Clinical and prognostic characteristics of metastatic colorectal cancer with minor RAS mutations
- Authors:
- Published online on: June 2, 2025 https://doi.org/10.3892/ol.2025.15123
- Article Number: 377
-
Copyright: © Kojitani et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Colorectal cancer (CRC) is a leading cause of cancer-related deaths worldwide, with metastatic CRC (mCRC) posing therapeutic challenges (1). Treatment strategies often rely on targeted therapies guided by biomarkers such as rat sarcoma virus (RAS) and rapidly accelerated fibrosarcoma (RAF) mutations. These mutations influence key biological processes, including angiogenesis, cell proliferation, and apoptosis, and serve as critical prognostic markers (2–13).
KRAS is a small GTP-binding protein that plays a critical role in transmitting growth signals downstream from the epidermal growth factor receptor (EGFR). KRAS gene mutations are present in approximately half of CRC cases. Approximately 90% of these mutations occurring in KRAS exon 2 (codon 12, 13) (1). KRAS exon 2 mutations are the most common predictor of resistance to the anti-EGFR drugs, cetuximab and panitumumab, in patients with mCRC, given that KRAS mutations reduce the intrinsic GTPase activity of Ras, causing it to remain in its active, GTP-bound state. Thus, despite EGFR inhibition, downstream proliferative signaling persists, leading to resistance (3–7,9). Subsequently, reports from the European consortium indicated that other KRAS mutations, including KRAS exons 3 (codon 59, 61) and 4 (codon 117, 146), and NRAS mutations, including NRAS exons 2 (codon 12, 13), 3 (codon 59, 61), and 4 (codon 117, 146), were also associated with resistance to anti-EGFR antibody therapy (14–21). These findings led to a consensus that all RAS mutations can predict resistance to anti-EGFR antibodies (8,10,11). However, KRAS exons 3 and 4, and NRAS mutations are relatively rare, and prior studies have examined only a limited number of cases. Additionally, in real-world clinical practice, mCRC with RAS mutations is commonly treated with chemotherapy regimens that include angiogenesis inhibitors, not anti-EGFR monoclonal antibodies. However, it remains unclear whether the prognosis in patients with KRAS exons 3 and 4, or NRAS mutations is comparable to that in patients with KRAS exon 2 mutations in this treatment setting.
Historically, only KRAS exon 2 mutations were detectable and therefore recognized as the primary RAS mutations associated with resistance to anti-EGFR antibody therapy. With advances in sequencing technologies, additional mutations in KRAS non-exon 2 regions of KRAS as well as NRAS mutations became identifiable. As a result, the definition of anti-EGFR resistance biomarkers expanded from KRAS exon 2 mutations alone to encompass the entire spectrum of RAS mutations. However, despite this unified classification, the biological characteristics, treatment responses, and prognostic implications of KRAS exon 2 mutations vs. KRAS non-exon 2 mutations remain insufficiently understood. Currently, patients with any RAS mutation are broadly categorized into a single group, although this approach may overlook meaningful heterogeneity within the RAS-mutated population.
Against the background this study aimed to focus on the relatively rare KRAS exons 3 and 4, and NRAS mutations to evaluate their impact on prognosis, clinical characteristics, and efficacy of angiogenesis inhibitors The study also sought to determine whether these impacts are comparable to those observed with KRAS exon 2 mutations. These mutations are categorized as minor RAS mutations in this study.
Patients and methods
Patient selection and characteristics
This retrospective cohort study was conducted at Osaka International Cancer Institute. Patients who underwent tissue RAS testing between August 2018 and December 2023 were included in this analysis. Tumor tissue samples for RAS testing were obtained as part of routine clinical care, and no additional samples were collected specifically for this study. As this was a retrospective observational study, no formal sample size calculation was performed. Instead, all eligible patients treated during the study period were included to enhance the representativeness and generalizability of the findings. Tumor tissue samples were analyzed to determine RAS mutation status using the MEBGEN RASKET™-B kit. Information regarding RAS mutation subtypes was extracted from existing medical records.
Patients with histologically confirmed colorectal adenocarcinoma and documented RAS mutations were included. Patients who had not received systemic chemotherapy for recurrent or metastatic CRC were excluded. For patients who experienced recurrence during or within 6 months of completing adjuvant chemotherapy, the start date of adjuvant chemotherapy was considered the initiation point for all statistical analyses, rather than the initiation point for mCRC treatment.
Demographic and clinical data, including age, sex, Eastern Cooperative Oncology Group (ECOG) performance status, location of the primary tumor, pathological differentiation, microsatellite instability status, metastatic disease characteristics, first-line chemotherapy regimen, and the best efficacy of first-line chemotherapy, were extracted from electronic medical records. Extracted metastatic characteristics included the number of metastatic organs and the presence or absence of liver and lung metastases. Tumor location was categorized both as right-sided (from the cecum to the transverse colon) or left-sided (from the splenic flexure to the rectum) and as colonic (from the cecum to the sigmoid colon) or rectal (rectum). RAS mutation subtypes were recorded and categorized into two groups: KRAS exon 2 mutations (codons 12 and 13) and minor RAS mutations (KRAS exons 3 and 4, and NRAS mutations). These categorizations allowed for further subgroup analyses based on clinical and molecular characteristics. We report the efficacy results using a data cutoff of December 2024.
RAS mutation analysis
Tumor tissues were obtained from primary or metastatic sites and preserved as formalin-fixed paraffin-embedded (FFPE) specimens. DNA was extracted from the FFPE blocks, and RAS mutation testing was performed using the MEBGEN RASKET™-B kit (22,23). Assays with the RASKET-B kit were performed according to the manufacturer's protocol. Briefly, this multiplex PCR-based assay was specifically designed to detect mutations in KRAS and NRAS genes across exons 2, 3, and 4. The mutations included those in KRAS codons 12 (G12S, G12C, G12R, G12D, G12V, and G12A), 13 (G13S, G13C, G13R, G13D, G13V, and G13A), KRAS codon 59 (A59T and A59G), 61 (Q61K, Q61E, Q61L, Q61P, Q61R, and Q61H), 117 (K117N), and 146 (A146T, A146P, and A146V), as well as NRAS codons 12 (G12S, G12C, G12R, G12D, G12V, and G12A), 13 (G13S, G13C, G13R, G13D, G13V, and G13A), 59 (A59T and A59G), 61 (Q61K, Q61E, Q61L, Q61P, Q61R, and Q61H), 117 (K117N), and 146 (A146T, A146P, and A146V). All procedures were conducted according to the manufacturer's protocol, ensuring accurate mutation identification with high sensitivity and specificity.
Assessment and statistical analysis
The primary outcome of the study was overall survival (OS), defined as the time from treatment initiation to death from any cause or the last follow-up date. The study included a comparison of OS between patients with KRAS exon 2 mutations and those with minor RAS mutations to assess differences in clinical outcomes. Patients who were alive at the end of the study period were censored at their most recent follow-up date (December 2024). Secondary outcomes included the prevalence of tumor location (analyzed as right-sided vs. left-sided and colon vs. rectum) by RAS mutation subtype, descriptive statistics of clinical characteristics, the relationship between metastatic disease features and survival outcomes, and progression-free survival (PFS) analysis for patients treated with bevacizumab in the first-line setting.
Survival analyses were conducted using the Kaplan-Meier method to generate survival curves, with differences between groups evaluated using the log-rank test. Cox proportional hazards regression models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for survival outcomes. χ2 tests or Fisher's exact test were applied to categorical variables, such as tumor location or the presence of liver and lung metastases, depending on the expected cell counts. P<0.05 was considered to indicate a statistically significant difference. Subgroup analyses were performed to explore the impact of RAS mutation subtypes, metastatic organ involvement, and other clinical factors on survival outcomes. Statistical analyses were conducted using EZR Version 1.63 (Saitama Medical Center, Jichi Medical University, Japan). Results were summarized as means with standard deviations, or medians with interquartile ranges, as appropriate.
Ethical considerations
This study, conducted following The Declaration of Helsinki, was approved by the institutional review board of Osaka International Cancer Institute (approval no. IRB 24122) (24). Given the retrospective nature of our study, which utilized anonymized patient data, the requirement for informed consent was waived.
Results
Patient characteristics and frequencies of RAS mutation subtypes
A total of 796 patients with CRC submitted the MEBGEN RASKET™-B kit at our hospital between August 2018 and December 2023. All samples were available for analysis. Of these, 429 patients with RAS wild-type mutations were excluded. The remaining 367 patients with RAS mutations included 202 individuals who had received systemic chemotherapy for advanced or recurrent CRC. Among these, 170 patients (84%) had KRAS exon 2 mutations, whereas 32 (16%) exhibited minor RAS mutations (Fig. 1). Analysis of RAS mutation subtypes revealed that KRAS codon 12 mutations were the most frequent, accounting for 67% of cases (n=135), followed by KRAS codon 13 (17%, n=35) and non-exon 2 mutations (10%, n=20), and NRAS mutations (6%, n=12) (Fig. 2). These findings are consistent with those from prior studies, highlighting the predominance of KRAS exon 2 mutations in mCRC and the relatively rare occurrence of minor RAS mutations (1).
Clinicopathological characteristics of patients with RAS Mutation subtypes
The demographic and clinicopathological characteristics of those patients are shown in Table I. Correlation between RAS mutation status and age, sex, ECOG PS, primary site of disease, tumor sidedness, pathological differentiation, microsatellite instability status, previous surgery, previous adjuvant chemotherapy, number of metastatic sites, liver metastasis, lung metastasis was evaluated. Minor RAS mutations were more common in left-sided colorectal cancer (81%); however, no significant differences in background were observed between the two groups in any category.
OS in patients with RAS mutation subtypes
The median OS in the KRAS exon 2 mutation group was 36.6 months (95% CI: 30.8–38.9), whereas that in the minor RAS mutation group was 23.8 months (95% CI: 21.1-not reached) (Fig. 3). The HR for OS between the groups was 0.95 (95% CI: 0.55–1.65, P=0.85), suggesting that the impact of KRAS exon 2 mutation and minor RAS mutation on prognosis is almost comparable.
OS and PFS in patients receiving first-line bevacizumab-containing therapy
Among 202 patients with RAS mutations, 156 received first-line treatment with bevacizumab-containing chemotherapy. The cohort included 134 patients with KRAS exon 2 mutations and 22 with minor RAS mutations. We investigated the relationship between RAS mutation subtype rate and age, sex, ECOG PS, tumor sidedness, number of metastatic sites, liver metastasis, lung metastasis, first-line systemic chemotherapy regimen, and the best efficacy of first-line chemotherapy (Table II). Liver metastases were significantly less common in the minor RAS group, reported in only 32% of cases compared to 56% in the KRAS exon 2 group (P=0.04). A trend toward improved OS (37.8 vs. 44.9 months, P=0.94) and PFS (11.0 vs. 12.3 months, P=0.46) was not noted between the two groups (Fig. 4).
 | Table II.Clinical characteristics of patients treated with bevacizumab at first line with RAS mutant metastatic colorectal cancer (N=156). |
The efficacy of the first-line chemotherapy was evaluated in 117 patients (100 with KRAS exon 2 mutations and 17 with minor RAS mutations) with target lesions. Complete response (CR), partial response (PR), stable disease (SD), and progressive disease (PD) were observed in 1, 48, 39, and 12%, respectively, for the KRAS exon 2 mutation group, and 6, 47, 41, and 6%, respectively, for minor RAS mutation group (Table III). The overall response rate (ORR) was 49% in patients with KRAS exon 2 mutations and 53% in those with minor RAS mutations (P=0.80).
| Table III.ORR in patients treated with bevacizumab with different subtypes of RAS mutations (N=117). |
Discussion
Minor RAS mutations are rare and not fully understood. Therefore, our study provides insights into the distinct clinical and prognostic characteristics of patients with mCRC and minor RAS mutations by comparing them with those with KRAS exon 2 mutations. Based on our real-world clinical experience, our initial hypothesis posited that minor RAS mutations would not confer a worse prognosis than KRAS exon 2 mutations.
This study investigated the frequency and subtypes of RAS mutations (KRAS exon 2 and minor RAS mutations) and evaluated the prognostic outcomes and the impact of first-line treatment with anti-angiogenic agents in both groups. Our data demonstrated that the median OS and PFS were comparable between the two groups. Consistent with our initial hypothesis, minor RAS and KRAS exon 2 mutations were suggested to have similar effects on prognosis and treatment outcomes. Accordingly, we believe that current treatment strategies for mCRC with RAS mutations remain appropriate and should not be altered based on the RAS mutation subtype. While our results align with this view, previous studies have reported conflicting findings. Some have indicated poorer prognoses in patients with minor RAS mutations compared to those with KRAS exon 2 mutations, whereas others have suggested that NRAS mutations may be associated with better outcomes (25–27). Interestingly, despite previous conflicting reports, the relatively favorable survival observed in the minor RAS group may be partially attributable to the lower incidence of liver metastases. Nonetheless, as no current evidence supports a causal relationship between minor RAS mutations and reduced liver involvement, further studies are warranted to elucidate the biological basis of this observation. In addition to metastatic patterns, molecular differences may also contribute to prognostic variability. For example, Takane et al demonstrated that CRC with NRAS mutations is associated with a distinct DNA methylation epigenotype (LME) compared to CRC with KRAS mutations (26), which could partly explain the differences in prognosis. Furthermore, Ogura et al reported that NRAS mutations were more prevalent in distal colon cancers compared to KRAS mutations, potentially contributing to a more favorable prognosis (27). These conflicting findings highlight the need for larger studies that can analyze NRAS and KRAS non-exon 2 mutations separately. Moreover, the small number of patients with NRAS or KRAS non-exon 2 mutations in most studies may limit statistical power and contribute to the inconsistent findings. This study did not assess the pathogenicity of individual minor RAS mutations, and such analysis was beyond the scope of this retrospective investigation.
KRAS mutations were initially recognized solely as biomarkers for resistance to anti-EGFR antibody therapies. However, recent advancements have led to the FDA approval of targeted therapies such as adagrasib plus cetuximab and sotorasib plus panitumumab for KRAS G12C mutations, expanding treatment options (28,29). Additionally, new drugs targeting KRAS G12D and KRAS G12V mutations are currently under development, with promising potential for clinical application. Moreover, several pan-RAS inhibitors are being developed, which may eventually address minor RAS mutations (30). Since minor RAS mutations are rare driver mutations, conducting randomized controlled trials in CRC is challenging. Therefore, the data from our study on the efficacy and survival outcomes of conventional chemotherapy in patients with minor RAS mutations could serve as valuable historical control data for future therapeutic developments. These findings may provide a foundational dataset for evaluating the efficacy of novel treatment strategies.
We also evaluated the clinical characteristics of patients in both groups. During the study period, the MEBGEN RASKET™-B kit was used to analyze 796 cases of CRC, of which 429 were tumors with wild-type RAS. Approximately half of the cases had RAS mutations, consistent with previous reports. Among these, KRAS exon 2 mutations accounted for 84% (67% KRAS codon 12 mutations and 17% KRAS codon 13 mutations), whereas minor RAS mutations accounted for 16% (10% KRAS non-exon 2 mutations and 6% NRAS mutations). KRAS exon 2 mutations are reportedly present in approximately 35–40% of CRC cases (30–35% KRAS codon 12 mutations and 4–8% KRAS codon 13 mutations), whereas minor RAS mutations are observed in about 10–15% (3–6% of mutations in KRAS exons 3 and 4, NRAS exons 2 and 3, and less than 1% in NRAS exon 4) (17,31). Considering that approximately half of CRC cases harbor RAS mutations, our findings regarding the proportion of each RAS mutation type within the RAS-mutant group were generally consistent with previously reported findings.
An investigation into the distribution of clinicopathological characteristics and RAS mutation subtypes revealed no statistically significant findings; however, the proportion of left-sided lesions in minor RAS mutations was 81%, indicating a high tendency. Consistent with prior studies, our study identified NRAS mutations most frequently in rectal and sigmoid colon cancers (18). Reports have suggested that CIMP-high is associated with a continuous increase in frequency from the rectum to the ascending colon. Conversely, KRAS codon 61 and 146 mutations had higher frequencies in cecal cancers, with a higher prevalence of CpG island methylator phenotype (CIMP)-low, compared to KRAS wild-type cases (32,33). These discrepancies may be due to small sample sizes in various studies. Notably, a few Japanese studies have reported a higher frequency of KRAS non-exon 2 mutations in left-sided CRC that aligns with our findings (25). Despite this predominance, no associations were identified with microsatellite instability (MSI)-H status or pathological differentiation. The biological mechanisms underlying the correlation between minor RAS mutations and left-sided tumors need to be further explored.
As a single-center study with an adequate number of cases, this research represents a significant contribution to understanding the characteristics of minor RAS mutations. Future studies with larger sample sizes, combined with data from the recently introduced OncoGuide™ EpiLight™ methylation detection kit in Japan, may help establish the statistical significance of the continuous model for mutation distribution (34–36).
In conclusion, this study elucidates the prognostic impact, clinical characteristics, and effects of anti-angiogenic therapy in patients with minor RAS and KRAS exon 2 mutations. Consistent with previously reported findings from Japan, minor RAS mutations were more common in left-sided colorectal cancer. The association of minor RAS mutations with left-sided tumors warrants further investigation into underlying biological mechanisms. The prognostic impact of minor RAS mutations appeared to be comparable to that of KRAS exon 2 mutations, suggesting that current treatment strategies may remain unchanged for RAS-mutant CRC. However, further studies should validate these findings. The results highlight the necessity of therapeutic advancements targeting all RAS mutations to improve the prognosis of mCRC with RAS mutations.
Acknowledgements
Not applicable.
Funding
Funding: No funding was received.
Availability of data and materials
The data generated in the present study may be requested from the corresponding author.
Authors' contributions
TK and YK conceived and designed the study. YK performed data acquisition. TK and YK confirm the authenticity of all the raw data. Data analysis was performed by TK and YK. All authors including DS, TO, YA, RM, MK, TS, TO, MN, MI, YK, JN, NS, TY, MT and MY contributed to the interpretation of clinical data. Statistical analysis was conducted by YK. The manuscript was prepared and edited by TK, MT and YK. All authors reviewed the manuscript. All authors read and approved the final manuscript.
Ethics approval and consent to participate
This study, conducted following The Declaration of Helsinki, was approved by the institutional review board of Osaka International Cancer Institute (approval no. IRB 24122). Given the retrospective nature of our study, which utilized anonymized patient data, the requirement for informed consent was waived.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Use of artificial intelligence tools
During the preparation of this work, AI tools (ChatGPT) were used to improve the readability and language of the manuscript, and subsequently, the authors revised and edited the content produced by the AI tools as necessary, taking full responsibility for the ultimate content of the present manuscript.
Glossary
Abbreviations
Abbreviations:
|
CRC |
colorectal cancer |
|
mCRC |
metastatic CRC |
|
RAS |
rat sarcoma virus |
|
RAF |
rapidly accelerated fibrosarcoma |
|
EGFR |
epidermal growth factor receptor |
|
ECOG |
Eastern Cooperative Oncology Group |
|
HR |
hazard ratio |
|
CI |
confidence interval |
|
OS |
overall survival |
|
PFS |
progression-free survival |
|
CR |
complete response |
|
PR |
partial response |
|
SD |
stable disease |
|
PD |
progressive disease |
|
ORR |
overall response rate |
|
MSI |
microsatellite instability |
References
|
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, Juan T, Sikorski R, Suggs S, Radinsky R, et al: Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 41:3278–3286. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Bokemeyer C, Bondarenko I, Hartmann JT, de Braud F, Schuch G, Zubel A, Celik I, Schlichting M and Koralewski P: Efficacy according to biomarker status of cetuximab plus FOLFOX-4 as first-line treatment for metastatic colorectal cancer: The OPUS study. Ann Oncol. 22:1535–1546. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Dahabreh IJ, Terasawa T, Castaldi PJ and Trikalinos TA: Systematic review: Anti-epidermal growth factor receptor treatment effect modification by KRAS mutations in advanced colorectal cancer. Ann Intern Med. 154:37–49. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, et al: Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: The PRIME study. J Clin Oncol. 28:4697–4705. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Karapetis CS, Khambata-Ford S, Jonker DJ, O'Callaghan CJ, Tu D, Tebbutt NC, Simes RJ, Chalchal H, Shapiro JD, Robitaille S, et al: K-ras mutations and benefit from cetuximab in advanced colorectal cancer. N Engl J Med. 359:1757–1765. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Lièvre A, Bachet JB, Le Corre D, Boige V, Landi B, Emile JF, Côté JF, Tomasic G, Penna C, Ducreux M, et al: KRAS mutation status is predictive of response to cetuximab therapy in colorectal cancer. Cancer Res. 66:3992–3995. 2006. View Article : Google Scholar : PubMed/NCBI | |
|
Schirripa M, Cohen SA, Battaglin F and Lenz HJ: Biomarker-driven and molecular targeted therapies for colorectal cancers. Semin Oncol. 45:124–132. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Van Cutsem E, Köhne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pintér T, Lim R, Bodoky G, et al: Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med. 360:1408–1417. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O'Neil BH, Atkins JN, et al: Effect of first-line chemotherapy combined with cetuximab or bevacizumab on overall survival in patients with KRAS wild-type advanced or metastatic colorectal cancer: A randomized clinical trial. JAMA. 317:2392–2401. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Watanabe J, Muro K, Shitara K, Yamazaki K, Shiozawa M, Ohori H, Takashima A, Yokota M, Makiyama A, Akazawa N, et al: Panitumumab vs bevacizumab added to standard first-line chemotherapy and overall survival among patients with RAS wild-type, left-sided metastatic colorectal cancer: A randomized clinical trial. JAMA. 329:1271–1282. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmüller C, Kahl C, Seipelt G, et al: FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): A randomised, open-label, phase 3 trial. Lancet Oncol. 15:1065–1075. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Jones JC, Renfro LA, Al-Shamsi HO, Schrock AB, Rankin A, Zhang BY, Kasi PM, Voss JS, Leal AD, Sun J, et al: Non-V600 BRAF mutations define a clinically distinct molecular subtype of metastatic colorectal cancer. J Clin Oncol. 35:2624–2630. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Bokemeyer C, Köhne CH, Ciardiello F, Lenz HJ, Heinemann V, Klinkhardt U, Beier F, Duecker K, van Krieken JH and Tejpar S: FOLFOX4 plus cetuximab treatment and RAS mutations in colorectal cancer. Eur J Cancer. 51:1243–1252. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, Kalogeras KT, Kotoula V, Papamichael D, Laurent-Puig P, et al: Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: A retrospective consortium analysis. Lancet Oncol. 11:753–762. 2010. View Article : Google Scholar : PubMed/NCBI | |
|
Douillard JY, Oliner KS, Siena S, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, et al: Panitumumab-FOLFOX4 treatment and RAS mutations in colorectal cancer. N Engl J Med. 369:1023–1034. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Kawazoe A, Shitara K, Fukuoka S, Kuboki Y, Bando H, Okamoto W, Kojima T, Fuse N, Yamanaka T, Doi T, et al: A retrospective observational study of clinicopathological features of KRAS, NRAS, BRAF and PIK3CA mutations in Japanese patients with metastatic colorectal cancer. BMC Cancer. 15:2582015. View Article : Google Scholar : PubMed/NCBI | |
|
Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, et al: Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: Results of the randomised phase 3 MRC COIN trial. Lancet. 377:2103–2114. 2011. View Article : Google Scholar : PubMed/NCBI | |
|
Peeters M, Oliner KS, Price TJ, Cervantes A, Sobrero AF, Ducreux M, Hotko Y, André T, Chan E, Lordick F, et al: Analysis of KRAS/NRAS mutations in a phase III study of panitumumab with FOLFIRI compared with FOLFIRI alone as second-line treatment for metastatic colorectal cancer. Clin Cancer Res. 21:5469–5479. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Sorich MJ, Wiese MD, Rowland A, Kichenadasse G, McKinnon RA and Karapetis CS: Extended RAS mutations and anti-EGFR monoclonal antibody survival benefit in metastatic colorectal cancer: A meta-analysis of randomized, controlled trials. Ann Oncol. 26:13–21. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Van Cutsem E, Lenz HJ, Köhne CH, Heinemann V, Tejpar S, Melezínek I, Beier F, Stroh C, Rougier P, van Krieken JH and Ciardiello F: Fluorouracil, leucovorin, and irinotecan plus cetuximab treatment and RAS mutations in colorectal cancer. J Clin Oncol. 33:692–700. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Taniguchi H, Okamoto W, Muro K, Akagi K, Hara H, Nishina T, Kajiwara T, Denda T, Hironaka S, Kudo T, et al: Clinical validation of newly developed multiplex kit using Luminex xMAP technology for detecting simultaneous RAS and BRAF mutations in colorectal cancer: Results of the RASKET-B study. Neoplasia. 20:1219–1226. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Yoshino T, Muro K, Yamaguchi K, Nishina T, Denda T, Kudo T, Okamoto W, Taniguchi H, Akagi K, Kajiwara T, et al: Clinical validation of a multiplex kit for RAS mutations in colorectal cancer: Results of the RASKET (RAS KEy testing) prospective, multicenter study. EBioMedicine. 2:317–323. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
World Medical Association, . World medical association declaration of Helsinki. Ethical principles for medical research involving human subjects. JAMA. 310:2191–2194. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Ikoma T, Shimokawa M, Kotaka M, Matsumoto T, Nagai H, Boku S, Shibata N, Yasui H and Satake H: Clinical and prognostic features of patients with detailed RAS/BRAF-mutant colorectal cancer in Japan. BMC Cancer. 21:5182021. View Article : Google Scholar : PubMed/NCBI | |
|
Takane K, Akagi K, Fukuyo M, Yagi K, Takayama T and Kaneda A: DNA methylation epigenotype and clinical features of NRAS-mutation(+) colorectal cancer. Cancer Med. 6:1023–1035. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Ogura T, Kakuta M, Yatsuoka T, Nishimura Y, Sakamoto H, Yamaguchi K, Tanabe M, Tanaka Y and Akagi K: Clinicopathological characteristics and prognostic impact of colorectal cancers with NRAS mutations. Oncol Rep. 32:50–56. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Yaeger R, Weiss J, Pelster MS, Spira AI, Barve M, Ou SI, Leal TA, Bekaii-Saab TS, Paweletz CP, Heavey GA, et al: Adagrasib with or without cetuximab in colorectal cancer with mutated KRAS G12C. N Engl J Med. 388:44–54. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Fakih MG, Salvatore L, Esaki T, Modest DP, Lopez-Bravo DP, Taieb J, Karamouzis MV, Ruiz-Garcia E, Kim TW, Kuboki Y, et al: Sotorasib plus panitumumab in refractory colorectal cancer with mutated KRAS G12C. N Engl J Med. 389:2125–2139. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Holderfield M, Lee BJ, Jiang J, Tomlinson A, Seamon KJ, Mira A, Patrucco E, Goodhart G, Dilly J, Gindin Y, et al: Concurrent inhibition of oncogenic and wild-type RAS-GTP for cancer therapy. Nature. 629:919–926. 2024. View Article : Google Scholar : PubMed/NCBI | |
|
Watanabe T, Yoshino T, Uetake H, Yamazaki K, Ishiguro M, Kurokawa T, Saijo N, Ohashi Y and Sugihara K: KRAS mutational status in Japanese patients with colorectal cancer: Results from a nationwide, multicenter, cross-sectional study. Jpn J Clin Oncol. 43:706–712. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Mima K, Cao Y, Chan AT, Qian ZR, Nowak JA, Masugi Y, Shi Y, Song M, da Silva A, Gu M, et al: Fusobacterium nucleatum in colorectal carcinoma tissue according to tumor location. Clin Transl Gastroenterol. 7:e2002016. View Article : Google Scholar : PubMed/NCBI | |
|
Imamura Y, Lochhead P, Yamauchi M, Kuchiba A, Qian ZR, Liao X, Nishihara R, Jung S, Wu K, Nosho K, et al: Analyses of clinicopathological, molecular, and prognostic associations of KRAS codon 61 and codon 146 mutations in colorectal cancer: Cohort study and literature review. Mol Cancer. 13:1352014. View Article : Google Scholar : PubMed/NCBI | |
|
Ouchi K, Takahashi S, Yamada Y, Tsuji S, Tatsuno K, Takahashi H, Takahashi N, Takahashi M, Shimodaira H, Aburatani H and Ishioka C: DNA methylation status as a biomarker of anti-epidermal growth factor receptor treatment for metastatic colorectal cancer. Cancer Sci. 106:1722–1729. 2015. View Article : Google Scholar : PubMed/NCBI | |
|
Yamauchi M, Lochhead P, Morikawa T, Huttenhower C, Chan AT, Giovannucci E, Fuchs C and Ogino S: Colorectal cancer: A tale of two sides or a continuum? Gut. 61:794–797. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Yamauchi M, Morikawa T, Kuchiba A, Imamura Y, Qian ZR, Nishihara R, Liao X, Waldron L, Hoshida Y, Huttenhower C, et al: Assessment of colorectal cancer molecular features along bowel subsites challenges the conception of distinct dichotomy of proximal versus distal colorectum. Gut. 61:847–854. 2012. View Article : Google Scholar : PubMed/NCBI |
