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The identification of activating EGFR gene mutations and the availability of effective target therapies such as gefitinib and erlotinib have radically changed the therapeutic approach and prognosis for patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, despite an initial response to EGFR tyrosine kinase inhibitors (TKIs), acquired resistance inevitably develops and the way to overcome it is an open challenge. We report the first case, to our knowledge, of a patient affected by metastatic EGFR-mutated NSCLC with T790M-driven acquired TKI resistance who obtained a significant response to afatinib. Considering the improvement achieved in all disease sites but those in the brain, this case puts a strain on afatinib's activity on brain metastases.

Background The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, particularly in triple negative breast cancer (TNBC) characterized by high cell proliferation, aggressive behavior, and chemo-resistance. Patients and methods This is an open-label, multicenter phase II study evaluating the combination of eribulin (0.88 mg/m2) plus gemcitabine (1000 mg/m2) on days 1 and 8 of a 21-day cycle as either first- or second-line treatment of locally advanced or metastatic TNBC. The primary endpoint was the objective response for evaluable patients. A prospective, molecular correlative study was carried out to assess the role of germinal BRCA pathogenic variants and single nucleotide polymorphisms (SNPs) in predicting efficacy and toxicity of the combination regimen. Results From July 2013 to September 2016, 83 evaluable patients were enrolled. They received a median number of six cycles of treatment. An overall response rate (ORR) of 37.3% (31 patients) was observed, with a complete response rate of 2.4% and a partial response rate of 34.9%; the clinical benefit rate was 48.8%. With a median follow-up of 28.8 months, the median response duration was 6.6 months, the median progression-free survival (PFS) was 5.1 months, and the median overall survival (OS) was 14.5 months. The most common grade 3-4 adverse events were aminotransferase elevation (in 25% of the patients) and neutropenia (in 23.8%). Women with BRCA1/2 pathogenic variants were associated with worse ORR, PFS, and OS than BRCA1/2 wild-type carriers. CYP3A4 and FGD4 SNPs were associated with increased risk of liver toxicity. Three different SNPs in CDA∗2, RRM1, and CYP2C8 genes were significantly associated with poorer OS. Conclusions The combination of eribulin and gemcitabine showed promising activity and a moderate toxicity profile in metastatic TNBC. BRCA status and pharmacogenetics tests may help identify patients with high probability of response with negligible toxicity. EudraCT number 2012-003505-10., Highlights • Eribulin plus gemcitabine showed a remarkable best ORR of 37.3% and a clinical benefit rate of 48.8%. • The most common grade 3/4 toxicities were liver toxicity and neutropenia without febrile neutropenia. • The study regimen partially lost its efficacy in patients harboring BRCA1/2 pathogenic variants. • SNPs in CYP3A4 and FGD4 genes were associated with increased risk of liver toxicity. • Three different SNPs in CDA∗2, RRM1, and CYP2C8 genes were significantly associated with poorer OS.

Antibody-dependent cellular cytotoxicity (ADCC), which is activated by effector cells via immunoglobulin G (IgG) fragment C receptors (FcRs), was proposed as a mechanism of cetuximab efficacy. Peripheral blood mononuclear cells (PBMCs) from 23 healthy donors and 13 patients with metastatic colorectal cancer (mCRC) treated with cetuximab were tested for FcγR polymorphisms and cetuximab-mediated ADCC. ADCC was measured by chromium-51 release on a epidermal growth factor receptor (EGFR)-positive human colon cancer cell line. Overall, 86 mCRC patients were genotyped for study purposes. PBMCs harbouring the FcγRIIIa 158 V/V genotype had a significantly higher cetuximab-mediated ADCC. No correlation was found between FcγR polymorphisms and response rate or time to progression after cetuximab-based therapy. Despite the in vitro analysis showing that the FcγRIIIa 158 V/V genotype is associated with higher ADCC, clinical data do not support a predictive role of FcγRIIIa polymorphisms in mCRC treated with cetuximab. © 2014 Macmillan Publishers Limited All rights reserved.

Background: The FAST was a factorial trial in first-line treatment of advanced non-small-cell lung cancer (NSCLC), addressing the role of replacing cisplatin with a non-platinum agent. The prognostic and predictive effect of ERCC1/BRCA1 expression and ERCC1/XPD/XRCC1-3 gene polymorphisms on outcomes of patients was examined.Methods:Patients were randomised to receive treatment with or without cisplatin. ERCC1/BRCA1 expression was determined by immunohistochemistry. ERCC1 (C8092A, C118T), XPD (Lys751Gln), XRCC1 (Arg399Gln) and XRCC3 (Thr241Met) gene polymorphisms were evaluated on tumour DNA by TaqMan allelic discrimination assay.Results:Tumour samples were available from 110 of 433 patients enrolled: 54.7% were ERCC1 positive and 51.4% were BRCA1 positive. Overall, ERCC1-negative patients had better response rate (P=0.004), progression-free survival (P=0.023) and overall survival (P=0.012) compared with positive ones, with no statistically significant treatment interaction. The BRCA1-positive patients showed numerically better outcomes, although not statistically significant, with no treatment interaction. Among DNA repair gene polymorphisms, only XRCC1 Gln/Gln genotype evidenced a potential prognostic role (P=0.036).Conclusion:This study confirms the prognostic role of ERCC1 expression and XRCC1 (Arg399Gln) polymorphism in advanced NSCLC treated with first-line chemotherapy. None of these biomarkers was shown to be a specific predictive factor of cisplatin efficacy. © 2013 Cancer Research UK. All rights reserved.

Introduction: Epidermal growth factor receptor (EGFR) gene intron I contains a polymorphic single sequence dinucleotide repeat (CA), whose length has been found to inversely correlate with transcriptional activity. This study was designed to assess the role of (CA)(n) polymorphism in predicting the outcome of gefitinib treatment in advanced non-small cell lung cancer (NSCLC). Methods: Blood and tumor tissue from 58 patients with advanced NSCLC submitted to gefitinib were collected. EGFR intron I gene polymorphism, along with EGFR gene mutation, gene copy number and immunohistochemistry expression were determined. Moreover, a panel of lung cancer cell lines characterized for EGFR intron I polymorphism was also studied. Results: EGFR intron I polymorphism showed a statistically significant correlation with the gefitinib response (response rate 25 versus 0%, for patients with a (CA)(16) and with a (CA)(else) genotype, respectively; p = 0.044). Patients with a (CA)(16) genotype had a longer survival compared with those with a (CA)(else) genotype (11.4 versus 4.8 months, respectively; p = 0.037). In addition, cell lines lacking the (CA)(16) allele showed a statistically significant higher IC50 compared with cell lines bearing at least one (CA)(16) allele (p = 0.003). Conclusions: This study supports a potential role of EGFR intron I polymorphism in predicting the outcome of gefitinib treatment in advanced NSCLC. RI goldoni, matteo/E-9153-2011

Early age at onset is generally considered an indicator of genetic susceptibility to breast cancer. To address both the proportion of early-onset breast cancer associated with BRCA-1 or BRCA-2 germline mutation and the contribution of germline mutations to the clinical features and outcome of these tumors, we analyzed molecular status and clinical variables of a population-based sample of 66 Italian women diagnosed with breast cancer before the age of 40 who were unselected for family history. BRCA mutations were screened by automated sequencing of the entire BRCA-1 and BRCA-2 coding regions and splice junctions. Twenty-eight late-onset (over 45 years), sporadic, breast cancers were designated as "control group" for comparisons with early-onset cases. BRCA mutations (10 BRCA-1 and 6 BRCA-2) were detected in 15 (22.7%) out of 66 tested patients. The combination of ER, PR, HER-2/neu negativity and p53 positivity was significantly more frequent in BRCA-1 positive tumors than in BRCA-2 positive and non-BRCA tumors (P = 0.03). Taken collectively, BRCA-positive tumors correlated with high histologic grade and ER negativity compared with non-BRCA and sporadic tumors (P = 0.05 and 0.003, respectively). There were no significant differences between BRCA-associated breast cancers (BABC) and non-BABC in relapse-free, event-free, and overall survival. Our data confirm that the combination of age at onset and tumor phenotype can provide an efficient model for identifying individuals with a high probability of carrying BRCA mutations and support the hypothesis that breast cancer in BRCA carriers is qualitatively distinct from other early-onset breast cancers and from late-onset, sporadic, breast carcinomas. Further studies on incident cases are necessary to define the independent prognostic significance of germline BRCA mutations. (c) 2007 Elsevier Ltd. All rights reserved.

We report the first case in Italy of a non-Ashkenazi double heterozygote for BRCA1 and BRCA2 genes. This finding is predictably rare, with a maximum frequency of 1/250,000. The proband and her mother were diagnosed with early-onset breast cancer. No other relatives with breast and/or ovarian cancer were observed. The implications of this case in regard to genetic testing and counseling are substantial.

Purpose To evaluate the clinical features of breast cancer patients with genetic susceptibility to this disease and to investigate the contribution of BRCA1 germline mutations to the phenotype of these tumors. Patients and Methods We reviewed the clinical and pathological records of 102 women with suspected inherited susceptibility to breast cancer consecutively seen at the Genetic Oncology Service of Parma, Italy. Sixty-two patients with a high probability of harboring a germline, cancer-predisposing mutation were tested for BRCA1 mutations. Exon 11 was screened using the protein truncation test and detected mutations were confirmed by direct sequencing (DS). All other exons were analyzed by DS. Results Among the 62 patients with a completed mutation analysis, 48 (77.4%) had wild-type BRCA1, six (9.6%) had variants of unclear significance, eight (13%) had deleterious mutations. BRCA1-associated breast cancers (BABC) were significantly less likely to be diagnosed at stage I than breast cancers in women without mutations (12.5% vs 51%; P = 0.045), more likely to have a high proliferation rate (100% vs 24%, PConclusion In this population-based study, BABC seems to present with adverse molecular features when compared with non-BABC, although the prognosis appears to be similar.