [overall survival (OS), local (peritoneal) disease-free survival (LDFS) and disease-free survival (DFS)].

Results: KRAS mutations occurred in 172 patients (47.5%) out of the 362 analyzed. Two different prognostic groups of KRAS mutation subtypes were identified: KRAS^MUT1 (G12R, G13A, G13C, G13V, Q61H, K117N, A146V), median OS > 120 months and KRAS^MUT2 (G12A, G12C, G12D, G12S, G12V, G13D, A59E, A59V, A146T), OS: 31.2 months. KRAS^MUT2 mutations mainly occurred in the P-loop region (P < 0.001) with decreased guanosine triphosphate (GTP) hydrolysis activity (P < 0.001) and were more frequently related to size (P < 0.001) and polarity change (P < 0.001) of the substituted amino acid (AA). When KRAS^MUT1 and KRAS^MUT2 were combined with other known prognostic factors (peritoneal cancer index, completeness of cytoreduction score, grading, signet ring cell, N status) in multivariate analysis, KRAS^MUT1 showed a similar survival rate to KRAS^WT patients, whereas KRAS^MUT2 was independently associated with poorer prognosis (hazard ratios: OS 2.1, P < 0.001; DFS 1.9, P < 0.001; LDFS 2.5, P < 0.0001).

Conclusions: In patients with CRC PM, different KRAS mutation subgroups can be determined according to specific codon substitution, with some mutations (KRAS^MUT1) that could have a similar prognosis to wild-type patients. These findings should be further investigated in larger series.

Keywords: HIPEC; KRAS; colorectal cancer (CRC); cytoreductive surgery (CRS); peritoneal metastases (PM).

Publication types

Multicenter Study

MeSH terms

Adult
Aged
Aged, 80 and over
Colorectal Neoplasms* / genetics
Colorectal Neoplasms* / mortality
Colorectal Neoplasms* / pathology
Cytoreduction Surgical Procedures
Disease-Free Survival
Female
Humans
Hyperthermic Intraperitoneal Chemotherapy
Male
Middle Aged
Mutation*
Peritoneal Neoplasms* / genetics
Peritoneal Neoplasms* / secondary
Prognosis
Proto-Oncogene Proteins p21(ras)* / genetics
Retrospective Studies

Substances

Proto-Oncogene Proteins p21(ras)
KRAS protein, human