The predictive value of<i>KRAS, NRAS, BRAF, PIK3CA</i>and PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis

Therkildsen, Christina; Bergmann, Troels K.; Henrichsen-Schnack, Tine; Ladelund, Steen; Nilbert, Mef

doi:10.3109/0284186x.2014.895036

Cited by 336 publications

(256 citation statements)

References 35 publications

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“…In the past few years, extensive effort has been made to elucidate the mechanisms of cetuximab resistance. At present, it is generally acknowledged that specific gene mutations are responsible for resistance to anti-EGFR therapies in patients with colorectal cancer, including the KRAS, BRAF, NRAS, PI3KCA (exon 20) genes or inactivation of the PTEN phosphatase (3,8,18). However, ~25% of colorectal cancer patients with wild-type KRAS, BRAF, NRAS, PI3KCA and PTEN genes do not respond to EGFR inhibitors (3), which suggests there exists some other mechanism of resistance.…”

Section: Discussionmentioning

confidence: 99%

Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells

Wang

Zhang

et al. 2015

Oncology Reports

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Abstract. Paxillin (PXN) encodes a 68-kDa focal adhesionassociated protein and plays an important role in signal transduction, regulation of cell morphology, migration, proliferation and apoptosis. The aim of the present study was to evaluate the relationship between PXN and clinicopathological factors in colorectal cancer, the role of PXN in cetuximab resistance, and whether knockdown of PXN expression could improve the sensitivity to cetuximab in colorectal cancer cells. In the present study, immunohistochemical staining in 148 colorectal carcinoma and 126 normal adjacent tissues was performed, which showed that the positive rate of PXN was significantly higher in the colorectal adenocarcinoma samples than that in the normal colorectal mucosa samples (P<0.001). Moreover, PXN presence was also positively correlated with TNM stage (P=0.023), distant metastasis (P=0.014), recurrence (P=0.032) and reduced survival (P=0.004). In vitro, PXN expression was positively correlated with the proliferation rate in colorectal cells insensitive to cetuximab. Inhibition of PXN expression by PXN-siRNA clearly increased apoptosis by downregulating the phosphorylation of extracellular signal regulated kinase (p-Erk) level, and overexpression of PXN by PXN-cDNA decreased apoptosis by upregulating the p-Erk level. This suggests that overexpression of PXN could be one of the reasons for cetuximab resistance, and downregulation of PXN plays an important role in improving sensitivity to cetuximab by suppressing the activitation of p-Erk in colorectal cancer cells. Above all, knockdown of PXN could represent a rational therapeutic strategy for increasing the sensitivity or overcoming cetuximab-resistance in patients with colorectal cancer.

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Section: Discussionmentioning

confidence: 99%

Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells

Wang

Zhang

et al. 2015

Oncology Reports

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“…MEK1 mutations have been identified in CRC patients with primary resistance to panitumumab, as well as acquired resistance to BRAF-directed therapy [19,35]. PI3K pathway alterations, including PIK3CA mutation and PTEN mutation and loss of expression, have been associated with poor overall response rate and shorter overall survival in patients with KRAS wild-type CRC treated with cetuximab and panitumumab [36][37][38]. However, PIK3CA mutation has been reported in both pre-and post-treatment biopsy specimens from CRC patients who have developed resistance to anti-EGFR therapies, and we and others observed high co-occurrence with other alterations, including RAS mutations, suggesting that the functional significance of PIK3CA mutation in CRC is less clear [21,29].…”

Section: Discussionmentioning

confidence: 99%

Broad Detection of Alterations Predicted to Confer Lack of Benefit From EGFR Antibodies or Sensitivity to Targeted Therapy in Advanced Colorectal Cancer

Rankin¹,

Klempner

Erlich³

et al. 2016

The Oncologist

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Introduction. A KRAS mutation represented the first genomic biomarker to predict lack of benefit from anti‐epidermal growth factor receptor (EGFR) antibody therapy in advanced colorectal cancer (CRC). Expanded RAS testing has further refined the treatment approach, but understanding of genomic alterations underlying primary and acquired resistance is limited and further study is needed. Materials and Methods. We prospectively analyzed 4,422 clinical samples from patients with advanced CRC, using hybrid‐capture based comprehensive genomic profiling (CGP) at the request of the individual treating physicians. Comparison with prior molecular testing results, when available, was performed to assess concordance. Results. We identified a RAS/RAF pathway mutation or amplification in 62% of cases, including samples harboring KRAS mutations outside of the codon 12/13 hotspot region in 6.4% of cases. Among cases with KRAS non‐codon 12/13 alterations for which prior test results were available, 79 of 90 (88%) were not identified by focused testing. Of 1,644 RAS/RAF wild‐type cases analyzed by CGP, 31% harbored a genomic alteration (GA) associated with resistance to anti‐EGFR therapy in advanced CRC including mutations in PIK3CA, PTEN, EGFR, and ERBB2. We also identified other targetable GA, including novel kinase fusions, receptor tyrosine kinase amplification, activating point mutations, as well as microsatellite instability. Conclusion. Extended genomic profiling reliably detects alterations associated with lack of benefit to anti‐EGFR therapy in advanced CRC, while simultaneously identifying alterations potentially important in guiding treatment. The use of CGP during the course of clinical care allows for the refined selection of appropriate targeted therapies and clinical trials, increasing the chance of clinical benefit and avoiding therapeutic futility. Implications for Practice: Comprehensive genomic profiling (CGP) detects diverse genomic alterations associated with lack of benefit to anti‐epidermal growth factor receptor therapy in advanced colorectal cancer (CRC), as well as targetable alterations in many other genes. This includes detection of a broad spectrum of activating KRAS alterations frequently missed by focused molecular hotspot testing, as well as other RAS/RAF pathway alterations, mutations shown to disrupt antibody binding, RTK activating point mutations, amplifications, and rearrangements, and activating alterations in downstream effectors including PI3K and MEK1. The use of CGP in clinical practice is critical to guide appropriate selection of targeted therapies for patients with advanced CRC.

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“…Wild-type RAS and BRAF are favorable predictive factors of anti-epidermal growth factor receptor (EGFR) treatment for CRC (16), whereas CRC harboring mutations of PIK3CA and wild-type RAS is resistant to anti-EGFR drugs (17). However, the association between bone marrow metastasis and tumor type, such as gene mutations, was unclear.…”

Section: Discussionmentioning

confidence: 99%

Favorable control of advanced colon adenocarcinoma with severe bone marrow metastasis: A case report

Hanamura

Shibata

Shirakawa

et al. 2016

Molecular and Clinical Oncology

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Abstract. Colorectal cancer (CRC) has a propensity to metastasize to the liver, lungs and regional abdominal lymph nodes, but rarely to the bone marrow. A 60-year-old man presented to the National Hospital Organization Kyushu Cancer Center with a 4-week history of persistent lower back pain, anorexia and difficulty defecating. Complete blood count revealed severe thrombocytopenia and erythroblastosis, suggesting a hematological malignancy. However, the bone marrow examination demonstrated involvement by a moderately to poorly differentiated adenocarcinoma, but no hematopoietic abnormalities. A computed tomography scan revealed thickening of the wall of the sigmoid colon, with para-aortic, hilar, mediastinal and supraclavicular lymphadenopathy. The patient was thus diagnosed with sigmoid colon adenocarcinoma with lymph node and bone marrow metastasis. Modified FOLFOX6 was promptly initiated, with concurrent therapy for disseminated intravascular coagulation (DIC). An increased number of thrombocytes was observed on day 6. After 3 cycles of treatment, the patient recovered from DIC and the levels of serum carcinoembryonic antigen and cytokeratin 19 fragment were decreased. Tumor biopsy during colonoscopy following recovery from DIC demonstrated poorly differentiated adenocarcinoma with mucin production, without mutations in the RAS, BRAF or PIK3CA genes, and a cytokeratin (CK) 7-negative, CK20-positive phenotype. The patient has been treated with chemotherapy for 150 days without disease progression. However, the efficacy of chemotherapy for rarely encountered bone marrow metastasis from CRC is poor. The present case was favorably maintained on chemotherapy and survived for 10 months. IntroductionBone marrow metastasis from malignant solid tumors may be occasionally encountered, particularly with cancers of the breast, stomach and prostate gland (1). Decreased blood cell count and abnormal coagulation status are often observed in cases with bone marrow metastasis from malignant tumors, and disseminated intravascular coagulation (DIC) or thrombotic thrombocytopenic purpura (TTP) occasionally develop. Supportive therapy against the abnormal coagulation status alone is inadequate in patients with DIC precipitated by malignancy, and simultaneous appropriate chemotherapy against the tumor is required to improve the coagulation abnormalities. Specific chemotherapeutic regimens against bone marrow metastasis have not been developed, and the majority of such patients have a poor prognosis (2-4).Colorectal cancer (CRC) is the third cause of cancer-related mortality worldwide (5). Approximately 40% of CRC patients present with distant metastases, either at diagnosis or during the course of treatment. Metastasis frequently affects the liver, abdominal lymph nodes, lungs and peritoneum. Systemic chemotherapy is employed as a standard therapy and the effectiveness of chemotherapy has recently improved in association with the use of cytotoxic and molecular-targeted agents.However, a limited number of CRC cases were reported to ...

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The predictive value ofKRAS, NRAS, BRAF, PIK3CAand PTEN for anti-EGFR treatment in metastatic colorectal cancer: A systematic review and meta-analysis

Cited by 336 publications

References 35 publications

Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells

Paxillin is positively correlated with the clinicopathological factors of colorectal cancer, and knockdown of Paxillin improves sensitivity to cetuximab in colorectal cancer cells

Broad Detection of Alterations Predicted to Confer Lack of Benefit From EGFR Antibodies or Sensitivity to Targeted Therapy in Advanced Colorectal Cancer

Favorable control of advanced colon adenocarcinoma with severe bone marrow metastasis: A case report

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