Research ArticleClinical Studies

Clinical Impact of Primary Tumor Location and RAS, BRAF V600E, and PIK3CA Mutations on Epidermal Growth Factor Receptor Inhibitor Efficacy as Third-line Chemotherapy for Metastatic Colorectal Cancer

TARO SATO, HIROKI OSUMI, EIJI SHINOZAKI, AKIRA OOKI, KEITARO SHIMOZAKI, DAISAKU KAMIIMABEPPU, IZUMA NAKAYAMA, TAKERU WAKATSUKI, MARIKO OGURA, DAISUKE TAKAHARI, KEISHO CHIN and KENSEI YAMAGUCHI
Anticancer Research August 2021, 41 (8) 3905-3915; DOI: https://doi.org/10.21873/anticanres.15186

Abstract

Background/Aim: Primary tumor location and RAS and BRAF V600E mutations are predictors of the efficacy of epidermal growth factor receptor (EGFR) inhibitors. However, there are limited reports on their effects on the outcomes of third-line chemotherapy with EGFR inhibitors in metastatic colorectal cancer (mCRC) patients. Patients and Methods: We retrospectively collected the clinical data of KRAS exon 2 wild type (WT) mCRC patients treated with EGFR inhibitor monotherapy or EGFR inhibitor plus irinotecan as third-line chemotherapy. The association between primary tumor location, RAS (KRAS exon 3, 4 or NRAS), BRAF V600E, and PIK3CA mutational status, and treatment outcome was evaluated. Results: A total of 72 patients were included in this study. In multivariate analysis, RAS (p=0.004) and BRAF mutations (p=0.00008) were independent factors for shorter PFS. Poor performance status (p=0.01) and BRAF mutation (p=0.00002) were independent factors for shorter OS, whereas primary tumor location and PIK3CA mutation did not influence survival. Conclusion: Additional analysis of RAS and BRAF mutations could contribute to the selection of patients who are likely to benefit from third-line EGFR inhibitors, regardless of primary tumor location.

Key Words:

In the current treatment strategy for metastatic colorectal cancer (mCRC), the presence of RAS or BRAF gene mutations and primary tumor location are widely used biomarkers for selecting a targeted therapeutic treatment (1, 2). The prognosis of right-sided mCRC is well known to be worse than that of left-sided mCRC (3). One of the reasons is that right-sided mCRC has a higher incidence of the BRAF V600E mutation, which is a negative predictor for the efficacy of epidermal growth factor receptor (EGFR) inhibitors (4-7) and is characterized by rapid disease progression (7-9). In contrast, the PIK3CA mutation, which is more frequent in the right-sided mCRC, is controversial in terms of whether it is a predictor for the chemotherapeutic effect of EGFR inhibitors (5, 10-13).

Initially, primary tumor location was drawing attention as a predictor of the efficacy of EGFR inhibitors in the post-hoc analysis of the NCIC CO.17 trial (14). Subsequently, Arnold et al. reported a post-hoc analysis of large-scale randomized clinical trials [CRYSTAL (15), FIRE-3 (16), CALGB/SWOG 80405 (17), PRIME (18), PEAK (19), and 20050181 (20)] to examine the relationship between the primary tumor location, prognosis, and the chemotherapeutic effect of molecularly targeted agents in front-line chemotherapy (21). The hazard ratio (HR) of progression-free survival (PFS) and overall survival (OS) in mCRC patients with right-sided tumors was worse than that of those with left-sided tumors, indicating that right-sided tumors had a worse prognosis (21). In addition, in terms of the efficacy of chemotherapy (PFS and OS), the HRs of chemotherapy with EGFR inhibitors were significantly better than those of chemotherapy with vascular endothelial growth factor (VEGF) inhibitors in mCRC patients with left-sided tumors (21). Based on the results of the analysis, chemotherapy with an EGFR inhibitor is recommended for RAS/BRAF wild type (WT) mCRC patients with left-sided tumors, and chemotherapy with a VEGF inhibitor is recommended for RAS/BRAF WT mCRC patients with right-sided tumors or RAS/ BRAF mutant (MT) mCRC patients (1, 2).

In clinical practice, RAS/BRAF WT mCRC patients with right-sided tumors are treated with chemotherapy plus VEGF inhibitor as first-line chemotherapy, and EGFR inhibitors are considered in the third line of treatment because they do not add to OS as the second-line treatment (20, 22). However, there are only a few detailed reports about the relationship between primary tumor location, RAS, BRAF V600E, and PIK3CA mutations, and the chemotherapeutic effects of EGFR inhibitors in third-line treatment compared to those in the first-line treatment (23). This study aimed to investigate the effects of primary tumor location and the mutations in the abovementioned genes on the treatment outcome with EGFR inhibitors as third-line chemotherapy.

Patients and Methods

Patients. A total of 219 mCRC patients treated with EGFR inhibitor monotherapy or EGFR inhibitor plus irinotecan as third-line chemotherapy, at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research, from April 2011 to September 2017 were retrospectively enrolled in this study. Clinical characteristics including patient background factors, laboratory and imaging data, and prognosis were collected, and the follow-up period ended (the time of data cut off) on March 12, 2020. This study was approved by the Institutional Review Board of the Japanese Foundation for Cancer Research (Tokyo, Japan, registry number 1098; approval number 2020-1310). The protocol was described on the hospital website and the subjects were provided with the opportunity to opt out; therefore, no new consent was required from patients. All methods were performed in accordance with the Declaration of Helsinki.

Tumor tissue DNA sequencing. Genomic DNA was extracted from formalin-fixed, paraffin-embedded tissues obtained from biopsies or surgical specimens. We analyzed the KRAS, NRAS, BRAF, and PIK3CA genotypes using the bead-based multiplexed immunoassay system (xMAP Technology; Luminex, Tokyo, Japan). KRAS codon 12 and 13 mutations (MTs) (KRAS G12A, G12C, G12D, G12R, G12S, G12V, G13D) were detected using the MEBGEN KRAS Mutation Detection Kit (MBL, Tokyo, Japan), according to the manufacturer’s instruction. MTs in KRAS codon 61 (Q61K, Q61E, Q61L, Q61P, Q61R, Q61H), codon 146 (A146T, A146S, A146P, A146E, A146V, A146G), and codon 600 (V600E), in NRAS codon 12 (G12S, G12C, G12R, G12D, G12V, G12A), codon 13 (G13S, G13C, G13R, G13D, G13V, G13A), and codon 61 (Q61K, Q61E, Q61L, Q61P, Q61R, Q61H), and in PIK3CA codon 542 (E542K), codon 545 (E545K), codon 546 (E546K), and codon 1047 (H1047R, H1047L) were detected using the GENOSEARCHTM Mu-PACKTM (MBL), according to the manufacturer’s instructions. Treatment. Irinotecan (CPT-11) plus cetuximab (C-mab) were administered intravenously at 150 mg/m2 and 500 mg/m2, respectively, every 2 weeks or as an initial dose of 400 mg/m2 C-mab followed by weekly intravenous infusions of 250 mg/m2 C-mab. CPT-11 plus panitumumab (P-mab) were administered intravenously every 2 weeks at 180 mg/m2 and 6 mg/kg, respectively. C-mab monotherapy was administered at an initial dose of 400 mg/m2 followed by weekly intravenous infusions of 250 mg/m2 or 500 mg/m2 C-mab every 2 weeks. P-mab monotherapy was administered intravenously every 2 weeks at a dose of 6 mg/kg P-mab. Dose reduction or interruption was performed based on the institutional standards of clinical practice.

Study endpoints. This study aimed to evaluate the relationship between clinical outcomes, primary tumor location and RAS (KRAS exon 3 or 4 and NRAS), BRAF V600E, and PIK3CA mutations in mCRC patients treated with chemotherapy including EGFR inhibitor as the third-line treatment. The primary tumor location was divided into right-sided and left-sided tumors; right-sided tumors were defined as tumors arising anywhere from the cecum to the transverse colon and left-sided tumors were defined as tumors arising from the splenic flexure to the anorectal junction. PFS was defined as the time from the start of third-line treatment to the date of disease progression and OS was the time from third-line treatment initiation to the date of death. The response rate (RR) was calculated as the proportion of patients with complete response (CR) plus partial response (PR). Disease control rate (DCR) was calculated as the proportion of patients with CR and PR plus stable disease (SD). Objective responses were evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Imaging evaluation, mainly by computed tomography, was performed every 1.5-2 months following standard institutional practice.

Statistical analysis. PFS and OS were estimated using the Kaplan– Meier method. All reported p-values are the results of two-sided tests, with p<0.05 considered statistically significant. In the Cox proportional hazard analysis, factors with p<0.05 in the univariate analysis were included in the multivariate analysis (backward stepwise methods). The statistical software EZR (Easy R, Y Kanda, Jichi Medical University Saitama Medical Center, Saitama, Japan), which is based on R and R commander, was used for all the statistical analyses (24).

Results

Patient characteristics. A total of 219 patients who received EGFR inhibitor monotherapy or EGFR inhibitor plus irinotecan as third-line chemotherapy and C-mab were enrolled. Among them, 72 patients were eligible for this study (Figure 1). Patient clinical characteristics are shown in Table I. The median age at the initiation of the third line chemotherapy was 64.0 years (range=33.0-85.0 years). Of the 72 patients, 36 were male (50.0%). The sites of metastases were liver (50; 69.4%), followed by the lungs (32; 44.4%), intraabdominal lymph nodes (33; 45.8%), and peritoneum (20; 27.8%). Precisely, 59 (81.9%) patients received EGFR inhibitor plus irinotecan and 13 (18.1%) received EGFR inhibitor monotherapy. Thirty-one patients (43.0%) had right-sided tumors. KRAS exon 3, KRAS exon 4, NRAS, BRAF, and PIK3CA mutations were present in 0%, 6.9%, 2.8%, 12.5%, and 12.8% of the tumors, respectively (Table I). The frequency of BRAF V600E and PIK3CA mutations was higher in patients with right-sided tumors than in those with left-sided tumors (BRAF V600E: 22.6% vs. 4.9%, p=0.03; PIK3CA: 19.2% vs. 4.8%, p=0.2, Table II).

Figure 1.
Figure 1.

Study design. Databases were queried for patients who were treated with EGFR inhibitor with or without irinotecan as third-line chemotherapy from April 2011 to September 2017. Patients with KRAS exon 2 mutation or BRAF V600E status unknown were excluded. The remaining patients were eligible for this study. EGFR: Epidermal growth factor receptor; mCRC: metastatic colorectal cancer; MT: mutations; WT: wild type.

View this table:
Table I.

Patient demographics and clinical characteristics.

Response and survival endpoints. RR, DCR, median PFS, and OS in all patients were 27.8%, 70.8%, 6.1 months (4.2-6.9), and 12.7 months (11.4-15.2), respectively. The ORR and DCR according to the RAS and BRAF V600E mutations and primary tumor location are shown in Figure 2. When mCRC patients with gene mutations were excluded, both ORR and DCR were elevated regardless of the primary tumor location (ORR: RAS WT 29.2%, RAS/BRAF WT 33.3%; DCR: RAS WT 75.4%, RAS/BRAF WT 84.2%, Figure 2A-C). The PFS of the RAS WT subgroup was also significantly longer than that of the RAS MT subgroup (6.5 vs. 2.3 months, p=0.009) irrespective of the primary tumor location (Figure 3A). In addition, the PFS and OS of the BRAF V600E WT subgroup were significantly longer than those of the BRAF V600E MT subgroup (PFS: 6.5 vs. 1.6 months, p=0.00007; OS: 13.4 vs. 2.9 months, p<0.00001) irrespective of the primary tumor location (Figure 3B). Furthermore, PFS of the RAS/BRAF WT subgroup was significantly longer than that of any MT subgroup (PFS: 6.8 vs. 1.9 months, p=0.000001) irrespective of the primary tumor location (Figure 3C). Similar to the response results, both the PFS and OS in the RAS WT or RAS/BRAF WT subgroup were longer than those in the KRAS exon 2 WT subgroup (median PFS: RAS WT 6.5 months, RAS/BRAF WT 6.8 months; OS: RAS WT 12.7 months, RAS/BRAF WT 14.0 months).

Figure 2.
Figure 2.

Tumor response according to RAS/BRAF status. A) Tumor response in all metastatic colorectal cancer (mCRC) patients according to the RAS (KRAS exon 3,4 or NRAS) and BRAF V600E status. B) Tumor response in mCRC patients with left-sided tumors according to RAS and BRAF V600E status. C) Tumor response in mCRC patients with right-sided tumors according to RAS and BRAF V600E status. CR: Complete response; PR: partial response; SD: stable disease; PR: progressive disease; WT: wild type; RR: response rate; DCR: disease control rate.

Figure 3.
Figure 3.

Kaplan–Meier estimates of progression-free survival (PFS) with respect to a) RAS (KRAS exon 3,4 or NRAS), b) BRAF V600E, c) RAS/BRAF V600E status and primary tumor location in mCRC patients treated with EGFR inhibitor with or without irinotecan as third-line chemotherapy. MT: Mutations; WT: wild type; CI: confidence interval; mCRC: metastatic colorectal cancer; EGFR: epidermal growth factor receptor. Comparison of PFS according to the RAS, BRAF V600E and RAS/BRAF V600E status (RAS or BRAF V600E or RAS/BRAF V600E wild vs. mutant) and primary tumor location (left-sided vs. right-sided). p-Values were calculated using log-rank test.

Univariate and multivariate analyses of predictors of clinical outcomes. In the univariate Cox proportional hazard analysis, lung metastasis, carbohydrate antigen 19-9 (CA 19-9) level, RAS mutation, and BRAF V600E mutation were predictors for PFS, and performance status (PS), lung metastasis, and BRAF V600E mutation were predictors for OS (Table III).

View this table:
Table II.

The incidence and distribution of KRAS exon 3, KRAS exon 4, NRAS, BRAF V600E, and PIK3CA mutations.

View this table:
Table III.

Cox proportional hazard analysis for factors associated with survival.

In the multivariate analysis, RAS and BRAF V600E mutations were independent factors for shorter PFS (RAS mutation: HR=3.46, p=0.004; BRAF V600E mutation: HR=4.44, p=0.00008, Table III). PS and BRAF V600E mutation were independent factors for shorter OS (PS: HR=2.18, p=0.01; BRAF V600E mutation: HR=6.06, p=0.00002, Table III). On the other hand, primary tumor location (PFS: HR=1.22, p=0.40; OS: HR=1.22, p=0.42 in univariate analysis), and PIK3CA mutation (PFS: HR=1.14, p=0.77; OS: HR=0.82, p=0.67 in univariate analysis) did not influence survival (Table III).

Discussion

The present study demonstrated that RAS and BRAF V600E mutations are predictors of shorter PFS, and BRAF V600E mutation is a predictor of shorter OS compared to the WT, although PIK3CA mutations and primary tumor location did not predict the clinical outcomes in KRAS exon 2 WT mCRC patients treated with EGFR inhibitors with or without CPT-11 as third-line chemotherapy.

Previously, in almost all reports on mCRC, the primary tumor location was divided into the rectum and colon. Therefore, since there are only a few reports discriminating between left-side and right-side primary tumor location especially in third-line treatment, it is difficult to evaluate the relationship between primary tumor location (left- and right-sided) and clinical outcomes of EGFR inhibitors. The summary of clinical outcomes of mCRC patients with right-sided tumors receiving later-line EGFR inhibitors is shown in Table IV (14, 23, 25, 26). Brule et al. examined whether the primary tumor location of colon cancer is a prognostic factor and a predictor of the benefits of C-mab using the results of the NCIC CO.17 trial (14). According to the results of this study, among KRAS exon 2 WT patients, those with left-sided tumors had a significantly improved PFS when treated with C-mab compared to best supportive care (BSC) (HR=0.28, p<0.0001), whereas those with right-sided tumors did not (HR=0.73, p=0.26, interaction p=0.002) (14). Furthermore, a recent additional analysis reported that patients with left-sided RAS/BRAF V600E WT tumors obtained a strong benefit of prolonged PFS following C-mab therapy (HR=0.20, p<0.0001), while right-sided tumors did not reach significance (HR=0.48; p=0.16) (25). Therefore, primary tumor location is a predictor of PFS benefit for C-mab therapy. On the other hand, Boeckx et al. reported the effect of primary tumor location on clinical outcomes of P-mab treatment in patients with RAS WT mCRC (23). A significant PFS benefit (HR=0.31; p<0.0001) was observed when P-mab was added to BSC for RAS WT left-sided mCRC patients (23). In contrast, no difference was observed in PFS of patients with right-sided tumors (HR=0.50; p=0.10) (22). Similar results were observed in RAS/BRAF WT patients receiving P-mab (23). However, the number of patients in both the studies was too small and insufficient for definitive conclusions. In the present study, in which CPT-11 plus EGFR inhibitor was used in more than 80% of the patients, the effect of EGFR inhibitor was observed in the right-sided tumors as well as the left-sided tumors, except for those with RAS and BRAF V600E mutations. Therefore, further studies are needed to clarify the effect of primary tumor location on the clinical outcomes of EGFR inhibitors as third-line chemotherapy.

View this table:
Table IV.

Previous reports of clinical outcomes in right-sided mCRC patients treated with third-line EGFR inhibitor with or without Irinotecan.

In several guidelines for mCRC treatment, C-mab, P-mab, CPT-11 plus C-mab/P-mab, regorafenib, and trifluridine/ tipiracil (FTD/TPI) (+bevacizumab) are recommended as third-line or later-line treatments. The summary of clinical outcomes of mCRC patients receiving later-line treatments is shown in Table V (27-36). Among them, regorafenib and TPI/FTD (+bevacizumab) have greatly expanded the options for the salvage treatment of mCRC (30, 33-35). However, the response rate of these therapies is very low (1.0%-4.0%), and they are aimed at disease progression and not at tumor shrinkage. Therefore, considering the perspective of response rate and survival, the use of EGFR inhibitors should be considered, even in mCRC patients with right-sided tumors except for those with RAS and BRAF V600E mutations. Currently, it is recommended to evaluate the RAS and BRAF status prior to first-line treatment (1, 2) but if only the results of KRAS exon 2 mutations are available, it is important to examine the other RAS (KRAS exon 3 ,4 or NRAS) and BRAF status prior to third line treatment in order to maximize the response to EGFR inhibitors.

View this table:
Table V.

Previous reports of clinical outcomes in mCRC patients treated with salvage line chemorherapy.

There are limitations to our study. This was a retrospective study with a relatively small sample size. However, even with these limitations, the results of this study provide important insights into the clinical use of EGFR inhibitors as the third-line treatment, especially in patients with RAS/BRAF WT right-sided tumors.

In conclusion, our data indicated that the additional analysis of RAS and BRAF V600E mutations could contribute to the selection of patients who are most likely to benefit from third-line EGFR inhibitors, regardless of primary tumor location.

Acknowledgements

The Authors would like to thank Ms. Yukie Naito and Ms. Yuki Horiike for providing data management services. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Footnotes

  • ↵* These Authors contributed equally to this work.

  • Authors’ Contributions

    Conception and design: TS, HO, ES, AO, and KY; acquisition of data: TS and HO; analysis and interpretation of data: TS, HO, ES, AO; writing, review and/or revision of the manuscript: all Authors; administrative, technical, or material support: TS, HO, ES; study supervision: KY.

  • Conflicts of Interest

    The Authors declare that they have no conflicts of interest in relation to this study.

  • Received May 6, 2021.
  • Revision received June 20, 2021.
  • Accepted June 23, 2021.

References

  1. ↵
    1. Yoshino T,
    2. Arnold D,
    3. Taniguchi H,
    4. Pentheroudakis G,
    5. Yamazaki K,
    6. Xu RH,
    7. Kim TW,
    8. Ismail F,
    9. Tan IB,
    10. Yeh KH,
    11. Grothey A,
    12. Zhang S,
    13. Ahn JB,
    14. Mastura MY,
    15. Chong D,
    16. Chen LT,
    17. Kopetz S,
    18. Eguchi-Nakajima T,
    19. Ebi H,
    20. Ohtsu A,
    21. Cervantes A,
    22. Muro K,
    23. Tabernero J,
    24. Minami H,
    25. Ciardiello F and
    26. Douillard JY
    : Pan-Asian adapted ESMO consensus guidelines for the management of patients with metastatic colorectal cancer: a JSMO-ESMO initiative endorsed by CSCO, KACO, MOS, SSO and TOS. Ann Oncol 29(1): 44-70, 2018. PMID: 29155929. DOI: 10.1093/annonc/mdx738
    OpenUrlCrossRefPubMed
  2. ↵
    1. Hashiguchi Y,
    2. Muro K,
    3. Saito Y,
    4. Ito Y,
    5. Ajioka Y,
    6. Hamaguchi T,
    7. Hasegawa K,
    8. Hotta K,
    9. Ishida H,
    10. Ishiguro M,
    11. Ishihara S,
    12. Kanemitsu Y,
    13. Kinugasa Y,
    14. Murofushi K,
    15. Nakajima TE,
    16. Oka S,
    17. Tanaka T,
    18. Taniguchi H,
    19. Tsuji A,
    20. Uehara K,
    21. Ueno H,
    22. Yamanaka T,
    23. Yamazaki K,
    24. Yoshida M,
    25. Yoshino T,
    26. Itabashi M,
    27. Sakamaki K,
    28. Sano K,
    29. Shimada Y,
    30. Tanaka S,
    31. Uetake H,
    32. Yamaguchi S,
    33. Yamaguchi N,
    34. Kobayashi H,
    35. Matsuda K,
    36. Kotake K,
    37. Sugihara K and Japanese Society for Cancer of the Colon and Rectum
    : Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2019 for the treatment of colorectal cancer. Int J Clin Oncol 25(1): 1-42, 2020. PMID: 31203527. DOI: 10.1007/s10147-019-01485-z
    OpenUrlCrossRefPubMed
  3. ↵
    1. Tejpar S,
    2. Stintzing S,
    3. Ciardiello F,
    4. Tabernero J,
    5. Van Cutsem E,
    6. Beier F,
    7. Esser R,
    8. Lenz HJ and
    9. Heinemann V
    : Prognostic and predictive relevance of primary tumor location in patients With RAS wild-type metastatic colorectal cancer: Retrospective analyses of the CRYSTAL and FIRE-3 trials. JAMA Oncol 3(2): 194-201, 2017. PMID: 27722750. DOI: 10.1001/jamaoncol.2016.3797
    OpenUrlCrossRefPubMed
  4. ↵
    1. Van Cutsem E,
    2. Köhne CH,
    3. Láng I,
    4. Folprecht G,
    5. Nowacki MP,
    6. Cascinu S,
    7. Shchepotin I,
    8. Maurel J,
    9. Cunningham D,
    10. Tejpar S,
    11. Schlichting M,
    12. Zubel A,
    13. Celik I,
    14. Rougier P and
    15. Ciardiello F
    : Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 29(15): 2011-2019, 2011. PMID: 21502544. DOI: 10.1200/JCO.2010.33.5091
    OpenUrlAbstract/FREE Full Text
  5. ↵
    1. Taniguchi H,
    2. Uehara K,
    3. Nakayama G,
    4. Nakayama H,
    5. Aiba T,
    6. Hattori N,
    7. Kataoka M,
    8. Nakano Y,
    9. Kawase Y,
    10. Okochi O,
    11. Matsuoka H,
    12. Utsunomiya S,
    13. Sakamoto E,
    14. Mori Y,
    15. Umeda S,
    16. Shikano T,
    17. Komori K,
    18. Tajika M,
    19. Kadowaki S,
    20. Muro K and
    21. Yatabe Y
    : Tumor location is associated with the prevalence of braf and pik3ca mutations in patients with wild-type ras colorectal cancer: A prospective multi-center cohort study in japan. Transl Oncol 13(7): 100786, 2020. PMID: 32428838. DOI: 10.1016/j.tranon.2020.100786
    OpenUrlCrossRefPubMed
    1. Sanchez-Ibarra HE,
    2. Jiang X,
    3. Gallegos-Gonzalez EY,
    4. Cavazos-González AC,
    5. Chen Y,
    6. Morcos F and
    7. Barrera-Saldaña HA
    : KRAS, NRAS, and BRAF mutation prevalence, clinicopathological association, and their application in a predictive model in Mexican patients with metastatic colorectal cancer: A retrospective cohort study. PLoS One 15(7): e0235490, 2020. PMID: 32628708. DOI: 10.1371/journal.pone.0235490
    OpenUrlCrossRefPubMed
  7. ↵
    1. Modest DP,
    2. Jung A,
    3. Moosmann N,
    4. Laubender RP,
    5. Giessen C,
    6. Schulz C,
    7. Haas M,
    8. Neumann J,
    9. Boeck S,
    10. Kirchner T,
    11. Heinemann V and
    12. Stintzing S
    : The influence of KRAS and BRAF mutations on the efficacy of cetuximab-based first-line therapy of metastatic colorectal cancer: an analysis of the AIO KRK-0104-trial. Int J Cancer 131(4): 980-986, 2012. PMID: 21960311. DOI: 10.1002/ijc.26467
    OpenUrlCrossRefPubMed
    1. Tie J,
    2. Gibbs P,
    3. Lipton L,
    4. Christie M,
    5. Jorissen RN,
    6. Burgess AW,
    7. Croxford M,
    8. Jones I,
    9. Langland R,
    10. Kosmider S,
    11. McKay D,
    12. Bollag G,
    13. Nolop K,
    14. Sieber OM and
    15. Desai J
    : Optimizing targeted therapeutic development: analysis of a colorectal cancer patient population with the BRAF(V600E) mutation. Int J Cancer 128(9): 2075-2084, 2011. PMID: 20635392. DOI: 10.1002/ijc.25555
    OpenUrlCrossRefPubMed
  9. ↵
    1. Venderbosch S,
    2. Nagtegaal ID,
    3. Maughan TS,
    4. Smith CG,
    5. Cheadle JP,
    6. Fisher D,
    7. Kaplan R,
    8. Quirke P,
    9. Seymour MT,
    10. Richman SD,
    11. Meijer GA,
    12. Ylstra B,
    13. Heideman DA,
    14. de Haan AF,
    15. Punt CJ and
    16. Koopman M
    : Mismatch repair status and BRAF mutation status in metastatic colorectal cancer patients: a pooled analysis of the CAIRO, CAIRO2, COIN, and FOCUS studies. Clin Cancer Res 20(20): 5322-5330, 2014. PMID: 25139339. DOI: 10.1158/1078-0432.CCR-14-0332
    OpenUrlAbstract/FREE Full Text
  10. ↵
    1. Sartore-Bianchi A,
    2. Martini M,
    3. Molinari F,
    4. Veronese S,
    5. Nichelatti M,
    6. Artale S,
    7. Di Nicolantonio F,
    8. Saletti P,
    9. De Dosso S,
    10. Mazzucchelli L,
    11. Frattini M,
    12. Siena S and
    13. Bardelli A
    : PIK3CA mutations in colorectal cancer are associated with clinical resistance to EGFR-targeted monoclonal antibodies. Cancer Res 69(5): 1851-1857, 2009. PMID: 19223544. DOI: 10.1158/0008-5472.CAN-08-2466
    OpenUrlAbstract/FREE Full Text
    1. De Roock W,
    2. Claes B,
    3. Bernasconi D,
    4. De Schutter J,
    5. Biesmans B,
    6. Fountzilas G,
    7. Kalogeras KT,
    8. Kotoula V,
    9. Papamichael D,
    10. Laurent-Puig P,
    11. Penault-Llorca F,
    12. Rougier P,
    13. Vincenzi B,
    14. Santini D,
    15. Tonini G,
    16. Cappuzzo F,
    17. Frattini M,
    18. Molinari F,
    19. Saletti P,
    20. De Dosso S,
    21. Martini M,
    22. Bardelli A,
    23. Siena S,
    24. Sartore-Bianchi A,
    25. Tabernero J,
    26. Macarulla T,
    27. Di Fiore F,
    28. Gangloff AO,
    29. Ciardiello F,
    30. Pfeiffer P,
    31. Qvortrup C,
    32. Hansen TP,
    33. Van Cutsem E,
    34. Piessevaux H,
    35. Lambrechts D,
    36. Delorenzi M and
    37. Tejpar S
    : 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(8): 753-762, 2010. PMID: 20619739. DOI: 10.1016/S1470-2045(10)70130-3
    OpenUrlCrossRefPubMed
    1. Karapetis CS,
    2. Jonker D,
    3. Daneshmand M,
    4. Hanson JE,
    5. O’Callaghan CJ,
    6. Marginean C,
    7. Zalcberg JR,
    8. Simes J,
    9. Moore MJ,
    10. Tebbutt NC,
    11. Price TJ,
    12. Shapiro JD,
    13. Pavlakis N,
    14. Gibbs P,
    15. Van Hazel GA,
    16. Lee U,
    17. Haq R,
    18. Virk S,
    19. Tu D,
    20. Lorimer IA and NCIC Clinical Trials Group and the Australasian Gastro-Intestinal Trials Group
    : PIK3CA, BRAF, and PTEN status and benefit from cetuximab in the treatment of advanced colorectal cancer— results from NCIC CTG/AGITG CO.17. Clin Cancer Res 20(3): 744-753, 2014. PMID: 24218517. DOI: 10.1158/1078-0432.CCR-13-0606
    OpenUrlAbstract/FREE Full Text
  13. ↵
    1. Peeters M,
    2. Oliner KS,
    3. Parker A,
    4. Siena S,
    5. Van Cutsem E,
    6. Huang J,
    7. Humblet Y,
    8. Van Laethem JL,
    9. André T,
    10. Wiezorek J,
    11. Reese D and
    12. Patterson SD
    : Massively parallel tumor multigene sequencing to evaluate response to panitumumab in a randomized phase III study of metastatic colorectal cancer. Clin Cancer Res 19(7): 1902-1912, 2013. PMID: 23325582. DOI: 10.1158/1078-0432.CCR-12-1913
    OpenUrlAbstract/FREE Full Text
  14. ↵
    1. Brulé SY,
    2. Jonker DJ,
    3. Karapetis CS,
    4. O’Callaghan CJ,
    5. Moore MJ,
    6. Wong R,
    7. Tebbutt NC,
    8. Underhill C,
    9. Yip D,
    10. Zalcberg JR,
    11. Tu D and
    12. Goodwin RA
    : Location of colon cancer (right-sided versus left-sided) as a prognostic factor and a predictor of benefit from cetuximab in NCIC CO.17. Eur J Cancer 51(11): 1405-1414, 2015. PMID: 25979833. DOI: 10.1016/j.ejca.2015.03.015
    OpenUrlCrossRefPubMed
  15. ↵
    1. Van Cutsem E,
    2. Köhne CH,
    3. Hitre E,
    4. Zaluski J,
    5. Chang Chien CR,
    6. Makhson A,
    7. D’Haens G,
    8. Pintér T,
    9. Lim R,
    10. Bodoky G,
    11. Roh JK,
    12. Folprecht G,
    13. Ruff P,
    14. Stroh C,
    15. Tejpar S,
    16. Schlichting M,
    17. Nippgen J and
    18. Rougier P
    : Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360(14): 1408-1417, 2009. PMID: 19339720. DOI: 10.1056/NEJMoa0805019
    OpenUrlCrossRefPubMed
  16. ↵
    1. Heinemann V,
    2. von Weikersthal LF,
    3. Decker T,
    4. Kiani A,
    5. Vehling-Kaiser U,
    6. Al-Batran SE,
    7. Heintges T,
    8. Lerchenmüller C,
    9. Kahl C,
    10. Seipelt G,
    11. Kullmann F,
    12. Stauch M,
    13. Scheithauer W,
    14. Hielscher J,
    15. Scholz M,
    16. Müller S,
    17. Link H,
    18. Niederle N,
    19. Rost A,
    20. Höffkes HG,
    21. Moehler M,
    22. Lindig RU,
    23. Modest DP,
    24. Rossius L,
    25. Kirchner T,
    26. Jung A and
    27. Stintzing S
    : 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(10): 1065-1075, 2014. PMID: 25088940. DOI: 10.1016/S1470-2045(14)70330-4
    OpenUrlCrossRefPubMed
  17. ↵
    1. Venook AP,
    2. Niedzwiecki D,
    3. Lenz HJ,
    4. Innocenti F,
    5. Fruth B,
    6. Meyerhardt JA,
    7. Schrag D,
    8. Greene C,
    9. O’Neil BH,
    10. Atkins JN,
    11. Berry S,
    12. Polite BN,
    13. O’Reilly EM,
    14. Goldberg RM,
    15. Hochster HS,
    16. Schilsky RL,
    17. Bertagnolli MM,
    18. El-Khoueiry AB,
    19. Watson P,
    20. Benson AB , 3rd,
    21. Mulkerin DL,
    22. Mayer RJ and
    23. Blanke C
    : 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(23): 2392-2401, 2017. PMID: 28632865. DOI: 10.1001/jama.2017.7105
    OpenUrlCrossRefPubMed
  18. ↵
    1. Douillard JY,
    2. Siena S,
    3. Cassidy J,
    4. Tabernero J,
    5. Burkes R,
    6. Barugel M,
    7. Humblet Y,
    8. Bodoky G,
    9. Cunningham D,
    10. Jassem J,
    11. Rivera F,
    12. Kocákova I,
    13. Ruff P,
    14. Błasińska-Morawiec M,
    15. Šmakal M,
    16. Canon JL,
    17. Rother M,
    18. Oliner KS,
    19. Wolf M and
    20. Gansert J
    : 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(31): 4697-4705, 2010. PMID: 20921465. DOI: 10.1200/JCO.2009.27.4860
    OpenUrlAbstract/FREE Full Text
  19. ↵
    1. Schwartzberg LS,
    2. Rivera F,
    3. Karthaus M,
    4. Fasola G,
    5. Canon JL,
    6. Hecht JR,
    7. Yu H,
    8. Oliner KS and
    9. Go WY
    : PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 32(21): 2240-2247, 2014. PMID: 24687833. DOI: 10.1200/JCO.2013.53.2473
    OpenUrlAbstract/FREE Full Text
  20. ↵
    1. Peeters M,
    2. Price TJ,
    3. Cervantes A,
    4. Sobrero AF,
    5. Ducreux M,
    6. Hotko Y,
    7. André T,
    8. Chan E,
    9. Lordick F,
    10. Punt CJ,
    11. Strickland AH,
    12. Wilson G,
    13. Ciuleanu TE,
    14. Roman L,
    15. Van Cutsem E,
    16. Tzekova V,
    17. Collins S,
    18. Oliner KS,
    19. Rong A and
    20. Gansert J
    : Randomized phase III study of panitumumab with fluorouracil, leucovorin, and irinotecan (FOLFIRI) compared with FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol 28(31): 4706-4713, 2010. PMID: 20921462. DOI: 10.1200/JCO.2009.27.6055
    OpenUrlAbstract/FREE Full Text
  21. ↵
    1. Arnold D,
    2. Lueza B,
    3. Douillard JY,
    4. Peeters M,
    5. Lenz HJ,
    6. Venook A,
    7. Heinemann V,
    8. Van Cutsem E,
    9. Pignon JP,
    10. Tabernero J,
    11. Cervantes A and
    12. Ciardiello F
    : Prognostic and predictive value of primary tumour side in patients with RAS wild-type metastatic colorectal cancer treated with chemotherapy and EGFR directed antibodies in six randomized trials. Ann Oncol 28(8): 1713-1729, 2017. PMID: 28407110. DOI: 10.1093/annonc/mdx175
    OpenUrlCrossRefPubMed
  22. ↵
    1. Sobrero AF,
    2. Maurel J,
    3. Fehrenbacher L,
    4. Scheithauer W,
    5. Abubakr YA,
    6. Lutz MP,
    7. Vega-Villegas ME,
    8. Eng C,
    9. Steinhauer EU,
    10. Prausova J,
    11. Lenz HJ,
    12. Borg C,
    13. Middleton G,
    14. Kröning H,
    15. Luppi G,
    16. Kisker O,
    17. Zubel A,
    18. Langer C,
    19. Kopit J and
    20. Burris HA , 3rd
    : EPIC: phase III trial of cetuximab plus irinotecan after fluoropyrimidine and oxaliplatin failure in patients with metastatic colorectal cancer. J Clin Oncol 26(14): 2311-2319, 2008. PMID: 18390971. DOI: 10.1200/JCO.2007.13.1193
    OpenUrlAbstract/FREE Full Text
  23. ↵
    1. Boeckx N,
    2. Koukakis R,
    3. Op de Beeck K,
    4. Rolfo C,
    5. Van Camp G,
    6. Siena S,
    7. Tabernero J,
    8. Douillard JY,
    9. André T and
    10. Peeters M
    : Effect of primary tumor location on second- or later-line treatment outcomes in patients with RAS wild-type metastatic colorectal cancer and all treatment lines in patients with RAS mutations in four randomized panitumumab studies. Clin Colorectal Cancer 17(3): 170-178.e3, 2018. PMID: 29627309. DOI: 10.1016/j.clcc.2018.03.005
    OpenUrlCrossRefPubMed
  24. ↵
    1. Kanda Y
    : Investigation of the freely available easy-to-use software ‘EZR’ for medical statistics. Bone Marrow Transplant 48(3): 452-458, 2013. PMID: 23208313. DOI: 10.1038/bmt.2012.244
    OpenUrlCrossRefPubMed
  25. ↵
    1. Loree JM,
    2. Dowers A,
    3. Tu D,
    4. Jonker DJ,
    5. Edelstein DL,
    6. Quinn H,
    7. Holtrup F,
    8. Price T,
    9. Zalcberg JR,
    10. Moore MJ,
    11. Karapetis CS,
    12. O’Callaghan CJ,
    13. Waring P,
    14. Kennecke HF,
    15. Hamilton SR and
    16. Kopetz S
    : Expanded low allele frequency RAS and BRAF V600E testing in metastatic colorectal cancer as predictive biomarkers for cetuximab in the randomized CO.17 trial. Clin Cancer Res 27(1): 52-59, 2021. PMID: 33087330. DOI: 10.1158/1078-0432.CCR-20-2710
    OpenUrlAbstract/FREE Full Text
  26. ↵
    1. Kim D,
    2. Kim SY,
    3. Lee JS,
    4. Hong YS,
    5. Kim JE,
    6. Kim KP,
    7. Kim J,
    8. Jang SJ,
    9. Yoon YK and
    10. Kim TW
    : Primary tumor location predicts poor clinical outcome with cetuximab in RAS wild-type metastatic colorectal cancer. BMC Gastroenterol 17(1): 121, 2017. PMID: 29169325. DOI: 10.1186/s12876-017-0694-6
    OpenUrlCrossRefPubMed
  27. ↵
    1. Jonker DJ,
    2. O’Callaghan CJ,
    3. Karapetis CS,
    4. Zalcberg JR,
    5. Tu D,
    6. Au HJ,
    7. Berry SR,
    8. Krahn M,
    9. Price T,
    10. Simes RJ,
    11. Tebbutt NC,
    12. van Hazel G,
    13. Wierzbicki R,
    14. Langer C and
    15. Moore MJ
    : Cetuximab for the treatment of colorectal cancer. N Engl J Med 357(20): 2040-2048, 2007. PMID: 18003960. DOI: 10.1056/NEJMoa071834
    OpenUrlCrossRefPubMed
    1. Van Cutsem E,
    2. Peeters M,
    3. Siena S,
    4. Humblet Y,
    5. Hendlisz A,
    6. Neyns B,
    7. Canon JL,
    8. Van Laethem JL,
    9. Maurel J,
    10. Richardson G,
    11. Wolf M and
    12. Amado RG
    : Open-label phase III trial of panitumumab plus best supportive care compared with best supportive care alone in patients with chemotherapy-refractory metastatic colorectal cancer. J Clin Oncol 25(13): 1658-1664, 2007. PMID: 17470858. DOI: 10.1200/JCO.2006.08.1620
    OpenUrlAbstract/FREE Full Text
    1. Cunningham D,
    2. Humblet Y,
    3. Siena S,
    4. Khayat D,
    5. Bleiberg H,
    6. Santoro A,
    7. Bets D,
    8. Mueser M,
    9. Harstrick A,
    10. Verslype C,
    11. Chau I and
    12. Van Cutsem E
    : Cetuximab monotherapy and cetuximab plus irinotecan in irinotecan-refractory metastatic colorectal cancer. N Engl J Med 351(4): 337-345, 2004. PMID: 15269313. DOI: 10.1056/NEJMoa033025
    OpenUrlCrossRefPubMed
  30. ↵
    1. Grothey A,
    2. Van Cutsem E,
    3. Sobrero A,
    4. Siena S,
    5. Falcone A,
    6. Ychou M,
    7. Humblet Y,
    8. Bouché O,
    9. Mineur L,
    10. Barone C,
    11. Adenis A,
    12. Tabernero J,
    13. Yoshino T,
    14. Lenz HJ,
    15. Goldberg RM,
    16. Sargent DJ,
    17. Cihon F,
    18. Cupit L,
    19. Wagner A,
    20. Laurent D and CORRECT Study Group
    : Regorafenib monotherapy for previously treated metastatic colorectal cancer (CORRECT): an international, multicentre, randomised, placebo-controlled, phase 3 trial. Lancet 381(9863): 303-312, 2013. PMID: 23177514. DOI: 10.1016/S0140-6736(12)61900-X
    OpenUrlCrossRefPubMed
    1. Price TJ,
    2. Peeters M,
    3. Kim TW,
    4. Li J,
    5. Cascinu S,
    6. Ruff P,
    7. Suresh AS,
    8. Thomas A,
    9. Tjulandin S,
    10. Zhang K,
    11. Murugappan S and
    12. Sidhu R
    : Panitumumab versus cetuximab in patients with chemotherapy-refractory wild-type KRAS exon 2 metastatic colorectal cancer (ASPECCT): a randomised, multicentre, open-label, non-inferiority phase 3 study. Lancet Oncol 15(6): 569-579, 2014. PMID: 24739896. DOI: 10.1016/S1470-2045(14)70118-4
    OpenUrlCrossRefPubMed
    1. Li J,
    2. Qin S,
    3. Xu R,
    4. Yau TC,
    5. Ma B,
    6. Pan H,
    7. Xu J,
    8. Bai Y,
    9. Chi Y,
    10. Wang L,
    11. Yeh KH,
    12. Bi F,
    13. Cheng Y,
    14. Le AT,
    15. Lin JK,
    16. Liu T,
    17. Ma D,
    18. Kappeler C,
    19. Kalmus J,
    20. Kim TW and CONCUR Investigators
    : Regorafenib plus best supportive care versus placebo plus best supportive care in Asian patients with previously treated metastatic colorectal cancer (CONCUR): a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet Oncol 16(6): 619-629, 2015. PMID: 25981818. DOI: 10.1016/S1470-2045(15)70156-7
    OpenUrlCrossRefPubMed
  33. ↵
    1. Mayer RJ,
    2. Van Cutsem E,
    3. Falcone A,
    4. Yoshino T,
    5. Garcia-Carbonero R,
    6. Mizunuma N,
    7. Yamazaki K,
    8. Shimada Y,
    9. Tabernero J,
    10. Komatsu Y,
    11. Sobrero A,
    12. Boucher E,
    13. Peeters M,
    14. Tran B,
    15. Lenz HJ,
    16. Zaniboni A,
    17. Hochster H,
    18. Cleary JM,
    19. Prenen H,
    20. Benedetti F,
    21. Mizuguchi H,
    22. Makris L,
    23. Ito M,
    24. Ohtsu A and RECOURSE Study Group
    .: Randomized trial of TAS-102 for refractory metastatic colorectal cancer. N Engl J Med 372(20): 1909-1919, 2015. PMID: 25970050. DOI: 10.1056/NEJMoa1414325
    OpenUrlCrossRefPubMed
    1. Kuboki Y,
    2. Nishina T,
    3. Shinozaki E,
    4. Yamazaki K,
    5. Shitara K,
    6. Okamoto W,
    7. Kajiwara T,
    8. Matsumoto T,
    9. Tsushima T,
    10. Mochizuki N,
    11. Nomura S,
    12. Doi T,
    13. Sato A,
    14. Ohtsu A and
    15. Yoshino T
    : TAS-102 plus bevacizumab for patients with metastatic colorectal cancer refractory to standard therapies (C-TASK FORCE): an investigator-initiated, open-label, single-arm, multicentre, phase 1/2 study. Lancet Oncol 18(9): 1172-1181, 2017. PMID: 28760399. DOI: 10.1016/S1470-2045(17)30425-4
    OpenUrlCrossRefPubMed
  35. ↵
    1. Pfeiffer P,
    2. Yilmaz M,
    3. Möller S,
    4. Zitnjak D,
    5. Krogh M,
    6. Petersen LN,
    7. Poulsen LØ,
    8. Winther SB,
    9. Thomsen KG and
    10. Qvortrup C
    : TAS-102 with or without bevacizumab in patients with chemorefractory metastatic colorectal cancer: an investigator-initiated, open-label, randomised, phase 2 trial. Lancet Oncol 21(3): 412-420, 2020. PMID: 31999946. DOI: 10.1016/S1470-2045(19)30827-7
    OpenUrlCrossRefPubMed
  36. ↵
    1. Sakai D,
    2. Taniguchi H,
    3. Sugimoto N,
    4. Tamura T,
    5. Nishina T,
    6. Hara H,
    7. Esaki T,
    8. Denda T,
    9. Sakamoto T,
    10. Okuda H,
    11. Satoh T,
    12. Tsushima T,
    13. Makiyama A,
    14. Tsuda T,
    15. Hosokawa A,
    16. Kuramochi H,
    17. Tokunaga S,
    18. Moriwaki T,
    19. Yasui H,
    20. Ishida H,
    21. Tsuji A,
    22. Otsu S,
    23. Shimokawa H,
    24. Baba E,
    25. Sato M,
    26. Matsumoto S,
    27. Ozaki Y,
    28. Shinozaki K,
    29. Tamagawa H,
    30. Goto M,
    31. Kadowaki S,
    32. Fujii H,
    33. Koh Y,
    34. Yamazaki K,
    35. Hironaka S,
    36. Kishimoto J,
    37. Boku N,
    38. Hyodo I and
    39. Muro K
    : Randomised phase II study of panitumumab plus irinotecan versus cetuximab plus irinotecan in patients with KRAS wild-type metastatic colorectal cancer refractory to fluoropyrimidine, irinotecan and oxaliplatin (WJOG 6510G). Eur J Cancer 135: 11-21, 2020. PMID: 32526634. DOI: 10.1016/j.ejca.2020.04.014
    OpenUrlCrossRefPubMed
Back to top

In this issue

Print
Download PDF
Article Alerts
Email Article
Citation Tools
Reprints and Permissions
Clinical Impact of Primary Tumor Location and RAS, BRAF V600E, and PIK3CA Mutations on Epidermal Growth Factor Receptor Inhibitor Efficacy as Third-line Chemotherapy for Metastatic Colorectal Cancer
TARO SATO, HIROKI OSUMI, EIJI SHINOZAKI, AKIRA OOKI, KEITARO SHIMOZAKI, DAISAKU KAMIIMABEPPU, IZUMA NAKAYAMA, TAKERU WAKATSUKI, MARIKO OGURA, DAISUKE TAKAHARI, KEISHO CHIN, KENSEI YAMAGUCHI
Anticancer Research Aug 2021, 41 (8) 3905-3915; DOI: 10.21873/anticanres.15186
Twitter logo Facebook logo Mendeley logo

Jump to section

Keywords