HER2 gene copy number status may influence clinical efficacy to anti-EGFR monoclonal antibodies in metastatic colorectal cancer patients

Institute of Pathology, Locarno 6600, Switzerland.
British Journal of Cancer (Impact Factor: 4.84). 01/2013; 108(3). DOI: 10.1038/bjc.2013.4
Source: PubMed


In metastatic colorectal cancer (mCRC), KRAS is the only validated biomarker used to select patients for administration of epidermal growth factor receptor (EGFR)-targeted therapies. To identify additional predictive markers, we investigated the importance of HER2, the primary EGFR dimerisation partner, in this particular disease.

We evaluated the HER2 gene status by fluorescence in situ hybridisation (FISH) in 170 KRAS wild-type mCRC patients treated with cetuximab or panitumumab.

Depending on HER2 gene copy number status, patients showed three distinct cytogenetic profiles: 4% of patients had HER2 gene amplification (R:HER2/CEP17⩾2) in all neoplastic cells (HER2-all-A), 61% of patients had HER2 gain due to polysomy or to gene amplification in minor clones (HER2-FISH+*), and 35% of patients had no or slight HER2 gain (HER2-FISH−). These subgroups were significantly correlated with different clinical behaviours, in terms of response rate (RR; P=0.0006), progression-free survival (PFS; P<0.0001) and overall survival (OS; P<0.0001). Patients with HER2-all-A profile experienced the worst outcome, patients with HER2-FISH− profile showed an intermediate behaviour and patients with HER2-FISH+* profile were related to the highest survival probability (median PFS in months: 2.5 vs 3.9 vs 7.6, respectively; median OS in months: 4.2 vs 9.7 vs 13, respectively).

HER2 gene copy number status may influence the clinical response to anti-EGFR-targeted therapy in mCRC patients.

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Available from: Vittoria Martin, May 28, 2014
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    • "Concomitantly, using a combination of resistant clones from cetuximab-sensitive cell lines and plasma and tissue samples from cetuximab-treated mCRC patients, Yonesaka and colleagues reported aberrant HER2 signaling (by either HER2 amplification or through overproduction of the HER3-activating ligand heregulin) as a mediator of lack of response [92]. In retrospective studies, patients with tumors featuring HER2 amplification or heregulin overexpression and treated with cetuximab or panitumumab experienced disease progression and shorter progression-free and overall survival compared with HER2 wild-type cases [91-93]. "
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    ABSTRACT: Only approximately 10 % of genetically unselected patients with chemorefractory metastatic colorectal cancer experience tumor regression when treated with the anti-epidermal growth factor receptor (EGFR) antibodies cetuximab or panitumumab (“primary” or “de novo” resistance). Moreover, nearly all patients whose tumors initially respond inevitably become refractory (“secondary” or “acquired” resistance). An ever-increasing number of predictors of both primary and acquired resistance to anti-EGFR antibodies have been described, and it is now evident that most of the underlying mechanisms significantly overlap. By trying to extrapolate a unifying perspective out of many idiosyncratic details, here, we discuss the molecular underpinnings of therapeutic resistance, summarize research efforts aimed to improve patient selection, and present alternative therapeutic strategies that are now under development to increase response and combat relapse.
    Full-text · Article · Jul 2014 · Journal of Molecular Medicine
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    • "The frequency of HER2 amplification is similar to other genes such as BRAF and NRAS [42], and the evaluation of the HER2 gene by FISH may in fact be an additional useful test for the identification of mCRC patients who will benefit from anti-EGFR targeted therapies. Martin et al. [57] concluded that patients with an increased HER2 gene copy number show a worse response to anti-EGFR antibodies. In addition, a phase I clinical trial demonstrated that anti-HER2 therapy combined with cetuximab in refractory CRC was associated with antitumor activity, although the combination was not tolerable due to overlapping toxicities [58]. "
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    ABSTRACT: Targeting epidermal growth factor receptor (EGFR) has been one of the most effective colorectal cancer strategies. Anti-EGFR antibodies function by binding to the extracellular domain of EGFR, preventing its activation, and ultimately providing clinical benefit. KRAS mutations in codons 12 and 13 are recognized prognostic and predictive biomarkers that should be analyzed at the clinic prior to the administration of anti-EGFR therapy. However, still an important fraction of KRAS wild-type patients do not respond to the treatment. The identification of additional genetic determinants of primary or secondary resistance to EGFR targeted therapy for further improving the selection of patients is urgent. Herein, we review the latest published literature highlighting the most important genes that may predict resistance to anti-EGFR monoclonal antibodies in colorectal cancer patients. According to the available findings, the evaluation of BRAF, NRAS, PIK3CA, and PTEN status could be the right strategy to select patients who are likely to respond to anti-EGFR therapies. In the future, the combination of those biomarkers will help establish consensus that can be introduced into clinical practice.
    Full-text · Article · Jun 2014 · BioMed Research International
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    ABSTRACT: Background To investigate whether MicroRNAs (MiRNAs) are predictive for sensitivity to anti-Epidermal Growth Factor Receptor (EGFR) monoclonal antibodies in metastatic colorectal cancer (mCRC) patients. Methods A total of 183 mCRC from two independent cohorts (cohort 1: 74 cases; validation cohort: 109 cases) treated with cetuximab/panitumumab were included onto the study. MiRNA arrays were analysed using Agilent’s miRNA platform. Results The study identified the cluster miR-99a/Let7c/miR-125b as associated with different outcome to anti-EGFR therapies. In the first cohort, patients with high signature had a significantly longer progression free survival (PFS, 6.1 versus 2.3 months, p=0.02) and longer overall survival (OS, 29.8 versus 7.0 months, p=0.08) than patients with low signature. In the validation cohort, patients with high signature had a significantly longer PFS and OS than individuals with low signature (PFS 7.8 versus 4.3 months, p=0.02; OS 12.8 versus 7.5 months, p=0.02). In the KRAS wild-type population (N=120), high signature patients had a significantly longer PFS (7.8 versus 4.6 months, p=0.016) and longer OS (16.1 versus 10.9 months, p=0.09) than low signature individuals, with no difference in KRAS mutated patients. Conclusions MiR-99a/Let7c/miR-125b signature may improve selection of KRAS wild-type mCRC patients candidate for anti-EGFR therapy.
    No preview · Article · Jan 2013 · Clinical Colorectal Cancer
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