Publications by authors named "Christian Rolfo"

227 Publications

Circulating tumor DNA in cancer: Predictive molecular pathology meets mathematics.

Crit Rev Oncol Hematol 2021 Jun 11;163:103394. Epub 2021 Jun 11.

Department of Public Health, University of Naples Federico II, Naples, Italy. Electronic address:

The cancer secretome is a valuable reservoir of cancer biomarkers. Besides containing circulating tumor cells, extracellular vesicles, and proteins, it is also rich in circulating tumor DNA (ctDNA)-a subpopulation of cell free DNA. The most efficient technology to capture ctDNA is next generation sequencing (NGS). Indeed, this analysis enables the identification of both quantitative (e.g., mutant allelic fraction - MAF) and qualitative (e.g., the variant type) information. Strikingly, by calculating these data in relation to time, cytopathologists can decodify and graphically report the ctDNA "message", which may help to diagnose cancer, define treatment, and monitor disease evolution. In this paper, we report the most compelling evidence steadily accumulating on the successful application of NGS-based ctDNA analysis in cancer diagnosis, treatment decision, and monitoring of cancer progression. We also propose a mathematical model that calculates MAF evolution in relation to time.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103394DOI Listing
June 2021

Intracranial Efficacy of Selpercatinib in Fusion-Positive Non-Small Cell Lung Cancers on the LIBRETTO-001 Trial.

Clin Cancer Res 2021 Jun 4. Epub 2021 Jun 4.

Memorial Sloan Kettering Cancer Center, New York, New York.

Purpose: We report the intracranial efficacy of selpercatinib, a highly potent and selective RET inhibitor, approved in the United States for fusion-positive non-small cell lung cancers (NSCLC).

Patients And Methods: In the global phase 1/2 LIBRETTO-001 trial (NCT03157128) in advanced -altered solid tumors, selpercatinib was dosed orally (160 mg twice every day) in 28-day cycles. Patients with baseline intracranial metastases had MRI/CT scans every 8 weeks for 1 year (12 weeks thereafter). In this pre-planned analysis of patients with fusion-positive NSCLC with baseline intracranial metastases, the primary endpoint was independently assessed intracranial objective response rate (ORR) per RECIST 1.1. Secondary endpoints included intracranial disease control rate, intracranial duration of response, and intracranial progression-free survival (PFS) independently reviewed.

Results: Eighty patients with NSCLC had brain metastases at baseline. Patients were heavily pretreated (median = 2 systemic therapies, range = 0-10); 56% of patients received ≥1 course of intracranial radiation (14% whole brain radiotherapy, 45% stereotactic radiosurgery). Among 22 patients with measurable intracranial disease at baseline, intracranial ORR was 82% [95% confidence interval (CI), 60-95], including 23% with complete responses. Among all intracranial responders (measurable and nonmeasurable, = 38), median duration of intracranial response was not reached (95% CI, 9.3-NE) at a median duration of follow-up of 9.5 months (IQR = 5.7, 12.0). At 12 months, 55% of intracranial responses were ongoing. In all 80 patients, median intracranial PFS was 13.7 months (95% CI, 10.9-NE) at a median duration of follow-up of 11.0 months (IQR = 7.4, 16.5). No new safety signals were revealed in patients with brain metastases compared with the full NSCLC trial population.

Conclusions: Selpercatinib has robust and durable intracranial efficacy in patients with fusion-positive NSCLC.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-0800DOI Listing
June 2021

Small Cell Lung Cancer: A New Era Is Beginning?

Cancers (Basel) 2021 May 28;13(11). Epub 2021 May 28.

Center for Thoracic Oncology, Tisch Cancer Institute, Mount Sinai System & Icahn School of Medicine, Mount Sinai, New York, NY 10128, USA.

Small cell lung cancer (SCLC) accounts for about 15% of all lung cancers and it is the most aggressive one [...].
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http://dx.doi.org/10.3390/cancers13112646DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8197965PMC
May 2021

Editorial: Emerging Biomarkers for NSCLC: Recent Advances in Diagnosis and Therapy.

Front Oncol 2021 14;11:694578. Epub 2021 May 14.

Thoracic Medical Oncology, Marlene and Stewart Greenebaum Cancer Center, University of Maryland, Baltimore, Baltimore, MD, United States.

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http://dx.doi.org/10.3389/fonc.2021.694578DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8160459PMC
May 2021

Small Cell Lung Cancer: State of the Art of the Molecular and Genetic Landscape and Novel Perspective.

Cancers (Basel) 2021 Apr 6;13(7). Epub 2021 Apr 6.

Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

Small cell lung cancer (SCLC) is a highly proliferative lung cancer that is not amenable to surgery in most cases due to the high metastatic potential. Precision medicine has not yet improved patients' survival due to the lack of actionable mutations. Intra- and intertumoral heterogeneity allow the neoplasms to adapt to various microenvironments and treatments. Further studying this heterogeneous cancer might yield the discovery of actionable mutations. First-line SCLC treatment has added immunotherapy to its armamentarium. There has been renewed interest in SCLC, and numerous clinical trials are underway with novel therapeutic approaches. Understanding the molecular and genetic landscape of this heterogeneous and lethal disease will pave the way for novel drug development.
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http://dx.doi.org/10.3390/cancers13071723DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8038650PMC
April 2021

Novel Clinical Trial Designs in Pursuit of Precision Oncology: Lung-MAP As a Model.

Clin Lung Cancer 2021 May 26;22(3):153-155. Epub 2021 Mar 26.

University of California Davis Comprehensive Cancer Center, Sacramento, CA.

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http://dx.doi.org/10.1016/j.cllc.2021.03.013DOI Listing
May 2021

Radiomics analysis for predicting pembrolizumab response in patients with advanced rare cancers.

J Immunother Cancer 2021 Apr;9(4)

Department of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

Background: We present a radiomics-based model for predicting response to pembrolizumab in patients with advanced rare cancers.

Methods: The study included 57 patients with advanced rare cancers who were enrolled in our phase II clinical trial of pembrolizumab. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and immune-related RECIST (irRECIST). Patients were categorized as 20 "controlled disease" (stable disease, partial response, or complete response) or 37 progressive disease). We used 3D-slicer to segment target lesions on standard-of-care, pretreatment contrast enhanced CT scans. We extracted 610 features (10 histogram-based features and 600 second-order texture features) from each volume of interest. Least absolute shrinkage and selection operator logistic regression was used to detect the most discriminatory features. Selected features were used to create a classification model, using XGBoost, for the prediction of tumor response to pembrolizumab. Leave-one-out cross-validation was performed to assess model performance.

Findings: The 10 most relevant radiomics features were selected; XGBoost-based classification successfully differentiated between controlled disease (complete response, partial response, stable disease) and progressive disease with high accuracy, sensitivity, and specificity in patients assessed by RECIST (94.7%, 97.3%, and 90%, respectively; p<0.001) and in patients assessed by irRECIST (94.7%, 93.9%, and 95.8%, respectively; p<0.001). Additionally, the common features of the RECIST and irRECIST groups also highly predicted pembrolizumab response with accuracy, sensitivity, specificity, and p value of 94.7%, 97%, 90%, p<0.001% and 96%, 96%, 95%, p<0.001, respectively.

Conclusion: Our radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer.

Interpretation: Our radiomics-based signature identified imaging differences that predicted pembrolizumab response in patients with advanced rare cancer.
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http://dx.doi.org/10.1136/jitc-2020-001752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8051405PMC
April 2021

Next generation sequencing for liquid biopsy based testing in non-small cell lung cancer in 2021.

Crit Rev Oncol Hematol 2021 May 26;161:103311. Epub 2021 Mar 26.

Department of Public Health, University of Naples Federico II, Naples, Italy. Electronic address:

Lung cancer is the leading cause of cancer death worldwide, with non-small cell lung cancer (NSCLC) representing its most commonly diagnosed sub-type. Despite the significant improvements in lung cancer biomarkers knowledge, accompanied by substantial technological advances in molecular tumor profiling, a considerable fraction (up to 30 %) of advanced NSCLC patient presents with major testing challenges or tissue unavailability for molecular analysis. In this context, liquid biopsy is on the rise, currently gaining considerable interest within the molecular pathology and oncology community. Molecular profiling of liquid biopsy specimens using next generation molecular biology methodologies is a rapidly evolving field with promising applications not exclusively limited to advanced stages but also more recently expanding to early stages cancer patients. Here, we offer an overview of some of the most consolidated and emerging applications of next generation sequencing technologies for liquid biopsy testing in NSCLC.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103311DOI Listing
May 2021

Refractory Bullous Pemphigoid in a Patient with Metastatic Lung Adenocarcinoma Treated with Pembrolizumab.

Case Rep Oncol 2021 Jan-Apr;14(1):386-390. Epub 2021 Mar 10.

Thoracic Oncology Unit, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico.

We present the case of a 73-year-old male patient with a history of tobacco use who presented with a central nervous system mass that was confirmed to be a lung adenocarcinoma metastasis. High PD-L1 expression as well as negativity to other targetable drivers led to initiation of pembrolizumab monotherapy and ablative stereotactic radiation therapy on oligo-residual disease, achieving a complete response after 2 years of therapy. Following discontinuation of systemic treatment, the patient developed widespread desquamative plaques. A skin biopsy revealed subepidermal blistering and eosinophilic infiltration in conjunction with C3 and IgG depositions on the basement membrane, detected by immunofluorescence. A diagnosis of bullous pemphigoid was obtained, and systemic corticosteroids were administered with lesion progression. Infliximab was also administered without meaningful clinical improvement. Metronomic cyclophosphamide achieved a complete resolution of skin lesions and up to this day the patient continues with tumor control and is free of dermatological findings. In conclusion, bullous pemphigoid is a very rare dermatological adverse effect related with pembrolizumab treatment. Only two cases, including this one, have been reported, especially with this medication for the treatment of non-small cell lung cancer. With more reported cases, management strategies can be optimized even in the steroid refractory setting.
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http://dx.doi.org/10.1159/000514144DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7983585PMC
March 2021

Live European School of Oncology e-Sessions (e-ESO).

Crit Rev Oncol Hematol 2021 Mar 16:103301. Epub 2021 Mar 16.

European School of Oncology, Milan, Italy.

The European School of Oncology (ESO) embarked on an online educational project, starting with live sessions in 2008 (e-ESO). Our scholars and young oncologists identified the need to be offered independent high-level online education with contributions from experts around the world, free of charge and available at any moment. We report on various types of e-sessions, such as grand-rounds, highlights, debates, clinical cases and other sessions. Our audience has grown over the last decade, reaching 11,123 users who have viewed a total of 77,041 sessions since the beginning of 2008. Moreover, our activities on social media platforms have enhanced our visibility, reaching more physicians around the globe. Due to the recent events surrounding the COVID-19 pandemic, online education has proven to be of great value in offering long-distance teaching. We have analyzed the growth of our audience and its attendance over the last 12 years.
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http://dx.doi.org/10.1016/j.critrevonc.2021.103301DOI Listing
March 2021

When Tissue is an Issue the Liquid Biopsy is Nonissue: A Review.

Oncol Ther 2021 Jun 10;9(1):89-110. Epub 2021 Mar 10.

Foundation for Clinical and Applied Cancer Research (FICMAC), Bogota, Colombia.

Precision medicine has impacted the field of medical oncology by introducing personalized therapies, improving all measurable outcomes. This field, in turn, has expanded to obtaining and analyzing a vast and ever-increasing amount of genomic information. One technique currently applied is the liquid biopsy, which consists of detecting and isolating DNA and exosomes in cancer patients. Newly developed techniques have made it possible to use the liquid biopsy in a wide range of settings. However, challenges regarding the validation of its clinical utility exist because of a lack of standardization across different techniques and tumor types, confounder genomic information, lack of appropriate clinical trial designs, and a non-measured, and therefore not estimated, economic impact on population health. Nowadays, liquid biopsy is not routinely used, but ongoing research is increasing its popularity, and a new era in oncology is developing. Therefore, it is essential to have an in-depth understanding of the liquid biopsy technique. In this review, we summarize the leading techniques and liquid biopsy applications in cancer.
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http://dx.doi.org/10.1007/s40487-021-00144-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8140006PMC
June 2021

Risk of development of brain metastases according to the IASLC/ATS/ERS lung adenocarcinoma classification in locally advanced and metastatic disease.

Lung Cancer 2021 05 27;155:183-190. Epub 2021 Jan 27.

Catalan Institute of Oncology, Germans Trials i Pujol Research Institute and Hospital Campus Can Ruti, Barcelona, Spain.

Introduction: Brain metastases (BM) are frequent among lung cancer patients, affecting prognosis and quality of life. The International Association for the Study of Lung Cancer (IASLC), American Thoracic Society (ATS) and European Respiratory Society (ERS) lung adenocarcinoma (LADC) classification (IASLC/ATS/ERS) has prognostic impact in early-stage disease; however, its role in the advanced setting is not precise. This study aims to determine the correlation between the predominant histological subtype and the risk of developing brain metastases (BM) in locally advanced and metastatic (stages IIIB-IV) LADC.

Methods: A total of 710 patients with LADC were treated at our institution from January 2010 to December 2017. After excluding patients with brain metastases at diagnoses (n = 151), they were categorized according to the IASLC/ATS/ERS LADC classification to estimate the risk of developing brain metastases. A competing risk analysis was employed, considering death a competing risk event.

Results: From 559 patients, the mean age was 59 ± 13.2 years, women (52.4 %), and clinical-stage IV (79.2 %). LADC subtypes distribution was lepidic (11.6 %), acinar (37.9 %), papillary (10.2 %), micropapillary (6.8 %), and solid (33.5 %). A total of 27.0 % of patients developed BM, 32.9 % died without brain affection, and 40.0 % did not progress. The predominantly solid subtype showed the greatest probability of all subtypes for developing BM [HR 4.0; 95 % CI (1.80-8.91), p = 0.0006], followed by micropapillary [HR1.11; 95 % CI (0.36-3.39), p = 0.85). The solid subtype, moderately differentiated tumors, age, and ECOG PS (>2) were associated with increased hazards in the multivariate analysis.

Conclusion: According to the IASLC/ATS/ERS classification, the predominantly solid pattern was significantly associated with an increased risk of developing BM in patients with locally advanced and metastatic LADC. Its prognostic value might help explore novel clinical approaches, modify monitoring for earlier detection, prevent complications, and reduce morbidity.
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http://dx.doi.org/10.1016/j.lungcan.2021.01.023DOI Listing
May 2021

Overcoming TKI resistance in fusion-driven NSCLC: new generation inhibitors and rationale for combination strategies.

Transl Lung Cancer Res 2020 Dec;9(6):2581-2598

Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.

During the last several years, multiple gene rearrangements with oncogenic potential have been described in NSCLC, identifying specific clinic-pathological subgroups of patients that benefit from a targeted therapeutic approach, including (), () and, more recently, () and () genes. Despite initial impressive antitumor activity, the use of targeted therapies in oncogene-addicted NSCLC subgroups is invariably associated with the development of acquired resistance through multiple mechanisms that can include both on-target and off-target mechanisms. However, the process of acquired resistance is a rapidly evolving clinical scenario that constantly evolves under the selective pressure of tyrosine kinase inhibitors. The development of increasingly higher selective and potent inhibitors, traditionally used to overcome resistance to first generation inhibitors, is associated with the development of novel mechanisms of resistance that encompass complex resistance mutations, highly recalcitrant to available TKIs, and bypass track mechanisms. Herein, we provide a comprehensive overview on the therapeutic strategies for overcoming acquired resistance to tyrosine kinase inhibitors (TKIs) targeting the most well-established oncogenic gene fusions in advanced NSCLC, including , , , and rearrangements.
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http://dx.doi.org/10.21037/tlcr-2019-cnsclc-06DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815353PMC
December 2020

Genotyping Squamous Cell Lung Carcinoma in Colombia (Geno1.1-CLICaP).

Front Oncol 2020 15;10:588932. Epub 2020 Dec 15.

Department of Medical Oncology, Catalan Institute of Oncology, Barcelona, Spain.

Background: Lung cancer is a public health problem, and squamous cell carcinoma (SCC) is the second most prevalent subtype of this neoplasm. Compared to other subtypes, including adenocarcinoma, SCC is less well understood in terms of molecular pathogenesis, limiting therapeutic options among targeted agents approved for other disease subgroups. In this study, we sought to characterize the SCC genomic profile using a validated Next Generation Sequencing (NGS) platform.

Methods: The comprehensive NGS assay () was used in order to target the full coding regions of 170 cancer-related genes on SCC samples. PD-L1 expression in tumor cells (TCs) was assessed using clone 22C3 (Dako). Clinical outcomes were correlated with molecular profile, including progression free survival (PFS), overall response rate (ORR), and overall survival (OS).

Results: A total of 26 samples were included, median age was 67 years (r, 33-83) and 53.8% were men. Tobacco consumption was identified in all subjects (mean 34-year package). For first-line treatment 80.8% of patients received cisplatin or carboplatin plus gemcitabine. In terms of molecular profile, we identified a high prevalence of inactivating mutations in TP53 (61.5%), PIK3CA (34.6%), MLL2 (34.6%), KEAP1 (38.4%), and NOTCH1 (26.9%). PD-L1 expression ranged from negative, 1, 2-49, and ≥50% in 23.1, 38.5, 26.9, and 11.5%, respectively. Interestingly, the genetic alterations did not have an effect in PFS, OS or ORR in this study. However, PDL1 expression was higher among those who had mutations in TP53 (p = 0.037) and greater expression of PDL1 was related to PIK3CA alterations (p = 0.05).

Conclusions: The genomic profile of SCC encompasses important genes including TP53, PIK3CA and KEAP1. TP53 mutations could be associated with PDL1 expression, generating hypothesis regarding specific treatment options.
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http://dx.doi.org/10.3389/fonc.2020.588932DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771515PMC
December 2020

Profile of entrectinib in the treatment of ROS1-positive non-small cell lung cancer: Evidence to date.

Hematol Oncol Stem Cell Ther 2020 Dec 1. Epub 2020 Dec 1.

Thoracic Oncology Program, Memorial Cancer Institute/Memorial Health Care System, Florida International University, Miami, FL, USA. Electronic address:

ROS proto-oncogene 1 (ROS1) encodes a type I integral membrane protein with tyrosine kinase activity and whose activating alterations are involved in the aggressiveness of several tumor types. Fusions involving ROS1 gene are present in 1-2% of lung adenocarcinomas and other solid tumors. Entrectinib, also known as RXDX-101, is a potent second-generation, multitarget oral inhibitor against NTRK1, NTRK2, NTRK3, ALK, and ROS1 with the ability to cross the blood-brain barrier. Results of Phase I and II trials have led the Food and Drug Administration to grant approval to entrectinib for the treatment of patients with metastatic, ROS1-positive non-small cell lung cancer (NSCLC). In this review, we will describe the biology of ROS1, as well as results of the efficacy and safety of different clinical trials evaluating entrectinib in ROS1-positive NSCLC.
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http://dx.doi.org/10.1016/j.hemonc.2020.11.005DOI Listing
December 2020

Development of autoimmune diabetes with severe diabetic ketoacidosis and immune-related thyroiditis secondary to durvalumab: a case report.

Transl Lung Cancer Res 2020 Oct;9(5):2149-2156

Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.

Immune-mediated endocrinopathies are among the most frequent immune-related adverse events (irAEs) with immune checkpoint inhibitors (ICIs) targeting programmed death-ligand 1 (PD-L1)/PD-1. However, the development of auto-immune diabetes is an uncommon event during PD(L)-1 blockade, either as monotherapy or in combination therapy. Here we report a case of a 75-year-old male with a mediastinal recurrence from a stage IA squamous cell carcinoma of the lung previously treated with stereotactic body radiotherapy (SBRT) who early developed a severe diabetic ketoacidosis (DKA) caused by new-onset auto-immune diabetes, with positive glutamic acid decarboxylase (GAD65) autoantibodies, during durvalumab consolidation therapy after concurrent chemoradiation. The patient had no personal or family history of diabetes or auto-immune diseases and was admitted after the second cycle of durvalumab to the intensive care unit (ICU) with severe DKA. During his hospitalization, insulin and fluid therapy were started and the patient had a favorable clinical course. Durvalumab treatment was interrupted and thyroiditis was verified during follow-up, without anti-thyroid antibodies, that progressed to subsequent hypothyroidism with need of thyroid hormone replacement therapy. This case highlights the rare irAE of autoimmune type 1 diabetes during anti-PD(L)-1 therapy, which can be life-threatening and requires adequate patient education and prompt medical treatment within a multidisciplinary team, including endocrinology and emergency medicine. Besides its low incidence, this case show how irAE must be taken in account about decision of ICI treatment, especially in curative setting, as they can be potentially fatal and impair overall survival. Furthermore, as reported in the present case, multiple endocrine irAEs can occur in the same patient either simultaneously or sequentially, suggesting that active surveillance is needed in those who develop endocrinopathies as a result of ICI treatment. Immune-mediated endocrinopathies are generally irreversible and cause life-long morbidity, which must be taken into consideration when deciding on further lines of treatment.
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http://dx.doi.org/10.21037/tlcr-20-408DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653143PMC
October 2020

Id1 and PD-1 Combined Blockade Impairs Tumor Growth and Survival of -mutant Lung Cancer by Stimulating PD-L1 Expression and Tumor Infiltrating CD8 T Cells.

Cancers (Basel) 2020 Oct 28;12(11). Epub 2020 Oct 28.

Department of Oncology, Clínica Universidad de Navarra, 31008 Pamplona, Spain.

The use of PD-1/PD-L1 checkpoint inhibitors in advanced NSCLC is associated with longer survival. However, many patients do not benefit from PD-1/PD-L1 blockade, largely because of immunosuppression. New immunotherapy-based combinations are under investigation in an attempt to improve outcomes. (inhibitor of differentiation 1) is involved in immunosuppression. In this study, we explored the potential synergistic effect of the combination of inhibition and pharmacological PD-L1 blockade in three different syngeneic murine -mutant lung adenocarcinoma models. TCGA analysis demonstrated a negative and statistically significant correlation between PD-L1 and expression levels. This observation was confirmed in vitro in human and murine -driven lung cancer cell lines. In vivo experiments in -mutant syngeneic and metastatic murine lung adenocarcinoma models showed that the combined blockade targeting and PD-1 was more effective than each treatment alone in terms of tumor growth impairment and overall survival improvement. Mechanistically, multiplex quantification of CD3/CD4/CD8 T cells and flow cytometry analysis showed that combined therapy favors tumor infiltration by CD8 T cells, whilst in vivo CD8 T cell depletion led to tumor growth restoration. Co-culture assays using CD8 cells and tumor cells showed that T cells present a higher antitumor effect when tumor cells lack expression. These findings highlight that blockade may contribute to a significant immune enhancement of antitumor efficacy of PD-1 inhibitors by increasing PD-L1 expression and harnessing tumor infiltration of CD8 T lymphocytes.
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http://dx.doi.org/10.3390/cancers12113169DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693788PMC
October 2020

Understanding EGFR heterogeneity in lung cancer.

ESMO Open 2020 10;5(5):e000919

Thoracic Oncology Department and Early Phase Clinical Trials Section, School of Medicine, University of Maryland, Baltimore, MD, United States.

The advances in understanding the inherited biological mechanisms of non-small cell lung cancer harbouring epidermal growth factor receptor (EGFR) mutations led to a significant improvement in the outcomes of patients treated with EGFR tyrosine kinase inhibitors. Despite these clinically impressive results, clinical results are not always uniform, suggesting the need for deepening the molecular heterogeneity of this molecularly defined subgroup of patients beyond the clinical and biological surface.The availability of tissue and blood-based tumour genotyping allows us to improve the understanding of molecular and genetic intratumor heterogeneity, driving the measurement of clonal evaluation in patients with lung cancer carrying EGFR mutations. Genetic diversification, clonal expansion and selection are highly variable patterns of genetic diversity, resulting in different biological entities, also a prerequisite for Darwinian selection and therapeutic failure.Such emerging pieces of evidence on the genetic diversity, including adaptive and immunomodulated aspects, provide further evidence for the role of the tumour microenvironment (TME) in drug-resistance and immune-mediated mechanisms. Matching in daily clinical practice, the detailed genomic profile of lung cancer disease and tracking the clonal evolution could be the way to individualise the further target treatments in EGFR-positive disease. Characterising the tumour and immune microenvironment during the time of the cancer evaluation could be the way forward for the qualitative leap needed from bench to bedside. Such a daring approach, aiming at personalising treatment selection in order to exploit the TME properties and weaken tumour adaptivity, should be integrated into clinical trial design to optimise patient outcome.
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http://dx.doi.org/10.1136/esmoopen-2020-000919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7569934PMC
October 2020

Precision Prevention and Cancer Interception: The New Challenges of Liquid Biopsy.

Cancer Discov 2020 11 9;10(11):1635-1644. Epub 2020 Oct 9.

Clinical and Translational Oncology Group, Clínica del Country, Bogotá, Colombia.

Despite major therapeutic progress, most advanced solid tumors are still incurable. Cancer interception is the active way to combat cancer onset, and development of this approach within high-risk populations seems a logical first step. Until now, strategies for the identification of high-risk subjects have been based on low-sensitivity and low-specificity assays. However, new liquid biopsy assays, "the Rosetta Stone of the new biomedicine era," with the ability to identify circulating biomarkers with unprecedented sensitivity, promise to revolutionize cancer management. This review focuses on novel liquid biopsy approaches and the applications to cancer interception. Cancer interception involves the identification of biomarkers associated with developing cancer, and includes genetic and epigenetic alterations, as well as circulating tumor cells and circulating epithelial cells in individuals at risk, and the implementation of therapeutic strategies to prevent the beginning of cancer and to stop its development. Large prospective studies are needed to confirm the potential role of liquid biopsy for early detection of precancer lesions and tumors.
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http://dx.doi.org/10.1158/2159-8290.CD-20-0466DOI Listing
November 2020

International liquid biopsy standardization alliance white paper.

Crit Rev Oncol Hematol 2020 Dec 30;156:103112. Epub 2020 Sep 30.

Friends of Cancer Research, United States.

The promise of precision medicine as a model to customize health care to the individual patient is heavily dependent upon new genetic tools to classify and characterize diseases and their hosts. Liquid biopsies serve as a safe alternative to solid biopsies and are thus a useful and critical component to fully realizing personalized medicine. The International Liquid Biopsy Standardization Alliance (ILSA) comprises organizations and foundations that recognize the importance of working towards the global use of liquid biopsy in oncology practice to support clinical decision making and regulatory considerations and seek to promote it in their communities. This manuscript provides an overview of the independent liquid biopsy- and standardization-based programs engaged with ILSA, their objectives and progress to date, and the tools and resources each is developing to contribute to the field. It also describes the unique areas of effort as well as synergy found within the group.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103112DOI Listing
December 2020

Impact of the COVID-19 Pandemic on Cancer Care: A Global Collaborative Study.

JCO Glob Oncol 2020 09;6:1428-1438

University of Maryland School of Medicine, Baltimore, MD.

Purpose: The COVID-19 pandemic affected health care systems globally and resulted in the interruption of usual care in many health care facilities, exposing vulnerable patients with cancer to significant risks. Our study aimed to evaluate the impact of this pandemic on cancer care worldwide.

Methods: We conducted a cross-sectional study using a validated web-based questionnaire of 51 items. The questionnaire obtained information on the capacity and services offered at these centers, magnitude of disruption of care, reasons for disruption, challenges faced, interventions implemented, and the estimation of patient harm during the pandemic.

Results: A total of 356 centers from 54 countries across six continents participated between April 21 and May 8, 2020. These centers serve 716,979 new patients with cancer a year. Most of them (88.2%) reported facing challenges in delivering care during the pandemic. Although 55.34% reduced services as part of a preemptive strategy, other common reasons included an overwhelmed system (19.94%), lack of personal protective equipment (19.10%), staff shortage (17.98%), and restricted access to medications (9.83%). Missing at least one cycle of therapy by > 10% of patients was reported in 46.31% of the centers. Participants reported patient exposure to harm from interruption of cancer-specific care (36.52%) and noncancer-related care (39.04%), with some centers estimating that up to 80% of their patients were exposed to harm.

Conclusion: The detrimental impact of the COVID-19 pandemic on cancer care is widespread, with varying magnitude among centers worldwide. Additional research to assess this impact at the patient level is required.
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http://dx.doi.org/10.1200/GO.20.00351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7529504PMC
September 2020

Strategies for the successful implementation of plasma-based NSCLC genotyping in clinical practice.

Nat Rev Clin Oncol 2021 01 11;18(1):56-62. Epub 2020 Sep 11.

UC Davis Comprehensive Cancer Center, Sacramento, CA, USA.

Upfront tumour genotyping is now considered an essential step in guiding treatment decision-making in the management of patients with advanced-stage non-small-cell lung cancer (NSCLC) in light of the ever-expanding toolbox of targeted therapies and immune-checkpoint inhibitors. However, genotyping of tumour biopsy samples is not feasible for all patients and, therefore, genomic analysis of circulating tumour DNA (ctDNA) has emerged as a compelling non-invasive option. Current guidelines universally recommend genotyping and support the use of ctDNA testing in certain settings, although they often omit the detail necessary for integrating these tests into clinical care on an individual basis. In this Perspective, we describe the rationale, promise and challenges associated with ctDNA-based NSCLC genotyping and suggest a framework for the implementation of these assays into routine clinical practice. We also offer considerations for the interpretation of ctDNA genotyping results, which, particularly when using next-generation sequencing panels, can be nuanced. Through the addition of this new approach to clinical practice, we propose that oncologists might finally be able to utilize effective genotyping in nearly all patients with advanced-stage NSCLC.
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http://dx.doi.org/10.1038/s41571-020-0423-xDOI Listing
January 2021

Targeted Therapies in Early Stage NSCLC: Hype or Hope?

Int J Mol Sci 2020 Aug 31;21(17). Epub 2020 Aug 31.

Thoracic Oncology Department and Early Phase Clinical Trials Section, School of Medicine, University of Maryland, Baltimore, MD 20742, USA.

Non-small-cell lung cancer (NSCLC) represents roughly 85% of lung cancers, with an incidence that increases yearly across the world. The introduction in clinical practice of several new and more effective molecules has led to a consistent improvement in survival and quality of life in locally advanced and metastatic NSCLC. In particular, oncogenic drivers have indeed transformed the therapeutic algorithm for NSCLC. Nearly 25% of patients are diagnosed in an early stage when NSCLC is still amenable to radical surgery. In spite of this, five-year survival rates for fully resected early stage remains rather disappointing. Adjuvant chemotherapy has shown a modest survival benefit depending on the stage, but more than half of patients relapse. Given this need for improvement, over the last years different targeted therapies have been evaluated in early-stage NSCLC with no survival benefit in unselected patients. However, the identification of reliable predictive biomarkers to these agents in the metastatic setting, the design of molecularly-oriented studies, and the availability of novel potent and less toxic agents opened the way for a novel era in early stage NSCLC treatment. In this review, we will discuss the current landscape of targeted therapeutic options in early NSCLC.
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http://dx.doi.org/10.3390/ijms21176329DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7504271PMC
August 2020

Corrigendum to "Challenges and opportunities of cfDNA analysis implementation in clinical practice: Perspective of the International Society of Liquid Biopsy (ISLB)" [Crit. Rev. Oncol. Hematol. 151 (July) (2020) 102978].

Crit Rev Oncol Hematol 2020 Oct 18;154:103058. Epub 2020 Aug 18.

Centre for Genomics and Oncological Research - GENYO, Pfizer, University of Granada, Andalusian Regional Government, Granada, Spain; Bio-Health Research Institute (Instituto de Investigación Biosanitaria ibs. GRANADA), Spain; Complejo Hospitalario Universitario Granada (CHUG), Department of Medical Oncology, University of Granada, Granada, Spain. Electronic address:

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http://dx.doi.org/10.1016/j.critrevonc.2020.103058DOI Listing
October 2020

Antibiotics impair immune checkpoint inhibitor effectiveness in Hispanic patients with non-small cell lung cancer (AB-CLICaP).

Thorac Cancer 2020 09 24;11(9):2552-2560. Epub 2020 Jul 24.

Thoracic Oncology Unit, Instituto Nacional de Cancerología, México City, Mexico.

Background: The intestinal microbiota is an important factor in modulating immune-mediated tumor cell destruction. Alterations in the microbiome composition have been linked to reduced efficacy of immune checkpoint inhibitor (ICI) therapies. Therefore, antibiotic treatment (ATB), which modifies the diversity of the gut bacteria populations, could lead to a reduced efficacy of ICI treatments.

Methods: This was a retrospective cohort study. Patients with advanced non-small cell lung cancer (NSCLC) treated with anti-programmed cell death ligand-1 (PD-L1) alone, or in combination in three different countries in Latin America were included. After identification, patients were placed into three groups: Non-ATB exposed (no-ATB), exposed within 30 days of the first dose of ICI (pre-ICI ATB) and patients receiving ATB concomitantly with ICI (ICI-ATB). Progression-free survival (PFS), overall survival (OS) and response rates to treatment with ICI were assessed.

Results: A total of 140 patients were included, of which 32 patients (23%) received ATB treatment. The most common ATB types were fluoroquinolones and B-lactams. No differences in survival according to antibiotic type were identified. Median OS in patients not exposed to ATB was 40.6 months (95% CI: 32-67.7), compared with 20.3 months (95% CI: 12.1-non-reached [NR]) for patients with pre-ICI ATB treatment and 24.7 months (95% CI: 13-NR) for patients treated with ATB concomitantly with ICI. There were no significant differences in terms of PFS, or response rates across all treatment groups.

Conclusions: Antibiotic treatment was associated with reduced OS in Hispanic patients with NSCLC treated with ICIs.
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http://dx.doi.org/10.1111/1759-7714.13573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7471049PMC
September 2020

Atypical Skin Manifestations During Immune Checkpoint Blockage in Coronavirus Disease 2019-Infected Patients With Lung Cancer.

J Thorac Oncol 2020 11 9;15(11):1767-1772. Epub 2020 Jul 9.

Thoracic Oncology Unit, Instituto Nacional de Cancerología (INCan), México City, México.

A new coronavirus, named severe acute respiratory syndrome-coronavirus-2 by the WHO, has rapidly spread around the world since its first reported case in late December of 2019 from Wuhan, the People's Republic of China. As of mid-April 2020, this virus has affected more than 180 countries and territories, infecting more than 1,650,000 individuals and causing over 100,000 deaths. With approximately 20 million new cases globally per year, cancer affects a substantial portion of the population. Individuals affected by cancer are more susceptible to infections owing to coexisting chronic diseases (cardiovascular, pulmonary, and diabetes), overall poor health status, and systemic immunosuppressive states caused by both cancer and the anticancer treatment. As a consequence, patients with malignancies, especially those with lung cancer who develop coronavirus disease 2019, experience more difficult outcomes. A recent multicenter study carried out by the Hubei Anti-Cancer Association has also documented that patients with lung cancer had an increased risk of death, intensive care unit requirement, risk of presenting severe or critical symptoms, and use of invasive mechanical ventilation. Here, we present two representative cases of patients with lung cancer and coronavirus disease 2019 without respiratory compromise and with atypical and severe skin manifestations-findings that could be influenced by the long-term use of anti-programmed cell death protein 1 antibody.
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http://dx.doi.org/10.1016/j.jtho.2020.06.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347325PMC
November 2020

Recommendations for detection, prioritization, and treatment of thoracic oncology patients during the COVID-19 pandemic: the THOCOoP cooperative group.

Crit Rev Oncol Hematol 2020 Sep 20;153:103033. Epub 2020 Jun 20.

Hospital La Católica Goicoechea, San José, Costa Rica.

The world currently faces a pandemic due to SARS-CoV-2. Relevant information has emerged regarding the higher risk of poor outcomes in lung cancer patients. As such, lung cancer patients must be prioritized in terms of prevention, detection and treatment. On May 7th, 45 experts in thoracic cancers from 11 different countries were invited to participate. A core panel of experts regarding thoracic oncology care amidst the pandemic gathered virtually, and a total of 60 initial recommendations were drafted based on available evidence, 2 questions were deleted due to conflicting evidence. By May 16th, 44 experts had agreed to participate, and voted on each of the 58 recommendation using a Delphi panel on a live voting event. Consensus was reached regarding the recommendations (>66 % strongly agree/agree) for 56 questions. Strong consensus (>80 % strongly agree/agree) was reached for 44 questions. Patients with lung cancer represent a particularly vulnerable population during this time. Special care must be taken to maintain treatment while avoiding exposure.
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http://dx.doi.org/10.1016/j.critrevonc.2020.103033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7305738PMC
September 2020

Precision medicine and its implementation in patients with NTRK fusion genes: perspective from developing countries.

Ther Adv Respir Dis 2020 Jan-Dec;14:1753466620938553

Germans Trias i Pujol Research Institute and Hospital (IGTP), Badalona, Catalunya, Spain.

Precision oncology is the field that places emphasis on the diagnosis and treatment of tumors that harbor specific genomic alterations susceptible to inhibition or modulation. Although most alterations are only present in a minority of patients, a substantial effect on survival can be observed in this subgroup. Mass genome sequencing has led to the identification of a specific driver in the translocations of the tropomyosin receptor kinase family (NTRK) in a subset of rare tumors both in children and in adults, and to the development and investigation of Larotrectinib. This medication was granted approval by the US Food and Drug Administration for NTRK-positive tumors, regardless of histology or age group, as such, larotrectinib was the first in its kind to be approved under the premise that molecular pattern is more important than histology in terms of therapeutic approach. It yielded significant results in disease control with good tolerability across a wide range of diseases including rare pediatric tumors, salivary gland tumors, gliomas, soft-tissue sarcomas, and thyroid carcinomas. In addition, and by taking different approaches in clinical trial design and conducting allocation based on biomarkers, the effects of target therapies can be isolated and quantified. Moreover, and considering developing nations and resource-limited settings, precision oncology could offer a tool to reduce cancer-related disability and hospital costs. In addition, developing nations also present patients with rare tumors that lack a chance of treatment, outside of clinical trials. This, in turn, offers the possibility for international collaboration, and contributes to employment, education, and health service provisions.
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http://dx.doi.org/10.1177/1753466620938553DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7350048PMC
July 2020

Selinexor (KPT-330), an Oral Selective Inhibitor of Nuclear Export (SINE) Compound, in Combination with FOLFOX in Patients with Metastatic Colorectal Cancer (mCRC) - Final Results of the Phase I Trial SENTINEL.

Curr Cancer Drug Targets 2020 ;20(10):811-817

II. Medical Clinic and Polyclinic, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Background: Selinexor is an oral Selective Inhibitor of Nuclear Export compound that specifically blocks Chromosomal Region Maintenance protein 1.

Objective: To evaluate the safety and tolerability of escalating doses of selinexor plus 5-fluorouracil, leucovorin and oxaliplatin (mFOLFOX6) in metastatic colorectal cancer (mCRC) patients.

Methods: In this multicenter phase I trial, mCRC patients, eligible for oxaliplatin-based treatment, were enrolled to receive oral selinexor on days 1, 3, and 8 plus mFOLFOX6 every two weeks. Primary endpoint was the maximum tolerated dose. Secondary endpoints were toxicity, overall response rate, progression free survival, and overall survival.

Results: Overall, 10 patients were enrolled, who had prior treatment with oxaliplatin (6/10), irinotecan (8/10), bevacizumab (6/10) or anti-EGFR therapy (5/10). Four consecutive patients received 40 mg selinexor plus mFOLFOX6. All four experienced dose-limiting toxicities and withdrew from the study after a median of two cycles. Thus, this dose level was regarded as toxic and no further patients were evaluated at this dose. Six patients were enrolled with 20 mg selinexor plus mFOLFOX6. Despite better tolerability, four patients withdrew (patient wish) after the first cycle and only two patients continued until disease progression. Most commonly reported treatment emergent adverse events were nausea (80%), diarrhea (70%), vomiting (60%), fatigue (60%), anorexia (40%), and impaired vision (40%). Due to the short treatment exposure, no relevant clinical activity was observed.

Conclusion: In patients with metastatic colorectal cancer, selinexor on this dose schedule plus mFOLFOX6 was not tolerable. Other dosing schedules or combinations may be evaluated. Clinical trial identifier NCT02384850.
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http://dx.doi.org/10.2174/1568009620666200628105727DOI Listing
January 2020

Scientific publications in cancer: in Latin America, strong scientific networks increase productivity (the TENJIN study).

J Clin Epidemiol 2020 10 12;126:1-8. Epub 2020 Jun 12.

Cancer Biology and Precision Medicine Program Catalan Institute of Oncology; Germans Trias i Pujol Health Sciences Institute and Hospital Badalona, Barcelona, Spain.

Objectives: The objectives of this study are to evaluate the relationship between authorship networking, socioeconomic factors, and scientific productivity across Latin America.

Methods: In a bibliometric analysis of cancer-related Latin-American publications, the relationship between authorship network indicators, sociodemographic factors, and number of peer-reviewed indexed publications per country was explored. A systematic review of the literature for cancer publications between 2000 and 2018 using the Scopus database limited to Latin-American authors was used for the construction of coauthorship and publication networks and their respective metrics. Sociodemographic variables including percentage of invested gross domestic product in research, population, and cancer incidence were also estimated. Multiple linear regression models were constructed to determine the relationship between productivity and the aforementioned variables.

Results: A total of 8,528 articles across nine countries were included. Brazil was the most productive nation with 41.8% of identified references followed by Mexico (16.6%) and Argentina (12.9%). Latin America experienced a 9% growth in number of publications across the studied time frame. After analyzing networking and sociodemographic variables, number of authors in a collaboration network and percentage of invested gross domestic product were associated with high productivity yielding a multiple regression model with an R2 value of 0.983.

Conclusions: This study indicates that extensive authorship networking and a high investment in research strongly predict cancer-related productivity.
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http://dx.doi.org/10.1016/j.jclinepi.2020.05.033DOI Listing
October 2020