Colorectal cancer (CRC) is one of the most prevalent cancers and the second leading cause of cancer-related deaths worldwide. The treatment strategy employed in CRC patients is becoming highly ...dependent on molecular characteristics present at diagnosis and during treatment. Liquid biopsy is an emerging field in the management of this cancer, and its relevance as a potential diagnostic, prognostic, monitoring, and therapeutic tool makes it a viable strategy in the clinical management of CRC patients. Liquid biopsy also has certain limitations, but these limitations seem to be at the reach of near-future technological development. In this letter, we focus on the clinical perspectives of liquid biopsy in CRC with particular regard to the various biomarkers recently identified that have been shown to be potentially useful in multiple aspects of early stage or metastatic CRC.
In the evolving landscape of precision oncology, genomic characterization of tumor has become crucial in order to move toward a molecular-based therapy for the vast majority of cancers. Recently, ...translational research has offered new perspectives in systemic cancer treatment thanks to the identification of novel oncogenic targets and the development of new targeted therapies, followed by the latest applications of genomic sequencing. Simultaneously, next-generation sequencing (NGS) has expanded its accessibility, being incorporated into clinical studies at the time of the initial screening, disease progression, and often in longitudinal monitoring of molecular changes. Consequently, new potentially targetable molecular alterations have been identified in several different types of tumors, leading to the development of tumor-agnostic treatments. Being highly selective for specific molecular alterations, these drugs are active against different subtypes of oncogene-addicted cancers. Three of these drugs-pembrolizumab an anti-programmed death 1 (PD-1) monoclonal antibody (MAb), larotrectinib a pan-tropomyosin receptor tyrosine kinase (TRK) inhibitor, and entrectinib a pan-TRK, anaplastic lymphoma kinase (ALK) and ROS-1 inhibitor-received US FDA approval in 2017, 2018, and 2019, respectively. In this article, we critically review the clinical studies responsible for FDA approval and the most recently updated results. We then discuss the benefits and limitations of these new methodological approaches, paying particular attention to the largest precision medicine master protocol, NCI-MATCH. Among the benefits, there are the increased chances of offering targeted therapies for patients with specific alterations identified in different types of tumors. Among the limitations, we highlight that the same driver mutation may require different therapeutic strategies in different types of cancers. Additionally, the complex study design undeniably requires a dynamic strategy to enroll patients with considerable economic and managerial efforts.
In recent years, the marketing of electronic nicotine delivery systems (ENDS) has changed the attitudes of people towards tobacco products. In addition, ENDS are becoming very popular among youth. ...Since a high percentage of young people use these delivery systems as the first products containing nicotine, the acute and chronic exposure to ENDS emissions and nicotine-induced effects on the adolescent's brain deserve a special attention. Given the extremely varied types of ENDS and the heterogeneous concentrations of substances emitted by specific devices, an overall risk assessment is particularly difficult. Here we critically review the evidence on the safety profile of ENDS, we also discuss the global policies with the leading role of the World Health Organization (WHO), which provides updated information and indications that must guide community and individual choices.
Diffuse large B-cell lymphoma (DLBCL) is the most common lymphoma representing approximately one third of all non-Hodgkin lymphomas and about 40% of patients do not benefit of the standard first-line ...immune-chemotherapeutic treatment (i.e., R-CHOP - rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) that is administered as upfront therapy to substantially all patients independently from the stage of disease and other prognostic parameters. The administration of other pharmacological treatments is in fact limited to selected patients, unfitting for R-CHOP.
Although clinical prognostic scores, i.e. International Prognostic Index (IPI), and molecular classifiers based on the cell of origin are available, at present no biomarkers predictive of R-CHOP response has been identified and validated. Constitutional polymorphisms of genes involved in the mechanism of action of drugs included in R-CHOP have been suggested by many authors to play a role in the efficacy and in some case in the toxicity of this treatment. Thus, it is conceivable that in the future, after proper validation, some polymorphisms can be used as pharmacogenetic biomarkers of therapeutic outcome in this disease setting.
This review discusses the status of the art on molecular biomarkers predictive of DLBCL prognosis and deals with the relevant issue of the variability in response to DLBCL drug treatment. Overall, this review focuses on single nucleotide polymorphisms (SNPs) that, based on a candidate gene approach or on a genome-wide association study (GWAS) analysis, have been suggested to play a role in response to R-CHOP. In particular, SNPs discovered by a candidate gene approach are related to genes involved in drug transport (i.e., ATP-binding cassette transporters), drug metabolism, drug detoxification enzymes, oxidative stress, apoptosis, DNA repair, immunity and angiogenesis.
Data from a GWAS analysis performed in DLBCL patients treated with R-CHOP, identified two SNPs associated with clinical outcomes related to genes involved in pivotal cellular processes and in transcriptional regulation and cell cycle progression, respectively.
Ongoing prospective pharmacogenetic clinical trials, including a GWAS study we performed, have also been discussed.
To date, treatment options for patients with chemorefractory cholangiocarcinoma (CCA) are limited. However, the advancements in molecular techniques have recently increased the opportunity to offer ...molecularly targeted therapies to patients with several cancer types and some targetable oncogenic alterations have been identified also in CCA.
Among these potentially actionable molecular alterations, isocitrate dehydrogenase-1 (IDH1) mutations have been detected in approximately 10–20% of intrahepatic CCA (iCCA). IDH1 is responsible for the accumulation of oncometabolites inducing epigenetic changes that are involved in various signaling pathways. Ivosidenib is the first IDH1 inhibitor which significantly improved progression-free survival (PFS) (2.7 vs 1.4 months) and overall survival (OS) (10.3 vs 5.1 months adjusted median OS) compared with placebo in chemorefractory IDH1-mutated CCA. The very low incidence of grade (G) 3–4 adverse events (AEs) and treatment discontinuation due to toxicity, associated with a significantly less marked decline in health-related quality of life for patients in the ivosidenib group than in placebo group, facilitates patient adherence and clinician confidence.
Here, we review the development of ivosidenib in CCA patients and evaluate the clinical impact of the results of the phase III ClarIDHy trial which was responsible for the Food and Drug Administration (FDA) approval for patients with IDH1-mutated CCA whose disease progressed after standard chemotherapy (CT). We also discuss the known primary and secondary resistance mechanisms, including concomitant and acquired mutations in other genes (e.g. IDH2 mutations), second-site mutation in IDH1, and enhanced activation of other pathways (e.g. PI3K/AKT/mTOR pathway). Finally we examine the future directions, as the opportunity to combine ivosidenib with other synergistic agents, including standard chemotherapy (CT), immune checkpoint inhibitors (ICIs), and IDH2 inhibitors.
Colorectal cancer (CRC) is the third most common cancer worldwide, with approximately 1.9 million new diagnoses and 935 000 deaths annually. Overall, there is accumulating evidence that receiving all ...available treatments leads to a survival advantage and, although tailored treatments might be appropriate for selected patients, the one-size-fits-all approach is still widely used in chemo-refractory patients. Currently, different antiangiogenics and multitarget agents are indicated in treatment of metastatic CRC (mCRC) whereas the identification of useful predictive factors for the treatment response is lacking. Analysis of potential predictive biomarkers of efficacy of regorafenib is still ongoing but may prove to be difficult because of its nonspecific activity across a wide range of angiogenic, oncogenic, stromal, and intracellular signaling kinases. We present a case of a 57-year-old Caucasian woman diagnosed with recurrence after curative surgery for rectal adenocarcinoma stage III (ypT3N2). Despite undergoing multiple lines of standard chemotherapy, disease control could not be maintained. Consequently, regorafenib, a multikinase inhibitor with antiangiogenic proprieties, was started as a late-line treatment and a dose reduction strategy allowed a long-term response of more than 9 years with good tolerability.
Since the introduction of antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies (moAbs), the treatment of metastatic colorectal cancer (mCRC) has become crucially dependent on the ...mutation profile of the tumour over the last two decades. Recently, rechallenge strategy with cetuximab-based chemotherapy has demonstrated to be active in a subgroup of patients whose tumour maintained wild-type RAS and RAF status. In this setting, liquid biopsy may replace tissue sample for the identification of specific subgroups of pretreated patients that may benefit from the reintroduction of anti-EGFR moAbs. In November 2014, a 64-year-old man with IVB stage BRAF, KRAS and NRAS wild-type mCRC was admitted in our hospital. He received FOLFIRI cetuximab as first-line treatment with deep and long-lasting partial response (PR), followed by cetuximab maintenance therapy until January 2016. At the time of disease progression, FOLFIRI cetuximab regimen was reintroduced resulting in stabilization of disease and he continued with capecitabine cetuximab therapy until disease progression in October 2016. Then, the patient consecutively received FOLFOX bevacizumab, TAS-102, regorafenib and FOLFIRI followed by de Gramont maintenance treatment. Finally, he was retreated with FOLFIRI cetuximab with disease progression within 3 months and died in May 2019. During his clinical course, liquid biopsy detected two mutationsone in KRAS Cd.12 and one in NRAS Cd. 61. The longitudinal assessment of RAS status offers considerable advantages in order to avoid side effects and economic costs for ineffective treatment choices. Liquid biopsy could help better monitor the disease and provide molecularly guided treatments.
Appendiceal neoplasms account for less than 1% of intestinal cancers and their clinical manifestation is typically, nonspecific and ambiguous. Appendiceal tumor infiltrating the urinary tract is ...extremely rare and few cases are mentioned in literature. A 72-year-old woman presented gross hematuria and right colic pain. No prior urologic disease was reported. Cystoscopic examination showed a large lesion on the right side of posterior bladder wall, with multiple ulcerated areas and microscopical examination of the specimen revealed a mucinous adenocarcinoma infiltrating urinary bladder. Contrast-enhanced computed tomography (CT) scan identified focal thickening of bladder dome 21 × 7 cm with a possible origin from the appendix and with an unclear relationship with the uterus and the right fallopian tube. These findings were discussed with the local gastrointestinal multidisciplinary team, where a decision to perform upfront surgery was made. Explorative laparotomy confirmed a tumor of the appendix invading the urinary bladder. We performed an en-bloc resection including right colon, 40 cm of terminal ileum with a partial cystectomy removing the infiltrated area of the right bladder wall, and an omentectomy. Reconstruction was made first with a full-thickness suture of the bladder, then with an ileo-colon stapled anastomosis. The postoperative course was uneventful and the CT scan at 9 months from surgery did not show any recurrence. Right hemicolectomy is considered the gold standard for all lesions with invasion beyond the mucosa, and, appendicectomy alone seems to be the ideal treatment for in situ and localized cases.
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Background: Immune Checkpoint Inhibitors (ICIs) changed the algorithm of treatment for Non-Small Cell Lung Cancer (NSCLC). Consequently, an increased incidence of specific immune-related ...adverse events (irAEs) were reported, although a clear relationship between toxicity and response to ICIs was not identified. To date no strong predictive factor of response to ICIs are univocally recognized in NSCLC. Methods: This is an observational, retro-prospective, monocentric study aimed to evaluate, in patients (pts) with NSCLC treated with ICIs, the predictive impact of selected blood biomarkers and the occurrence of irAEs on survival. Differential cells count, and specifically the Absolute Eosinophil Count (AEC, N°/μL), were registered at baseline to evaluate their impact on response to ICIs. Patients were divided in two groups: those with high AEC ( > 190/µL, group A), and those with low basal AEC ( < 190/µL, group B). Results: We enrolled 48 pts, median age was 70 years. All pts were treated with an ICI as single-agent: 5 (10%) with Nivolumab (N), 37 (77%) with Pembrolizumab (P), and 5 pts received Atezolizumab (A). Thirty-seven pts were treated in first-line setting, 9 pts in second-line, and 2 pts in successive lines. Of total, 63% pts (30/48) developed at least one irAE: an endocrine event occurred in 11 pts (23%), gastrointestinal toxicity in 10 pts (21%), dermatological events in 19 pts (40%), while a pulmonary irAE in 6 pts (13%). Progression free survival (PFS) was higher in group A than in group B (16 vs 9.5, p = 0.041) with a trend for a superior median Overall Survival (mOS) (median not reached vs 23 months, p = 0.07, respectively). At a median follow-up of 18 months (mos), pts who developed at least one irAE had a significant benefit in PFS (15mos vs 8mos, p = 0.027), reporting a trend for better PFS for pts with endocrine toxicities (p = 0.057) and GI- toxicities (p = 0.051) vs no toxicities. Pulmonary irAEs are significantly related to a better PFS: median not reached vs 12 mos, p = 0.025. Conclusions: In this real-life experience we observed that baseline AEC values correlates with PFS in pts with NSCLC treated with ICIs. Additional analyses are ongoing to identify appropriate cut-offs of AEC to better stratify patients. Moreover, our study underlines that the development of toxicities, in particular pulmonary ones, could be considered as a predictive indicator of response to ICIs in NSCLC. With all the limitations of being a small analysis, our real-life experience is innovative and explored prospectively the potential role of differential cell count and irAEs as predictive biomarkers of survival in NSCLC patients treated with ICIs.
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