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

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

M Tonello  1 , D Baratti  2 , P Sammartino  3 , A Di Giorgio  4 , M Robella  5 , C Sassaroli  6 , M Framarini  7 , M Valle  8 , A Macrì  9 , L Graziosi  10 , F Coccolini  11 , P V Lippolis  12 , R Gelmini  13 , M Deraco  2 , D Biacchi  3 , M Aulicino  4 , M Vaira  5 , S De Franciscis  14 , F D'Acapito  7 , F Carboni  8 , E Milone  9 , A Donini  10 , P Fugazzola  15 , P Faviana  16 , L Sorrentino  13 , E Pizzolato  1 , C Cenzi  17 , P Del Bianco  17 , A Sommariva  18
Affiliations
Multicenter Study

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

M Tonello et al. ESMO Open. 2024 Apr.

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: KRASMUT1 (G12R, G13A, G13C, G13V, Q61H, K117N, A146V), median OS > 120 months and KRASMUT2 (G12A, G12C, G12D, G12S, G12V, G13D, A59E, A59V, A146T), OS: 31.2 months. KRASMUT2 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 KRASMUT1 and KRASMUT2 were combined with other known prognostic factors (peritoneal cancer index, completeness of cytoreduction score, grading, signet ring cell, N status) in multivariate analysis, KRASMUT1 showed a similar survival rate to KRASWT patients, whereas KRASMUT2 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 (KRASMUT1) 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).

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Figures

Figure 1
Figure 1
Frequency of KRAS mutations and survival analysis according to KRAS class. (A) Frequency of KRAS-specific mutations and classification, with mutated protein domain. (B) OS. (C) DFS. (D) LDFS. DFS, disease-free survival; LDFS, local (peritoneal) disease-free survival; OS, overall survival.
Figure 2
Figure 2
Amino acid characteristics and relation with KRASMUTclass. (A) Summary of protein function, site of mutation and amino acid characteristics (polarity, size). (B) Analysis of relation with KRASMUT class. GTP, guanosine triphosphate.
See this image and copyright information in PMC

References

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