Effect of RAS gene mutation on survival after liver metastasis resection for patients with colorectal cancer combined with liver metastasis: integrated analysis_CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Authors：

YUE Yumin ¹ , CHEN Xi ² , WANG Hui ³ , CAI Xiangren ³ ,  ZHENG Bobo ¹

1. The First Department of General Surgery, Shaanxi Provincial People’s Hospital, Xi’an 710068, P. R. China;
2. Yan’an University, Yan’an, Shaanxi 716000, P. R. China;
3. Xi’an Medical College, Xi’an 710021, P. R. China;

Corresponding author：

ZHENG Bobo, Email: zhengbo816@126.com

Keywords：

colorectal cancer; liver metastasis; RAS gene; mutation; survival; integrated analysis

DOI：

10.7507/1007-9424.202206031

Video：

Export PDF Favorites Scan Get Citation

Abstract Full text Figures/Tables Video References Cited by

Objective To evaluate effect of RAS gene mutation after liver metastasis resection on overall survival (OS) and disease-free survival (DFS) for patients with colorectal cancer combined with liver metastasis. Methods A comprehensive and systematic literature search in the PubMed and other databases was conducted, with the final search ending on January 5, 2022. The impact of RAS gene mutation after liver metastasis resection on survival of patients with colorectal cancer combined with liver metastasis was analyzed by the Stata 12.0 software and Review Manager version 5.3 software, meanwhile which were analyzed according to subgroups, including study type (retrospective and prospective studies), region (Asian and European), and number of RAS gene mutation sites (>2 and ≤2). Results A total of 26 studies with 13 356 patients were included. The integrated analysis results showed that the patients with RAS mutations had statistically shorter OS [HR=1.54, 95%CI (1.43, 1.65), P<0.001] and DFS [HR=1.32, 95%CI (1.19, 1.44), P<0.001] as compared with RAS wild-type. Except the 1-year overall survival rate, the 2–5-year overall survival rate and 1–5-year disease-free survival rate of patients with RAS gene mutation were statistically lower than those of patients with RAS wild-type (P<0.05). The results of subgroup analysis showed that no matter retrospective and prospective studies, as well as studies in Asian and European countries, it was found that the OS and DFS for patients with RAS gene mutation were shorter than those of patients with wild-type (P<0.05); At the same time, subgroup analysis of the number of RAS gene mutation sites showed that OS and DFS of patients with number of mutation sites >2 were shortened as compared with ≤2 (P<0.05). Conclusion From the overall analysis results, the survival of patients with RAS gene mutation after liver metastasis resection is worse than that of patients with RAS wild-type for patients with colorectal cancer combined with liver metastasis.

Citation： YUE Yumin, CHEN Xi, WANG Hui, CAI Xiangren, ZHENG Bobo. Effect of RAS gene mutation on survival after liver metastasis resection for patients with colorectal cancer combined with liver metastasis: integrated analysis. CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY, 2022, 29(12): 1583-1590. doi: 10.7507/1007-9424.202206031 Copy

1.	Lu B, Li N, Luo CY, et al. Colorectal cancer incidence and mortality: the current status, temporal trends and their attributable risk factors in 60 countries in 2000–2019. Chin Med J (Engl), 2021, 134(16): 1941-1951.
2.	Karagkounis G, Torbenson MS, Daniel HD, et al. Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases. Cancer, 2013, 119(23): 4137-4144.
3.	Pikoulis E, Papaconstantinou D, Pikouli A, et al. Reevaluating the prognostic value of RAS mutation status in patients with resected liver metastases from colorectal cancer: a systematic review and meta-analysis. J Hepatobiliary Pancreat Sci, 2021, 28(8): 637-647.
4.	Sakai N, Furukawa K, Takayashiki T, et al. Differential effects of KRAS mutational status on long-term survival according to the timing of colorectal liver metastases. BMC Cancer, 2021, 21(1): 412. doi: 10.1186/s12885-021-08144-5.
5.	Margonis GA, Sasaki K, Gholami S, et al. Genetic and Morphological Evaluation (GAME) score for patients with colorectal liver metastases. Br J Surg, 2018, 105(9): 1210-1220.
6.	Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed on April 10, 2017.
7.	王丹, 翟俊霞, 牟振云, 等. Meta分析中的异质性及其处理方法. 中国循证医学杂志, 2009, 9(10): 1115-1118.
8.	Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ, 2003, 327(7414): 557-560.
9.	Gholami S, Kemeny NE, Boucher TM, et al. Adjuvant hepatic artery infusion chemotherapy is associated with improved survival regardless of KRAS mutation status in patients with resected colorectal liver metastases: a retrospective analysis of 674 patients. Ann Surg, 2020, 272(2): 352-356.
10.	Margonis GA, Buettner S, Andreatos N, et al. Association of BRAF mutations with survival and recurrence in surgically treated patients with metastatic colorectal liver cancer. JAMA Surg, 2018, 153(7): e180996. doi: 10.1001/jamasurg.2018.0996.
11.	Wang K, Xu D, Yan XL, et al. The impact of primary tumour location in patients undergoing hepatic resection for colorectal liver metastasis. Eur J Surg Oncol, 2018, 44(6): 771-777.
12.	Yamashita S, Brudvik KW, Kopetz SE, et al. Embryonic origin of primary colon cancer predicts pathologic response and survival in patients undergoing resection for colon cancer liver metastases. Ann Surg, 2018, 267(3): 514-520.
13.	Shindoh J, Nishioka Y, Yoshioka R, et al. KRAS mutation status predicts site-specific recurrence and survival after resection of colorectal liver metastases irrespective of location of the primary lesion. Ann Surg Oncol, 2016, 23(6): 1890-1896.
14.	Shoji H, Yamada Y, Taniguchi H, et al. Clinical impact of c-MET expression and genetic mutational status in colorectal cancer patients after liver resection. Cancer Sci, 2014, 105(8): 1002-1007.
15.	Isella C, Mellano A, Galimi F, et al. MACC1 mRNA levels predict cancer recurrence after resection of colorectal cancer liver metastases. Ann Surg, 2013, 257(6): 1089-1095.
16.	Umeda Y, Nagasaka T, Mori Y, et al. Poor prognosis of KRAS or BRAF mutant colorectal liver metastasis without microsatellite instability. J Hepatobiliary Pancreat Sci, 2013, 20(2): 223-233.
17.	Stremitzer S, Stift J, Gruenberger B, et al. KRAS status and outcome of liver resection after neoadjuvant chemotherapy including bevacizumab. Br J Surg, 2012, 99(11): 1575-1582.
18.	Petrowsky H, Sturm I, Graubitz O, et al. Relevance of Ki-67 antigen expression and K-ras mutation in colorectal liver metastases. Eur J Surg Oncol, 2001, 27(1): 80-87.
19.	Tsilimigras DI, Hyer JM, Bagante F, et al. Resection of colorectal liver metastasis: prognostic impact of tumor burden vs KRAS mutational status. J Am Coll Surg, 2021, 232(4): 590-598.
20.	Baldin P, Van den Eynde M, Mlecnik B, et al. Prognostic assessment of resected colorectal liver metastases integrating pathological features, RAS mutation and Immunoscore. J Pathol Clin Res, 2021, 7(1): 27-41.
21.	Hatta AAZ, Pathanki AM, Hodson J, et al. The effects of resection margin and KRAS status on outcomes after resection of colorectal liver metastases. HPB (Oxford), 2021, 23(1): 90-98.
22.	Zhang Q, Peng J, Ye M, et al. KRAS mutation predicted more mirometastases and closer resection margins in patients with colorectal cancer liver metastases. Ann Surg Oncol, 2020, 27(4): 1164-1173.
23.	Dolatkhah R, Dastgiri S, Eftekhar Sadat AT, et al. Impact of RAS/RAF mutations on clinical and prognostic outcomes in metastatic colorectal cancer. Bioimpacts, 2021, 11(1): 5-14.
24.	Kim HS, Lee JM, Kim HS, et al. Prognosis of synchronous colorectal liver metastases after simultaneous curative-intent surgery according to primary tumor location and KRAS mutational status. Ann Surg Oncol, 2020, 27(13): 5150-5158.
25.	Moro A, Mehta R, Tsilimigras DI, et al. Prognostic factors differ according to KRAS mutational status: a classification and regression tree model to define prognostic groups after hepatectomy for colorectal liver metastasis. Surgery, 2020, 168(3): 497-503.
26.	Kawaguchi Y, Kopetz S, Lillemoe HA, et al. A new surveillance algorithm after resection of colorectal liver metastases based on changes in recurrence risk and RAS mutation status. J Natl Compr Canc Netw, 2020, 18(11): 1500-1508.
27.	Jácome AA, Vreeland TJ, Johnson B, et al. The prognostic impact of RAS on overall survival following liver resection in early versus late-onset colorectal cancer patients. Br J Cancer, 2021, 124(4): 797-804.
28.	Kawaguchi Y, Kopetz S, Tran Cao HS, et al. Contour prognostic model for predicting survival after resection of colorectal liver metastases: development and multicentre validation study using largest diameter and number of metastases with RAS mutation status. Br J Surg, 2021, 108(8): 968-975.
29.	Takeda Y, Mise Y, Takahashi Y, et al. Limited prognostic value of KRAS in patients undergoing hepatectomy for colorectal liver metastases. Ann Surg Oncol, 2022, 29(4): 2383-2391.
30.	Kawaguchi Y, Kopetz S, Kwong L, et al. Genomic sequencing and insight into clinical heterogeneity and prognostic pathway genes in patients with metastatic colorectal cancer. J Am Coll Surg, 2021, 233(2): 272-284.
31.	Margonis GA, Amini N, Buettner S, et al. The prognostic impact of primary tumor site differs according to the KRAS mutational status: a study by the international genetic consortium for colorectal liver metastasis. Ann Surg, 2021, 273(6): 1165-1172.
32.	Amini N, Andreatos N, Margonis GA, et al. Mutant KRAS as a prognostic biomarker after hepatectomy for rectal cancer metastases: does the primary disease site matter? J Hepatobiliary Pancreat Sci, 2022, 29(4): 417-427.
33.	刘佳明, 刘伟, 徐达, 等. RAS基因突变对结直肠癌肝转移患者肝切除术后预后的影响. 中华肝胆外科杂志, 2020, 26(1): 1-5.
34.	Bruera G, Pepe F, Malapelle U, et al. KRAS, NRAS and BRAF mutations detected by next generation sequencing, and differential clinical outcome in metastatic colorectal cancer (MCRC) patients treated with first line FIr-B/FOx adding bevacizumab (BEV) to triplet chemotherapy. Oncotarget, 2018, 9(41): 26279-26290.
35.	Yoshino T, Portnoy DC, Obermannová R, et al. Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE—a global phase Ⅲ study. Ann Oncol, 2019, 30(1): 124-131.
36.	Rose JS, Serna DS, Martin LK, et al. Influence of KRAS mutation status in metachronous and synchronous metastatic colorectal adenocarcinoma. Cancer, 2012, 118(24): 6243-6252.
37.	Russo A, Migliavacca M, Bazan V, et al. Prognostic significance of proliferative activity, DNA-ploidy, p53 and Ki-ras point mutations in colorectal liver metastases. Cell Prolif, 1998, 31(3-4): 139-153.
38.	Pellino G, Warren O, Mills S, et al. Comparison of Western and Asian guidelines concerning the management of colon cancer. Dis Colon Rectum, 2018, 61(2): 250-259.
39.	Pang XL, Li QX, Ma ZP, et al. Association between clinicopathological features and survival in patients with primary and paired metastatic colorectal cancer and KRAS mutation. Onco Targets Ther, 2017, 10: 2645-2654.
40.	Sasaki K, Margonis GA, Wilson A, et al. Prognostic implication of KRAS status after hepatectomy for colorectal liver metastases varies according to primary colorectal tumor location. Ann Surg Oncol, 2016, 23(11): 3736-3743.

1. Lu B, Li N, Luo CY, et al. Colorectal cancer incidence and mortality: the current status, temporal trends and their attributable risk factors in 60 countries in 2000–2019. Chin Med J (Engl), 2021, 134(16): 1941-1951.
2. Karagkounis G, Torbenson MS, Daniel HD, et al. Incidence and prognostic impact of KRAS and BRAF mutation in patients undergoing liver surgery for colorectal metastases. Cancer, 2013, 119(23): 4137-4144.
3. Pikoulis E, Papaconstantinou D, Pikouli A, et al. Reevaluating the prognostic value of RAS mutation status in patients with resected liver metastases from colorectal cancer: a systematic review and meta-analysis. J Hepatobiliary Pancreat Sci, 2021, 28(8): 637-647.
4. Sakai N, Furukawa K, Takayashiki T, et al. Differential effects of KRAS mutational status on long-term survival according to the timing of colorectal liver metastases. BMC Cancer, 2021, 21(1): 412. doi: 10.1186/s12885-021-08144-5.
5. Margonis GA, Sasaki K, Gholami S, et al. Genetic and Morphological Evaluation (GAME) score for patients with colorectal liver metastases. Br J Surg, 2018, 105(9): 1210-1220.
6. Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. Available at: http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp. Accessed on April 10, 2017.
7. 王丹, 翟俊霞, 牟振云, 等. Meta分析中的异质性及其处理方法. 中国循证医学杂志, 2009, 9(10): 1115-1118.
8. Higgins JP, Thompson SG, Deeks JJ, et al. Measuring inconsistency in meta-analyses. BMJ, 2003, 327(7414): 557-560.
9. Gholami S, Kemeny NE, Boucher TM, et al. Adjuvant hepatic artery infusion chemotherapy is associated with improved survival regardless of KRAS mutation status in patients with resected colorectal liver metastases: a retrospective analysis of 674 patients. Ann Surg, 2020, 272(2): 352-356.
10. Margonis GA, Buettner S, Andreatos N, et al. Association of BRAF mutations with survival and recurrence in surgically treated patients with metastatic colorectal liver cancer. JAMA Surg, 2018, 153(7): e180996. doi: 10.1001/jamasurg.2018.0996.
11. Wang K, Xu D, Yan XL, et al. The impact of primary tumour location in patients undergoing hepatic resection for colorectal liver metastasis. Eur J Surg Oncol, 2018, 44(6): 771-777.
12. Yamashita S, Brudvik KW, Kopetz SE, et al. Embryonic origin of primary colon cancer predicts pathologic response and survival in patients undergoing resection for colon cancer liver metastases. Ann Surg, 2018, 267(3): 514-520.
13. Shindoh J, Nishioka Y, Yoshioka R, et al. KRAS mutation status predicts site-specific recurrence and survival after resection of colorectal liver metastases irrespective of location of the primary lesion. Ann Surg Oncol, 2016, 23(6): 1890-1896.
14. Shoji H, Yamada Y, Taniguchi H, et al. Clinical impact of c-MET expression and genetic mutational status in colorectal cancer patients after liver resection. Cancer Sci, 2014, 105(8): 1002-1007.
15. Isella C, Mellano A, Galimi F, et al. MACC1 mRNA levels predict cancer recurrence after resection of colorectal cancer liver metastases. Ann Surg, 2013, 257(6): 1089-1095.
16. Umeda Y, Nagasaka T, Mori Y, et al. Poor prognosis of KRAS or BRAF mutant colorectal liver metastasis without microsatellite instability. J Hepatobiliary Pancreat Sci, 2013, 20(2): 223-233.
17. Stremitzer S, Stift J, Gruenberger B, et al. KRAS status and outcome of liver resection after neoadjuvant chemotherapy including bevacizumab. Br J Surg, 2012, 99(11): 1575-1582.
18. Petrowsky H, Sturm I, Graubitz O, et al. Relevance of Ki-67 antigen expression and K-ras mutation in colorectal liver metastases. Eur J Surg Oncol, 2001, 27(1): 80-87.
19. Tsilimigras DI, Hyer JM, Bagante F, et al. Resection of colorectal liver metastasis: prognostic impact of tumor burden vs KRAS mutational status. J Am Coll Surg, 2021, 232(4): 590-598.
20. Baldin P, Van den Eynde M, Mlecnik B, et al. Prognostic assessment of resected colorectal liver metastases integrating pathological features, RAS mutation and Immunoscore. J Pathol Clin Res, 2021, 7(1): 27-41.
21. Hatta AAZ, Pathanki AM, Hodson J, et al. The effects of resection margin and KRAS status on outcomes after resection of colorectal liver metastases. HPB (Oxford), 2021, 23(1): 90-98.
22. Zhang Q, Peng J, Ye M, et al. KRAS mutation predicted more mirometastases and closer resection margins in patients with colorectal cancer liver metastases. Ann Surg Oncol, 2020, 27(4): 1164-1173.
23. Dolatkhah R, Dastgiri S, Eftekhar Sadat AT, et al. Impact of RAS/RAF mutations on clinical and prognostic outcomes in metastatic colorectal cancer. Bioimpacts, 2021, 11(1): 5-14.
24. Kim HS, Lee JM, Kim HS, et al. Prognosis of synchronous colorectal liver metastases after simultaneous curative-intent surgery according to primary tumor location and KRAS mutational status. Ann Surg Oncol, 2020, 27(13): 5150-5158.
25. Moro A, Mehta R, Tsilimigras DI, et al. Prognostic factors differ according to KRAS mutational status: a classification and regression tree model to define prognostic groups after hepatectomy for colorectal liver metastasis. Surgery, 2020, 168(3): 497-503.
26. Kawaguchi Y, Kopetz S, Lillemoe HA, et al. A new surveillance algorithm after resection of colorectal liver metastases based on changes in recurrence risk and RAS mutation status. J Natl Compr Canc Netw, 2020, 18(11): 1500-1508.
27. Jácome AA, Vreeland TJ, Johnson B, et al. The prognostic impact of RAS on overall survival following liver resection in early versus late-onset colorectal cancer patients. Br J Cancer, 2021, 124(4): 797-804.
28. Kawaguchi Y, Kopetz S, Tran Cao HS, et al. Contour prognostic model for predicting survival after resection of colorectal liver metastases: development and multicentre validation study using largest diameter and number of metastases with RAS mutation status. Br J Surg, 2021, 108(8): 968-975.
29. Takeda Y, Mise Y, Takahashi Y, et al. Limited prognostic value of KRAS in patients undergoing hepatectomy for colorectal liver metastases. Ann Surg Oncol, 2022, 29(4): 2383-2391.
30. Kawaguchi Y, Kopetz S, Kwong L, et al. Genomic sequencing and insight into clinical heterogeneity and prognostic pathway genes in patients with metastatic colorectal cancer. J Am Coll Surg, 2021, 233(2): 272-284.
31. Margonis GA, Amini N, Buettner S, et al. The prognostic impact of primary tumor site differs according to the KRAS mutational status: a study by the international genetic consortium for colorectal liver metastasis. Ann Surg, 2021, 273(6): 1165-1172.
32. Amini N, Andreatos N, Margonis GA, et al. Mutant KRAS as a prognostic biomarker after hepatectomy for rectal cancer metastases: does the primary disease site matter? J Hepatobiliary Pancreat Sci, 2022, 29(4): 417-427.
33. 刘佳明, 刘伟, 徐达, 等. RAS基因突变对结直肠癌肝转移患者肝切除术后预后的影响. 中华肝胆外科杂志, 2020, 26(1): 1-5.
34. Bruera G, Pepe F, Malapelle U, et al. KRAS, NRAS and BRAF mutations detected by next generation sequencing, and differential clinical outcome in metastatic colorectal cancer (MCRC) patients treated with first line FIr-B/FOx adding bevacizumab (BEV) to triplet chemotherapy. Oncotarget, 2018, 9(41): 26279-26290.
35. Yoshino T, Portnoy DC, Obermannová R, et al. Biomarker analysis beyond angiogenesis: RAS/RAF mutation status, tumour sidedness, and second-line ramucirumab efficacy in patients with metastatic colorectal carcinoma from RAISE—a global phase Ⅲ study. Ann Oncol, 2019, 30(1): 124-131.
36. Rose JS, Serna DS, Martin LK, et al. Influence of KRAS mutation status in metachronous and synchronous metastatic colorectal adenocarcinoma. Cancer, 2012, 118(24): 6243-6252.
37. Russo A, Migliavacca M, Bazan V, et al. Prognostic significance of proliferative activity, DNA-ploidy, p53 and Ki-ras point mutations in colorectal liver metastases. Cell Prolif, 1998, 31(3-4): 139-153.
38. Pellino G, Warren O, Mills S, et al. Comparison of Western and Asian guidelines concerning the management of colon cancer. Dis Colon Rectum, 2018, 61(2): 250-259.
39. Pang XL, Li QX, Ma ZP, et al. Association between clinicopathological features and survival in patients with primary and paired metastatic colorectal cancer and KRAS mutation. Onco Targets Ther, 2017, 10: 2645-2654.
40. Sasaki K, Margonis GA, Wilson A, et al. Prognostic implication of KRAS status after hepatectomy for colorectal liver metastases varies according to primary colorectal tumor location. Ann Surg Oncol, 2016, 23(11): 3736-3743.

CHINESE JOURNAL OF BASES AND CLINICS IN GENERAL SURGERY

Effect of RAS gene mutation on survival after liver metastasis resection for patients with colorectal cancer combined with liver metastasis: integrated analysis

Abstract Full text Figures/Tables Video References Cited by

Previous Article

Next Article

Format

Content