Mario Scartozzi
Department of Medical Science and Public Health
Telephone: +39-070-5109 3215
E-mail: marioscartozzi@unica.it
Personal webpage: here
Main areas of expertise: Translational studies with targeted agents in patients with gastrointestinal tumours; Prospective validation of biological markers of response/resistance in gastrointestinal cancer patients receiving treatment directed against the Epidermal Growth Factor Receptor or tumour angiogenesis
♦ Translational Studies with anti-EGFR therapy
Clinical reports with the use of monoclonal antibodies directed against the ligand-binding site of the epidermal growth factor receptor (EGFR) have shown practice-changing results in the treatment of colorectal cancer and will hopefully further improve in the next future available therapeutic options for patients diagnosed with this highly deadly disease.
In first-line, randomised trials objective response rate approached in fact 50-60% with the use of chemotherapy in combination with anti-EGFR treatment (cetuximab or panitumumab), thus suggesting that a nonnegligible proportion of patients, ranging from 50% to 40%, did not fully benefit from the use of anti-EGFR targeted antibodies although in the absence of a mutation of the RAS genes. Most of the biological factors analysed in the attempt to improve patients selection in this setting focused either on the EGFR-downstream signalling pathway or on the receptor itself. Published research data suggested that EGFR gene copy number, PI3KCA mutations and BRAF mutational status may all represent predictive determinants for anti- EGFR therapy. However these factors were not incorporated into clinical practice particularly because prospective validation is lacking. Biologically enriched, prospective clinical trials are clearly needed in order to further identify the proportion of patients more likely to benefit from the use of first-line anti-EGFR antibodies. We then designed translational analyses in order to prospectively define a molecular panel able to identify patients more likely to benefit from the use of first-line anti-EGFR treatment in combination with chemotherapy.
♦ Translational Studies with treatment directed against tumour-driven angiogenesis
Tumour-driven neoangiogenesis represents one of the main biological target of regorafenib. Molecular mechanisms underlying angiogenesis may be then considered as potentially interesting in the search of predictive factors for clinical outcome during regorafenib. Preliminary findings from our group suggested, that the VEGF-A rs2010963 polymorphism might have an independent correlation with PFS and OS (respectively HR: 0.49, 95% CI: 0.33-0.81, p=0.003 and HR: 0.52, 95% CI: 0.34-0.99, p=0.04). On the other hand further analyses focused on factors such as neutrophil to lymphocyte ratio, platelets count and LDH serum levels to define a biological profile of responding/resistant patients. Unfortunately these factors have been all analysed separately and, more importantly, retrospectively, thus preventing clinicians to incorporate findings from these studies into clinical practice. Pre-treated colorectal cancer patients, clinically candidates to treatment with regorafenib as per label indication in Italy will be then prospectively analysed for the panel of clinical and biological markers resulted independently associated with clinical outcome in order to prospectively define a molecular panel able to identify patients more likely to benefit from the use of first-line anti-EGFR treatment in combination with chemotherapy.
♦ Aim of the ongoing studies
Results from these studies will hopefully allow us to verify whether a prospective patients stratification based on genetic and clinical profiling analysed before the start of treatment, will be able to predict patients’ clinical outcome. These findings will ultimately help clinicians to optimize patients’ selection for regorafenib and anti-EGFR treatment, reducing unnecessary toxicities for patients unlikely to benefit from such a treatment approach.
Key Publications:
Scartozzi M, et al. (2014) VEGF and VEGFR genotyping in the prediction of clinical outcome for HCC patients receiving sorafenib: the ALICE-1 study. International Journal of Cancer 135: 1247-1256
Scartozzi M, et al. (2012) Analysis of HER-3, insulin growth factor-1, nuclear factor-kB and epidermal growth factor receptor gene copy number in the prediction of clinical outcome for K-RAS wild-type colorectal cancer patients receiving irinotecan-cetuximab. Annals of Oncology 23: 1706-1712
Scartozzi M, et al. (2010) Insulin-like growth factor 1 expression correlates with clinical outcome in K-RAS wild type colorectal cancer patients treated with cetuximab and irinotecan. International Journal of Cancer 127: 1941-1947
Scartozzi M, et al. (2009) Arterial hypertension correlates with clinical outcome in colorectal cancer patients treated with first-line bevacizumab. Annals of Oncology 20: 227-230
Scartozzi M, et al. (2007) Nuclear factor-kB tumor expression predicts response and survival in irinotecan refractory metastatic colorectal cancer treated with cetuximab-irinotecan therapy. Journal of Clinical Oncology 25: 3930-3935
Scartozzi M, et al. (2004) Epidermal growth factor receptor (EGFR) status in primary colorectal tumors does not correlate with EGFR expression in related metastatic sites: implications for treatment with EGFR-targeted monoclonal antibodies. Journal of Clinical Oncology 22: 4772-4778
Scartozzi M, et al. (2002) Mutations of hMLH1 and hMSH2 in patients with suspected hereditary nonpolyposis colorectal cancer: correlation with microsatellite instability and abnormalities of mismatch repair protein expression. Journal of Clinical Oncology 20: 1203-1208