Mutation abundance affects the therapeutic efficacy of EGFR-TKI in patients with advanced lung adenocarcinoma: A retrospective analysis

Purpose: To investigate the influence of mutation abundance and sites of epidermal growth factor receptor (EGFR) on therapeutic efficacies of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) treatments of patients with advanced non-small cell lung carcinoma (NSCLC).

Methods: EGFR mutational sites and mutation abundance were analyzed by amplification refractory mutation system (ARMS) in paraffin-embedded tissue sections taken from primary or metastatic tumors of 194 NSCLC patients.

Results: The median progression-free survival (PFS) time of the enrolled patients was 9.3 months (95% CI, 8.2–10.8 months). The PFS was significantly different with EGFR gene mutation abundance after EGFR-TKI therapy (P = 0.014). The median PFS was significantly longer when the cut-off value of EGFR mutation abundance of exon 19 or exon 21, and solely exon 19 was > 26.7% and 61.8%, respectively. For patients who received EGFR-TKI as first-line treatment, the median PFS was significantly longer in the high mutation abundance group than in the low mutation abundance group (12.7 vs 8.7 months, P = 0.002).

Conclusion: The PFS benefits were greater in patients with a higher abundance of exon 19 deletion mutations in the EGFR gene after EGFR-TKI treatment and first line EGFR-TKI treatment led to improved PFS in high mutation abundance patients.     

EGFR expression in circulating tumor cells from high-grade metastatic soft tissue sarcomas

Introduction: Soft tissue Sarcomas (STS) are rare malignances, with high mortality rates. Half of patients develop metastasis. The presence of isolated Circulating Tumor Cells (CTCs) and Circulating Tumor Microemboli (CTM) in the blood may be early markers of tumor invasion. Epidermal Growth Factor (EGF) family receptors can also influence this process.

Objectives: to quantify CTCs and identify CTM as well as the EGF Receptor (EGFR) protein expression in these cells and correlate with clinical outcome in metastatic STS.

Materials and methods: Approximately 8mL of blood was prospectively collected from patients with different types of high-grade STS, before the beginning of chemotherapy. The samples were processed and filtered by ISET (Rarecells, France) for the isolation and quantification of CTCs and CTMs. EGFR expression was analyzed by immunocytochemistry (ICC) on CTCs/ CTMs.

Results: We analyzed 18 patients with median age of 49 years (18-77 y). The positivity for EGFR protein expression in CTCs was observed in 93.75% of the patients. This result shows that targeting EGFR positive CTCs from STS origen can be translated in clinical benefit for some patients. In addition, if target therapy is chosen, the EGFR expression in CTCs can be used in follow-up to measure treatment effectiveness.

Conclusions: This is the first study to demonstrate the expression of EGFR protein in CTCs from sarcoma patients. It may open an area for future investigations. The next step is to characterize CTCs in a larger cohort of patients to better understand the role of EGFR in sustaining tumor metastasis in sarcomas.     

The liquid biopsy: a tool for a combined diagnostic and theranostic approach for care of a patient with late-stage lung carcinoma presenting with bilateral ocular metastases

Introduction: Liquid biopsies (LB) are used routinely in clinical practice in two situations for late stage non-small-cell lung cancer (NSCLC) patients, (i) at the initial diagnosis when looking for activating mutations in EGFR in the absence of analyzable tissue DNA and, (ii) during tumor progression on a tyrosine kinase inhibitor treatment to look for the resistance mutation T790M in EGFR. LB is not presently recommended in daily practice for the diagnosis of NSCLC.

Areas covered: We report the diagnosis of a NSCLC in a patient with bilateral ocular metastases after detection of a deletion in exon 19 of EGFR when using plasma DNA. Without histological analysis, the origin of the primary ocular metastasis was uncertain. In this context, a LB showing an activating mutation in EGFR and circulating tumor cells positive for TTF1 led to the diagnosis of NSCLC and targeted therapy.

Expert commentary: When no tumor tissue sample is available a LB can be used to diagnose for metastatic NSCLC, when a mutation in EGFR is identified. While a tissue biopsy is the gold standard approach for the diagnosis of a NSCLC and for identification of activating mutations, LB can exceptionally provide both a diagnosis of the primitive tumor and indicate appropriate therapy based on a molecular analysis.     

Overcoming resistance to EGFR tyrosine kinase inhibitors in lung cancer,focusing on non-T790M mechanisms

Introduction: despite initial dramatic efficacy of EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung cancer patients, emergence of acquired resistance is almost inevitable. The EGFR T790M secondary mutation that accounts for ~50% of resistance is now treatable with osimertinib. However, for the remaining 50% of patients who develop resistance mechanisms other than T790M mutation, cytotoxic chemotherapies are still the standard of care and novel treatment strategies are urgently needed.

Areas covered: In this review, we discuss current experimental and clinical evidence to develop better treatment strategies to overcome or prevent acquired resistance to EGFR-TKIs in lung cancers, focusing on non-T790M mechanisms.

Expert commentary: There are numerous non-T790M resistant mechanisms to EGFR-TKIs, and therefore, strategies that can be applied to many of these resistance mechanisms may be reasonable and useful in clinical practice. Although the combination of cytotoxic chemotherapy plus an EGFR-TKI has proved to be detrimental following front-line EGFR-TKI treatment failure, promising experimental and/or early clinical data have been reported for the combination of bevacizumab or anti-EGFR monoclonal antibody plus EGFR-TKIs. Upfront polytherapy, which co-targets potential resistance mechanisms or other important signaling for EGFR-mutant lung cancer cells, is also a promising strategy.     

Capture-based ultra-deep sequencing in plasma ctDNA reveals the resistance mechanism of ALK inhibitors in a patient with advanced ALK-positive NSCLC

Background: Anaplastic lymphoma kinase (ALK) is a validated molecular target in non–small-cell lung cancer (NSCLC). However, the clinical benefits of ALK inhibitors are almost universally limited by the emergence of drug resistance.

Methods: We monitored the plasma circulating tumor DNA (ctDNA) using captured-based ultra-deep sequencing analysis of one patient with metastatic ALK-positive NSCLC who had received therapies including first-, second- and third-generation ALK inhibitors. Functional in vitro studies were further undertaken to elucidate the mechanism of resistance.

Results: ALK T1151Sins mutation was detected when the patient developed resistance to ceritinib, and undetectable when she responded to lorlatinib. MET amplification was present when the tumor developed resistance to lorlatinib, and reduced when the patient received combination therapy of lorlatinib with crizotinib, which corresponded to clinical radiologic responses. In addition, further functional in vitro studies demonstrated that ALK harboring the T1151Sins mutation, while conferring resistance to ceritinib, was inhibited by lorlatinib.

Conclusions: Clinical evidence and in vitro validation revealed the clinical usefulness of captured-base ultra-deep sequencing on longitudinal plasma ctDNA in revealing the underlying resistance mechanism and guiding the precise administration of ALK inhibitors in patients with advanced ALK-positive NSCLC.     

Advanced non-small cell lung cancer (NSCLC) with activating EGFR mutations: first-line treatment with afatinib and other EGFR TKIs

Introduction: Based on the results of several randomised controlled trials, epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have now replaced platinum-based chemotherapy as first-line therapy for advanced non-small cell lung cancer (NSCLC) harboring an activating EGFR mutation.

Areas covered: This review describes the EGFR pathway and its abnormalities in NSCLC and discusses the differential molecular and clinical activity of first and next-generation EGFR TKIs in the first-line treatment of tumors with an activating EGFR mutation, with a special focus on the second-generation agent afatinib. A comprehensive literature search was conducted to identify all relevant clinical trials including abstracts from most recent meetings to provide up-to-date information on this topic.

Expert commentary: While the first-generation EGFR TKIs erlotinib and gefitinib exhibited good tolerability and improved progression-free survival compared with a platinum doublet, they failed to improve overall survival (OS). In contrast, clinical trials of afatinib (LUX-Lung 3 and 6) demonstrated a significant OS advantage over a platinum doublet, particularly in patients whose tumors harbored the Del19 mutation. Moreover, in a head-to-head comparison afatinib improved efficacy versus gefitinib in patients with common EGFR mutations across a range of clinically relevant endpoints. Afatinib is therefore a promising first-line option in these patients.     

Combined therapy with epidermal growth factor receptor tyrosine kinase inhibitors for non–small cell lung cancer

Introduction: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have a pronounced clinical benefit for patients with advanced non–small cell lung cancer (NSCLC) positive for EGFR activating mutations. Such individuals inevitably develop resistance to these drugs, however, new treatment strategies to overcome such resistance are being actively pursued. The clinical benefit of EGFR-TKIs for patients with locally advanced NSCLC remains to be clarified.

Areas covered: This review summarizes the recent progress in combination treatment with EGFR-TKIs and either chemotherapy or radiotherapy for patients with NSCLC positive for EGFR activating mutations.

Expert commentary: Combination therapy with EGFR-TKIs and various other treatment options are under investigation in clinical studies. Although early studies failed to show a clinical benefit for such combination therapy because of a lack of patient selection, clinical studies with patient selection based on EGFR mutation status have shown promising results. Such combination therapy might eventually replace the current standard treatment for patients with NSCLC positive for EGFR activating mutations.     

First-line treatment of NSCLC with bevacizumab: real world data from an Italian regional based survey

Background: We aimed to explore the use of platinum plus bevacizumab in a real world NSCLC population.

Patients and methods: We retrospectively collected data from patients affected by NS-NSCLC treated with platinum plus bevacizumab across Tuscany.

Results: We evaluated 62 (median age: 63.5 [30–77] years) pts. All but one presented with adenocarcinoma and the majority had ECOG PS of 0/1. 17.7% presented with central lesion, 11.3% with brain metastasis, 38.7% with hypertension and 4.8% with mild haemoptysis. We observed a median time to progression (TTP) of 6.5 [2–37] and a median overall survival (OS) of 10.5 [2–39] months. Overall response rate (ORR) was 59.6% with a disease control rate (DCR) of 80.6%. Safety profile was acceptable. We observed five cardiovascular events and two major bleedings with no toxic deaths.

Conclusion: Safety and efficacy real world data are consistent with those from clinical trials even in a less selected population.     

Application of microwave ablation in the emergent control of intraoperative life-threatening tumor hemorrhage during hepatic surgeries

Purpose: This study was designed to evaluate the efficacy and safety of microwave ablation (MWA) in the treatment of intraoperative life-threatening tumour haemorrhage during hepatic surgeries.

Methods: Three cases of MWA application in the emergent control of life-threatening hepatic tumour haemorrhage were analysed and reported.

Results: Satisfactory hemostasis for hepatic tumour rupture was achieved by MWA in all three cases. No major complications, such as post-operative haemorrhage, bile duct injury, liver abscess, colon perforation, skin burns, tumour seeding or renal dysfunction, were identified.

Conclusions: MWA may be a feasible, effective and simple strategy for the emergent control of intraoperative hepatic tumour bleeding. To the best of our knowledge, this study represents the first reported cases of this novel application of MWA.     

Targeting pathways mediating resistance to anti-EGFR therapy in squamous cell carcinoma of the head and neck

Introduction: As epidermal growth factor receptor (EGFR) is overexpressed in approximately 90% of squamous cell carcinomas of the head and neck (SCCHN), several therapeutic agents that target EGFR have been evaluated for the treatment of SCCHN. Although patients with SCCHN derive clinical benefit from anti-EGFR agents, most notably the EGFR monoclonal antibody cetuximab, these patients eventually become resistant to EGFR-based therapies; preclinical studies have shown activation of secondary signaling pathways that lead to resistance to EGFR inhibition and, as such, serve as potential therapeutic targets to overcome resistance to EGFR inhibitors.

Areas covered: This review summarizes the results of recently completed trials of anti-EGFR agents in SCCHN, highlights the various mechanisms that drive resistance to EGFR inhibitors in SCCHN, and focuses on several novel targeted agents that could potentially help overcome resistance to EGFR-based therapies in SCCHN.

Expert commentary: Due to the development of resistance to EGFR-targeted therapies, novel treatment approaches to overcome resistance are a key unmet need for SCCHN.     

NGS analysis on tumor tissue and cfDNA for genotype-directed therapy in metastatic NSCLC patients. Between hope and hype?

Introduction: The advent of genomic based precision medicine led to the implementation of biomarker testing in metastatic non-small cell lung cancer (NSCLC) patients. Next generation sequencing (NGS) has been recently implemented to routine diagnostic requirements in lung oncology.

Areas covered: Two cases of patients with metastatic NSCLC for whom NGS analysis performed on both tumor and liquid biopsy has not improved the clinical course of their disease are reported. These cases illustrate the difficulty of the so-called ‘personalized or precision’ medicine in clinical routine practice for metastatic NSCLC.

Expert commentary: Discovery and detection of critical cancer-gene alterations better indicates targeted therapies that must be administered to improve the care of NSCLC patients in the personalized medicine era. There has been much interest in the literature and the scientific community for NGS tailored therapies approach for patients. However, there may be a gap between this theoretical stratified medicine and clinical practice. The advantages and drawbacks of NGS on tumor tissue and cell-free DNA for metastatic NSCLC are discussed.     

Risk factors for acute kidney injury associated with the treatment of bacterial endocarditis at a tertiary academic medical center*

Background: Acute kidney injury (AKI) is a common complication of endocarditis.

Objective: To determine risk factors for the development of AKI in patients treated for endocarditis.

Methods: This single centre, retrospective univariate and multivariate analysis to determine risk factors for the development of AKI included patients diagnosed with endocarditis between January 2009 and October 2013.

Results: Of 211 included patients, a total of 84 (39.8%) patients developed AKI. We identified multiple independent variables associated with the development of AKI, including: age ≥ 65 years, presence of hardware, chronic kidney disease, AKI on admission, infection with Staphylococcus spp, receipt of nafcillin or oxacillin or aminoglycoside and nafcillin or oxacillin or aminoglycoside and vancomycin, vancomycin trough level ≥ 20.0 mcg/ml, aminoglycoside total daily dose reduction, duration of vancomycin exceeding three days, receipt of loop diuretic or more than three concomitant nephrotoxins and duration of loop diuretic or non-steroidal anti-inflammatory drug therapy exceeding seven days.

Conclusions: In patients treated for endocarditis, multiple risk factors for AKI were identified. Prospective studies are needed to evaluate these variables for causation of AKI in patients treated for endocarditis.     

Anti–PD-1/PD-L1 antibodies in non-small cell lung cancer: the era of immunotherapy

Introduction: Advanced non-small cell lung cancer (NSCLC) has been conventionally treated with cytotoxic chemotherapy with short-lived responses and significant toxicities. Monoclonal antibodies to programmed death-1 receptor (PD-1) and programmed death ligand 1 (PD-L1) have shown tremendous promise in the treatment of advanced NSCLC in various clinical trials.

Areas covered: In this article, we will review the outcomes of various trials of anti-PD-1/anti-PD-L1 antibodies in the treatment of NSCLC. We will also discuss their mechanism of action and toxicities.

Expert commentary: Anti-PD-1/PD-L1 antibodies offer several advantages including significant antitumor activity, induction of long lasting responses, and favorable safety profile. Several trials are now being conducted to evaluate their efficacy as first line agents as well as in combination with other agents. More research is also needed to identify other biomarkers, in addition to PD-L1 expression, that could more reliably predict response to these drugs, and aid in better patient selection.     

Use of specific immunoglobulins and vaccines for the management of accidental needlestick injury in the child: a practical review in the anti-vaccination movement era

Introduction: Accidental needle injury is a common but still discussed problem.

Objective: We discuss possible options to optimize the management of injured children in light of the available literature findings.

Results: The risk of viral infection is low. However, blood investigations are mandatory, as well as appropriate counselling. Anti-HBV immunoglobulins are recommended in all unvaccinated subjects exposed to a HBsAg-positive source; however, there is no agreement regarding their administration in unvaccinated children. Use of anti-tetanus immunoglobulins in unvaccinated child with minor and clean wound is well defined; however, wound type classification in the event of needlestick injury may be difficult and subjective. There is no agreement on the routine use of antiretroviral prophylaxis.

Conclusion: From a practical point of view, several unsolved issues have emerged regarding the management of the children with needlestick injury, which appear particularly relevant in the anti-vaccination movement era. International guidelines should be encouraged at this regard.     

The safety and efficacy of sonidegib for the treatment of locally advanced basal cell carcinoma

Introduction: Basal cell carcinomas (BCCs) are the commonest malignancy in the Western world. Locally advanced BCCs (laBCCs) represent tumours that have developed in difficult-to-treat facial sites, aggressively recurrent tumours, large neglected tumours and those in which current treatment options are excluded by clinical or patient-driven criteria. It is estimated laBCCs represent 1% of BCCs.

Areas covered: Sonidegib is an oral hedgehog pathway inhibitor with a novel structure. It has recently been licensed for the treatment of laBCC.

This article provides a comprehensive review of the literature regarding sonidegib, detailing the pharmacology of the compound, clinical trial data, competitor compounds and a future perspective.

Expert commentary: Sonidegib is a novel smoothened (SMO) inhibitor with comparable efficacy to vismodegib, with patient response rates of 44% (sonidegib) and 43% (vismodegib). The adverse effect profile of these two treatments is similar with the main effects being considered to be class effects of SMO inhibitors.     

Preventing central nervous system metastases in non-small cell lung cancer

Introduction: There are no effective central nervous system (CNS) metastases prevention methods in lung cancer patients. Prophylactic cranial irradiation has a limited effectiveness and relatively high toxicity. Systemic chemotherapy is not relevant in reducing the risk of CNS in lung cancer patients. The understanding of molecular background of brain metastases in non-small cell lung cancer (NSCLC) patients could contribute to the development of personalized treatments for such patients.

Areas covered: This article summarizes the latest clinical trials concerning the use of radiotherapy, chemotherapy, molecularly targeted therapies, and immunotherapy in lung cancer patients, with particular consideration of brain lung cancer metastasis prevention. The literature search was undertaken via PubMed and EMBASE searches and relevant articles are included in this review.

Expert commentary: The recent data supports that EGFR-TKIs and ALK inhibitors are clinically relevant for first-line treatment to prevent and treat CNS metastases in molecularly selected NSCLC patients. In the future, high hopes for the prevention of CNS metastases in NSCLC patients are associated with immunotherapy concerning immune check-points inhibitors.     

The safety and efficacy of olaparib therapy in patients with relapsed ovarian cancer

Introduction: PARP inhibition is an exciting new anticancer strategy. Olaparib has recently obtained a first in class license in Europe and the USA for the treatment of relapsed BRCA-mutant ovarian cancer.

Areas covered: We review the key preclinical and clinical data surrounding its use in the maintenance setting.

Expert commentary: We also consider the market profile, regulatory issues surrounding the agent and offer a five year speculative viewpoint of its future development in ovarian cancer.     

Evaluating the addition of oxaliplatin to single agent fluoropyrimidine in the treatment of locally advanced rectal cancer: a systematic review and meta-analysis

Introduction: Multimodality treatment of patients with locally advanced rectal cancer (LARC) has significantly improved local disease control, however the unaltered overall survival (OS) implicates an inability to further control micrometastases, providing rationale for intensified systemic treatment.

A systematic review was conducted to evaluate the efficacy and toxicity of adding oxaliplatin to a fluoropyrimidine (intervention) compared with fluoropyrimidine alone (control) in the treatment of LARC.

Methods: We searched CENTRAL, Medline Ovid, PubMed and EMBASE databases. Randomised trials comparing the intervention and control delivered either pre- or post-operatively were included.

Results: Seven trials involving 4444 patients were identified; five studies evaluated the intervention vs control preoperatively; one study peri-operatively; and one, post-operatively. There was no significant difference in OS with oxaliplatin addition, HR 0.89, 95% CI, 0.75 to 1.06. There was however an improvement in disease free survival, 3-year local and distant recurrence rates (RR) favouring oxaliplatin. Preoperative oxaliplatin improved pathological complete response (pCR), but with a greater toxicity and reduced compliance with radiation.

Conclusion: There is no OS benefit with oxaliplatin, despite improved pCR, local and distant RR. Before drawing definitive conclusions, longer follow-up in included trials and availability of published data from other eligible studies, including the induction setting, are needed.     

CT-guided radiofrequency ablation of spinal osteoblastoma: treatment and long-term follow-up

Objective: Osteoblastoma (OB) is a painful, rare, benign bone tumour usually observed in young populations, and this condition involves the spine in up to one-third of cases. We sought to focus on the minimally invasive treatment of spinal OB with radiofrequency ablation (RFA) under computed tomography (CT) guidance. When performed near the spinal cord, surgery can lead to instability of the spine, sometimes requiring additional interventions to stabilise the segments involved, and can cause the precocious onset of arthrosis or other degenerative diseases.

The results were evaluated both clinically and with the aid of diagnostic imaging techniques during a 5-year follow-up study.

Materials and methods: Eleven patients affected by spinal OB were treated in a single session with biopsy and CT-guided RFA. Pre- and post-evaluations of the patients were performed both clinically and with CT and magnetic resonance imaging (MRI).

Results: Complete success in terms of pain relief was achieved in all patients. Additional treatments were not required in any patients. There were no complications. During follow-up, neither complications nor pathological findings related to the treatment were observed.

Conclusions: Our experience demonstrates that RFA for spinal OB is safe and effective. One of the main advantages of this technique is represented by its lower grade of invasiveness compared with that for potentially hazardous surgical manoeuvres.