Gene copy number for epidermal growth factor receptor (EGFR) and clinical response to antiEGFR treatment in colorectal cancer: a cohort study

BACKGROUND: The antiepidermal growth factor receptor (antiEGFR) monoclonal antibodies cetuximab and panitumumab have good clinical activity in about 10% of patients with metastatic colorectal cancer that is resistant to chemotherapy. The molecular mechanisms underlying clinical response or resistance to these agents are unknown. METHODS: Tumours from 31 patients with metastatic colorectal cancer who had either an objective response (n=10) or stable disease or progressive disease (n=21) after treatment with cetuximab or panitumumab were screened for genetic changes in EGFR or its immediate intracellular effectors. Specifically, we assessed the EGFR copy number and the mutation profile of the EGFR catalytic domain and of selected exons in KRAS, BRAF, and PIK3CA. RESULTS: Eight of nine of patients with objective responses who were assessable by fluorescence in-situ hybridisation (FISH) had an increased EGFR copy number. By contrast, one of 21 non-responders assessable by FISH had an increased EGFR copy number (p<0.0001 for responders vs non-responders, Fisher's exact test). The mutation status of the EGFR catalytic domain and its immediate downstream effectors PIK3CA, KRAS, and BRAF did not correlate with disease response. In colorectal-cancer cell lines, the concentration of cetuximab that completely inhibited proliferation of cells with amplified EGFR copy number did not affect proliferation of cells with unamplified EGFR. INTERPRETATION: We propose that the response to antiEGFR treatment has a genetic basis and suggest that patients might be selected for treatment on the basis of EGFR copy number.     

Personalized therapeutic strategies in HER2-driven gastric cancer

Gastric Cancer - Trastuzumab is the only approved targeted therapy in patients with HER2-amplified metastatic gastric cancer (GC). Regrettably, in clinical practice, only a fraction of them...     

Pooled Analysis of Clinical Outcome of Patients with Chemorefractory Metastatic Colorectal Cancer Treated within Phase I/II Clinical Studies Based on Individual Biomarkers of Susceptibility: A Single-Institution Experience

Background

Patients with metastatic colorectal cancer (mCRC) refractory to standard therapies have a poor prognosis. In this setting, recruitment into clinical trials is warranted, and studies driven by selection according to individual tumor molecular characteristics are expected to provide added value.

Objective

We retrospectively analyzed data from patients with mCRC refractory to or following failure of standard therapies who were enrolled into phase I/II clinical studies at the Niguarda Cancer Center based on the presence of a specific molecular profile expected to represent the target of susceptibility to the experimental drug(s).

Patients and Methods

From June 2011 to May 2016, 2044 patients with mCRC underwent molecular screening. Eighty patients (3.9%) were enrolled in ad hoc studies; the median age was 60 years (range 36–86) and the median number of previous treatment lines was five (range 2–8). Molecular characteristics exploited within these studies were MGMT promoter hypermethylation (48.7%), HER2 amplification (28.8%), BRAF ^V600E mutation (20%), and novel gene fusions involving ALK or NTRK (2.5%).

Results

One patient (1%) had RECIST (Response Evaluation Criteria In Solid Tumors) complete response (CR), 13 patients (16.5%) experienced a partial response (PR), and 28 (35%) stable disease (SD). Median progression-free survival (PFS) was 2.8 months (range 2.63–3.83), with 24% of patients displaying PFS >5 months. Median growth modulation index (GMI) was 0.85 (range 0–15.61) and 32.5% of patients had GMI >1.33. KRAS exon 2 mutations were found in 38.5% of patients, and among the 78 patients with known KRAS status, those with wild-type tumors had longer PFS than those with mutated tumors (3.80 [95% CI 2.80–5.03] vs. 2.13 months [95% CI 1.77–2.87], respectively, p = 0.001). Median overall survival (OS) was 7.83 months (range 7.17–9.33) for all patients, and patients with KRAS wild-type tumors had longer OS than those with mutated tumors (7.83 [95% CI 7.33–10.80] vs. 7.18 months [95% CI 5.63–9.33], respectively, p = 0.06).

Conclusions

This single-institution retrospective study indicates that in a heavily pretreated population approximately 4% of mCRC tumors display a potential actionable molecular context suitable for therapeutic intervention. Application of molecular selection is challenging but improves clinical outcome even in later lines of treatment.

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Is Codon 13 KRAS Mutation Biologically Different from Codon 12 Mutation?

The introduction into clinical practice of KRAS mutational status for selection of patients has dramatically improved the results from use of anti-EGFR monoclonal antibodies cetuximab or panitumumab for metastatic colorectal cancer. More refined selection of patients by means of other molecular alterations, for example BRAF, PIK3CA, and NRAS has enabled further increases in responses to first-line and other therapy for metastatic disease. Elucidation of differences among specific subtypes of KRAS mutations affecting sensitivity, and identification of other mechanisms by which tumor cell resistance is acquired, revealing ??druggable?? molecular targets to overcome resistance, are clearly a priority of clinical research. Recent data have revealed potentially different activity of the G13D KRAS mutation in conferring resistance to cetuximab. This review examines the most recent evidence available on codon 13 mutation in metastatic colorectal cancer, including both preclinical and available clinical data, indicating differences between codon 13 and other KRAS mutations and analyzing its prognostic and predictive use in EGFR-targeted therapy.     

Gemcitabine and oxaliplatin in the treatment of patients with immunotherapy-resistant advanced renal cell carcinoma: final results of a single-institution Phase II study

BACKGROUND: Currently, there is no standard treatment for patients with advanced renal cell carcinoma (RCC) who do not experience a response to first-line immunotherapy. In the current Phase II study, the authors explored the antitumor activity of a combination of gemcitabine and oxaliplatin (L-OHP) in this setting. METHODS: Forty-two patients with RCC who had progressive disease following immunotherapy received gemcitabine (1000 mg/m2 intravenously on Days 1 and 8 every 21 days) and L-OHP (90 mg/m2 intravenously on Day 1 every 21 days) for a minimum of 2 cycles before responses were evaluated. Responses to treatment and toxicity were recorded according to the Response Evaluation Criteria in Solid Tumors and the National Cancer Institute Common Toxicity Criteria, respectively. RESULTS: No complete responses were recorded; however, 6 patients experienced a partial response (14.28%; 95% confidence interval, 5.43-28.5%), 11 patients (26.19%) had temporary stable disease as a best response, and the remaining 25 patients (59.52%) experienced progression despite receiving treatment. The median time to disease progression was 2.5 months (mean, 3.86 months; range, 1.5-11.0 months), whereas the median overall survival was 9.5 months (mean, 10.46 months; range, 4.0-22.5 months). With regard to toxicity, treatment generally was well tolerated, with only one episode of Grade 4 toxicity and expected episodes of Grade 3 toxicity, including myelosuppression and neuropathy. CONCLUSIONS: The current results suggest that the combination of gemcitabine and L-OHP possesses a certain level of activity and an acceptable toxicity profile in patients with immunotherapy-resistant advanced RCC.     

Controversial evaluation of EGFR protein and gene status in predicting response to anti-EGFR monoclonal antibodies in metastatic colorectal cancer: a case report and review of the literature

Clinical studies showed that only 10% of patients with metastatic colorectal cancer (mCRC) respond to treatment with the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies panitumumab or cetuximab, regardless of the line of treatment. The current tool used to select patients, i.e. immunohistochemistry (IHC) evaluation of EGFR expression by EGFR pharmDx™ Kit, is not reliable in predicting response. Retrospective analyses of factors such as increased EGFR gene copy number and KRAS and/or BRAF mutations showed that such molecular changes could affect clinical benefit from anti-EGFR monoclonal antibodies. We report here the case of a 66-year-old man with chemorefractory mCRC, considered not eligible to salvage treatment with the anti-EGFR monoclonal antibody cetuximab and irinotecan because the primary adenocarcinoma of the rectum was found not expressing EGFR protein by IHC. However, FISH analysis of EGFR gene copy number and evaluation of KRAS and/or BRAF specific mutations by gene sequencing showed characteristics associated with favourable clinical outcome to anti-EGFR therapy. Based on the EGFR protein expression by IHC in a liver metastasis, the patient was then treated with cetuximab plus irinotecan, obtaining symptoms improvement and a dramatic objective tumor response in all sites of disease, lasting 4.2 months. We also discuss literature findings about the role of different biological characteristics in predicting clinical benefit from anti-EGFR therapy in patients with mCRC. Supported by research grants from Associazione Italiana Ricerca Cancro (AIRC) and Oncologia Ca’ Granda ONLUS Fondazione.     

Intrapleural interleukin-2 induces nitric oxide production in pleural effusions from malignant mesothelioma: a possible mechanism of interleukin-2-mediated cytotoxicity?

Due to the frequent use of intrapleural interleukin-2 (IL-2) to treat pleural effusions from malignant mesothelioma (MMe), we measured nitric oxide (NO) end product nitrite (NO(2)(-)) in pleural effusions of 12 MMe patients with chronic or chronic-relapsing pleurisy. Through high performance liquid chromatography analysis, NO(2)(-) was found in the initial pleural fluid sample of all patients (156.25 pmol ml(-1)), and increased significantly following IL-2 intrapleural instillation, both at 24 (589.91 pmol ml(-1), P < or = 0.0005) and 48 h (756 pmol ml(-1), P< or = 0.0005). Even though it is difficult to argue if the large amounts of NO end product NO(2)(-) we observed is produced by IL-2-stimulated and recruited immune cells, by MMe cells themselves, or by both, it is possible that NO could contribute to the complex antitumor activity of IL-2.