Correlation between K-ras mutations status and benefit from cetuximab treatment in advanced colorectal cancer

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e15084-e15084
Author(s):  
L. Xie ◽  
R. Lai ◽  
X. Wu ◽  
S. Zhang ◽  
X. Tang ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Disease Control ◽  
Advanced Colorectal Cancer ◽  
Response Rate ◽  
Disease Control Rate ◽  
East China ◽  
Wild Type ◽  
Ras Gene ◽  
Ras Mutations ◽  
Type K

e15084 Background: Cetuximab is a monoclonal antibody that specifically blocks the EGFR. We follow -up study the efficacy and toxicity of cetuximab with chemotherapy in the treatment of advanced colorectal cancer from Chinese in East China. Methods: We analyzed tumor samples from 120 patients with advanced colorectal cancer by direct sequencing, to observe the mutations status in exon 2,3 of K-ras gene. And 30 patients were followed up according the RECIST standard for their treatment outcome of cetuximab plus chemotherapy at 2 -12 months. Results: K-ras mutations were identified in 48 of 120(40%) patients with colorectal cancer in exon2, which including 8 mutation types; 38/48(79.2%) mutations in 12 codon(G12D 43.7%,G12V 25%,G12C 10.4%,G12R 6%,G12S 4%,G12A 2%) and 10/48(18.7%) in 13 codon(G13D 18.7%,G13C 2%). None mutation was found in 61codon of exon3. we observed the clinical efficacy of 30 patients treated by cetuximab plus chemotherapy, of 21 patients with wild-type K-ras tumors as compared with 9 patients with mutated K-ras significantly improved the response rate (5/21 21.8% vs 1/9 11.1%,P<0.01)and the disease control rate (19/21 90.4% vs,2/9 22.2%,P<0.01). There were a few patients with mutated K-ras tumors benefit from cetuximab, in which the fluorescence intensity of mutation cells of all detected tumor tissue approach to 1:3 status by sequencing analysis. The major toxicities of treatment were acne-like rash, which were found in 14/21(66.6%)of patients with wild-type K- ras, and 5/9(55.5%)of patients with mutated K-ras . Conclusions: The East-China patients share the same (40%) mutation frequency and type of k-ras gene with other races . Patients with wild type K-ras mutation have significantly higher Response rate and disease control rate on cetuximab plus chemotherapy treatment .Our results once again show that somatic mutations status of k-ras is a major determinant of cetuximab response in advanced colorectal cancer. There was no statistical correlation between acne-like rash of the major toxicities and mutations status of k-ras. There were a few patients bearing mutated k-ras did benefit from cetuximab, that would need to be validation between Chinese or Ethnicity association phenotype by a large numbers of samples. No significant financial relationships to disclose.

scholarly journals Inflammatory Markers Predict Survival in Patients With Advanced Gastric and Colorectal Cancers Receiving Anti–PD-1 Therapy

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiaona Fan ◽  
Dan Wang ◽  
Wenjing Zhang ◽  
Jinshuang Liu ◽  
Chao Liu ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Disease Control ◽  
Inflammatory Markers ◽  
Overall Response Rate ◽  
Response Rate ◽  
Progression Free Survival ◽  
Disease Control Rate ◽  
Free Survival ◽  
Lymphocyte Ratio

There is a lack of useful biomarkers for predicting the efficacy of anti–programmed death-1 (PD-1) therapy for advanced gastric and colorectal cancer. To address this issue, in this study we investigated the correlation between inflammatory marker expression and survival in patients with advanced gastric and colorectal cancer. Data for 111 patients with advanced gastric and colorectal cancer treated with anti–PD-1 regimens were retrospectively analyzed. Neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio (MLR), platelet-to-lymphocyte ratio (PLR), and clinical characteristics of each patient were selected as the main variables. Overall response rate, disease control rate, and progression-free survival were primary endpoints, and overall survival and immune-related adverse events (irAEs) were secondary endpoints. The chi-squared test and Fisher’s exact test were used to evaluate relationships between categorical variables. Uni- and multivariate Cox regression analyses were performed, and median progression-free survival and overall survival were estimated with the Kaplan–Meier method. The overall response rate and disease control rate of anti–PD-1therapy in advanced gastric and colorectal tumors were 12.61 and 66.66%, respectively. The patients with MLR &lt; 0.31, NLR &lt; 5, and PLR &lt; 135 had a significantly higher disease control rate than those with MLR &gt; 0.31, NLR &gt; 5, and PLR &gt; 135 (P &lt; 0.05). The multivariate analysis revealed that MLR &lt; 0.31, BMI &gt; 18.5, and anti–PD-1 therapy in first-line were associated with prolonged PFS. MLR &lt; 0.31 and BMI &gt; 18.5 were associated with prolonged overall survival. The irAE rate differed significantly between PLR groups, and PLR &lt; 135 was associated with an increased rate of irAEs (P = 0.028). These results indicate that the inflammatory markers NLR, MLR, and PLR have clinical utility for predicting survival or risk of irAEs in patients with advanced gastric cancer and colorectal cancer.

The impact of dose reduction and time delay in irinotecan- and oxaliplatin-based chemotherapies on outcomes in metastatic colorectal cancer.

2014 ◽  
Vol 32 (3_suppl) ◽  
pp. 631-631
Author(s):  
Naoki Mashita ◽  
Goro Nakayama ◽  
Naomi Hayashi ◽  
Chie Tanaka ◽  
Daisuke Kobayashi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Time Delay ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Total Dose ◽  
Dose Reduction ◽  
Response Rate ◽  
Progression Free Survival ◽  
Disease Control Rate ◽  
Free Survival

631 Background: This study was designed to evaluate the influence of dose reduction and schedule modification on outcomes in patients with metastatic colorectal cancer (mCRC). Methods: Pooled datasets from two previous phase II trials of FOLFIRI (CCOG-0502; n = 36) and mFOLFOX6 (CCOG-0704; n = 30) in patients with mCRC were analyzed retrospectively. The RDIs of irinotecan and oxaliplatin were compared to response rate (RR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). To assess the effects of dose reduction and time delay, we defined ‘dose index (DI)’ as the ratio of the actual delivered total dose to the planned total dose and ‘time index (TI)’ as the ratio of the planned duration to the actual duration of therapy. Relative dose intensity (RDI) was computed by multiplying DI by TI. DI and TI of irinotecan and oxaliplatin were compared to response rate (RR), disease control rate (DCR) and progression-free survival (PFS). Results: In patients receiving FOLFIRI therapy, the median DI and TI of irinotecan were 0.92 and 0.90, respectively. RRs were 59% vs. 12% in the higher vs. lower DI groups (p < 0.01), and 35% vs. 35% in the higher vs. lower TI groups (p = 1.00), respectively. Median PFS was 10.2 vs. 5.0 months in the higher vs. lower DI groups (p < 0.01), and 6.1 vs. 6.7 months in the higher vs. lower TI groups (p = 0.48), respectively. In mFOLFOX6 therapy, the median DI and TI of oxaliplatin were 0.97 and 0.82, respectively. RRs were 44% vs. 36% in the higher vs. lower DI groups (p = 0.65), and 44% vs. 36% in the higher vs. lower TI groups (p = 0.65), respectively. Median PFS was 7.7 vs. 6.7 months in the higher vs. lower DI groups (p = 0.13), and 8.5 vs. 5.9 months in the higher vs. lower TI groups (p = 0.02), respectively. Multivariate analyses showed that DI of irinotecan (HR 8.48; 95% CI, 2.94-24.51, p < 0.01) and TI of oxaliplatin (HR 2.74; 95% CI, 1.02-7.33, p = 0.04) were the independent prognostic factors for PFS. Conclusions: Dose reductions in irinotecan and time delays in oxaliplatin could have significant impact on PFS in patients receiving FOLFIRI and FOLFOX6, respectively.

Apatinib monotherapy for chemotherapy-refractory metastatic colorectal cancer: A multicenter, single-arm, prospective study.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3527-3527 ◽  
Author(s):  
Fen Wang ◽  
Shubin Wang ◽  
Xia Yuan ◽  
Jun Jia ◽  
Xiaoxia Bi ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Overall Survival ◽  
Prospective Study ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Disease Control Rate ◽  
Free Survival

3527 Background: Apatinib is an oral highly-selective tyrosine kinase inhibitor (TKI) that blocks vascular endothelial growth factor receptor 2 (VEGFR-2). This exploratory study evaluated the efficacy and safety of apatinib monotherapy in patients with chemotherapy-refractory metastatic colorectal cancer. Methods: In this multicenter, single-arm, prospective study, 48 patients with metastatic colorectal cancer who had failed at least two lines standard chemotherapies including fluorouracil, oxaliplatin and irinotecan were recruited from 14 centers in Guangdong, China. Apatinib at a 500mg dose was administered daily continuously. Each cycle was 4 weeks (28 days). The primary endpoint was progression free survival (PFS). Secondary end points included overall survival (OS), objective response rate (ORR), disease control rate (DCR), quality of life (QoL) and toxicity. Results: A total of 48 patients was enrolled in the study from September 3, 2015 to June9, 2017. Four patients achieved a partial response, and 22 achieved stable disease, representing a response rate of 8.3% and a disease control rate of 60.4%. Median follow-up time was 10.3 months. Median progression-free survival (PFS) and overall survival (OS) of evaluable patients (n=41) were 4.7 months (95% confidence interval [CI] 3.7-5.9) and 9.7 months (95% CI 5.9-13.6). The most common grade 3 or 4 adverse events (AE) were hypertension (12.5%), hand-foot syndrome (10.4%), thrombocytopenia (10.4%), proteinuria (8.3%) and mucositis oral (6.3%). Conclusions: Apatinib monotherapy shows promising efficacy and manageable toxicities in patients with chemotherapy-refractory metastatic colorectal cancer. Further phase 3 trial is warranted. Clinical trial information: ChiCTR1900020503.

FOLFOX-4 vs. FOLFIRI vs. IROX as first line chemotherapy for metastatic colon cancer: efficacy and toxicity

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13541-13541
Author(s):  
D. L. Stanculeanu ◽  
R. Matache ◽  
L. Minea ◽  
A. Cringeanu ◽  
R. Anghel
Keyword(s):  
Colorectal Cancer ◽  
Colon Cancer ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Response Rate ◽  
Objective Response ◽  
Disease Control Rate ◽  
Disease Rate ◽  
Metastatic Colon Cancer ◽  
First Line

13541 Background: The combination of OXA or IRI with 5FU-LV are accepted as standard treatment for metastatic colorectal cancer. However, the right sequence in first or second line is still under debate. We developed a non-randomised prospective study in first line metastatic colorectal cancer comparing the efficacy and the toxicity of three different chemotherapy regimens - FOLFOX-4 vs. FOLFIRI vs. IROX. Methods: From January 2004 to January 2005 we included in the study 57 patients with metastatic non-resectable colon cancer - 22 in FOLFOX arm, 18 in FOLFIRI arm and 17 in IROX arm. In the FOLFOX arm patients received OXA 85 mg/m2 d1, LV 200 mg/m2 d1,2, 5FU 400 mg/m2 bolus d1,2, 5FU 600 mg/m2 as 22 hours CI d1,2 q15d; in the FOLFIRI arm - IRI 180 mg/m2, LV 400 mg/m2, 5FU 400 mg/m2 bolus and 5FU 2400 mg/m2 as 46 hours CI, q15d; in the IROX arm - IRI 300 mg/m2 d1, OXA 85 mg/m2 d2, q3w. The main patients characteristics were: median age 60 vs 62 vs 59; number of metastatic sites ≥ 2: 41% vs 33.33% vs 35.3%; performance status ECOG 0–1: 86.3% vs 83.3% vs 88.2%. The primary end-point was the objective response rate (CR + PR) and the secondary end-points was the toxicity. The objective response was evaluated every 3 months; at disease progression patients were offered to switch to a comparator regimen. Results: The objective response was 63.6% in FOLFOX arm (with a CR of 9%), 44% in FOLFIRI arm (CR - 5.5%) and 53% in IROX arm (CR - 11,7%); the stable disease rate - 27.3% in FOLFOX arm, 44.4% in FOLFIRI arm, 35.3% in IROX arm and the disease control rate - 91% in FOLFOX arm, 88.8% in FOLFIRI arm and 88.2% in IROX arm. The main grade 3–4 toxicities were: neutropenia - 22.7% vs 16.66% vs 29.4%; febrile neutropenia - 4.5% vs 5.5% vs 11.76%; diarrhea - 9% vs 22.2% vs 23.5%; nausea/vomiting - 4.5% vs 5.5% vs. 11.76%; neuropathy - 18.18% vs 0% vs 17.6%. No patients stoped the treatment because of side effects. Conclusions: All three regimens were well tolerated, with comparable results - with a slightly better disease control rate in the FOLFOX arm and a tendance of a better complete response rate in the IROX arm. The FOLFOX regimen had lower rates of nausea, vomiting, diarrhea; sensitive neuropathy and neutropenia were more common with regimens containing oxaliplatine. The IROX regimen had a higer incidence of adverse effects. No significant financial relationships to disclose.

Regorafenib plus PD-1 inhibitors in Chinese patients with microsatellite stable/mismatch repair proficient metastatic colorectal cancer: A real-world study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15585-e15585
Author(s):  
Kaili Yang ◽  
Lu Han ◽  
Yun-Bo Zhao ◽  
Yang Ge ◽  
Qin LI ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Liver Metastases ◽  
Disease Control ◽  
Metastatic Colorectal Cancer ◽  
Mismatch Repair ◽  
Real World ◽  
Objective Response ◽  
Disease Control Rate ◽  
Chinese Patients ◽  
Hand Foot Syndrome

e15585 Background: A previous phase 1b trial has shown encouraging efficacy of regorafenib plus nivolumab in patients with microsatellite stable/mismatch repair proficient (MSS/pMMR) metastatic colorectal cancer (mCRC). We aimed to evaluate the efficacy and safety of this regimen in Chinese patients in the real world. Methods: We retrospectively identified patients with MSS/pMMR mCRC who received at least one dose of programmed cell death-1 (PD-1) inhibitors plus regorafenib from 5/2019 to 2/2021 in 10 Chinese medical centers. The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR) and the safety. Results: Fifty-two patients were identified. Liver metastases were presented in 35 patients (67%). A total of 48 patients (92%) received regorafenib plus a PD-1 inhibitor as the third or later line treatment. At the data cut-off, 11 patients (21%) were still on treatment. Other patients terminated treatment because of progressive disease (45%), treatment-related adverse events (TRAEs) (14%) or treatment-unrelated deaths (6%). The median treatment cycle was 3 (range, 1-18). At a median follow-up of 4.9 months, the median OS was 17.3 months (95% CI, 10.2-NR) and the median PFS was 3.1 months (95%CI, 2.5-6.0). Baseline liver metastases were associated with inferior PFS (2.7 versus 6.3 months, p <0.05), but not OS (17.3 months versus NR, p =0.6). Among 38 patients evaluable for response, two patients (5%) achieved partial response, and 17 patients (45%) experienced stable disease as the best response. The DCR was 50% (95%CI, 5.0-NR) and was similar among different PD-1 inhibitors (Table). TRAEs were observed in 30 patients (58%). Fatigue (21%), hand-foot syndrome (19%) and rash (13%) were the most common TRAEs. Eight patients (15%) experienced grade 3-4 TRAEs, including rash (n=3), hand-foot syndrome (n=2), hypertension (n=1), myocardial enzyme elevation (n=1) and visual field loss (n=1). No treatment-related death occurred. Conclusions: The combination of regorafenib plus PD-1 inhibitors was generally tolerated and exhibited potential benefit in terms of OS and DCR. The presence of baseline liver metastases was predictive for shorter PFS but requires further investigation. Disease control rate of different PD-1 inhibitors.[Table: see text]

scholarly journals RAS and BRAF mutations in cell‐free DNA are predictive for outcome of cetuximab monotherapy in patients with tissue‐tested RAS wild‐type advanced colorectal cancer

2019 ◽  
Vol 13 (11) ◽  
pp. 2361-2374 ◽  
Author(s):  
Erik J. Helden ◽  
Lindsay Angus ◽  
C. Willemien Menke‐van der Houven van Oordt ◽  
Daniëlle A. M. Heideman ◽  
Eline Boon ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Wild Type ◽  
Braf Mutations ◽  
Cell Free Dna ◽  
Free Dna

scholarly journals The Presence of Mutations in the K-RAS Gene Does Not Affect Survival after Resection of Pulmonary Metastases from Colorectal Cancer

ISRN Surgery ◽  
2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
Jon Zabaleta ◽  
Borja Aguinagalde ◽  
José M. Izquierdo ◽  
Nerea Bazterargui ◽  
Stephany M. Laguna ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Cox Regression ◽  
Pulmonary Metastases ◽  
Direct Sequencing ◽  
Lymph Node Involvement ◽  
Ras Gene ◽  
Surgical Interventions ◽  
Cox Regression Analysis ◽  
Ras Mutations ◽  
Time To Recurrence

Introduction. Our objective was to identify mutations in the K-RAS gene in cases of pulmonary metastases from colorectal cancer (CRC) and determine whether their presence was a prognostic factor for survival. Methods. We included all patients with pulmonary metastases from CRC operated on between 1998 and 2010. K-RAS mutations were investigated by direct sequencing of DNA. Differences in survival were explored with the Kaplan-Meier method log-rank tests and multivariate Cox regression analysis. Results. 110 surgical interventions were performed on 90 patients. Factors significantly associated with survival were disease-free interval (P=0.002), age (P=0.007), number of metastases (P=0.001), lymph node involvement (P=0.007), size of the metastases (P=0.013), and previous liver metastasis (P=0.003). Searching in 79 patients, K-RAS mutations were found in 30 cases. We did not find statistically significant differences in survival (P=0.913) comparing native and mutated K-RAS. We found a higher rate of lung recurrence (P=0.040) and shorter time to recurrence (P=0.015) in patients with K-RAS mutations. Gly12Asp mutation was associated with higher recurrence (P=0.022) and lower survival (P=0.389). Conclusions. The presence of K-RAS mutations in pulmonary metastases does not affect overall survival but is associated with higher rates of pulmonary recurrence.

Phase II study of irinotecan in the treatment of advanced colorectal cancer in chemotherapy-naive patients and patients pretreated with fluorouracil-based chemotherapy.

1997 ◽  
Vol 15 (1) ◽  
pp. 251-260 ◽  
Author(s):  
P Rougier ◽  
R Bugat ◽  
J Y Douillard ◽  
S Culine ◽  
E Suc ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Adverse Events ◽  
Metastatic Colorectal Cancer ◽  
Advanced Colorectal Cancer ◽  
Response Rate ◽  
Objective Response ◽  
World Health ◽  
Who Grade ◽  
Pretreated Patients ◽  
Grade 3

PURPOSE To assess the efficacy of irinotecan (CPT-11) in the treatment of advanced colorectal cancer in both chemotherapy-naive and pretreated patients. PATIENTS AND METHODS Two hundred thirteen patients (aged 18 to 75 years) with metastatic colorectal cancer, World Health Organization (WHO) performance status < or = 2, and life expectancy > or = 3 months were treated with CPT-11 350 mg/m2 every 3 weeks. All 178 patients eligible for efficacy analysis had not received more than one prior fluorouracil (5-FU)-based chemotherapy regimen (adjuvant or palliative) and had adequate hematologic, renal, and hepatic function. RESULTS Primary tumor sites were the colon (71%) and rectum (28%). Sixty-six percent of the patients had > or = two metastatic sites. Ninety-eight percent of the patients had undergone previous surgery, and 77.5% had received prior chemotherapy. Thirty-two of 178 eligible patients achieved on objective response (four complete responses [CRs] and 28 partial responses [PRs]; response rate, 18%; 95% confidence interval, 12.6% to 24.4%), 65 were stable, and 59 progressed. The response rate was 17.7% in the pretreated group and 18.8% in the chemotherapy-naive group. Within the former subgroup, response rates of 16.1% were reported in patients who were progressive on prior 5-FU chemotherapy and 19.1% in patients who were progressive off such treatment. The median duration of objective response (9.1 months) and median time to achievement of a response (9.3 weeks) did not differ between chemotherapy-naive and pretreated patients. The most frequent adverse events were neutropenia, which developed in 80% of the patients, delayed diarrhea (87%), alopecia (88%), fatigue (81%), and nausea/vomiting (77%). All these adverse events were manageable. Severe (WHO grade 3 or 4) neutropenia was only observed in 18% of the cycles, leukopenia in 11%, delayed diarrhea in 11%, and nausea and vomiting in 3%. Development of simultaneous grade 3 or 4 neutropenia and delayed diarrhea during 4% of the cycles was the safety issue of greatest concern. CONCLUSION CPT-11 has definite activity in the treatment of advanced metastatic colorectal cancer both in chemotherapy-naive and in pretreated patients who experienced disease progression on 5-FU, which suggests a lack of cross-resistance between CPT-11 and 5-FU. Diarrhea and neutropenia, the major toxicities of CPT-11, contribute to the risk to develop febrile neutropenic sepsis.

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