Article

Wild-Type BRAF Is Required for Response to Panitumumab or Cetuximab in Metastatic Colorectal Cancer

Azienda Ospedaliera Niguarda Ca' Granda, Milano, Lombardy, Italy
Journal of Clinical Oncology (Impact Factor: 17.88). 11/2008; 26(35):5705-12. DOI: 10.1200/JCO.2008.18.0786
Source: PubMed

ABSTRACT PURPOSE Cetuximab or panitumumab are effective in 10% to 20% unselected metastatic colorectal cancer (CRC) patients. KRAS mutations account for approximately 30% to 40% patients who are not responsive. The serine-threonine kinase BRAF is the principal effector of KRAS. We hypothesized that, in KRAS wild-type patients, BRAF mutations could have a predictive/prognostic value. PATIENTS AND METHODS We retrospectively analyzed objective tumor responses, time to progression, overall survival (OS), and the mutational status of KRAS and BRAF in 113 tumors from cetuximab- or panitumumab-treated metastatic CRC patients. The effect of the BRAF V600E mutation on cetuximab or panitumumab response was also assessed using cellular models of CRC. Results KRAS mutations were present in 30% of the patients and were associated with resistance to cetuximab or panitumumab (P = .011). The BRAF V600E mutation was detected in 11 of 79 patients who had wild-type KRAS. None of the BRAF-mutated patients responded to treatment, whereas none of the responders carried BRAF mutations (P = .029). BRAF-mutated patients had significantly shorter progression-free survival (P = .011) and OS (P < .0001) than wild-type patients. In CRC cells, the introduction of BRAF V600E allele impaired the therapeutic effect of cetuximab or panitumumab. Treatment with the BRAF inhibitor sorafenib restored sensitivity to panitumumab or cetuximab of CRC cells carrying the V600E allele. CONCLUSION BRAF wild-type is required for response to panitumumab or cetuximab and could be used to select patients who are eligible for the treatment. Double-hit therapies aimed at simultaneous inhibition of epidermal growth factor receptor and BRAF warrant exploration in CRC patients carrying the V600E oncogenic mutation.

1 Bookmark
 · 
275 Views
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: At present, a radical shift in cancer treatment is occurring in terms of predictive, preventive and personalised medicine (PPPM). Individual patients will participate in more aspects of their health care. During the development of PPPM, many rapid, specific, and sensitive new methods for earlier detection of cancer will result in more efficient management of the patient, and hence a better quality of life. Coordination of the various activities among different healthcare professionals in primary, secondary, and tertiary care requires well-defined competencies, implementation of training and educational programs, sharing of data, and harmonized guidelines. In this position paper the current knowledge to understand cancer pre-disposition and risk factors, the cellular biology of cancer, predictive markers and treatment outcome, the improvement in technologies to screen, diagnose and provision of better drug development solutions, are discussed in the context of a better implementation of personalised medicine. Recognition of the major risk factors for cancer initiation is the key for preventive strategies [1]. Of interest, cancer predisposing syndromes in particular the monogenic subtypes that lead to cancer progression are well defined and one should focus on implementation strategies to identify individuals at risk to allow preventive measures and early screening/diagnosis. Implementation of such measures are disturbed by improper use of the data, with breach of data protection as one of the risks to be heavily controlled. Population screening requires in depth cost-benefit analysis to justify health care costs and the parameters screened should provide information that allow an actionable deliverable, for better health care provision.
    EPMA Journal, The 02/2015;
  • [Show abstract] [Hide abstract]
    ABSTRACT: Colorectal cancer (CRC) is the third most common cancer diagnosed worldwide and continues to be a major healthcare concern. Molecular heterogeneity of CRC is believed to be one of the main factors responsible for the considerable variability in treatment response. With the recent development of powerful genomic technologies, novel insights in tumor biology of CRC have now been provided, facilitating the recognition of new molecular subtypes with prognostic and predictive implications. The purpose of this review article is to summarize current knowledge about genomic, epigenomic, and proteomic characteristics of CRC, as well as their implications for biomarker identification and individualized targeted therapy. Supplementing the findings from several previous studies, the Cancer Genome Atlas (TCGA) project recently finalized the systematic characterization of CRC resulting in the first tumor dataset with complete molecular measurements at DNA, RNA, and protein levels. The challenge now is to translate these findings into a robust and reproducible CRC classification system linking molecular features of the tumor to precision medicine.
    Langenbeck s Archives of Surgery 02/2015; 400(2). DOI:10.1007/s00423-015-1276-0 · 2.16 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: BRAF mutation and expression of extracellular signal regulated kinase (ERK) are linked with colorectal carcinogenesis through the serrated pathway. BRAF and ERK1/2 play important roles in the activation of mitogen-activated protein (MAP) kinase signaling pathways. The present study investigated the clinicopathologic outcomes of BRAF mutation and ERK1/2 expression in patients with colorectal cancer (CRC) and the possibility of using them as prognostic indicators. Dual-priming oligonucleotide-based multiplex polymerase chain reaction for BRAF (V600E) mutation and immunohistochemical analysis of ERK1/2 were performed using 65 formalin-fixed, paraffin-embedded samples from patients with CRC. We analyzed the dependences of the clinicopathologic features on BRAF mutation and ERK1/2 expression. Out of 65 samples from CRC patients, BRAF mutation was detected in 3 (4.6%). The 3 patients with BRAF mutation presented with T3 CRC with lymph node metastasis (stage III) showing moderately or poorly differentiated histology. ERK1 and ERK2 were positively detected in 73.8% and 15.4% of the patients with CRC, respectively. ERK1 expression was significantly correlated with lymph node metastasis (P = 0.049). ERK2 expression was significantly correlated with tumor emboli (P < 0.05), tumor invasion (P = 0.035), lymph node metastasis (P = 0.017), and stage (P = 0.02). BRAF mutation and ERK1/2 expression may be associated with advanced or more aggressive CRC. These molecular markers might play prognostic roles in CRC developed through the serrated pathway.

Full-text

Download
215 Downloads
Available from
May 21, 2014