A Real-World Application of Liquid Biopsy in Metastatic Colorectal Cancer: The Poseidon Study.

Background: First-line decision making is the key to the successful care of mCRC patients and status is crucial to select the best targeted agent. In hub centers, a relevant proportion of patients referred from small volume centers may not have standard tissue-based (STB) molecular results available at the time of the first visit (T0). Liquid biopsy (LB) may help circumvent these hurdles.

Detection of Molecular Residual Disease Using Personalized Circulating Tumor DNA Assay in Patients With Colorectal Cancer Undergoing Resection of Metastases.

Purpose: More than 50% of patients with stage IV colorectal cancer (metastatic colorectal cancer [mCRC]) relapse postresection. The efficacy of postoperative systemic treatment is limited in this setting. Thus, these patients would greatly benefit from the use of a reliable prognostic biomarker, such as circulating tumor DNA (ctDNA) to identify minimal or molecular residual disease (MRD).

Synaptophysin expression in mutated advanced colorectal cancers identifies a new subgroup of tumours with worse prognosis.

Background: Neuroendocrine differentiation has been extensively associated with worse prognosis and to mechanisms of therapy resistance in several epithelial cancers. A high prevalence of neuroendocrine differentiation was recently described in mutated (BRAFmt) metastatic colorectal cancers (mCRCs) but no data are available about its prognostic impact in this setting.

Methods: We assessed synaptophysin immunohistochemical expression in a multi-institutional series of 159 BRAFmt mCRCs with matched clinical and pathological information.

The heterogeneous clinical and pathological landscapes of metastatic -mutated colorectal cancer.

Colorectal cancer (CRC) is a complex and molecularly heterogeneous disease representing one of the most frequent causes of cancer-related death worldwide. About 8-15% of CRCs harbor a mutation in gene, a proto-oncogene involved in cell proliferation, differentiation and survival through the MAPK signaling cascade. The acquisition of mutation is an early event in the "serrated" CRC carcinogenetic pathway and is associated with specific and aggressive clinico-pathological and molecular features.

Prediction of Benefit from Checkpoint Inhibitors in Mismatch Repair Deficient Metastatic Colorectal Cancer: Role of Tumor Infiltrating Lymphocytes.

Background: Immunotherapy with immune checkpoint inhibitors (ICIs) is highly effective in microsatellite instability-high (MSI-H) metastatic colorectal cancer (mCRC); however, specific predictive biomarkers are lacking.

Patients And Methods: Data and samples from 85 patients with MSI-H mCRC treated with ICIs were gathered. Tumor infiltrating lymphocytes (TILs) and tumor mutational burden (TMB) were analyzed in an exploratory cohort of "super" responders and "clearly" refractory patients; TILs were then evaluated in the whole cohort of patients.

Prognostic Role of a New Index (RAPID Index) in Advanced Hepatocellular Carcinoma Patients Receiving Sorafenib: Training and Validation Cohort.

Background And Aims: The aim of the present study is to evaluate a new index influenced by the balance between the immune system, α-fetoprotein (AFP), and lactate dehydrogenase (LDH) (RAPID index) as a prognostic factor in patients treated with sorafenib.

Methods: This study was conducted on a training cohort of 159 hepatocellular carcinoma (HCC) patients and a validation cohort of 68 HCC patients treated with sorafenib. The RAPID index was calculated as neutrophil/lymphocyte count × LDH × AFP.

CK7 and consensus molecular subtypes as major prognosticators in BRAF mutated metastatic colorectal cancer.

Background: BRAF mutated metastatic colorectal cancer (mCRC) is a subtype (10%) with overall poor prognosis, but the clinical experience suggests a great heterogeneity in survival. It is still unexplored the real distribution of traditional and innovative biomarkers among BRAF mutated mCRC and which is their role in the improvement of clinical prediction of survival outcomes.

Methods: Data and tissue specimens from 155 BRAF mutated mCRC patients treated at eight Italian Units of Oncology were collected.

A validated prognostic classifier for BRAF-mutated metastatic colorectal cancer: the 'BRAF BeCool' study.

Background: Despite the well-known negative prognostic value of the BRAF mutation in patients with metastatic colorectal cancer (mCRC), its outcome is quite heterogeneous, and the basis for this prognostic heterogeneity should be better defined.

Methods: Two large retrospective series of BRAF-mutated mCRC from 22 institutions served as an exploratory and validation set to develop a prognostic score. The model was internally and externally validated.

Class 1, 2, and 3 -Mutated Metastatic Colorectal Cancer: A Detailed Clinical, Pathologic, and Molecular Characterization.

Purpose: mutations are grouped in activating -independent signaling as monomers (class 1-V600E) or as dimers (class 2-codons 597/601), and -dependent with impaired kinase activity (class 3-codons 594/596). Although clinical, pathologic, and molecular features of -mutated metastatic colorectal cancer (mCRC) are well known, limited data are available from the two other classes.

Experimental Design: Data from 117 patients with (92 class 1, 12 class 2, and 13 class 3)-mutated mCRC were collected.

A New Genetic Risk Score to Predict the Outcome of Locally Advanced or Metastatic Breast Cancer Patients Treated With First-Line Exemestane: Results From a Prospective Study.

Introduction: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival.

Candidate germline polymorphisms of genes belonging to the pathways of four drugs used in osteosarcoma standard chemotherapy associated with risk, survival and toxicity in non-metastatic high-grade osteosarcoma.

This study aimed to identify associations between germline polymorphisms and risk of high-grade osteosarcoma (HGOS) development, event-free survival (EFS) and toxicity in HGOS patients treated with neo-adjuvant chemotherapy and surgery.Germline polymorphisms of 31 genes known to be relevant for transport or metabolism of all four drugs used in HGOS chemotherapy (methotrexate, doxorubicin, cisplatin and ifosfamide) were genotyped in 196 patients with HGOS and in 470 healthy age and gender-matched controls. Of these 196 HGOS patients, a homogeneously treated group of 126 patients was considered for survival analyses (survival cohort).

miRNA pharmacogenomics: the new frontier for personalized medicine in cancer?

In recent years pharmacogenomic research has highlighted several genetic biomarkers of treatment toxicity and efficacy, dealing with drug metabolism, transport and mechanism of action. More recently, polymorphisms in miRNA encoding genes, their targets or factors involved in their maturation are rising as new pharmacogenomic markers in cancer. miRNAs are brief ncRNAs involved in DNA translational control, with an effect on mRNA and protein-expression levels.

Polymorphic thymidylate synthase gene impacts on overall survival of patients with epithelial ovarian cancer after platinum-based chemotherapy.

Aim: High levels of TS have been associated with a worse clinical outcome in several cancers including epithelial ovarian cancer (EOC). The TS gene (TYMS) is highly polymorphic and has an effect on mRNA/protein expression.

Materials & Methods: Six TYMS polymorphisms were investigated for overall survival (OS) in 216 EOC patients: TYMS 1494ins/del, TSER (variable number of tandem repeats of 28 bp), TSER G>C, TYMS 1053C>T, TYMS IVS6-68C>T and TYMS 1122A>G.

Drug interactions among the epidermal growth factor receptor inhibitors, other biologics and cytotoxic agents.

The epidermal growth factor receptor (EGFR) signalling pathway is a key element in the growth of several epithelial malignancies. Small molecules tyrosine kinase inhibitors (TKIs) and anti-EGFR monoclonal antibodies (mAbs) prevent the phosphorylation of the receptor, leading to cell cycle arrest at G(1) phase, apoptosis, inhibition of angiogenesis and metastasis. To increase the antitumoral effects of EGFR inhibitors (EGFRIs), a number of combinatory regimens have been evaluated and planned with standard cytotoxic drugs and/or inhibitors of EGFR complementary pathways such as mTOR, VEGF and Ras/Raf/ERK.

Effect of TP53 Arg72Pro and MDM2 SNP309 polymorphisms on the risk of high-grade osteosarcoma development and survival.

Purpose: The germ-line polymorphisms TP53 Arg72Pro and MDM2 SNP309 T>G are risk factors for tumor development and affect response to chemotherapy and survival in several cancers, but their prognostic and predictive value in patients with high-grade osteosarcomas is not yet defined. The purpose of this study was to investigate the effect of the TP53 Arg72Pro and the MDM2 SNP309 on the risk of osteosarcoma development and survival.

Experimental Design: The relative risk to develop osteosarcomas and the overall survival associated to TP53 Arg72Pro and MDM2 SNP309 polymorphisms were investigated in 201 patients.

Predictive role of the UGT1A1, UGT1A7, and UGT1A9 genetic variants and their haplotypes on the outcome of metastatic colorectal cancer patients treated with fluorouracil, leucovorin, and irinotecan.

Purpose: UGT1A1*28 is considered the main pharmacogenetic predictor of the toxicity outcome of irinotecan-treated patients. We evaluated the effect of other UGT1A variants and haplotypes involved in 7-ethyl-10-hydroxycamptothecin (SN-38) glucuronidation on severe toxicity and efficacy of fluorouracil, leucovorin, and irinotecan (FOLFIRI).

Patients And Methods: In addition to UGT1A1*28, UGT1A1*60, UGT1A1*93, UGT1A7*3, and UGT1A9*22 were genotyped in 250 metastatic colorectal cancer patients, and associations with severe hematologic and nonhematologic toxicity, objective response, time to progression (TTP), and overall survival were evaluated.

The role of UGT1A1*28 polymorphism in the pharmacodynamics and pharmacokinetics of irinotecan in patients with metastatic colorectal cancer.

Purpose: UGT1A1*28 polymorphism has been associated with decreased glucuronidation of SN38, the active metabolite of irinotecan. This could increase toxicity with this agent.

Patients And Methods: In a prospective study, 250 metastatic colorectal cancer patients were treated with irinotecan, fluorouracil, and leucovorin as first-line treatment.

Carboxylesterase isoform 2 mRNA expression in peripheral blood mononuclear cells is a predictive marker of the irinotecan to SN38 activation step in colorectal cancer patients.

Purpose: Irinotecan (CPT11) is a prodrug activated in humans mainly by carboxylesterase 2 (CES2) generating the SN38 metabolite responsible for the drug efficacy and toxicity. The interpatients variability in CPT11 activation step could cause unpredictable toxicity. To identify a predictive molecular marker for CPT11 activation in cancer patients, we investigated the CES2 mRNA expression in peripheral blood mononuclear cells (PBMC) and correlated it to CPT11 activation rate, toxic effects, and response.

Sarcomas and pharmacogenetics.

Sarcomas are a heterogeneous group of tumors, requiring different chemotherapeutic approaches. Recently, several regimens for metastatic tumors were evaluated with respect to the different responses to conventional chemotherapy of the various histologic subtypes of sarcomas. The impact of pharmacogenetics in the progress of chemotherapy appears to be crucial in defining the clinical response to many drugs, such as anthracycline or alkylating agents, that are widely used in treatment regimens for soft tissue sarcomas (STS) or sarcomas of the bone.