A randomized clinical study on the impact of Comprehensive Geriatric Assessment (CGA) based interventions on the quality of life of elderly, frail, onco-hematologic patients candidate to anticancer therapy: protocol of the ONCO-Aging study.

BACKGROUND: Age is considered as one of the most important risk-factor for many types of solid and hematological cancers, as their incidence increases with age in parallel to the ever-growing elderly population. Moreover, cancer incidence is constantly increasing as a consequence of the increase in life expectancy that favors the process of cellular senescence. Geriatric assessment has been increasingly recognized as predictive and prognostic instrument to detect frailty in older adults with cancer. In particular, the G8 score is a simple and reproducible instrument to identify elderly patients who should undergo full geriatric evaluation. Due to their frailty, elderly patients may be often under-treated and a therapeutic choice based also on a comprehensive geriatric assessment (CGA) is recommended. With these premises, we aim to test the impact of the CGA based interventions on the quality of life (QoL) of frail elderly onco-hematological patients, identified by the G8 screening, candidate for innovative target directed drugs or treatments including the combination of radiotherapy and chemotherapy (RT + CT). METHODS: Patients aged > 65 years, candidate to target directed agents or to RT + CT treatments are screened for frailty by the G8 test; those patients classified as frail (G8 ≤ 14) are randomized to receive a CGA at baseline or to conventional care. The primary endpoint is QoL, assessed by EORTC QLQ-C30C. As collateral biological study, the potential prognostic/predictive role of T-cell senescence and myeloid derived suppressor cells (MDSC) are evaluated on plasma samples. DISCUSSION: This trial will contribute to define the impact of CGA on the management of frail elderly onco-hematologic patients candidate to innovative biological drugs or to integrated schedules with the association of RT + CT. Furthermore, the use of plasma samples to assess the potential prognostic value of imbalance of immune-competent cells is expected to contribute to the individualized care of elderly patients, resulting into a fine tuning of the therapeutic strategies. TRIAL REGISTRATION: ClinicalTrials.gov ID: NCT04478916 . registered July 21, 2020 - retrospectively registered.

Radiation-Related Deregulation of TUBB3 and BRCA1/2 and Risk of Secondary Lung Cancer in Women With Breast Cancer.

INTRODUCTION: Breast cancer survivors are at increased risk of developing unrelated primary cancers, particularly lung cancer. Evidence indicates that sex hormones as well as a deregulation of DNA-repair pathways may contribute to lung cancer onset. We investigated whether the hormone status and expression of markers involved in DNA repair (BRCA1/2, ERCC1, and P53R2), synthesis (TS and RRM1), and cell division (TUBB3) might be linked to lung cancer risk. PATIENTS AND METHODS: Thirty-seven breast cancer survivors with unrelated lung cancer and 84 control subjects comprising women with breast cancer (42/84) or lung cancer (42/84) were enrolled. Immunohistochemistry on tumor tissue was performed. Geometric mean ratio was used to assess the association of marker levels with patient groups. RESULTS: Estrogen receptor was expressed in approximately 90% of the breast cancer group but was negative in the majority of the lung cancer group, a result similar to the lung cancer control group. Likewise, ER isoform ß was weakly expressed in the lung cancer group. Protein analysis of breast cancer versus control had a significantly lower expression of BRCA1, P53R2, and TUBB3. Likewise, a BRCA1 reduction was observed in the lung cancer group concomitant with a BRCA2 increase. Furthermore, BRCA2 and TUBB3 increased in ipsilateral lung cancer in women who had previously received radiotherapy for breast cancer. CONCLUSION: The decrease of DNA-repair proteins in breast cancer could make these women more susceptible to therapy-related cancer. The increase of BRCA2 and TUBB3 in lung cancer from patients who previously received radiotherapy for breast cancer might reflect a tissue response to exposure to ionizing radiation.

Retreatment with anti-EGFR monoclonal antibodies in metastatic colorectal cancer: Systematic review of different strategies.

BACKGROUND: Despite advances in precision oncology and immunotherapy of tumors, little progress has been made in metastatic colorectal cancer (mCRC) in recent years. Therefore, making the most of available therapies is a necessity. Several studies, based on the pulsatile behavior of RAS clones under EGFR blockade, investigated whether readministration of EGFR-targeted agents is effective beyond second line. METHODS: A systematic review of studies of retreatment with anti-EGFR monoclonal antibodies has been performed from January 2005 to December 2018 according to PRISMA criteria from PubMed, ESMO and ASCO meetings libraries and Clinicaltrial.gov. Efficacy has been evaluated as objective response rate and survival in available publications. In addition, type and incidence of side effects occurring during on anti-EGFR retreatment have been considered. RESULTS: 26 publications have been retrieved, of which 20 full-text articles and 6 abstracts and categorized as for the retreatment strategy into five groups: rechallenge (n = 10), reintroduction (n = 4), sequence (n = 5), dose escalation (n = 1) and mixed (n = 6). Data of efficacy displayed high heterogeneity across different strategies (objective response rate, ORR = 0.0-53.8%; disease control rate, DCR = 24.0-89.7%), with best results in the setting of rechallenge (ORR = 2.9-53.8%; DCR = 40.0-89.7%). CONCLUSIONS: Rechallenge with anti-EGFR provides clinical benefit in molecularly selected mCRC patients beyond second line. Further ctDNA-guided studies comparing this option of treatment with current approved advanced line treatments are warranted.

Pooled Analysis of Clinical Outcome of Patients with Chemorefractory Metastatic Colorectal Cancer Treated within Phase I/II Clinical Studies Based on Individual Biomarkers of Susceptibility: A Single-Institution Experience.

BACKGROUND: Patients with metastatic colorectal cancer (mCRC) refractory to standard therapies have a poor prognosis. In this setting, recruitment into clinical trials is warranted, and studies driven by selection according to individual tumor molecular characteristics are expected to provide added value. OBJECTIVE: We retrospectively analyzed data from patients with mCRC refractory to or following failure of standard therapies who were enrolled into phase I/II clinical studies at the Niguarda Cancer Center based on the presence of a specific molecular profile expected to represent the target of susceptibility to the experimental drug(s). PATIENTS AND METHODS: From June 2011 to May 2016, 2044 patients with mCRC underwent molecular screening. Eighty patients (3.9%) were enrolled in ad hoc studies; the median age was 60 years (range 36-86) and the median number of previous treatment lines was five (range 2-8). Molecular characteristics exploited within these studies were MGMT promoter hypermethylation (48.7%), HER2 amplification (28.8%), BRAF V600E mutation (20%), and novel gene fusions involving ALK or NTRK (2.5%). RESULTS: One patient (1%) had RECIST (Response Evaluation Criteria In Solid Tumors) complete response (CR), 13 patients (16.5%) experienced a partial response (PR), and 28 (35%) stable disease (SD). Median progression-free survival (PFS) was 2.8 months (range 2.63-3.83), with 24% of patients displaying PFS >5 months. Median growth modulation index (GMI) was 0.85 (range 0-15.61) and 32.5% of patients had GMI >1.33. KRAS exon 2 mutations were found in 38.5% of patients, and among the 78 patients with known KRAS status, those with wild-type tumors had longer PFS than those with mutated tumors (3.80 [95% CI 2.80-5.03] vs. 2.13 months [95% CI 1.77-2.87], respectively, p = 0.001). Median overall survival (OS) was 7.83 months (range 7.17-9.33) for all patients, and patients with KRAS wild-type tumors had longer OS than those with mutated tumors (7.83 [95% CI 7.33-10.80] vs. 7.18 months [95% CI 5.63-9.33], respectively, p = 0.06). CONCLUSIONS: This single-institution retrospective study indicates that in a heavily pretreated population approximately 4% of mCRC tumors display a potential actionable molecular context suitable for therapeutic intervention. Application of molecular selection is challenging but improves clinical outcome even in later lines of treatment.

Circulating Cell-Free DNA and Circulating Tumor Cells as Prognostic and Predictive Biomarkers in Advanced Non-Small Cell Lung Cancer Patients Treated with First-Line Chemotherapy.

Cell-free DNA (cfDNA) and circulating tumor cells (CTCs) are promising prognostic and predictive biomarkers in non-small cell lung cancer (NSCLC). In this study, we examined the prognostic role of cfDNA and CTCs, in separate and joint analyses, in NSCLC patients receiving first line chemotherapy. Seventy-three patients with advanced NSCLC were enrolled in this study. CfDNA and CTC were analyzed at baseline and after two cycles of chemotherapy. Plasma cfDNA quantification was performed by quantitative PCR (qPCR) whereas CTCs were isolated by the ScreenCell Cyto (ScreenCell, Paris, France) device and enumerated according to malignant features. Patients with baseline cfDNA higher than the median value (96.3 hTERT copy number) had a significantly worse overall survival (OS) and double the risk of death (hazard ratio (HR): 2.14; 95% confidence limits (CL) = 1.24-3.68; p-value = 0.006). Conversely, an inverse relationship between CTC median baseline number (6 CTC/3 mL of blood) and OS was observed. In addition, we found that in patients reporting stable disease (SD), the baseline cfDNA and CTCs were able to discriminate patients at high risk of poor survival. cfDNA demonstrated a more reliable biomarker than CTCs in the overall population. In the subgroup of SD patients, both biomarkers identified patients at high risk of poor prognosis who might deserve additional/alternative therapeutic interventions.

Fibroblast Growth Factor Receptor (FGFR): A New Target for Non-small Cell Lung Cancer Therapy.

Lung cancer is still the leading cause of cancer related death worldwide. Fibroblast growth factor receptor (FGFR) is a tirosine-kinase receptor that is seen to be amplified or mutated in non-small cell lung cancer (NSCLC) and it plays a crucial role in tumour development and maintenance. The authors analyzed the state of the art of FGFR by reviewing the current literature. Fibroblast growth factor (FGF)-FGFR pathway and their aberrations are described, with the evaluation of their possible prognostic role in NSCLC and in particular in squamous cell carcinomas, in which FGFR is more often amplified. New therapeutic agents targeting FGFR signaling have been developed and are now in clinical evaluation. Dysregulation of FGF signaling in tumour cells is related to FGFR gene amplification or mutation, although it is still uncertain which of these aberrations represents a real predictor of response to specific inhibitors. However, recent evidence has questioned whether FGFR is a real target in squamous cell histology. The effectiveness of FGFR inhibitors is also still unclear since there are no clinical data on selected patients. Moreover, the management of specific side effects related to inhibition of the physiological role of FGF should be more thorough.

Next generation sequencing in non-small cell lung cancer: new avenues toward the personalized medicine.

Non-small cell lung cancer (NSCLC) is one of the most common causes of cancer-related death worldwide. Based on the patient's stage of disease, treatment options include surgery, radiotherapy, and chemotherapy. Although chemotherapy remains the main therapeutic approach for advanced NSCLC, targeted therapy represents a good chance of treatment for this subgroup of patients. Currently this approach is based on previous evaluation of clinically relevant mutations and the Sanger sequencing is the main approach to assign mutational status and to guide the appropriate treatment; however this tool is characterized by a low sensitivity. Recently, the advent of next-generation sequencing (NGS) has dramatically revolutionized the molecular knowledge of cancer by increasing the feasibility and possibility to sequence DNA ranging from large scale studies to targeted regions. This review reports an overview of different applications of the NGS as novel approach to study NSCLC, thereby providing information about mutational spectrum of this cancer in order to identify novel targetable mutations and to predict the emergence of drug resistance. All studies demonstrated several advantages of this approach over the traditional tools. In particular the NGS was also able to reveal mutations in low percentage, and to screen the mutational status of different critical samples such as biopsies, cytological samples and circulating plasma DNA, offering innovative diagnostic opportunities. Despite several problems have to be overcome toward the personalized therapy, the NGS represents a highly attractive system to identify mutations improving the outcome of patients with this deadly disease.

Oral vinorelbine in the treatment of non-small-cell lung cancer.

INTRODUCTION: Originally formulated as an intravenous (i.v.) agent, vinorelbine is also currently available as an oral chemotherapeutic agent. Oral vinorelbine has demonstrated significant activity in different settings for NSCLC, including adjuvant treatment for resected disease, concurrent chemoradiation for locally advanced NSCLC and palliative chemotherapy for recurrent/metastatic NSCLC, as part of combination schedules or as a single-agent treatment. AREAS COVERED: The authors explored the available data describing the use of oral vinorelbine in NSCLC. PubMed articles and abstracts presented at international conferences were analysed, and relevant trials were reported and discussed. Specific settings, including the treatment of elderly and unfit patients and metronomic schedules including oral vinorelbine, were evaluated. Available pharmacoeconomic data were also assessed. EXPERT OPINION: Oral vinorelbine is an appealing agent, particularly as part of combination regimens containing platinum derivatives, although it can have a role as a single-agent treatment as well. Its safety profile is generally favourable and its route of administration is generally preferred by patients receiving chemotherapy. Compared to i.v. vinorelbine and other antineoplastic agents, oral vinorelbine has been reported to be advantageous in terms of cost savings.

Ipilimumab in non-small cell lung cancer and small-cell lung cancer: new knowledge on a new therapeutic strategy.

INTRODUCTION: Despite recent advances with new chemotherapeutic agents and target therapies, the prognosis of NSCLC remains poor. Recent results from clinical trials of immunotherapeutic agents, especially with immune checkpoint inhibitors, make this approach very exciting in NSCLC. Ipilimumab is a monoclonal antibody directed against cytotoxic T-lymphocyte antigen 4 that is able to stimulate the antitumour immune response by promoting T-cell activation. AREAS COVERED: We have reviewed the literature and have described the most important results obtained with ipilimumab in NSCLC in recent trials with a specific focus on its peculiar toxicity profile and pattern of response. Trials ongoing with ipilimumab are also reported. EXPERT OPINION: The results from clinical trials with ipilimumab are promising. Some important issues in the near future will be to identify prognostic and predictive biomarkers to select patients who could benefit from this drug. Further studies are warranted to understand how to combine ipilimumab with other anticancer strategies.

Afatinib for the treatment of advanced non-small-cell lung cancer.

INTRODUCTION: The inhibition of the epidermal growth factor receptor (EGFR) through tyrosine kinase inhibitors (TKIs) represents an effective strategy for EGFR-mutated NSCLC. Afatinib is an irreversible erythroblastosis oncogene B (ErbB) family blocker, able to inhibit the kinase domains of EGFR, HER2 and HER4, and the transphosphorylation of ErbB3 that has recently been approved in the United States for the first-line treatment of EGFR-mutated NSCLC and in Europe and Japan for the treatment of EGFR-mutated TKI-naive patients. AREAS COVERED: The authors analyzed the pharmacology and the clinical activity of afatinib in NSCLC through a review of the literature. Trials exploring different settings have been reported, including LUX-Lung 3 and LUX-Lung 6, where the drug achieved better outcomes in terms of response rate, progression-free survival and quality of life compared with chemotherapy. The main toxicities of afatinib are gastrointestinal and skin-related adverse events. EXPERT OPINION: Afatinib showed remarkable efficacy as a first-line treatment in the presence of common EGFR mutations. Afatinib showed some activity in NSCLC with acquired resistance to EGFR TKIs, although, currently, its efficacy after the failure of erlotinib or gefitinib has not been clearly stated. Direct clinical data comparing the activity and tolerability of different inhibitors are still needed.