Treatment of advanced non-small cell lung cancer with driver mutations: current applications and future directions / 医学前沿

With the improved understanding of driver mutations in non-small cell lung cancer (NSCLC), expanding the targeted therapeutic options improved the survival and safety. However, responses to these agents are commonly temporary and incomplete. Moreover, even patients with the same oncogenic driver gene can respond diversely to the same agent. Furthermore, the therapeutic role of immune-checkpoint inhibitors (ICIs) in oncogene-driven NSCLC remains unclear. Therefore, this review aimed to classify the management of NSCLC with driver mutations based on the gene subtype, concomitant mutation, and dynamic alternation. Then, we provide an overview of the resistant mechanism of target therapy occurring in targeted alternations ("target-dependent resistance") and in the parallel and downstream pathways ("target-independent resistance"). Thirdly, we discuss the effectiveness of ICIs for NSCLC with driver mutations and the combined therapeutic approaches that might reverse the immunosuppressive tumor immune microenvironment. Finally, we listed the emerging treatment strategies for the new oncogenic alternations, and proposed the perspective of NSCLC with driver mutations. This review will guide clinicians to design tailored treatments for NSCLC with driver mutations.

Research progress of breast cancer driver genes and precision therapy / 中国药理学通报

A large number of genetic mutations occur in the development of tumors, but only driver mutations determine the evolutionary direction of tumors. A variety of algorithmic tools and stationary analysis processes are available to search for driver genes with driver mutations. AS driver genes are different in different times and spaces, they are not the same in different stages of the development of breast cancer, leading to the different sensitivity of breast cancer patients to targeted therapy, which has become a major challenge for targeted therapy of breast cancer. This article reviews the progress and challenges of precision therapy for breast cancer from the perspective of driver genes.

Biomarker testing for advanced lung cancer by next-generation sequencing; a valid method to achieve a comprehensive glimpse at mutational landscape

Background: Next-generation sequencing (NGS) based assay for finding an actionable driver in non-small-cell lung cancer is a less used modality in clinical practice. With a long list of actionable targets, limited tissue, arduous single-gene assays, the alternative of NGS for broad testing in one experiment looks attractive. We report here our experience with NGS for biomarker testing in hundred advanced lung cancer patients. Methods: Predictive biomarker testing was performed using the Ion AmpliSeq™ Cancer Hotspot Panel V2 (30 tumors) and Oncomine™ Solid Tumor DNA and Oncomine™ Solid Tumor Fusion Transcript kit (70 tumors) on IonTorrent sequencing platform. Results: One-seventeen distinct aberrations were detected across 29 genes in eighty-six tumors. The most commonly mutated genes were TP53 (43% cases), EGFR (23% cases) and KRAS (17% cases). Thirty-four patients presented an actionable genetic variant for which targeted therapy is presently available, and fifty-two cases harbored non-actionable variants with the possibility of recruitment in clinical trials. NGS results were validated by individual tests for detecting EGFR mutation, ALK1 rearrangement, ROS1 fusion, and c-MET amplification. Compared to single test, NGS exhibited good agreement for detecting EGFR mutations and ALK1 fusion (sensitivity- 88.89%, specificity- 100%, Kappa-score 0.92 and sensitivity- 80%, specificity- 100%, Kappa-score 0.88; respectively). Further, the response of patients harboring tyrosine kinase inhibitor (TKI) sensitizing EGFR mutations was assessed. The progression-free-survival of EGFR positive patients on TKI therapy, harboring a concomitant mutation in PIK3CAmTOR and/or RAS-RAF-MAPK pathway gene and/or TP53 gene was inferior to those with sole-sensitizing EGFR mutation (2 months vs. 9.5 months, P = 0.015). Conclusions: This is the first study from South Asia looking into the analytical validity of NGS and describing the mutational landscape of lung cancer patients to study the impact of co-mutations on cancer biology and treatment outcome. Our study demonstrates the clinical utility of NGS testing for identifying actionable variants and making treatment decisions in advanced lung cancer

A clinico-epidemiological, pathological, and molecular study of lung cancer in Northwestern India

Introduction: Lung cancer is the most common malignant disease and is the topmost cause of cancer deaths in the world across all age groups and in both sexes. It is the most common cause of cancer deaths in developed countries and is also rising at an alarming rate in the developing countries. Objective: The present study was undertaken to explore the clinicopathological and molecular profile of bronchogenic carcinoma in northwestern population of India. Materials and Methods: A total of 136 consecutive patients with histologically proven bronchogenic carcinoma, registered between May 2014 and April 2016 at a tertiary care hospital in New Delhi, India, were analyzed. Results: Out of a total of 136 diagnosed cases, 6% were in the third to fourth decade of life, 49% in the fifth to sixth decade, and 45% in the seventh decade and above. Seventy-one percent of patients were male. Smoking was the major risk factor in 65.40% of patients. About 33% of female patients were smokers with a significant overlap in the use of smoking objects. Twenty-one percent of patients had been initially empirically treated with antitubercular therapy. Most common symptoms at presentation were cough, dyspnea, weight loss, and chest pain. Pleural effusion, paraneoplastic phenomenon, clubbing, peripheral lymphadenopathy, and Pancoast syndrome were the major signs at presentation. Twenty-one percent of nonsmokers and 40% of smoker patients presented with ECOG Performance Status 3 or 4. Ninety-three percent of patients presented in stage III or IV. Metastases to skeleton, brain, liver, pleura, adrenals, lung, and distant lymph nodes were present in 30.8%, 16.9%, 15.4%, 15.4%, 14.7%, 13.2%, and 11.8%, respectively. Fiberoptic bronchoscopy was found to be the most efficient diagnostic procedure as compared to transthoracic and thoracoscopic methods. Histologically, squamous cell carcinoma, adenocarcinoma, and small cell carcinoma and its variants were seen in 35.30%, 44.9%, and 15.40% cases, respectively. Nearly 4.4% of patients were diagnosed as poorly differentiated carcinoma. Driver mutations (epidermal growth factor receptor or anaplastic lymphoma kinase) were detected in 48% (25 of 52 tested) of adenocarcinomas and 55.55% (5 of 9 tested) of young, nonsmoker, female squamous cell carcinoma patients. Conclusion: This study highlights that the adenocarcinoma incidence is surpassing squamous cell carcinoma in Indian lung cancer patients also, as observed in Western population. Mean age at diagnosis is about one decade earlier than in the Western population. Driver mutations are more common in India than in the West as also reported in other Asian studies

Mutações drivers em câncer de pulmão não-pequenas células (CPNPC) / Driver mutations in non-small cell lung cancer

O câncer de pulmão não pequenas células (CPNPC) foi durante muito tempo descrito como uma única doença. A partir do maior conhecimento dos mecanismos de carcinogênese e dos avanços da biologia molecular, foram identificados subtipos moleculares específicos. Essas alterações moleculares são consideradas condutoras (drivers), quando são capazes de guiar o comportamento clínico dos tumores. Com esse conhecimento novas drogas foram desenvolvidas, capazes de inibir a ativação dessas proteínas mutantes. O primeiro exemplo de sucesso foi visto com os inibidores de tirosina quinase de EGFR, em pacientes com a presença de mutações específicas nesse gene. A partir daí muitas outras alterações vem sendo descritas e deparamo-nos com os benefícios clínicos impressionantes da medicina de precisão.

Non-small cell lung cancer has long been described as a unique disease. Since the last advances and better understanding of carcinogenesis mechanisms and molecular biology, specific molecular subtypes have been identified. These alterations are considered drivers, when they guide tumor clinical behavior. After driver mutations identification, new drugs have been developed to inhibit the activation of these mutant proteins. The first successful example was seen with tyrosine kinase EGFR inhibitors in patients with positive specific mutations in this gene. After this discovery many other molecular subtypes have been described and are resulting on these impressive clinical benefits from precision medicine.

Pathogenesis and Mutations of Myeloproliferative Neoplasms: An Overview.

Chronic myeloproliferative neoplasms (MPNs), clonal disorders of hematopoietic system resulting in abnormal proliferation of one or more hematopoietic cell lineages, express different clinical, hematologic and biological features. The majority of classical MPNs -95% of polycythemia vera (PV) and half of essential thrombocythemia (ET) and myelofibrosis (MF) patients- display alterations in the JAK2 gene. JAK2 wild-type ET, and MF patients lack features of PV. Driver mutations in pathogenesis of Philadelpiha-negative MPNs - JAK2, MPL and calreticulin (CALR)- all play pivotal roles in cytokine signaling in hematopoiesis. Negative regulators of signaling pathways, LNK and CBL are infrequently targeted genes in MPNs. Mutated or deleted transcription factors such as IKZF1, EZH2, Tp53 and RUNX1, are present in a low proportion of patients with MPN. Some of these factors, such as IKZF1 and Tp53, were associated with transformation to acute myeloid leukemia (AML), yet their prognostic impact needs to be elucidated. Mutations of CHEK2, the tumor suppressor gene against uncontrolled cell growth, were associated with susceptibility to ET. Mutations of NRAS gene, a member of MAPK signaling pathway frequently mutated in MPNs, seem to affect expression of JAK2 target genes and are primarily associated with transformation to AML. Mutations in epigenetic regulators including TET2, DNMT3A, ASXL1, EZH2, and IDH1/2 were described in MPNs and other myeloid malignancies at variable frequencies. The somatic mutation of SRSF2, one of the RNA splicing machinery genes, was associated with worse survival and increased leukemic transformation in PMF. Alterations in DNMT3A, ASXL1, EZH2, and IDH1/2 are more frequent in PMF than PV and ET. Recent studies suggest that for Ph-negative MPNs, mutations affecting epigenetic regulation might be prognostically more relevant than mutations affecting JAK-STAT signaling. Mutations in CALR were newly discovered in a majority of JAK2V617F- and MPL-negative ET and MF patients. In MPNs, genetic abnormalities affecting epigenetic regulation are often expressed in patients carrying JAK2, MPL, or CALR mutations, indicating a cooperation between these two classes of mutations in MPN pathogenesis. This review summarizes pathogenesis and molecular events of MPNs.

Síndrome de Marfan, mutaciones nuevas y modificadoras del gen FBN1 / Síndrome de Marfan, mutaciones nuevas y modificadoras del gen FBN1

El síndrome de Marfan (SM) es un trastorno sistémico causado por mutaciones en la proteína de la matriz extracelular fibrilina 1 (FBN1). Con un patrón de herencia autosómico dominante, los pacientes se caracterizan por presentar compromiso ocular, cardiovascular y esquelético dentro de un espectro clínico variable. Se ha sugerido que la variabilidad fenotípica intrafamiliar e interfamiliar característica del síndrome ocurre por la asociación de otras mutaciones denominadas modificadoras (driver mutations). Si bien hay claridad acerca de la causalidad genética clásica de la enfermedad, las mutaciones modificadoras descritas recientemente aún no están bien dilucidadas. Se presenta un caso de SM con una mutación no descrita previamente en el gen de la fibrilina 1; se aplica la nosología de Ghent revisada y se analiza el papel de esta mutación nueva y de las mutaciones modificadoras en la génesis de la enfermedad.

Marfan syndrome (MS) is a systemic disorder caused by mutations in the extracellular matrix protein fibrillin 1 (FBN1). With a dominant autosomal pattern, MS patients are characterized by ocular, cardiovascular and skeletal involvement, all within a variable clinical spectrum. It has been suggested that the intrafamilial and interfamilial phenotypic variability, characteristic of the syndrome, occurs by the association of other mutations called driver mutations. Even though there is a clear genetic causation, the recently described driver mutations are not yet fully elucidated. We present a MS case with a mutation not previously described in the fibrilin 1 gene, applying the revised Ghent nosology and analyzing the role of this new mutation and of the driver mutations in the genesis of the disease.

Research progress of driver mutations in non-small cell lung adenocarcinoma / 肿瘤研究与临床

With the development of the main tumor gene sequencing projects,driver mutations have been put into the highlight due to its significant meaning on the cancer occurrence,development as well as treatment.In the past decade,based on the finding of new driver mutations,the knowledge of non-small cell lung cancer (NSCLC) have been improved from the traditional pathological classification to the current molecular classification.Meanwhile,NSCLC patients are no longer looked as an assembly of the same type tumor but various individuals with different molecular biology behavior with the different sensitivity to the targeted drugs.This article focuses on the recent discovery advances of driver mutations in lung adenocarcinoma.