Resectability and resection rates of colorectal liver metastases according to RAS and BRAF mutational status: prospective study.
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ABSTRACT:
SUBMITTER: Uutela A
PROVIDER: S-EPMC10361677 | biostudies-literature | 2023 Jul
REPOSITORIES: biostudies-literature
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Resectability and resection rates of colorectal liver metastases according to RAS and BRAF mutational status: prospective study.
Uutela Aki A Nordin Arno A Osterlund Emerik E Halonen Päivi P Kallio Raija R Soveri Leena-Maija LM Salminen Tapio T Ålgars Annika A Ristimäki Ari A Ovissi Ali A Lamminmäki Annamarja A Muhonen Timo T Kononen Juha J Ristamäki Raija R Heervä Eetu E Stedt Hanna H Lehtomäki Kaisa K Kytölä Soili S Sundström Jari J Mäkinen Markus J MJ Nieminen Lasse L Kuopio Teijo T Keinänen Mauri M Osterlund Pia P Isoniemi Helena H
The British journal of surgery 20230701 8
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Project description:BackgroundOutcomes after metastasectomy for metastatic colorectal cancer (mCRC) vary with RAS and BRAF mutational status, but their effects on resectability and conversion rates have not been extensively studied.MethodsThis substudy of the prospective RAXO trial included 906 patients recruited between 2011 and 2018. We evaluated repeated centralised resectability assessment, conversion/resection rates and overall survival (OS), according to RAS and BRAF status.ResultsPatients included 289 with RAS and BRAF wild-type (RAS and BRAFwt), 529 with RAS mutated (RASmt) and 88 with BRAF mutated (BRAFmt) mCRC. Metastatic prevalence varied between the RAS and BRAFwt/RASmt/BRAFmt groups, for liver (78%/74%/61%), lung (24%/35%/28%) and peritoneal (15%/15%/32%) metastases, respectively. Upfront resectability (32%/29%/15%), conversion (16%/13%/7%) and resection/local ablative therapy (LAT) rates (45%/37%/17%) varied for RASa and BRAFwt/RASmt/BRAFmt, respectively. Median OS for patients treated with resection/LAT (n = 342) was 83/69/30 months, with 5-year OS-rates of 67%/60%/24%, while systemic therapy-only patients (n = 564) had OS of 29/21/15 months with 5-year OS-rates of 11%/6%/2% in RAS and BRAFwt/RASmt/BRAFmt, respectively. Resection/LAT was associated with improved OS in all subgroups.ConclusionsThere were significant differences in resectability, conversion and resection/LAT rates according to RAS and BRAF status. OS was also significantly longer for RAS and BRAFwt versus either mutant. Patients only receiving systemic therapy had poorer long-term survival, with variation according to molecular status.Clinical trial registrationNCT01531621/EudraCT2011-003158-24.
| S-EPMC9381729 | biostudies-literature
Project description:Despite reports on poor survival outcomes after hepatectomy for colorectal liver metastases (CRLM) with BRAF V600E mutation (mBRAF) exist, the role of mBRAF testing for technically resectable cases remains unclear. A single-center retrospective study was performed to investigate the survival outcomes of patients who underwent upfront hepatectomy for solitary resectable CRLM with mBRAF between January 2005 and December 2017 and to compare them with those of unresectable cases with mBRAF. Of 172 patients who underwent initial hepatectomy for solitary resectable CRLM, mBRAF, RAS mutations (mRAS), and wild-type RAS/BRAF (wtRAS/BRAF) were observed in 5 (2.9%), 73 (42.4%), and 93 (54.7%) patients, respectively. With a median follow-up period of 72.8 months, mBRAF was associated with a significantly shorter OS (median, 14.4 months) than wtRAS/BRAF (median, not reached [NR]) (hazard ratio [HR], 27.6; p < 0.001) and mRAS (median, NR) (HR, 9.9; p < 0.001), and mBRAF had the highest HR among all the indicators in the multivariable analysis (HR, 17.0; p < 0.001). The median OS after upfront hepatectomy for CRLM with mBRAF was identical to that of 28 unresectable CRLM with mBRAF that were treated with systemic chemotherapy (median, 17.2 months) (HR, 0.78; p = 0.65). When technically resectable CRLM are complicated with mBRAF, its survival outcome becomes as poor as unresectable cases; therefore, those with mBRAF should be considered as oncologically unresectable. Patients with CRLM should undergo pre-treatment mBRAF testing regardless of technical resectability. Clinical trial registration number: UMIN000034557.
| S-EPMC8525127 | biostudies-literature
Project description:BackgroundTumor assessments after first-line therapy of RAS wild-type mCRC with cetuximab (cet) versus bevacizumab (bev) in combination with FOLFIRI were evaluated for factors influencing resectability, conversion to resectability, and survival after best response.MethodsConversion to resectability was defined as conversion of initially unresectable to resectable disease at best response as determined by retrospective assessment. Univariate and multivariate logistic models were fitted with resectability at best response as response variable. A Cox model comparing the survival from best response was used to measure the influence of treatment, resectability at best response, and resection. Interaction of resection and treatment arm on survival was tested by likelihood ratio test.ResultsOverall, 270 patients were evaluable (127 cet-arm, 143 bev-arm). Lung metastases (odds ratio [OR] 0.35, 95% confidence response [CI] 0.19-0.63), BRAF mutation (OR 0.33, 95% CI 0.12-0.82), and elevated alkaline phosphatase (OR 0.42, 95% CI 0.18-0.9) before randomization were associated with less chance of successful conversion and were integrated into a nomogram. Early tumor shrinkage (OR 1.86, 95% CI 1.06-3.3; p 0.034) and depth of response (OR 1.02, 95% CI 1.01-1.03; p < 0.001) were associated with successful conversion therapy. Resection of metastases improved post-best-response survival (hazard ratio 0.53, 95% CI 0.29-0.97; p = 0.039), predominantely in cet-treated patients (interaction test, p = 0.02).ConclusionsConversion to resectability is significantly associated with baseline characteristics that can be used in a nomogram to predict conversion. Moreover, early efficacy parameters (ETS and DpR) are associated with successful conversion therapy. In FIRE-3, resection of metastases was associated with improved post-best response survival, this effect originated predominantly from the cetuximab-based study arm.
| S-EPMC7311511 | biostudies-literature
Project description:We determined prognostic impact of KRAS, BRAF, PIK3CA and TP53 mutation status and mutation heterogeneity among 164 colorectal cancer (CRC) patients undergoing liver resections for metastatic disease. Mutation status was determined by Sanger sequencing of a total of 422 metastatic deposits. In univariate analysis, KRAS (33.5%), BRAF (6.1%) and PIK3CA (13.4%) mutations each predicted reduced median time to relapse (TTR) (7 vs. 22, 3 vs. 16 and 4 vs. 17 months; p < 0.001, 0.002 and 0.023, respectively). KRAS and BRAF mutations also predicted a reduced median disease-specific survival (DSS) (29 vs. 51 and 16 vs. 49 months; p <0.001 and 0.008, respectively). No effect of TP53 (60.4%) mutation status was observed. Postoperative, but not preoperative chemotherapy improved both TTR and DSS (p < 0.001 for both) with no interaction with gene mutation status. Among 94 patients harboring two or more metastatic deposits, 13 revealed mutation heterogeneity across metastatic deposits for at least one gene. Mutation heterogeneity predicted reduced median DSS compared to homogeneous mutations (18 vs. 37 months; p = 0.011 for all genes; 16 vs. 26 months; p < 0.001 analyzing BRAF or KRAS mutations separately). In multivariate analyses, KRAS or BRAF mutations consistently predicted poor TRR and DSS. Mutation heterogeneity robustly predicted DSS but not TTR, while postoperative chemotherapy improved both TTR and DSS. Our findings indicate that BRAF and KRAS mutations as well as mutation heterogeneity predict poor outcome in CRC patients subsequent to liver resections and might help guide treatment decisions.
| S-EPMC5071774 | biostudies-literature
Project description:BackgroundThe optimal surveillance strategy after resection of colorectal liver metastases (CLM) is unknown. We evaluated changes in recurrence risk after CLM resection and developed a surveillance algorithm.MethodsPatients undergoing CLM resection during 1998 to 2015 were identified from a prospectively compiled database and analyzed if they had the potential for follow-up longer than the longest observed time to recurrence in this cohort. Changes in recurrence risk and risk factors for recurrence were evaluated. All statistical tests were 2-sided.ResultsAmong 2,105 patients who were initially identified and underwent CLM resection, the latest recurrence was observed at 87 months; 1,221 consecutive patients from 1998 through 2011 with the potential for at least 87 months of follow-up were included. The risk of recurrence was highest at 0 to 2 years after CLM resection, lower at 2 to 4 years after CLM resection, and steadily lower after 4 years after CLM resection. Factors associated with increased recurrence risk at the time of surgery were primary lymph node metastasis (hazard ratio [HR], 1.54; 95% CI, 1.21-1.97; P<.001), multiple CLM (HR, 1.31; 95% CI, 1.06-1.63; P=.015), largest liver metastasis diameter >5 cm (HR, 1.64; 95% CI, 1.23-2.19; P<.001), and RAS mutation (HR, 1.29; 95% CI, 1.04-1.59; P=.020). In patients without recurrence at 2 years, the only factor still associated with increased recurrence risk was RAS mutation. In those patients, the recurrence rate at 4 years was 59.3% in patients with RAS mutation versus 27.8% in patients with RAS wild-type (P=.019).ConclusionsFor patients who have undergone CLM resection, we propose surveillance every 3 to 4 months during years 0 to 2, every 3 to 4 months (if mutant RAS) versus every 4 to 6 months (if RAS wild-type) during years 2 to 4, and every 6 to 12 months if recurrence-free at 4 years.
| S-EPMC10547101 | biostudies-literature
Project description:ImportanceAspirin use reduces the risk of colorectal carcinoma. Experimental evidence implicates a role of RAF kinases in up-regulation of prostaglandin-endoperoxide synthase 2 (PTGS2, cyclooxygenase 2), suggesting that BRAF-mutant colonic cells might be less sensitive to the antitumor effects of aspirin than BRAF-wild-type neoplastic cells.ObjectiveTo examine whether the association of aspirin intake with colorectal cancer risk differs according to status of tumor BRAF oncogene mutation.Design and settingWe collected biennial questionnaire data on aspirin use and followed up participants in the Nurses' Health Study (from 1980) and the Health Professionals Follow-up Study (from 1986) until July 1, 2006, for cancer incidence and until January 1, 2012, for cancer mortality. Duplication-method Cox proportional cause-specific hazards regression for competing risks data was used to compute hazard ratios (HRs) for colorectal carcinoma incidence according to BRAF mutation status.Main outcomes and measuresIncidence of colorectal cancer cases according to tumor BRAF mutation status.ResultsAmong 127,865 individuals, with 3,165,985 person-years of follow-up, we identified 1226 incident rectal and colon cancers with available molecular data. Compared with nonuse, regular aspirin use was associated with lower BRAF-wild-type cancer risk (multivariable HR, 0.73; 95% CI, 0.64 to 0.83; age-adjusted incidence rate difference [RD], -9.7; 95% CI, -12.6 to -6.7 per 100,000 person-years). This association was observed irrespective of status of tumor PTGS2 expression or PIK3CA or KRAS mutation. In contrast, regular aspirin use was not associated with a lower risk of BRAF-mutated cancer (multivariable HR, 1.03; 95% CI, 0.76 to 1.38; age-adjusted, incidence RD, 0.7; 95% CI, -0.3 to 1.7 per 100,000 person-years: P for heterogeneity = .037, between BRAF-wild-type vs BRAF-mutated cancer risks). Compared with no aspirin use, aspirin use of more than 14 tablets per week was associated with a lower risk of BRAF-wild-type cancer (multivariable HR, 0.43; 95% CI, 0.25 to 0.75; age-adjusted incidence RD, -19.8; 95% CI, -26.3 to -13.3 per 100,000 person-years). The relationship between the number of aspirin tablets per week and colorectal cancer risk differed significantly by BRAF mutation status (P for heterogeneity = .005).Conclusions and relevanceRegular aspirin use was associated with lower risk of BRAF-wild-type colorectal cancer but not with BRAF-mutated cancer risk. These findings suggest that BRAF-mutant colon tumor cells may be less sensitive to the effect of aspirin. Given the modest absolute risk difference, further investigations are necessary to determine clinical implications of our findings.
| S-EPMC3743040 | biostudies-literature
Project description:BackgroundIn metastatic colorectal cancer (mCRC), BRAFV600E mutation has been variously associated to specific clinico-pathological features.MethodsTwo 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.ResultsIn 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.ConclusionsThree simple and easy-to-collect characteristics define a useful nomogram for predicting BRAF status in mCRC with high specificity and sensitivity.
| S-EPMC4716533 | biostudies-literature
Project description:PurposeSomatic gene mutations have been increasingly recognized to impact prognosis following resection of colorectal liver metastases (CLM). We aimed to determine the impact of combinations of somatic mutations on survival in patients undergoing CLM resection.Experimental designWe identified patients who underwent initial CLM resection during 2007-2017 and had genetic sequencing data available. Risk factors for overall survival (OS) and recurrence-free survival (RFS) were determined using Cox proportional hazards models.ResultsOf 1460 patients who underwent CLM resection during the study period, 507 met the inclusion criteria. Multigene testing revealed mutation rates greater than 10% for TP53 (mutated in 70.8% of patients), APC (53.5%), RAS (50.7%), PIK3CA (15.8%), and SMAD4 (11.0%). BRAF was mutated in 2.0% of patients. BRAF, RAS, TP53, and SMAD4 mutations were significantly associated with OS, and RAS, TP53, and SMAD4 mutations were significantly associated with RFS. Coexisting mutations in RAS, TP53, and SMAD4 were associated with significantly worse OS and RFS than coexisting mutations in any 2 of these genes and mutations in 1 or none of these genes. Coexisting mutations in 2 genes conferred significantly worse OS and RFS than single mutation or no mutations. OS and RFS did not differ significantly between patients with RAS mutation and wild-type TP53 and SMAD4 and patients with wild-type RAS (P = 0.858 and 0.729, respectively).ConclusionsRAS mutation status alone is not sufficient for precisely predicting prognosis after CLM resection.
| S-EPMC6774854 | biostudies-literature
Project description:BackgroundDespite major advances in the management of metastatic colorectal cancer (mCRC) with liver-only involvement, relapse rates are high and reliable prognostic markers are needed.MethodsTo assess the prognostic impact of BRAF and RAS mutations in a large series of liver-resected patients, medical records of 3024 mCRC patients were reviewed. Eligible cases undergoing potentially curative liver resection were selected. BRAF and RAS mutational status was tested on primary and/or metastases by means of pyrosequencing and mass spectrometry genotyping assay. Primary endpoint was relapse-free survival (RFS).ResultsIn the final study population (N=309) BRAF mutant, RAS mutant and all wild-type (wt) patients were 12(4%), 160(52%) and 137(44%), respectively. Median RFS was 5.7, 11.0 and 14.4 months respectively and differed significantly (Log-rank, P=0.043). At multivariate analyses, BRAF mutant had a higher risk of relapse in comparison to all wt (multivariate hazard ratio (HR)=2.31; 95% CI, 1.09-4.87; P=0.029) and to RAS mutant (multivariate HR=2.06; 95% CI, 1.02-4.14; P=0.044). Similar results were obtained in terms of overall survival. Compared with all wt patients, RAS mutant showed a higher risk of death (HR=1.47; 95% CI, 1.05-2.07; P=0.025), but such effect was lost at multivariate analyses.ConclusionsBRAF mutation is associated with an extremely poor median RFS after liver resection and with higher probability of relapse and death. Knowledge of BRAF mutational status may optimise clinical decision making in mCRC patients potentially candidate to hepatic surgery. RAS status as useful marker in this setting might require further studies.
| S-EPMC4580391 | biostudies-literature
Project description:Objective:RAS gene testing on tumor tissue biopsies is required for metastatic colorectal cancer (CRC) patients. However, it is infeasible for patients after curative surgery and repeated biopsy. This study is aimed at evaluating the consistency of RAS genes in patient's plasma, stool, and tumor tissue samples, to explore whether plasma and stool samples can supplement or replace tumor tissue to assess baseline RAS gene status. Methods:Between June 2016 and October 2017, 53 patients with stage I-IV CRC from the Liaoning Cancer Hospital and the Department of Medical Oncology of the First Hospital of China Medical University were enrolled in the study. Patient tissues, peripheral blood, and stool samples were collected, and RAS gene tests were performed. Results:Analysis of the KRAS gene in tissue, plasma, and stool samples from 53 CRC patients detected 25 cases (47%) of KRAS gene mutations in the tissue samples, 20 cases (38%) of KRAS gene mutations in plasma, and 18 (34%) KRAS gene mutations in fecal samples. The overall consistency of KRAS gene status between tissue samples and plasma samples was 77.4% (p ? 0.05) and between tissue samples and stool samples was 83% (p ? 0.05). In stage IV cases, the agreement of KRAS gene status between tissue and plasma samples was 93.8% (p ? 0.05) and 93.8% (p ? 0.05) between tissue and stool samples. Conclusion:There was a high overall consistency in KRAS mutational assessment between plasma, stool, and tissue samples. In stage IV patients, the consistency of KRAS gene detection between tissue and stools or plasma was higher.
| S-EPMC7174943 | biostudies-literature