MicroRNAs (miRNAs) are short non-coding RNA molecules playing regulatory roles by repressing translation or cleaving RNA transcripts. Although the number of verified human miRNA is still expanding, only few have been functionally described. However, emerging evidences suggest the potential involvement of altered regulation of miRNA in pathogenesis of cancers and these genes are thought to function as both tumours suppressor and oncogenes.In our study, we examined by Real-Time PCR the expression of 156 mature miRNA in colorectal cancer. The analysis by several bioinformatics algorithms of colorectal tumours and adjacent nonneoplastic tissues from patients and colorectal cancer cell lines allowed identifying a group of 13 miRNA whose expression is significantly altered in this tumor. The most significantly deregulated miRNA being miR-31, miR-96, miR-133b, miR-135b, miR-145, and miR-183. In addition, the expression level of miR-31 was correlated with the stage of CRC tumor.Our results suggest that miRNA expression profile could have relevance to the biological and clinical behavior of colorectal neoplasia.

The multifactorial likelihood analysis method has demonstrated utility for quantitative assessment of variant pathogenicity for multiple cancer syndrome genes. Independent data types currently incorporated in the model for assessing BRCA1 and BRCA2 variants include clinically calibrated prior probability of pathogenicity based on variant location and bioinformatic prediction of variant effect, co‐segregation, family cancer history profile, co‐occurrence with a pathogenic variant in the same gene, breast tumor pathology, and case‐control information. Research and clinical data for multifactorial likelihood analysis were collated for 1,395 BRCA1/2 predominantly intronic and missense variants, enabling classification based on posterior probability of pathogenicity for 734 variants: 447 variants were classified as (likely) benign, and 94 as (likely) pathogenic; and 248 classifications were new or considerably altered relative to ClinVar submissions. Classifications were compared with information not yet included in the likelihood model, and evidence strengths aligned to those recommended for ACMG/AMP classification codes. Altered mRNA splicing or function relative to known nonpathogenic variant controls were moderately to strongly predictive of variant pathogenicity. Variant absence in population datasets provided supporting evidence for variant pathogenicity. These findings have direct relevance for BRCA1 and BRCA2 variant evaluation, and justify the need for gene‐specific calibration of evidence types used for variant classification.

A distinct angiogenesis-related expression pattern characterizes metastatic CRC cell lines. Factors other than VEGF appear as prognostic markers and intervention targets in the metastatic CRC setting.

Background:To identify whether circulating levels of angiogenesis-related factors may be predictive of bevacizumab efficacy in pre-treated metastatic colorectal cancer (mCRC) patients.Methods:Pre-treatment serum levels of 24 cytokines were measured using a multiplex bead assay (MBA) in 32 pre-treated mCRC patients treated with irinotecan plus bevacizumab-based salvage therapy. Macrophage-derived chemokine (MDC), interleukins (ILs) 8 and 6 levels were also validated by enzyme-linked immunosorbent assay (ELISA) at different time points during therapy.Results:Higher epidermal growth factor (EGF) and MDC baseline levels (2.2- and 1.4-fold, respectively) and lower IL-10, IL-6 and IL-8 levels (0.2-, 0.6-, and 0.6-fold, respectively, P<0.05) were observed in patients responding to therapy. Baseline levels of these five serum factors compose a risk signature that may define the subset of patients most likely to benefit from bevacizumab-based therapy in terms of response rate and survival times. A positive correlation was found between MBA and ELISA results (P<0.01). Treatment exposure increased MDC and had opposite effects on IL-8 levels, which were decreased (P<0.05).Conclusion:This study suggests that a set of inflammatory and angiogenesis-related serum markers may be associated with the efficacy of bevacizumab-containing regimen.

Background Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. Methods 483 BRCA1 and 1,318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were three versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen-receptor (ER) negative (PRSER-) or ER-positive (PRSER+) breast cancer risk. Results PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07-1.83) for BRCA1 and 1.33 (95% CI = 1.16-1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for both BRCA1 (OR = 1.73, 95% CI = 1.28-2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34-1.91) carriers. The estimated breast cancer ORs were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. Conclusions Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and to inform clinical management.

Background:To determine the dose-limiting toxicity (DLT), maximum tolerated dose, recommended dose (RD) and preliminary evidence of activity of escalating doses of irinotecan (CPT-11) fixed-dose-rate infusional gemcitabine (FDR-GMB) and bevacizumab in pretreated metastatic colorectal cancer (mCRC) patients. Pharmacogenomic analysis was performed to investigate the association between VEGF single-nucleotide polymorphisms and clinical outcome.Patients and methods:A total of 89 mCRC patients were recruited in a two-step study design; 28 were included in the dose-finding study and 59 in the pharmacogenomic analysis. The FDR-GMB of 1000 mg m–2, bevacizumab 5 mg kg–1 and CPT-11 doses ranging from 100 to 160 mg m–2 were explored. The VEGF protein serum levels were quantified by EIA. Allelic discrimination was performed to genotype polymorphisms in the VEGF gene.Results:CPT-11 RD was 150 mg m–2. Diarrhoea and neutropenia were the DLT. After a median follow-up of 42 months, the median time to progression (TTP) and overall survival were 5.2 and 19.9 months, respectively. VEGF levels were significantly correlated with VEGF-2578AA and VEGF-460CC genotypes, and a trend was observed with VEGF+405GG genotype. The presence of any of these genotypes correlated with a longer median TTP (8.8 vs 4.5 months, P=0.04).Conclusion:The triplet combination tested in this study is effective and well tolerated. A possible predictive role for VEGF gene polymorphisms and baseline VEGF circulating levels is suggested.

Interindividual differences in the toxicity and response to anticancer therapies are currently observed in practically all available treatment regimens. A goal of cancer therapy is to predict patient response and toxicity to drugs in order to facilitate the individualization of patient treatment. Identification of subgroups of patients that differ in their prognosis and response to treatment could help to identify the best available drug therapy according the genetic profile. Several mechanisms have been suggested to contribute to chemo-therapeutic drug resistance: amplification or overexpression of membrane transporters, changes in cellular proteins involved in detoxification or in DNA repair, apoptosis and activation of oncogenes or tumor suppressor genes. Colorectal cancer (CRC) is regarded as intrinsically resistant to chemotherapy. Several molecular markers predictive of CRC therapy have been included during the last decade but their results in different studies complicate their application in practical clinical. The simultaneous testing of multiple markers predictive of response could help to identify more accurately the true role of these polymorphisms in CRC therapy. This review analyzes the role of genetic variants in genes involved in the action mechanisms of the drugs used at present in colorectal cancer.

Introduction: Data from the Phase II GALEN study suggest that chemo-free induction and maintenance with obinutuzumab (G), a glycoengineered type II anti-CD20 antibody, plus lenalidomide (LEN) may have favorable activity and tolerable safety in patients (pts) with relapsed/refractory (R/R) FL (Morschhauser et al. Hematol Oncol 2017). The combination of G and the anti-programmed death-ligand 1 (PD-L1) antibody atezolizumab (atezo), which has a complementary mode of action to anti-CD20 antibodies, has shown activity in R/R FL (Palomba et al. Hematol Oncol 2017). Atezo-G-LEN has the potential to enhance anti-tumor immune response in R/R FL. Interim data from a Phase Ib/II study (NCT02631577) assessing the safety and efficacy of induction and maintenance with atezo-G-LEN in pts with R/R FL are reported. Methods: This is an ongoing, open-label, multicenter study of pts with R/R FL (excluding grade [Gr] 3b) who have received ≥1 prior anti-CD20 antibody-containing chemo-immunotherapy regimen. The study comprises an initial 3+3 dose-escalation phase (to determine the recommended Phase II dose [RP2D] of LEN for the triplet regimen) followed by an expansion phase (RP2D of LEN). Pts receive induction treatment with six 28-day cycles of: G 1000mg IV on day (D) 1, D8, and D15 of Cycle (C) 1 and D1 of C2-6; atezo 840mg IV on D1 and D15 of C2-6; and LEN 15mg or 20mg (dose escalation), or at the RP2D (expansion), PO on D1-21 of C1-6. Pts with a complete response (CR), partial response, or stable disease at the end of induction (EOI) receive 24 months of maintenance with G 1000mg on D1 every 2 months, atezo 840mg on D1 and D2 monthly, and LEN 10mg on D1-21 monthly (months 1-12). Primary endpoints are dose-limiting toxicities (DLTs) during C2, safety/tolerability, and CR (PET-CT) rate by Independent Review Committee (IRC) at EOI (modified Lugano 2014 criteria) in the LEN 20mg (RP2D) expansion cohort. Data cut-off was February 28, 2018. Results: At the time of interim analysis (IA), 29 pts were enrolled and treated (LEN 15mg, n=4; LEN 20mg, n=25). Three pts were receiving induction treatment, 5 had discontinued during induction (death due to progressive disease [PD], n=3; PD, n=1; withdrawal of consent, n=1), 21 had completed induction, and 20 were still receiving maintenance. Baseline characteristics at study entry were: median age, 62 years (range 38-79); male, 52%; Ann Arbor Stage III-IV, 86%; FLIPI high risk (≥3), 28%; bulky disease (≥7cm), 21%; ≥2 prior lines of therapy, 52%; refractory to last treatment line, 48%; and pts with early progression (within 24 months) on first-line treatment (POD24), 31%. No DLTs were reported during C2 at either LEN dose during dose escalation; therefore, LEN 20mg was selected as the RP2D for expansion. Median dose intensity for all 3 study drugs was 95-100% during induction and 100% during maintenance. Twenty-eight pts (97%) had ≥1 adverse event (AE): 18 (62%) Gr ≥3 AEs; 9 (31%) serious AEs; 2 (7%) AEs leading to discontinuation of any study drug (Gr 2 pneumonitis and Gr 2 myalgia secondary to myositis, both leading to discontinuation of atezo); 3 (10%) AEs leading to LEN dose reduction; and 22 (75%) AEs requiring interruption of any treatment (including LEN dose reduction, missed doses or dose delays); no Gr 5 AEs were reported. Common AEs (all-Gr and Gr ≥3) are shown in Table 1. The most common Gr ≥3 AEs were hematologic toxicities (neutropenia [35%], thrombocytopenia [17%], and anemia [10%]) and infections (10%). The most common AEs of special interest (≥4 pts) were infusion-related reactions (35%), dyspnea (21%), hyperthyroidism (17%), hypothyroidism (14%), and pyrexia (17%); all events were mild or moderate, except one case of dyspnea (Gr 3). One second primary malignancy (meningioma) was reported. Among 20 efficacy-evaluable pts, the PET-CT CR rate at EOI was 80% by IRC and 85% by investigator (modified Lugano 2014 criteria) (Table 2). All pts receiving maintenance had durable clinical responses (Figure). Conclusions: At this IA, the overall safety profile observed for the chemo-free triplet regimen atezo-G-LEN is consistent with the known AE profiles for the individual drugs, with acceptable safety and tolerability. Response rates at EOI with atezo-G-LEN compare favorably with those reported for currently available treatments for R/R FL, with preliminary evidence of durable activity. Disclosures Salles: Amgen: Honoraria; Novartis: Consultancy, Honoraria; Morphosys: Honoraria; BMS: Honoraria, Other: Advisory Board; Epizyme: Honoraria; Servier: Honoraria, Other: Advisory Board; Celgene: Honoraria, Other: Advisory Board, Research Funding; Abbvie: Honoraria; Janssen: Honoraria, Other: Advisory Board; Takeda: Honoraria; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Merck: Honoraria; Acerta: Honoraria; Servier: Honoraria; Pfizer: Honoraria; Gilead: Honoraria, Other: Advisory Board. Ghosh:PCYC: Consultancy, Research Funding, Speakers Bureau; TG Therapeutics: Honoraria, Research Funding; SGN: Consultancy, Research Funding, Speakers Bureau; F. Hoffman-La Roche Ltd: Research Funding; Spectrum: Consultancy; Forty seven Inc: Research Funding; Abbvie: Consultancy, Speakers Bureau; Juno: Consultancy, Research Funding; Genentech: Research Funding; Gilead: Consultancy, Speakers Bureau; Pharmacyclics, an Abbvie Company: Consultancy, Research Funding, Speakers Bureau; Celgene: Consultancy. Lossos:Affimed: Research Funding. Palomba:Pharmacyclics: Consultancy; Celgene: Consultancy. Mehta:Incyte: Research Funding; Kite: Consultancy, Speakers Bureau; Spectrum: Consultancy; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy, Research Funding; F. Hoffmann-La Roche Ltd: Research Funding; Merck: Research Funding; Epizyme: Research Funding; Gilead: Consultancy, Speakers Bureau; Seattle Genetics: Research Funding; AstraZeneca: Consultancy, Speakers Bureau; Carevive: Other: Patient engagement; Medpage: Other: Medical website. Casasnovas:Celgene: Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria, Research Funding; F. Hoffmann-La Roche Ltd: Consultancy, Honoraria, Research Funding; Karyopharm: Consultancy, Honoraria; Merck: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Stevens:Bayer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Abajo:F. Hoffman-La Roche Ltd: Employment, Other: Ownership interests PLC. Nielsen:F. Hoffmann-La Roche Ltd: Employment, Other: Ownership interests PLC. Chitra:Genentech/Roche: Employment. Wenger:F. Hoffmann-La Roche Ltd: Employment, Equity Ownership, Other: Ownership interests PLC. Morschhauser:Gilead: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Servier: Membership on an entity's Board of Directors or advisory committees; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees.