Maria Alessandra Calegari

KRAS mutational status affects oxaliplatin-based chemotherapy independently from basal mRNA ERCC-1 expression in metastatic colorectal cancer patients

Background:In this study, we evaluated the possibility that KRAS mutational status might be predictive of oxaliplatin (OXA) efficacy. We also explored the role of excision repair cross complementing group-1 (ERCC-1).Methods:Ninety anti-epidermal growth factor receptor-naive advanced colorectal cancer patients were retrospectively analysed. In all patients KRAS mutational status was assessed. In 60 patients mRNA ERCC-1 expression was also investigated. Response rate (RR) and progression-free survival (PFS) after FOLFOX-6±bevacizumab were evaluated according to KRAS status and mRNA ERCC-1 expression.Results:Among 90 patients 47% wild-type (wt) and 53% mutated (mt) KRAS tumours were found. Response rate was 26% in the wt KRAS group, whereas it was 56% in the mt KRAS group; the difference is statistically significant in the total sample (P=0.008) and when only patients receiving FOLFOX-6±bevacizumab as first-line are considered (P=0.01). Progression-free survival was longer in mt than in wt KRAS patients over all patients (10 vs 8 months, respectively, P=0.001) and in those treated as first-line (10 vs 8 months, respectively, P=0.0069). Mt KRAS patients experienced a longer survival (24 vs 18 months; P=0.01). ERCC-1 mRNA expression was not found to correlate with FOLFOX activity in our analysis.Conclusion:Our results suggest that activating mutation of KRAS oncogene may predict response to OXA. Basal expression of ERCC-1 mRNA does not explain the high efficacy of FOLFOX-6 in mt KRAS patients.

A phase 2 study of temozolomide in pretreated metastatic colorectal cancer with MGMT promoter methylation

Background:Presently, few options are available for refractory colorectal cancer (CRC). O6-methyl-guanine-DNA-methyltransferase (MGMT) promoter methylation is a frequent and early event in CRC tumourigenesis. This epigenetic silencing is a predictor of response to the alkylating drug temozolomide in glioblastoma. Preclinical evidences and some case reports showed temozolomide activity in CRC with MGMT silencing, but the available data from clinical trials are inconsistent.Methods:This was a multicentre, phase 2 trial, planned according to a two-stage Simon’s optimal design to investigate activity and safety of temozolomide in refractory CRC harbouring MGMT promoter methylation. The primary end point was overall response rate (ORR). Patients who failed two or more prior treatments received temozolomide at a dose of 150–200 mg m−2 per day on days 1–5 every 28 days.Results:From July 2012 to June 2016, 225 patients were screened, 80 showed MGMT promoter methylation and 41 were enrolled. Overall response rate was 10% and disease control rate was 32%. Median progression-free survival and overall survival were 1.9 and 5.1 months, respectively.Conclusions:Temozolomide showed a modest activity in this heavily pretreated population and the study did not meet its primary end point. The role of temozolomide in CRC remains still controversial and further research is warranted.

ERCC1 Induction after Oxaliplatin Exposure May Depend on KRAS Mutational Status in Colorectal Cancer Cell Line: In Vitro Veritas

Introduction: Oxaliplatin (Oxa) is widely used in metastatic colorectal cancer (mCRC), but currently there are not valid predictors of response to this drug. In the control arms both of OPUS and PRIME studies Oxa seems more active in patients with mCRC with mutated (mt) KRAS than in those with wild type (wt) KRAS. Recently we have retrospectively confirmed this suggestion, therefore we have hypothesized that the mutational status of KRAS could influence the expression of ERCC1, one of the main mechanisms of Oxa resistance. Material and Methods: We used four cell lines of colorectal cancer: two KRAS wild type (wt) (HCT-8 and HT-29) and two KRAS mt (SW620 and SW480). We evaluated the sensitivity of these cell lines to Oxa by MTT-test as well the ERCC1 levels before and after 24 h exposure to Oxa by Real-Time PCR. We silenced KRAS in a KRAS mt cell line (SW620LV) to evaluate the impact on Oxa sensitivity and ERCC1 levels. Lastly, ERCC1 was also silenced in order to confirm the importance of this protein as an Oxa resistance factor. Results: The KRAS mt cell lines resulted more sensitive to Oxa (OR 2.68; IC 95% 1.511-4.757 p<0.001). The basal levels of ERCC1 did not show significant differences between KRAS mt and wt cell lines, however, after 24 h exposure to Oxa, only the wt KRAS lines showed the ability to induce ERCC1, with a statistically significant difference (OR 42.9 IC 95% 17.260-106.972 p<0.0005). By silencing KRAS, sensitivity to Oxa was reduced in mt KRAS cell lines and this effect was associated with the acquisition of ability to induce ERCC1. Silencing of ERCC1, in turn, enhanced the sensitivity to Oxa in wt KRAS cell lines and restored sensitivity to Oxa in SW620LV cell line. Conclusion: KRAS mutated cell lines were more sensitive to Oxa. This feature seems secondary to the inability of these cells to induce ERCC1 after exposure to Oxa. Thus, KRAS mutational status might be a predictor of response to Oxa in CRC surrogating the cell ability to induce ERCC1.

Phase III study with FOLFIRI + cetuximab versus FOLFIRI + cetuximab followed by cetuximab alone in RAS and BRAF WT mCRC

The optimal duration and intensity of first-line therapy in metastatic colorectal cancer patients once they have achieved an objective response is controversial. In a molecularly selected RAS and BRAF wild-type (wt) population, this concern is amplified. Once disease control has been achieved with a combination therapy including an anti-EGFR antibody, further exposure both to cytotoxic drugs and targeted therapy might result only in increased toxicity. In unresectable metastatic RAS and BRAF wt colorectal cancer patients, a deintensified therapy could represent a valuable option that might preserve quality of life. We designed a study to compare FOLFIRI/cetuximab to FOLFIRI/cetuximab for eight cycles followed by cetuximab alone in first-line treatment of RAS and BRAF (wt) metastatic colorectal cancer patients.

Diffuse liver infiltration by lobular breast carcinoma: Shear wave elastography as gold standard imaging study

F IGURE 1 Imaging studies performed after the admission to the Hospital (January 2015). Ultrasound with color-Doppler study with reversal flow in portal vein and a small hypoechoic liver lesion in the III segment of the liver (arrow) (A); CT-scan (B), MRI (C), and FDG PETTC (D) do not show focal liver lesions; Supersonic Shear Wave Elastography shows a diffuse increase in tissue stiffness in the whole liver parenchyma, displaying a mean value of 62.5 kPa (E) [Color figure can be viewed at wileyonlinelibrary.com] Received: 29 November 2016 | Revised: 6 December 2016 | Accepted: 13 December 2016 DOI: 10.1111/tbj.12989

LUX-Lung 7: is there enough data for a final conclusion?

www.thelancet.com/oncology Vol 17 July 2016 e267 the ErbB family of receptors, and the theoretical mechanism of its acquired resistance might not be identical to that of the fi rst-generation EGFR tyrosine-kinase inhibitors. Until now, large-scale clinical data for the mechanism of acquired resistance to afatinib have not been reported. A retrospective study in Taiwan indicated that first-line treatment with afatinib in patients with EGFR mutation-positive NSCLC resulted in 14 patients undergoing biopsy after clinically acquired resistance, of whom seven had secondary T790M mutations. The mechanism of acquired resistance to first-line afatinib treatment, and especially the incidence of T790M mutation, requires further verifi cation. With respect to NSCLC targeted therapy, the rationale of overall management has become increasingly important. No effective clinical treatment is available for patients with acquired resistance to fi rst-generation EGFR tyrosine-kinase inhibitors not involving T790M mutations, whereas for patients with secondary T790M mutations, the effi cacy of osimertinib has been confi rmed. If the incidence of the T790M mutation after fi rst-line afatinib treatment is significantly lower than that after treatment with fi rst-generation EGFR tyrosine-kinase inhibitors, then it might not be best to choose afatinib over gefi tinib for fi rst-line management of patients with EGFR mutation-positive NSCLC.

DEBIRI and capecitabine in refractory prevalently liver metastases of colorectal cancer: A phase II study.

724 Background: Treatment options for metastatic colorectal cancer (mCRC) patients refractory to chemotherapy are limited and clinical outcome is poor. In mCRC patients with liver-dominant disease hepatic locoregional therapy might be a treatment option. In this pilot study we evaluated the safety, tolerance, and efficacy of drug-eluting beads irinotecan (DEBIRI) in combination with capecitabine in the treatment of patients with mCRC with predominally liver disease. Methods: Twenty patients affected by liver metastasis of colorectal cancer were included in this study. All patients had progression of disease after two or more lines of chemotherapy and liver was the major or the predominant site of disease. DEBIRI, beads loaded with 100 mg irinotecan, was administered biweekly via hepatic artery. All patients assumed capecitabine 1,000 mg/m2 twice daily on days 1 to 14 every 3 weeks, until disease progression. Primary endpoints were safety, tolerance and overall responce rate (ORR); secondary endpoints were...