KRASandBRAFMutations in Advanced Colorectal Cancer Are Associated With Poor Prognosis but Do Not Preclude Benefit From Oxaliplatin or Irinotecan: Results From the MRC FOCUS Trial

PurposeActivating mutation of the KRAS oncogene is an established predictive biomarker for resistance to anti–epidermal growth factor receptor (anti-EGFR) therapies in advanced colorectal cancer (aCRC). We wanted to determine whether KRAS and/or BRAF mutation is also a predictive biomarker for other aCRC therapies.Patients and MethodsThe Medical Research Council Fluorouracil, Oxaliplatin and Irinotecan: Use and Sequencing (MRC FOCUS) trial compared treatment sequences including first-line fluorouracil (FU), FU/irinotecan or FU/oxaliplatin in aCRC. Tumor blocks were obtained from 711 consenting patients. DNA was extracted and KRAS codons 12, 13, and 61 and BRAF codon 600 were assessed by pyrosequencing. Mutation (mut) status was assessed first as a prognostic factor and then as a predictive biomarker for the benefit of adding irinotecan or oxaliplatin to FU. The association of BRAF-mut with loss of MLH1 was assessed by immunohistochemistry.ResultsThree hundred eight (43.3%) of 711 patients had KRAS-mut and 56 (7.9%) of 711 had BRAF-mut. Mutation of KRAS, BRAF, or both was present in 360 (50.6%) of 711 patients. Mutation in either KRAS or BRAF was a poor prognostic factor for overall survival (OS; hazard ratio [HR], 1.40; 95% CI, 1.20 to 1.65; P < .0001) but had minimal impact on progression-free survival (PFS; HR, 1.16; 95% CI, 1.00 to 1.36; P = .05). Mutation status did not affect the impact of irinotecan or oxaliplatin on PFS or OS. BRAF-mut was weakly associated with loss of MLH1 staining (P = .012).ConclusionKRAS/BRAF mutation is associated with poor prognosis but is not a predictive biomarker for irinotecan or oxaliplatin. There is no evidence that patients with KRAS/BRAF mutated tumors are less likely to benefit from these standard chemotherapy agents.

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Reintroduction of Oxaliplatin Is Associated With Improved Survival in Advanced Colorectal Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2006.10.4380 ◽

2007 ◽

Vol 25 (22) ◽

pp. 3224-3229 ◽

Cited By ~ 94

Author(s):

Aimery de Gramont ◽

Marc Buyse ◽

Jose Cortinas Abrahantes ◽

Tomasz Burzykowski ◽

Emmanuel Quinaux ◽

...

Keyword(s):

Colorectal Cancer ◽

Advanced Colorectal Cancer ◽

Reference Group ◽

Cox Model ◽

Progression Free Survival ◽

Second Line ◽

Treatment Groups ◽

Number Of Patients ◽

Baseline Factors ◽

The Impact

Purpose In the OPTIMOX1 trial, previously untreated patients with advanced colorectal cancer were randomly assigned to two different schedules of leucovorin, fluorouracil, and oxaliplatin that were administered until progression in the control arm or in a stop-and-go fashion in the experimental arm. The randomly assigned treatment groups did not differ significantly in terms of response rate, progression-free survival, and overall survival (OS). However, the impact of oxaliplatin reintroduction on OS was potentially masked by the fact that a large number of patients did not receive the planned oxaliplatin reintroduction or received oxaliplatin after second-line therapy in both treatment groups. Patients and Methods A Cox model was fitted with all significant baseline factors plus time-dependent variables reflecting tumor progression, reintroduction of oxaliplatin, and use of second-line irinotecan. A shared frailty model was fitted with all significant baseline factors plus the number of lines of chemotherapy received by the patient and the percentage of patients with oxaliplatin reintroduction in the center. An adjusted hazard ratio (HR) was calculated for three reintroduction classes (1% to 20%, 21% to 40%, and > 40%), using centers with no reintroduction (0%) as the reference group. Results Oxaliplatin reintroduction had an independent and significant impact on OS (HR = 0.56, P = .009). The percentage of patients with oxaliplatin reintroductions also had a significant impact on OS. Centers in which more than 40% of the patients were reintroduced had an adjusted HR for OS of 0.59 compared with centers in which no patient was reintroduced. Conclusion Oxaliplatin reintroduction is associated with improved survival in patients with advanced colorectal cancer.

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Impact of expression of SIRT1 and SIRT2 on outcome in the very elderly patients with colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e15107 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e15107-e15107

Author(s):

In Sook Woo ◽

Yun Hwa Jung ◽

In Kyu Lee

Keyword(s):

Colorectal Cancer ◽

Prognostic Factor ◽

Elderly Patients ◽

Young Patients ◽

High Expression ◽

Very Elderly ◽

Poor Prognostic Factor ◽

Younger Patients ◽

Sirt1 Expression ◽

The Impact

e15107 Background: Surtuins(SIRTs), NAD+-dependent deacetylases, participate in cell metabolism and ageing associated diseases including cancer. The elderly has higher cancer incidence and mortality compared to the young. Many of patients with colorectal cancer are over the age of 80. The role of SIRT 1 and 2 in tumorigenesis remains debated and it has not been reported for the very elderly patients with cancer. We investigated the relationship of clinicopathologic parameters and expression of SIRT1 and 2 in colorectal cancer patients 80 years of age or older and the impact of ageing comparing with the younger patients. Methods: The expression of SIRT1 and 2 were evaluated in colorectal cancer tissues of 101 patients aged ≥80 years and 29 patients aged ≤40 years by immunohistochemistry. And correlations between expression of these proteins and clinicopathological features were analyzed. Results: High expression of SIRT1 was observed in 65/101 (64.4%) elderly patients and 11/29 (37.9%) young patients(p = 0.011). Similarly, high expression of SIRT2 was more commonly observed in 58/99 (58.6%) elderly patients than 8/29 (27.6%) young patients(p = 0.003). In all patients high SIRT2 expression was associated with comorbid DM, and stage of CRC were not associated with SIRT1 or SIRT2 expression status. Comparison of Kaplan-Meier survival curve using log rank test revealed that high expressions of SIRT1 and SIRT2 were significantly associated with worse prognosis (median OS 24.9ms vs 38.6ms, p = 0.027) and better prognosis (median OS 37.9ms vs 17.3ms, p = 0.006) respectively in elderly patients. No prognostic significances were observed in younger patients. In multivariate analysis, only high SIRT1 expression retained statistical significance as a poor prognostic factor in elderly patients with CRC. Conclusions: :High SIRT1 expression might become a significant poor prognostic factor for elderly CRC patients although further study is needed for younger patients to clarify the difference of expression according to the age between elderly and young patients with CRC. High SIRT2 expression showed association with comorbid DM, further studies are warranted to establish prognostic significance in CRC patients.

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The nationwide genomic screening project for gastrointestinal cancer in Japan (GI-SCREEN): Simultaneous identification of KRAS, NRAS, BRAF, and PIK3CA mutation in advanced colorectal cancer (aCRC) (GI-SCREEN 2013-01).

Journal of Clinical Oncology ◽

10.1200/jco.2015.33.3_suppl.578 ◽

2015 ◽

Vol 33 (3_suppl) ◽

pp. 578-578 ◽

Cited By ~ 2

Author(s):

Kohei Shitara ◽

Satoshi Fujii ◽

Tadamichi Denda ◽

Takeshi Kajiwara ◽

Satoshi Yuki ◽

...

Keyword(s):

Colorectal Cancer ◽

Clinical Trials ◽

Targeted Therapies ◽

Gastrointestinal Cancer ◽

Braf Mutation ◽

Advanced Colorectal Cancer ◽

Pik3ca Mutation ◽

Exon 2 ◽

Genomic Screening ◽

The Impact

578 Background: Recent studies confirmed that minor KRAS or NRAS mutations are associated with the resistance to anti-EGFR therapy for advanced colorectal cancer (aCRC). Although the impact of BRAF or PIK3CA mutation on efficacy of anti-EGFR therapy is still controversial, targeting agents for these mutations are under developing. Efficient screening systems for these relatively minor mutations with short turnaround time are necessary for the successful development of targeted therapies. Methods: This study was initiated in February 2014 as one of new nationwide genomic screening projects for advanced gastrointestinal cancer patients in Japan. Patients with aCRC who are planned to receive systemic chemotherapy were eligible. A total of 36 mutations of KRAS codon 61, 146, NRAS codon 12, 13, 61, BRAF codon 600, PIK3CA codon 542, 545, 546 and 1047 in genomic DNA of cancer cells were simultaneously analyzed at a quality-controlled central laboratory using Luminex (xMAP) technology in a single reaction using 50 ng of DNA. Results: As of August 31, 2014, this study is ongoing with the participation of 16 major cancer centers in Japan. A total of 437 aCRC patients were enrolled to this study and 361 tumor samples has been analyzed with success rate for genomic analysis of 100%. Among the 237 patients with KRAS exon 2 wild type, 28 patients (11.8%) had other RAS mutations and 15 patients (6.3%) had BRAF mutation. Twenty-seven of 437 patients had PIK3CA mutations (6.2%). One patient with BRAF mutation was enrolled in early clinical trials of BRAF inhibitors in combination with anti-EGFR antibody and most of other patients are still treated with standard chemotherapies, which may become future candidates for early clinical trials. Conclusions: From our preliminary results, this nationwide screening system enabled to detect rare mutations using limited amounts of samples from aCRC, which may facilitate the enrollment of patients in IND registration trials for targeted therapies as well as optimal individualized treatment.

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Transgelin is a poor prognostic factor associated with advanced colorectal cancer (CRC) stage promoting tumor growth and migration in a TGFβ-dependent manner

Cell Death and Disease ◽

10.1038/s41419-020-2529-6 ◽

2020 ◽

Vol 11 (5) ◽

Cited By ~ 3

Author(s):

Mona Elsafadi ◽

Muthurangan Manikandan ◽

Sami Almalki ◽

Amer Mahmood ◽

Tasneem Shinwari ◽

...

Keyword(s):

Colorectal Cancer ◽

Prognostic Factor ◽

Tumor Growth ◽

Advanced Colorectal Cancer ◽

Dependent Manner ◽

Poor Prognostic Factor ◽

And Migration

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KRASMutations As an Independent Prognostic Factor in Patients With Advanced Colorectal Cancer Treated With Cetuximab

Journal of Clinical Oncology ◽

10.1200/jco.2007.12.5906 ◽

2008 ◽

Vol 26 (3) ◽

pp. 374-379 ◽

Cited By ~ 1051

Author(s):

Astrid Lièvre ◽

Jean-Baptiste Bachet ◽

Valérie Boige ◽

Anne Cayre ◽

Delphine Le Corre ◽

...

Keyword(s):

Colorectal Cancer ◽

Prognostic Factor ◽

Kras Mutation ◽

Prognostic Value ◽

Advanced Colorectal Cancer ◽

Progression Free Survival ◽

Skin Toxicity ◽

Independent Prognostic Factor ◽

Allelic Discrimination ◽

Kras Mutations

PurposeCetuximab is efficient in advanced colorectal cancer (CRC). We previously showed that KRAS mutations were associated with resistance to cetuximab in 30 CRC patients. The aim of this study was to validate, in an independent larger series of 89 patients, the prognostic value of KRAS mutations on response to cetuximab and survival.Patients and MethodsEighty-nine metastatic CRC patients treated with cetuximab after treatment failure with irinotecan-based chemotherapy were analyzed for KRAS mutation by allelic discrimination on tumor DNA. The association between KRAS mutations and tumor response, skin toxicity, progression-free survival (PFS) and overall survival (OS) was analyzed.ResultsA KRAS mutation was present in 27% of the patients and was associated with resistance to cetuximab (0% v 40% of responders among the 24 mutated and 65 nonmutated patients, respectively; P < .001) and a poorer survival (median PFS: 10.1 v 31.4 weeks in patients without mutation; P = .0001; median OS: 10.1 v 14.3 months in patients without mutation; P = .026). When we pooled these 89 patients with patients from our previous study, the multivariate analysis showed that KRAS status was an independent prognostic factor associated with OS and PFS, whereas skin toxicity was only associated with OS. In a combined analysis, median OS times of patients with two, one, or no favorable prognostic factors (severe skin toxicity and no KRAS mutation) was of 15.6, 10.7, and 5.6 months, respectively.ConclusionThese results confirm the high prognostic value of KRAS mutations on response to cetuximab and survival in metastatic CRC patients treated with cetuximab.

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Lonsurf (trifluridine/tipiracil): Assessing the impact of dose related toxicities and progression free survival in (refractory) metastatic colorectal cancer

Journal of Oncology Pharmacy Practice ◽

10.1177/10781552211017973 ◽

2021 ◽

pp. 107815522110179

Author(s):

Olivia R Court

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Dose Reduction ◽

Progression Free Survival ◽

Electronic Patient Records ◽

Free Survival ◽

Length Of Treatment ◽

Common Grade ◽

Grade 3 ◽

The Impact

In the RECOURSE trial which lead to its accreditation, Lonsurf (trifluridine/tipiracil) was shown to extend progression free survival (PFS) by 1.8 months in metastatic colorectal cancer. This Trust audit aims to assess the average quantity of cycles of Lonsurf received by participants and the length of time it extends PFS. Similarly, to identify how many participants required a dose-reduction or experienced toxicities which necessitated supportive therapies. Quantitative data was collected retrospectively from all participants who had received ≥1 cycle of Lonsurf from The Clatterbridge Cancer Centre (CCC) from 2016 until June 2020. Participant electronic patient records were accessed to identify toxicity grading, length of treatment received, the date progression was identified, if dose reductions were applied and if supportive therapies were administered. Lonsurf extends PFS in patients with metastatic colorectal cancer at CCC by 3.0 months (95% CI: 2.73–3.27) and average treatment length was 2.4 months. However, 78 participants (41.5%) received a dose reduction due to toxicities. A total of 955 toxicities were recorded by participants; the most commonly reported toxicities irrespective of grade were fatigue (33.8%), diarrhoea (13.8%) and nausea (12.3%). The most common grade ≥3 toxicities were constipation and infection. The most frequently utilised supportive therapies were loperamide (49.6%) and domperidone (49.1%). Granulocyte colony stimulating factor (GCSF) was required by patients on 5 occasions (0.3%) in total. Lonsurf extends median PFS in patients with metastatic colorectal cancer by 3.0 months. The most common grade ≥3 toxicities which necessitated supportive therapies or a dose reduction were gastrointestinal and infection.

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Treatment with Antiangiogenic Drugs in Multiple Lines in Patients with Metastatic Colorectal Cancer: Meta-Analysis of Randomized Trials

Gastroenterology Research and Practice ◽

10.1155/2016/9189483 ◽

2016 ◽

Vol 2016 ◽

pp. 1-9 ◽

Cited By ~ 5

Author(s):

R.-D. Hofheinz ◽

U. Ronellenfitsch ◽

S. Kubicka ◽

A. Falcone ◽

I. Burkholder ◽

...

Keyword(s):

Colorectal Cancer ◽

Metastatic Colorectal Cancer ◽

Kinase Inhibitors ◽

Meta Analysis ◽

Progression Free Survival ◽

Optimal Sequence ◽

Primary Endpoints ◽

Disease Stabilization ◽

Antiangiogenic Drugs ◽

The Impact

Background. In metastatic colorectal cancer (mCRC), continuing antiangiogenic drugs beyond progression might provide clinical benefit. We synthesized the available evidence in a meta-analysis.Patients and Methods. We conducted a meta-analysis of studies investigating the use of antiangiogenic drugs beyond progression. Eligible studies were randomized phase II/III trials. Primary endpoints were overall survival (OS) and progression-free survival (PFS). Secondary endpoints were the impact of continuing antiangiogenic drugs (i) in subgroups, (ii) in different types of compounds targeting the VEGF-axis (monoclonal antibodies versus tyrosine kinase inhibitors), and (iii) on remission rates and prevention of progression.Results. Eight studies (3,668 patients) were included. Continuing antiangiogenic treatment beyond progression significantly improved PFS (HR 0.64; 95%-CI, 0.55–0.75) and OS (HR 0.83; 95%-CI, 0.76–0.89). PFS was significantly improved in all subgroups with comparable HR. OS was improved in all subgroups stratified by age, gender, and ECOG status. The rate of patients achieving at least stable disease was improved with an OR of 2.25 (95%-CI, 1.41–3.58).Conclusions. This analysis shows a significant PFS and OS benefit as well as a benefit regarding disease stabilization when using antiangiogenic drugs beyond progression in mCRC. Future studies should focus on the optimal sequence of administering antiangiogenic drugs.

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