Hepatocellular carcinoma (HCC) accounts for the majority of primary liver cancers. To date, most patients with HCC are diagnosed at an advanced tumor stage, excluding them from potentially curative ...therapies (
., resection, liver transplantation, percutaneous ablation). Treatments with palliative intent include chemoembolization and systemic therapy. Among systemic treatments, the small-molecule multikinase inhibitor sorafenib has been the only systemic treatment available for advanced HCC over 10 years. More recently, other small-molecule multikinase inhibitors (
., regorafenib, lenvatinib, cabozantinib) have been approved for HCC treatment. The promising immune checkpoint inhibitors (
., nivolumab, pembrolizumab) are still under investigation in Europe while in the US nivolumab has already been approved by FDA in sorafenib refractory or resistant patients. Other molecules, such as the selective CDK4/6inhibitors (
., palbociclib, ribociclib), are in earlier stages of clinical development, and the c-MET inhibitor tivantinib did not show positive results in a phase III study. However, even if the introduction of targeted agents has led to great advances in patient response and survival with an acceptable toxicity profile, a remarkable inter-individual heterogeneity in therapy outcome persists and constitutes a significant problem in disease management. Thus, the identification of biomarkers that predict which patients will benefit from a specific intervention could significantly affect decision-making and therapy planning. Germ-line variants have been suggested to play an important role in determining outcomes of HCC systemic therapy in terms of both toxicity and treatment efficacy. Particularly, a number of studies have focused on the role of genetic polymorphisms impacting the drug metabolic pathway and membrane translocation as well as the drug mechanism of action as predictive/prognostic markers of HCC treatment. The aim of this review is to summarize and critically discuss the pharmacogenetic literature evidences, with particular attention to sorafenib and regorafenib, which have been used longer than the others in HCC treatment.
Lenvatinib (LENVA) is an oral antineoplastic drug used for the treatment of hepatocellular carcinoma and thyroid carcinoma. LENVA therapeutic drug monitoring (TDM) should be mandatory for a precision ...medicine to optimize the drug dosage. To this end, the development of a sensitive and robust quantification method to be applied in the clinical setting is essential. The aim of this work was to develop and validate a sensitive, rapid, and cost-effective LC-MS/MS method for the quantification of LENVA in human plasma. On this premise, sample preparation was based on a protein precipitation and the chromatographic separation was achieved on a Synergi Fusion RP C18 column in 4 min. The method was completely and successfully validated according to European Medicines Agency (EMA) and Food and Drug Administration (FDA) guidelines, with good linearity in the range of 0.50-2000 ng/mL (R≥0.9968). Coefficient of variation (CV) for intra- and inter-day precision was ≤11.3% and accuracy ranged from 96.3 to 109.0%, internal standard normalized matrix effect CV% was ≤2.8% and recovery was ≥95.6%. Successful results were obtained for sensitivity (signal to noise (S/N) ratio >21) and selectivity, dilution integrity (CV% ≤ 4.0% and accuracy 99.9-102%), and analyte stability under various handling and storage conditions both in matrix and solvents. This method was applied to quantify LENVA in patient's plasma samples and covered the concentration range achievable in patients. In conclusion, a sensitive and robust quantification method was developed and validated to be applied in the clinical setting.
Hepatocellular carcinoma (HCC) is the seventh most common cancer worldwide and the second leading cause of cancer-related mortality. HCC typically arises within a cirrhotic liver, but in about 20% of ...cases occurs in absence of cirrhosis. Among non-cirrhotic risk factors, non-alcoholic fatty liver disease (NAFLD) currently represents the most important emerging cause of HCC in developed countries. It has been estimated that annual incidence of HCC among patients with non-cirrhotic NAFLD is approximately 0.1-1.3 per 1000 patients/year and ranges from 0.5% to 2.6% among patients with non-alcoholic steatohepatitis (NASH) cirrhosis. However, only a few clinical trials enrolling HCC patients actually distinguished NAFLD/NASH-related cases from other non-cirrhotic causes and therefore evidence is still lacking in this subset of patients. This review aims to describe the biology underpinning NAFLD development, to investigate the main molecular pathways involved in its progression to NASH and HCC and to describe how different pathogenetic mechanisms underlying the onset of HCC can have an impact in clinical practice. We hereby also provide an overview of current HCC treatment options, with a particular focus on the available data on NAFLD-related cases in practice-changing clinical trials.
Background: Emerging data suggest that gender-related immune system composition affects both immune response and efficacy of immunotherapy in cancer patients (pts). This study aimed to investigate ...the sex-related prognostic role of MLR in metastatic colorectal cancer (mCRC) pts. Methods: We analyzed a retrospective consecutive cohort of 490 mCRC patients treated from 2009 to 2018 at the Oncology Departments of Aviano and Pordenone (training set) and Udine (validation set), Italy. The prognostic impact of MLR on overall survival (OS) was evaluated with uni- and multivariable Cox regression models. The best cut-off value to predict survival was defined through ROC analyses. Results: Overall, we identified 288 males (59%) and 202 females (41%); 161 patients (33%) had a right-sided, 202 (42%) a left-sided primary, and 122 (25%) a rectal tumor. Interestingly, gender was associated with MLR (p = 0.004) and sidedness (p = 0.006). The obtained cut-off value for MLR in females and males was 0.27 and 0.49, respectively. According to univariate analysis of the training set, MLR (HR 9.07, p ≤ 0.001), MLR > 0.27 in females (HR 1.95, p = 0.003), and MLR > 0.49 in males (HR 2.65, p = 0.010) were associated with poorer OS, which was also confirmed in the validation set. In multivariate analysis, MLR > 0.27 in females (HR 2.77, p = 0.002), MLR > 0.49 in males (HR 5.39, p ≤ 0.001), BRAF mutation (HR 3.38, p ≤ 0.001), and peritoneal metastases (HR 2.50, p = 0.003) were still independently associated with worse OS. Conclusions: Males and females have a different immune response. Our study showed that high MLR, both in males and females, is an unfavorable Independent prognostic factor. Further prospective studies are needed to confirm these data.
Polymorphisms contribute to inter-individual differences and show a promising predictive role for chemotherapy-related toxicity in colon cancer (CC). TOSCA is a multicentre, randomized, ...non-inferiority, phase III study conducted in high-risk stage II/stage III CC patients treated with 6 vs 3 months of FOLFOX-4 or XELOX adjuvant chemotherapy. During this post-hoc analysis, 218 women and 294 men were genotyped for 17 polymorphisms: TYMS (rs34743033, rs2853542, rs11280056), MTHFR (rs1801133, rs1801131), ERCC1 (rs11615), XRCC1 (rs25487), XRCC3 (rs861539), XPD (rs1799793, rs13181), GSTP1 (rs1695), GSTT1/GSTM1 (deletion +/-), ABCC1 (rs2074087), and ABCC2 (rs3740066, rs1885301, rs4148386). The aim was to assess the interaction between these polymorphisms and sex, on safety in terms of time to grade ≥3 haematological (TTH), grade ≥3 gastrointestinal (TTG) and grade ≥2 neurological (TTN) toxicity. Interactions were detected on TTH for rs1801133 and rs1799793, on TTG for rs13181 and on TTN for rs11615. Rs1799793 GA genotype (p = 0.006) and A allele (p = 0.009) shortened TTH in men. In women, the rs11615 CC genotype worsened TTN (co-dominant model p = 0.008, recessive model p = 0.003) and rs13181 G allele improved the TTG (p = 0.039). Differences between the two sexes in genotype distribution of rs1885301 (p = 0.020) and rs4148386 (p = 0.005) were found. We highlight that polymorphisms could be sex-specific biomarkers. These results, however, need to be confirmed in additional series.
To explore the feasibility and efficacy of a dose intensification with Intensity Modulated Radiation Therapy and Simultaneous Integrated Boost (IMRT-SIB) in locally advanced esophageal and ...gastroesophageal cancer (GEJ).
We retrospectively analyzed a series of 69 patients with esophageal or GEJ cancer treated at our Institute, between 2016 and 2019, with preoperative IMRT and SIB up to 52.5-54 Gy in 25 fractions in 5 weeks and concurrent carboplatin (AUC2) and paclitaxel (50 mg/m
), as in the CROSS regimen.
All patients completed the planned IMRT-SIB program with a median of four (range 1-5) cycles of concurrent paclitaxel/carboplatin. Compliance to IMRT-SIB was 93%, whereas 54% of patients received four to five cycles and 87% at least three cycles of concurrent carboplatin/paclitaxel. Grade 3 toxicity was reported in 19% of patients. Complete clinical response (cCR) was achieved in 48%, and 13% had disease progression after chemoradiation (CRT). Overall, 49% of patients underwent surgery; reasons for non-operation included cCR in cervical tumor location (10%) or cCR and patient decision (13%). A pathologic complete response (pCR) was achieved in 44% of resected patients. Postoperative complications and mortality rates were 21 and 6%, respectively. At a median follow-up of 12 months (6-25), 2-year overall and progression-free (PFS) survival rates were 81 and 54%, respectively. No difference in PFS by histologic type in operated patients was reported. Non-operated cCR patients had higher PFS, including cervical locations and selected cCR patients who decided for non-operation (75
30%, p < 0.01).
The study reported favorable results in safety and feasibility of the IMRT-SIB dose intensification in our preoperative CRT program. The toxicity was acceptable, allowing a high compliance to intensified radiation doses with dose reduction of concurrent paclitaxel/carboplatin in some patients. The high rate of cCR and pCR suggested this intensified program is effective in the preoperative CRT and, for selected responsive patients, in the non-operative approach to esophageal and GEJ cancer. The 2-year survival rates were promising. A prospective study is being planned to confirm these observations.
Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, are characterized by activating mutations in
or
genes. The vast majority of GISTs are ...sporadic, but rare hereditary forms have been reported, often featuring multifocality and younger age of onset. We here report the identification of a novel kindred affected by familial GIST caused by a
germline mutation in exon 13 (N655K). No family affected by hereditary GIST due to this
variant has been reported in literature so far. We were able to track the mutation in three members of the family (proband, mother, and second-degree cousin), all affected by multiple GISTs. Due to its rarity, the N655K variant is poorly characterized. We conducted in vitro drug sensitivity assays that indicated that most tyrosine kinase inhibitors (TKIs) currently included in the therapeutic armamentarium for GISTs have a limited inhibitory activity toward this mutation. However, when compared to a classical imatinib-resistant
mutation (T670I), N655K was slightly more sensitive to imatinib, and encouraging responses were observed with last-generation TKIs.
Pharmacogenetic (PGx) guidelines for the precise dosing and selection of drugs remain poorly implemented in current clinical practice. Among the barriers to the implementation process is the lack of ...clinical decision support system (CDSS) tools to aid health providers in managing PGx information in the clinical context. The present study aimed to describe the first Italian endeavor to develop a PGx CDSS, called FARMAPRICE. FARMAPRICE prototype was conceived for integration of patient molecular data into the clinical prescription process in the Italian Centro di Riferimento Oncologico (CRO)-Aviano Hospital. It was developed through a coordinated partnership between two high-tech companies active in the computerization of the Italian healthcare system. Introducing FARMAPRICE into the clinical setting can aid physicians in prescribing the most efficacious and cost-effective pharmacological therapy available.
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