Advanced Lung Adenocarcinoma with EGFR 19-del Mutation Transformed into SCC after EGFR-tyrosine Kinase inhibitors Treatment:A Case report

BACKGROUND Epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs)significantly improve the survival of patients with Epidermal growth factor receptor(EGFR)sensitive mutations in non-small cell lung cancer(NSCLC).CASE SUMMARY A 67-year-old female patient in advanced lung adenocarcinoma suffered from drug resistance after EGFR-TKIs treatment.Secondary pathological tissue biopsy confirmed squamous cell carcinoma(SCC)transformation.Patients inevitably encountered drug resistance issues after receiving EGFR-TKIs treatment for a certain period of time,while EGFR-TKIs can significantly improve the survival of patients with EGFR-sensitive mutations in NSCLC.Notably,EGFR-TKIs resistance includes primary and acquired.Pathological transformation is one of the mechanisms of acquired resistance in EGFR-TKIs,with SCC transformation being relatively rare.Our results provide more detailed results of the patient’s diagnosis and treatment process on SCC transformation after EGFR-TKIs treatment for lung adenocarcinoma.CONCLUSION Squamous cell carcinoma transformation is one of the acquired resistance mechanisms of EGFR-TKIs in advanced lung adenocarcinoma with EGFR mutations.

Advanced lung adenocarcinoma with EGFR 19-del mutation transforms into squamous cell carcinoma after EGFR tyrosine kinase inhibitor treatment

In this editorial we comment on the article by Ji et al.We focus specifically on the EGFR tyrosine kinase inhibitor(EGFR-TKI)treatment and the development of drug resistance to EGFR-TKIs.

Efficacy of EGFR Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer Patients Harboring Different Types of EGFR Mutations:A Retrospective Analysis

With the development of molecular pathology, many types of epidermal growth factor receptor（EGFR） mutations have been identified. The efficacy of EGFR tyrosine kinase inhibitors（EGFR-TKIs） in non-small cell lung cancer（NSCLC） patients with different types of EGFR mutations, especially in patients with single rare mutations or complex mutations（co-occurrence of two or more different mutations）, has not been fully understood. This study aimed to examine the efficacy of EGFR-TKIs in NSCLC patients with different types of EGFR mutations. Clinical data of 809 NSCLC patients who harbored different types of EGFR mutations and treated from January 2012 to October 2016 at Renmin Hospital and Zhongnan Hospital, Wuhan, were retrospectively reviewed. The clinical characteristics of these patients and the efficacy of EGFR-TKIs were analyzed. Among these patients, 377 patients had only the EGFR del-19 mutation, 362 patients the EGFR L858R mutation in exon 21, 33 patients single rare mutations and 37 patients complex mutations. Among these 809 patients, 239 patients were treated with EGFR-TKIs. In all the 239 patients, the disease control rate（DCR） was 93.7% with two patients（0.2%） achieving complete response（CR）, the median progression free survival（PFS） was 13.0 months（95% confidence interval [CI], 11.6–14.4 months）, and the median overall survival（OS） was 55.0 months（95% CI, 26.3–83.7 months）. Subgroup analysis revealed that the DCR in patients harboring single rare or complex mutations of EGFR was significantly lower than in those with del-19 or L858 R mutation（P〈0.001）. Patients with classic mutations（del-19 and/or L858 R mutations） demonstrated longer PFS（P〈0.001） and OS（P=0.017） than those with uncommon mutations（single rare and/or complex mutations）. Furthermore, the patients with single rare mutations had shorter median OS than in those with other mutations. Multivariate Cox regression analysis identified that the type of EGFR mutations was an independent risk factor for PFS（hazard ratio [HR]=0.308, 95% CI, 0.191–0.494, P〈0.001） and OS（HR=0.221, 95% CI, 0.101–0.480, P〈0.001）. The results suggest that the single rare or complex EGFR mutations confer inferior efficacy of EGFR-TKIs treatment to the classic mutations. The prognosis of the single rare EGFR mutations is depressing. EGFR-TKIs may be not a good choice for NSCLC patients with single rare mutations of EGFR. Further studies in these patients with uncommon mutations（especially for the patients with single rare mutations） are needed to determine a better precision treatment.

The efficacy of Kanglaite injection during treatment with tyrosine kinase inhibitor in elderly patients with non-small cell lung cancer

Objective Epidermal growth factor receptor–tyrosine kinase inhibitors(EGFR–TKIs) are widely used in the treatment of EGFR mutation-positive non-small cell lung cancer(NSCLC) patients. The Kanglaite injection(KLT) is a novel broad-spectrum anti-cancer injection produced from traditional Chinese medicinal herbs(coix seed). After its approval in 1995, KLT has become the most popular anti-cancer drug in China. As of this writing, no standard treatment guideline is available for elder patients with NSCLC, and the role of traditional Chinese medicinal herbs, including KLT, combined with TKI treatment remains unknown. This retrospective study evaluated the efficacy and safety of KLT in elderly NSCLC patients during TKI treatment.Methods Thirty elderly patients aged 71-79 years with histopathologically confirmed NSCLC attending the General Hospital of the Shenyang Military Region were enrolled in the study and received EGFR-TKI treatment. All participants received 200 m L KLT injections at the same time on days 1–21. Erlotinib(150 mg) or gefitinib(250 mg) was administered daily from days 1 to 21, and the cycle was repeated every 21 days. The endpoint of the primary study was the disease control rate.Results Thirty elderly patients were enrolled in this study. The objective response rate was 21.3% [95% confidence interval(CI): 8.6% to 35.2%], whereas the disease control rate was 80.4%(95% CI: 71.8% to 97.0%). The grade 3 or 4 adverse effects included leucopenia(13.7%), neutropenia(13.4%), anemia(2.9%), and nausea or vomiting(2.7%). Conclusion The administration of KLT combined with erlotinib or gefitinib showed high efficacy in elderly NSCLC patients. The adverse effects of the drug combination were well tolerated by the patients. KLT combined with TKI treatment might provide a satisfactory therapeutic strategy for elderly NSCLC patients.

Associations Between Epidermal Growth Factor Receptor Gene Mutation and Serum Tumor Markers in Advanced Lung Adenocarcinomas: A Retrospective Study

Objective To investigate the associations between epidermal growth factor receptor （EGFR） gene mutations and serum tumor markers in advanced lung adenocarcinomas. Methods We investigated the association between EGFR gene mutations and clinical features, including serum tumor marker levels, in 97 advanced lung adenocarcinomas patients who did not undergo the treatment of EGlaR tyrosine kinase inhibitors. EGFR gene mutation was detected by real-time PCR at exons 18, 19, 20, and 21. Serum tumor marker concentrations were analyzed by chemiluminescence assay kit at the same time. Results EGFR gene mutations were detected in 42 （43%） advanced lung adenocarcinoma patients. Gender （P=0.003）, smoking status （P=0.001）, and abnormal serum status of carcinoembryonic antigen （CEA, P=0.028） were significantly associated with EGFR gene mutation incidence. Multivariate analysis showed the abnormal CEA level in serum was independently associated with the incidence of EGFR gene mutation （P=0.046） with an odds ratio of 2.613 （95% Ch 1.018-6.710）. However, receiver operating characteristic （ROC） curve analysis revealed CEA was not an ideal predictive marker for EGFR gene mutation status in advanced lung adenocarcinoma （the area under the ROC curve was 0.608, P=0.069）. Conclusions EGFR gene mutation status is significantly associated with serum CEA status in advanced lung adenocarcinmoas. However, serum CEA is not an ideal predictor for EGFR mutation.

Possible biological and translational significance of mast cells density in colorectal cancer

Mast cells (MCs), located ubiquitously near blood vessels, are descended from CD34+ hematopoietic stem cells. Initially, although their role has been well defined in hypersensitivity reactions, the discovery of their sharing in both innate and adaptive immunity has allowed to redefine their crucial interplay on the regulatory function between inflammatory and tumor cells through the release of mediators granule-associated (mainly tryptase and vascular endothelial growth factor). In particular, in several animal and human malignancies it has been well demonstrated that activated c-Kit receptor (c-KitR) and tryptase (an agonist of the proteinase-activated receptor-2) take pivotal part in tumor angiogenesis after the MCs activation, contributing to tumor cells invasion and metastasis. In this review, we focused on crucial MCs density (MCD) role in colorectal cancer (CRC) development and progression angiogenesis-mediated; then, we will analyze the principal studies that have focused on MCD as possible prognostic factor. Finally, we will consider a possible role of MCD as novel therapeutic target mainly by c-KitR tyrosine kinase inhibitors (imatinib, masitinib) and tryptase inhibitors (gabexate and nafamostat mesylate) with the aim to prevent CRC progression.

Histological transformation of non-small cell lung cancer:Clinical analysis of nine cases

BACKGROUND Histological transformation is one of the numerous mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors(EGFRTKIs).Given its rarity,the underlying transformational mechanisms,clinical features,and therapeutic prognoses are only studied through limited case reports.AIM To analyze the clinical characteristics and underlying mechanisms in non-small cell lung cancer(SCLC)patients with histological transformation after treatment with EGFR-TKIs.METHODS We retrospectively investigated nine patients diagnosed with non-SCLC transforming to SCLC,large-cell neuroendocrine carcinoma(LCNEC),or squamous cell carcinoma on re-biopsy after first-or third-generation EGFR-TKIs.RESULTS The median age of nine patients was 60 years.Among them,six patients had the EGFR 19del mutation,one had the L858R mutation,and one had wild-type EGFR.The level of plasma NSE was measured in six patients with SCLC or LCNEC transformation when transformation occurred,and five patients had elevated plasma NSE levels.All patients received standard chemotherapy after transformation with the exception of one patient who received chemotherapy and anlotinib.CONCLUSION Tumor re-biopsy should be performed routinely when EGFR-TKI therapy fails in lung cancer patients to avoid ignoring histological transformation and to select a subsequent therapeutic strategy.The transformed tumor retained the original EGFR mutation,indicating that histological transformation represents an evolution from the initial tumor.

Effect of EGFR-TKI retreatment following chemotherapy for advanced non-small cell lung cancer patients who underwent EGFR-TKI

Objective： Non-small cell lung cancer （NSCLC） patients with epidermal growth factor receptor （EGFR）-activating mutations have higher response rate and more prolonged survival following treatment with single-agent EGFR tyrosine kinase inhibitor （EGFR-TKI） compared with patients with wild-type EGFR. However, all patients treated with reversible inhibitors develop acquired resistance over time. The mechanisms of resistance are complicated. The lack of established therapeutic options for patients after a failed EGFR-TKI treatment poses a great challenge to physicians in managing this group of lung cancer patients. This study evaluates the influence of EGFR-TKI retreatment following chemotherapy after failure of initial EGFR-TKI within at least 6 months on NSCLC patients. Methods： ＇i-he data of 27 patients who experienced treatment failure from their initial use of EGFR-TKI within at least 6 months were analyzed. After chemotherapy, the patients were retreated with EGFR-TKI （gefitinib 250 mg qd or erlotinib 150 mg qd）, and the tumor progression was observed. The patients were assessed for adverse events and response to therapy. Targeted tumor lesions were assessed with CT scan. Results： Of the 27 patients who received EGFR-TKI retreatment~ 1 （3.7%） patient was observed in complete response （CR）, 8 （29.6%） patients in partial response （PR）, 14 （51.9%） patients in stable disease （SD）, and 4 （14.8%） patients in progressive disease （PD）. The disease control rate （DCR） was 85.2% （95% CI： 62%-94%）. The median progression-free survival （mPFS） was 6 months （95% CI： 1-29）. Of the 13 patients who received the same EGFR-TKI, 1 patient in CR, 3 patients in PR, 8 patients in SD, and 2 patients in PD were observed. The DCRwas 84.6%, and the mPFS was 5 months. Of the 14 patients who received another EGFR-TKI, no patient in CR~ 6 patients in PR, 6 patients in SD, and 2 patients in PD were observed. The DCRwas 85.7%, and the mPFS was 9.5 months. Significant difference was found between the two groups in PFS but not in response rate or D CR. Conclusion： Retreatment of EGFR-TKIs can be considered an option after failure of chemotherapy for patients who were previously controlled by EGFR-TKI treatment.

Updates in the management of brain(leptomeningeal) metastasis of lung cancer

Brain(leptomeningeal) metastasis is one of the most common and severe complications of lung cancer. This article interprets expert consensus on the treatment advice for brain(leptomeningeal) metastasis of lung cancer, expounding on its epidemiology, diagnostic standards, efficacy assessment, treatment advice, and other aspects.

Fruquintinib beneficial in elderly patient with neoplastic pericardial effusion from rectal cancer:A case report

BACKGROUND Neoplastic pericardial effusion(NPE)is a rare consequence of rectal cancer and carries a poor prognosis.Optimal management has yet to be determined.Fruquintinib is an oral anti-vascular endothelial growth factor receptor tyrosine kinase inhibitor approved by the China Food and Drug Administration in September 2018 as third-line treatment of metastatic colorectal cancer.CASE SUMMARY Herein,we report an elderly patient with NPE from rectal cancer who responded to the use of fruquintinib.In March 2015,a 65-year-old Chinese woman diagnosed with KRAS-mutated adenocarcinoma of the rectum was subjected to proctectomy,adjuvant concurrent chemoradiotherapy,and adjuvant chemotherapy.By October 2018,a mediastinal mass was detected via computed tomography.The growth had invaded parietal pericardium and left hilum,displaying features of rectal adenocarcinoma in a bronchial biopsy.FOLFIRI and FOLFOX chemotherapeutic regimens were administered as first-and second-line treatments.After two cycles of second-line agents,a sizeable pericardial effusion resulting in tamponade was drained by pericardial puncture.Fluid cytology showed cells consistent with rectal adenocarcinoma.Single-agent fruquintinib was initiated on January 3,2019,as a third-line therapeutic.Ten cycles were delivered before the NPE recurred and other lesions progressed.The recurrence-free interval for NPE was 9.2 mo,attesting to the efficacy of fruquintinib.Ultimately,the patient entered a palliative care unit for best supportive care.CONCLUSION Fruquintinib may confer good survival benefit in elderly patients with NPEs due to rectal cancer.

Paradigm shift of chemotherapy and systemic treatment for biliary tract cancer

Biliary tract cancers(BTC)are frequently identified at late stages and have a poor prognosis due to limited systemic treatment regimens.For more than a decade,the combination of gemcitabine and cis-platin has served as the first-line standard treatment.There are few choices for second-line chemo-therapy.Targeted treatment with fibroblast growth factor receptor 2 inhibitors,neurotrophic tyrosine receptor kinase inhibitors,and isocitrate dehydrogenase 1 inhibitors has had important results.Immune checkpoint inhibitors(ICI)such as pembrolizumab are only used in first-line treatment for microsatellite instability high patients.The TOPAZ-1 trial's outcome is encouraging,and there are several trials underway that might soon put targeted treatment and ICI combos into first-line options.Newer targets and agents for existing goals are being studied,which may represent a paradigm shift in BTC management.Due to a scarcity of targetable mutations and the higher toxicity profile of the current medications,the new category of drugs may occupy a significant role in BTC therapies.

Small cell lung cancer transformations from non-small cell lung cancer: Biological mechanism and clinical relevance

Lung cancer is a leading cause of cancer deaths worldwide,consisting of two major histological subtypes:small-cell lung cancer(SCLC)and non-small-cell lung cancer(NSCLC).In some cases,NSCLC patients may undergo a histological transformation to SCLC during clinical treatments,which is associated with resistance to targeted therapy,immunotherapy,or chemotherapy.The review provides a comprehensive analysis of SCLC transfor-mation from NSCLC,including biological mechanism,clinical relevance,and potential treatment options after transformation,which may give a better understanding of SCLC transformation and provide support for further research to define better therapy options.

Leptomeningeal metastases from non-small cell lung cancer:state of the art and recent advances

Patients with leptomeningeal metastases(LM)from non-small cell lung cancer(NSCLC)have a poor outcome with survival of less than 1 year regardless of advancements in treatment strategy.In the past,some randomized clinical trials have been conducted with heterogeneous inclusion criteria,diagnostic parameters,response evaluation and primary endpoints.Efforts to develop a standardized magnetic resonance imaging(MRI)assessment and liquid biopsy techniques to monitor disease evolution in plasma or cerebrospinal fluid(CSF)are underway.This review aims to cover the main clinical and diagnostic challenges of LM from NSCLC,in particular the role of MRI,CSF cytology and liquid biopsy for the diagnosis and monitoring of the disease,as well as the most recent clinical trials on targeted therapies.Targeted therapy,such as epidermal growth factor receptor tyrosine kinase inhibitors and anaplastic lymphoma kinase rearranged inhibitors,represent a feasible treatment with encouraging results in terms of disease control and survival.For ineligible patients,immune checkpoint inhibitors could represent a therapeutic option with acceptable tolerance,although clinical trials focused on LM from NSCLC are lacking and represent a research focus for the future.

RET in breast cancer:pathogenic implications and mechanisms of drug resistance

Initiation,progression,outcome and sensibility to therapies in breast cancer(BC),the most frequent cancer in women,are driven by somatic and germline mutations.Although the effectiveness of hormonal therapies is well-founded,it is prescribed for cancers which express steroid hormone receptors,such as estrogen receptor(ER).RET is a proto-oncogene encoding a transmembrane tyrosine kinase receptor that is activated by one of its four ligands(GDNF,neurturin,artemin or persephin)and one of its coreceptors(Gfrα1-4).Loss-of-function mutations in RET are responsible for Hirschsprung disease,while gain-of-function mutations for multiple endocrine neoplasia type 2.In addition,deregulation of its intracellular signaling,due to mutations,gene rearrangements,overexpression or transcriptional upregulation,can cause several neuroendocrine and epithelial tumors.In BC,amplification of receptor tyrosine kinases,such as ERBB2,EGFR,IGFR and FGFR1,and/or their upregulation contribute to cancer initiation and progression.RET can also have an important role in BC,but only in the subset of ER-positive(ER+)tumors,where it is found overexpressed.Targeting the RET pathway and shedding light on molecular basis of the resistance to hormone therapy may lead to new therapies in ER+BC,improving treatment outcome and preventing tumor-related events.Thus,here,we review the state of the art of RET biology in BC and agents targeting RET tested in the clinical trials and discuss the specificity of the still available RET inhibitors and the molecular mechanisms underlying the BC resistance to endocrine therapy.

Emerging role of nuclear factor erythroid 2-related factor 2 in the mechanism of action and resistance to anticancer therapies

Nuclear factor E2-related factor 2(NRF2),a transcription factor,is a master regulator of an array of genes related to oxidative and electrophilic stress that promote and maintain redox homeostasis.NRF2 function is well studied in in vitro,animal and general physiology models.However,emerging data has uncovered novel functionality of this transcription factor in human diseases such as cancer,autism,anxiety disorders and diabetes.A key finding in these emerging roles has been its constitutive upregulation in multiple cancers promoting pro-survival phenotypes.The survivability pathways in these studies were mostly explained by classical NRF2 activation involving KEAP-1 relief and transcriptional induction of reactive oxygen species(ROS)neutralizing and cytoprotective drug-metabolizing enzymes(phase I,II,III and 0).Further,NRF2 status and activation is associated with lowered cancer therapeutic efficacy and the eventual emergence of therapeutic resistance.Interestingly,we and others have provided further evidence of direct NRF2 regulation of anticancer drug targets like receptor tyrosine kinases and DNA damage and repair proteins and kinases with implications for therapy outcome.This novel finding demonstrates a renewed role of NRF2 as a key modulatory factor informing anticancer therapeutic outcomes,which extends beyond its described classical role as a ROS regulator.This review will provide a knowledge base for these emerging roles of NRF2 in anticancer therapies involving feedback and feed forward models and will consolidate and present such findings in a systematic manner.This places NRF2 as a key determinant of action,effectiveness and resistance to anticancer therapy.