Chapter 3: Management of kidney injury caused by cancer drug therapy, from clinical practice guidelines for the management of kidney injury during anticancer drug therapy 2022.

Cisplatin should be administered with diuretics and Magnesium supplementation under adequate hydration to avoid renal impairment. Patients should be evaluated for eGFR (estimated glomerular filtration rate) during the treatment with pemetrexed, as kidney injury has been reported. Pemetrexed should be administered with caution in patients with a CCr (creatinine clearance) < 45 mL/min. Mesna is used to prevent hemorrhagic cystitis in patients receiving ifosfamide. Febuxostat is effective in avoiding hyperuricemia induced by TLS (tumor lysis syndrome). Preventative rasburicase is recommended in high-risk cases of TLS. Thrombotic microangiopathy could be triggered by anticancer drugs and there is no evidence of efficacy of plasma exchange therapy. When proteinuria occurs during treatment with anti-angiogenic agents or multi-kinase inhibitors, dose reductions or interruptions based on grading should be considered. Grade 3 proteinuria and renal dysfunction require urgent intervention, including drug interruption or withdrawal, and referral to a nephrologist should be considered. The first-line drugs used for blood pressure elevation due to anti-angiogenic agents are ACE (angiotensin-converting enzyme) inhibitors and ARBs (angiotensin receptor blockers). The protein binding of drugs and their pharmacokinetics are considerably altered in patients with hypoalbuminemia. The clearance of rituximab is increased in patients with proteinuria, and the correlation with urinary IgG suggests similar pharmacokinetic changes when using other antibody drugs. AIN (acute interstitial nephritis) is the most common cause of ICI (immune checkpoint inhibitor)-related kidney injury that is often treated with steroids. The need for renal biopsy in patients with kidney injury that occurs during treatment with ICI remains controversial.

Japanese Society for Cancer of the Colon and Rectum (JSCCR) guidelines 2020 for the Clinical Practice of Hereditary Colorectal Cancer.

Hereditary colorectal cancer (HCRC) accounts for < 5% of all colorectal cancer cases. Some of the unique characteristics commonly encountered in HCRC cases include early age of onset, synchronous/metachronous cancer occurrence, and multiple cancers in other organs. These characteristics necessitate different management approaches, including diagnosis, treatment or surveillance, from sporadic colorectal cancer management. There are two representative HCRC, named familial adenomatous polyposis and Lynch syndrome. Other than these two HCRC syndromes, related disorders have also been reported. Several guidelines for hereditary disorders have already been published worldwide. In Japan, the first guideline for HCRC was prepared by the Japanese Society for Cancer of the Colon and Rectum (JSCCR), published in 2012 and revised in 2016. This revised version of the guideline was immediately translated into English and published in 2017. Since then, several new findings and novel disease concepts related to HCRC have been discovered. The currently diagnosed HCRC rate in daily clinical practice is relatively low; however, this is predicted to increase in the era of cancer genomic medicine, with the advancement of cancer multi-gene panel testing or whole genome testing, among others. Under these circumstances, the JSCCR guidelines 2020 for HCRC were prepared by consensus among members of the JSCCR HCRC Guideline Committee, based on a careful review of the evidence retrieved from literature searches, and considering the medical health insurance system and actual clinical practice settings in Japan. Herein, we present the English version of the JSCCR guidelines 2020 for HCRC.

Phase II Study of the Reuse of Trastuzumab with Docetaxel beyond Progression after First-Line Treatment in Second-Line Treatment for Unresectable, Metastatic Gastric Cancer (T-CORE1203).

Whether trastuzumab use beyond disease progression is beneficial in second-line treatment for patients with unresectable human epidermal growth factor receptor 2 (HER2)-positive gastric cancer remains to be elucidated. We conducted this phase II study to assess whether trastuzumab plus docetaxel was effective for patients with previously treated advanced HER2-positive gastric cancer. This trial was a single-arm, open-label, multicenter, phase II study, conducted by Tohoku Clinical Oncology Research and Education Society (T-CORE). Patients aged 20 years or older who had advanced HER2-positive gastric cancer and were refractory to trastuzumab, fluoropyrimidine, and cisplatin were enrolled. Patients were treated with 6 mg/kg trastuzumab and 60 mg/m2 docetaxel every 3 weeks. The primary endpoint was the overall response rate. The threshold overall response rate was estimated to be at 15%. Secondary endpoints were progression-free survival, 6-month survival rate, overall survival, and toxicities. A total of 27 patients were enrolled from 7 hospitals. The median age was 67 years. Partial response was seen in 3 patients among the 26 evaluated patients. The overall response rate was at 11.5% (90% confidence interval 1.2%-21.8%). The median progression-free survival was 3.2 months, the 6-month survival rate was 85%, and the median overall survival was 11.6 months. Febrile neutropenia was observed in 14.8%. The most frequently observed grade 3 non-hematologic toxicity was anorexia (14.8%). The primary endpoint was not achieved. The results support a current consensus that the continuation of trastuzumab in second-line therapy for gastric cancer is not a recommended option.

First-line chemotherapy with S-1 alone or S-1 plus cisplatin for elderly patients with advanced gastric cancer: a multicenter propensity score matched study.

BACKGROUND: Fluoropyrimidine and platinum combination is the standard treatment for advanced or recurrent gastric cancer (AGC). However, fluoropyrimidine monotherapy is commonly used for elderly patients with AGC because of its good tolerability. METHODS: In this multicenter retrospective study, we collected clinical data of AGC patients aged 70 years or older, treated with S-1 alone or S-1 plus cisplatin (SP) as the first-line treatment between January 2009 and December 2011. Propensity score matched cohorts (PSMC) were used for reducing the confounding effects to compare efficacy and safety between the two treatment groups. Cox regression analysis was performed to clarify the prognostic factors. RESULTS: PSMC (n = 109 in each group) were selected from among 444 eligible patients (S-1 group, 210; SP group, 234); the S-1 group included more patients deemed unfit for intensive chemotherapy than the SP group (e.g., higher age, poorer PS, poor renal function). In the PSMC, patients' characteristics were comparable between groups, except the male ratio (S-1 group, 64.2%; SP group, 77.1%; p = 0.04). No significant differences were observed in either overall survival [hazard ratio (HR) 0.93, p = 0.63] or progression-free survival (HR 1.09, p = 0.61). Severe adverse events (AEs) and hospitalization due to AEs were more frequent in the SP group than in the S-1 group (p < 0.001 each). CONCLUSION: Our findings do not support the survival benefit of SP over S-1 in elderly patients with AGC. We are now conducting a prospective comparative study to optimize treatment strategy and explore applicability of the geriatric assessment for these patients.

Patient perceptions of curability and physician-reported disclosures of incurability in Japanese patients with unresectable/recurrent cancer: a cross-sectional survey.

BACKGROUND: Although reports have described the perceptions of curability among patients with unresectable/recurrent cancer and the quality of death and dying, the association between patients' perceptions and physicians' disclosures of incurability remained unexplored. This survey aimed to evaluate the association between patients' perceptions of curability and physicians' disclosures of incurability. METHODS: In this cross-sectional, multicenter, observational study in Japan, we asked outpatients with unresectable/recurrent solid cancers about their perceptions of incurability. The patient inclusion criteria were unresectable/recurrent solid cancer, failure of first-line chemotherapy and an age ≥ 20 years. Additionally, we surveyed their primary responsible physicians regarding disclosures to patients regarding incurability. RESULTS: Although we estimated the necessary sample size as 250, we discontinued recruitment because the responsible researcher transferred to another hospital. Among the 135 included and surveyed patients, 39% responded that their cancer was incurable, 33% responded that their cancer was curable and 23% responded 'I don't know' or 'I don't wish to answer'. No significant association was observed between patients' perceptions of curability and physician-reported disclosures of incurability. CONCLUSION: In this Japanese population, 39% of patients with unresectable/recurrent solid cancers perceived that their cancers were incurable. However, such perceptions did not appear to be significantly affected by physician-reported disclosures. We recommend additional research to determine the best disclosure method to ensure that patients truly understand their disease status.

Intermittent Withdrawal of Oxaliplatin for Alleviating Neurotoxicity during Oxaliplatin-Based Chemotherapy for Japanese Patients with Inoperable or Metastatic Colorectal Cancer: A Phase 2 Multicenter Study.

Oxaliplatin-based chemotherapy is a well-established regimen for patients with inoperable and metastatic colorectal cancer. However, one of the major limitations of oxaliplatin-based chemotherapy is sensory neuropathy. It was previously reported that introduction of intermittent oxaliplatin treatment to an oxaliplatin-based regimen has a significant benefit on efficacy or safety. Here, we prospectively assessed whether efficacy and safety of first-line chemotherapy for advanced colorectal cancer are achieved by introduction of withdrawal of oxaliplatin treatment for a certain period (intermittent oxaliplatin treatment). The primary endpoint of the present study is to assess the progression free survival time on patients treated with chemotherapy (mFOLFOX6 (levofolinate, 5-fluorouracil and oxaliplatin combination therapy) plus bevacizumab or CapeOX (oxaliplatin and capecitabine combination therapy) plus bevacizumab) with intermittent oxaliplatin treatment. Bevacizumab is a humanized anti-vascular endothelial growth factor antibody. Median progression-free survival by the mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or the CapeOX plus bevacizumab with intermittent oxaliplatin treatment were 10.6 months (95% confidential interval [CI], 8.3-13.4 months) or 8.0 months (95% CI, 4.2-16.8 months), respectively. Overall response rate by the mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or CapeOX plus bevacizumab with intermittent oxaliplatin treatment was 55.1% or 42.1%, respectively. Grade 3 or 4 neuropathy was observed in 4.1% or 10.5% of patients treated with mFOLFOX6 plus bevacizumab with intermittent oxaliplatin treatment or CapeOX plus bevacizumab with intermittent oxaliplatin treatment, respectively. Introduction of intermittent oxaliplatin treatment has improved severe neuropathy in mFOLFOX6 plus bevacizumab regimen without reducing treatment efficacy.

[Molecular Targeted Therapies for Hereditary Cancer Syndrome].

Development of molecular targeted drugs has achieved remarkable improvement of systemic cancer therapy. Recently, the several molecular targeted drugs have become available which associated with the status of responsible genes for hereditary cancer syndrome. These drugs would allow to establish specific strategy for hereditary cancer syndrome or sporadic cancers with similar biological phenotype with hereditary cancer. Genetic tests for the diagnosis of hereditary cancer syndrome will have the meaning of biomarker for predicting the efficacy of these molecular targeted drugs. This review summarized the molecular targeted drugs including immune checkpoint inhibitors with potential effects for hereditary cancer syndrome, such as anti-PD-1 antibody for Lynch syndrome, PARP inhibitor for hereditary breast and ovarian cancer syndrome, multi-kinase inhibitor for multiple endocrine neoplasia type 2.

microRNA-193a-3p is specifically down-regulated and acts as a tumor suppressor in BRAF-mutated colorectal cancer.

BACKGROUND: The aim of this study was to identify miRNAs specifically dysregulated in BRAF-mutated colorectal cancer, which could lead to a better understanding of the molecular mechanisms underlying oncogenesis of this malignant subtype of colorectal cancer. METHODS: Candidate dysregulated miRNAs were selected in genome-wide miRNA expression array analysis using a screening set composed of 15 BRAF-mutated and 15 non-KRAS/BRAF-mutated colorectal cancers. The miRNA expressions were validated in another set of patients. The functional roles of the miRNAs were analyzed by cell growth and invasion assays. The association between miRNA expression status and the clinical outcome of patients treated with various chemotherapies was analyzed. RESULTS: Within the top five of the miRNAs screened, we validated miRNA-31 (miR-31) and miR-135b as up-regulated, while miR-193a-3p was down-regulated in BRAF-mutated cancer. Moreover, miR-193a-3p inhibited cell growth, and invasion of colorectal cancer cells. Low miR-193a-3p expression was associated with shorter progression-free survival in patients who received anti-EGFR therapy. CONCLUSIONS: Our results disclose a novel tumor suppressive role of miR-193a-3p in colorectal cancer. These results could lead to novel therapeutic strategies for colorectal cancer, particularly in BRAF-mutated colorectal cancer.

[Management of Kidney Disease on Cancer Chemotherapy with Other Drugs than Platinum Agents].

"Japanese clinical practice guidelines for the management of kidney disease in cancer survivors"have been published. This guideline recommended several managements for nephrotoxicity of other agents than platinum such as the urinary alkylation during methotrexate administration, suspending of anti-angiogenetic agent for the grade 2 or more proteinuria, dose modification of bisphosphonate based on the renal function. Understanding the background of these recommendations will contribute for safe cancer chemotherapy.

[A Case of Curatively Resected Ascending Colon Cancer with Ovarian Metastasis and Peritoneal Dissemination after Chemotherapy].

A52 -year-old woman was diagnosed with ascending colon cancer with ovarian metastasis and peritoneal dissemination. Since the patient did not have symptoms with intestinal obstruction, mFOLFOX6 plus bevacizumab(Bmab)was performed for 12 cycles. After chemotherapy, the tumors of ascending colon and ovary were significantly shrunken and novel distant metastasis was not observed by CT scans. Therefore, the tumors were considered to be resectable and curative resection was performed. In the surgical findings, the peritoneal disseminations were localized, and right colectomy, bilateral oophorectomy and extirpation of the peritoneal disseminations were performed. R0 resection was pathologically achieved and adjuvant chemotherapy with UFT/UZEL was administrated for 6 months. The patient is alive without recurrence for 1 year. Since right sided colon cancer is less likely to have obstruction, upfront chemotherapy can be a strategy for locally advanced right sided colon cancer with distant metastasis.

Efficacy and Safety of Carboplatin and Etoposide Combination Chemotherapy for Extrapulmonary Neuroendocrine Carcinoma: A Retrospective Case Series.

BACKGROUND: Neuroendocrine carcinoma (NEC) is a rare tumor type, and a standard therapy for NEC has not yet been established. From 2008 to 2013, carboplatin-etoposide combination therapy has been used to treat almost all NEC patients in our department, and the objective of the present study was to investigate the therapeutic effects of carboplatin-etoposide combination therapy in NEC. METHODS: This retrospective study was conducted based on medical records from 2008 to 2013. Eligible patients had been pathologically diagnosed with NEC and had received a carboplatin-etoposide combination as first-line chemotherapy. RESULTS: Nineteen patients were included in the study, and the overall response rate was 47.4%. The median overall survival was 12.7 months, and the median progression-free survival was 7.0 months. The median survival times were 10.8 and 8.9 months in NEC patients with primary sites in the gastrointestinal tract and hepatobiliary-pancreatic system, respectively. Median progression-free survival times were 5.0 and 3.1 months, respectively. The major toxicities were grade 3 and 4 leukopenia (73.7%), neutropenia (78.9%), anemia (31.6%), and thrombocytopenia (26.3%). CONCLUSIONS: Carboplatin-etoposide combination therapy for NEC may have comparable effectiveness and milder adverse events than cisplatin-etoposide combination therapy.

Efficacy and Safety Assessment of Paclitaxel in Patients with Docetaxel-Resistant Esophageal Squamous Cell Carcinoma.

BACKGROUND: Incomplete cross-resistances between paclitaxel (PTX) and docetaxel (DTX) has been demonstrated in several types of cancer. The objective of the present study was to assess the existence of cross-resistance between PTX and DTX in esophageal squamous cell carcinoma. METHODS: Patients in the PTX group received PTX without DTX pretreatment, patients in the prior DTX (Pr-DTX) group received PTX after the development of resistance to DTX, and patients in the DTX group received DTX without subsequent PTX treatment. RESULTS: A total of 73 patients were enrolled. The response rates to PTX in the PTX and Pr-DTX groups were 22.7 and 20.0%, respectively. The median progression-free survival times from the first day of PTX treatment in the PTX and Pr-DTX groups were 113 (95% CI 56-154) and 97 days (95% CI 36-189), respectively. The median overall survival times from the first day of DTX treatment in the Pr-DTX and DTX groups were 315 (95% CI 124-453) and 148 days (95% CI 139-177), respectively. CONCLUSIONS: There is no or incomplete clinical cross-resistance between PTX and DTX in esophageal squamous cell carcinoma. Replacement of DTX with PTX is a suitable treatment option for patients with DTX-resistant esophageal squamous cell carcinoma.

CpG island methylator phenotype is associated with the efficacy of sequential oxaliplatin- and irinotecan-based chemotherapy and EGFR-related gene mutation in Japanese patients with metastatic colorectal cancer.

BACKGROUND: The CpG island methylator phenotype (CIMP) with multiple promoter methylated loci has been observed in a subset of human colorectal cancer (CRC) cases. CIMP status, which is closely associated with specific clinicopathological and molecular characteristics, is considered a potential predictive biomarker for efficacy of cancer treatment. However, the relationship between the effect of standard chemotherapy, including cytotoxic drugs and anti-epidermal growth factor receptor (EGFR) antibodies, and CIMP status has not been elucidated. METHODS: In 125 metastatic colorectal cancer (mCRC) patients, we investigated how clinical outcome of chemotherapy was related to CIMP status as detected by methylation-specific PCR (MSP) and to genetic status in five EGFR-related genes (KRAS, BRAF, PIK3CA, NRAS, and AKT1) as detected by direct sequencing. RESULTS: CIMP-positive status was significantly associated with proximal tumor location and peritoneum metastasis (all P values <0.05). The progression-free survival of patients with CIMP-positive tumors receiving sequential therapy with FOLFOX as the first-line treatment followed by irinotecan-based therapy as the second-line treatment (median = 6.6 months) was inferior to that of such patients receiving the reverse sequence (median = 15.2 months; P = 0.043). Furthermore, CIMP-positive tumors showed higher mutation frequencies for the five EGFR-related genes (74.1 %) than the CIMP-negative tumors did (50.0 %). Among the KRAS wild-type tumors, CIMP-positive tumors were associated with a worse clinical outcome than CIMP-negative tumors following anti-EGFR antibody therapy. CONCLUSION: Sequential FOLFOX followed by an irinotecan-based regimen is unfavorable in patients with CIMP-positive tumors. High frequencies of mutation in EGFR-related genes in CIMP-positive tumors may cause the lower response to anti-EGFR antibody therapy seen in patients with wild-type KRAS and CIMP-positive tumors.

Functional Complementation Assay for 47 MUTYH Variants in a MutY-Disrupted Escherichia coli Strain.

MUTYH-associated polyposis (MAP) is an adenomatous polyposis transmitted in an autosomal-recessive pattern, involving biallelic inactivation of the MUTYH gene. Loss of a functional MUTYH protein will result in the accumulation of G:T mismatched DNA caused by oxidative damage. Although p.Y179C and p.G396D are the two most prevalent MUTYH variants, more than 200 missense variants have been detected. It is difficult to determine whether these variants are disease-causing mutations or single-nucleotide polymorphisms. To understand the functional consequences of these variants, we generated 47 MUTYH gene variants via site-directed mutagenesis, expressed the encoded proteins in MutY-disrupted Escherichia coli, and assessed their abilities to complement the functional deficiency in the E. coli by monitoring spontaneous mutation rates. Although the majority of variants exhibited intermediate complementation relative to the wild type, some variants severely interfered with this complementation. However, some variants retained functioning similar to the wild type. In silico predictions of functional effects demonstrated a good correlation. Structural prediction of MUTYH based on the MutY protein structure allowed us to interpret effects on the protein stability or catalytic activity. These data will be useful for evaluating the functional consequences of missense MUTYH variants detected in patients with suspected MAP.

Biochemical, biological and structural properties of romidepsin (FK228) and its analogs as novel HDAC/PI3K dual inhibitors.

Romidepsin (FK228, depsipeptide) is a potent histone deacetylase (HDAC) inhibitor that has FDA approval for the treatment of cutaneous and peripheral T-cell lymphomas. We have previously reported that FK228 and its analogs have an additional activity as phosphatidylinositol 3-kinase (PI3K) inhibitors, and are defined as HDAC/PI3K dual inhibitors. Because a combination of an HDAC inhibitor and a PI3K inhibitor induces apoptosis in human cancer cells in a synergistic manner, development of an HDAC/PI3K dual inhibitor will provide an attractive novel drug for cancer therapy. Using structure-based optimization of the analogs, FK-A11 was identified as the most potent analog. FK-A11 inhibited phosphorylation of AKT and accelerated histone acetylation at lower concentrations, resulting in stronger cytotoxic effects than FK228 and the other analogs in human cancer cells. In this study, we have characterized the biochemical, biological and structural properties of FK228 analogs as PI3K inhibitors. First, FK-A11 is an ATP competitive PI3K inhibitor. Second, FK-A11 is a pan-p110 isoform inhibitor. Third, FK-A11 selectively inhibits PI3K among 22 common cellular kinases. Fourth, conformational changes of FK228 analogs by reduction of an internal disulfide bond have no effect on PI3K inhibitory activity, unlike HDAC inhibitory activity. Finally, molecular modeling of PI3K-FK228 analogs and analyses of the binding affinities identified the structure that defines potency for PI3K inhibitory activity. These results prove our concept that a series of FK228 analogs are HDAC/PI3K dual inhibitors. These findings should help in the development of FK228 analogs as novel HDAC/PI3K dual inhibitors.

DNA methylation status as a biomarker of anti-epidermal growth factor receptor treatment for metastatic colorectal cancer.

Anti-epidermal growth factor receptor (EGFR) treatment is an effective option for metastatic colorectal cancer (CRC) treatment. However, there are few reliable biomarkers to predict the clinical response to anti-EGFR treatment. We investigated the genome-wide DNA methylation status in metastatic colorectal cancer to identify associations between the methylation status and clinical response to anti-EGFR antibody. We retrospectively reviewed the medical records of 97 patients (45 patients for the first cohort and 52 patients for the second cohort) who received anti-EGFR treatment for KRAS wild-type metastatic CRC. Then we analyzed the associations between genome-wide DNA methylation status and clinical response to anti-EGFR treatment, and evaluated the predictive power and value of the methylation status statistically. As a result, each cohort was classified into highly methylated CRC and low methylated CRC subgroups by unsupervised clustering analyses. In the first cohort, clinical outcomes were significantly better in the low methylated CRC subgroup than in the highly methylated CRC subgroup (response rate, 35.7% vs 6.3%, P = 0.03; disease control rate, 75% vs 31.3%, P = 0.005; hazard ratio for progression-free survival, 0.27; 95% confidence interval, 0.13-0.57, P < 0.001; overall survival, 0.19; 95% confidence interval, 0.06-0.54, P < 0.001). These results were reproducible in the second cohort. The genome-wide methylation status was a predictive factor of progression-free survival and overall survival independently of RAS mutation status. In conclusion, we found that the genome-wide DNA methylation status is a powerful epigenetic predictor of anti-EGFR treatment in patients with KRAS wild-type metastatic colorectal cancer (UMIN000005490).

Gene-expression profiles correlate with the efficacy of anti-EGFR therapy and chemotherapy for colorectal cancer.

BACKGROUND: Comprehensive gene-expression analysis is very useful for classifying specific cancers into subgroups on the basis of their biological characteristics; it is used both prognostically and predictively. The purpose of this study was to classify unresectable advanced or recurrent colorectal cancer (CRC) by gene-expression profiling of formalin-fixed paraffin-embedded tissues and to correlate CRC subgroups with clinicopathological and molecular features and clinical outcomes. METHODS: One hundred patients with advanced or recurrent CRC were enrolled. RNA extracted from FFPE tissues was subjected to gene-expression microarray analysis. RESULTS: The patients were stratified into four subgroups (subtypes A1, A2, B1, and B2) by unsupervised hierarchical clustering. By use of principle-components analysis (PCA), the patients were divided into subtypes A and B on the basis of component 1 and into subtypes 1 and 2 on the basis of component 2. Subtype A was significantly enriched among patients without the KRAS mutation and with an earlier clinical stage at diagnosis. With regard to anti-EGFR therapy, progression-free survival (PFS) was better for patients in subtype A without the KRAS mutation than for those with the KRAS mutation (P = 0.047). PFS for patients without the KRAS mutation in subtype B was comparable with that for patients with the KRAS mutation (P = 0.55). Similar results were observed in a validation set. CONCLUSION: We found that gene-expression profiles enabled stratification of CRC patients into four subgroups. The efficacy of anti-EGFR therapy was correlated with component 1 from PCA. This comprehensive study may explain the heterogeneity of unresectable advanced or recurrent CRC and could be useful for identifying novel biomarkers for CRC treatment.

Phase II trial of cetuximab plus irinotecan for oxaliplatin- and irinotecan-based chemotherapy-refractory patients with advanced and/or metastatic colorectal cancer: evaluation of efficacy and safety based on KRAS mutation status (T-CORE0801).

BACKGROUND: Mutations in the KRAS gene have been identified as negative predictors of response to anti-epidermal growth factor receptor (EGFR) monoclonal antibody therapy by patients with metastatic colorectal cancer (mCRC). However, it has been based on the study of mainly Caucasian mCRC patients. This prospective study investigated the relationship between the mutation status of EGFR-related genes including KRAS and the response rate (RR) to cetuximab plus irinotecan therapy in Japanese mCRC patients. METHODS: Samples taken from 43 chemotherapy-refractory mCRC patients who had undergone cetuximab plus irinotecan therapy at 11 medical centers in Japan were subjected to direct DNA sequencing to determine the KRAS, BRAF, PIK3CA, NRAS, and AKT1 mutation status. The clinical outcome after the treatment was evaluated for each mutation status. RESULTS: KRAS mutations were detected in 31.7% of 41 eligible patients. The RR to cetuximab plus irinotecan therapy was found to be 17.9 and 0% in the KRAS wild-type and mutant subgroups, respectively. CONCLUSION: Despite the identification of a lower-than-expected RR to treatment by the KRAS wild-type subgroup, KRAS mutation status appears to be a useful predictive marker of response to cetuximab plus irinotecan therapy in Japanese mCRC patients.