RET Rearrangements Research Articles

Characterization of Computed Tomography Imaging of Rearranged During Transfection-rearranged Lung Cancer

BackgroundRearranged during transfection (RET)-rearranged non–small-cell lung cancer (NSCLC) is relatively rare and the clinical and computed tomography (CT) image characteristics of patients with an advanced disease stage have not been well documented. Patients and MethodsWe identified patients with advanced-stage RET-rearranged NSCLC treated in the Cancer Institute Hospital, Japanese Foundation for Cancer Research, and analyzed the clinical and CT imaging characteristics. ResultsIn 21 patients with advanced RET-rearranged NSCLC, RET rearrangements were identified using fluorescence in situ hybridization and/or reverse transcriptase-polymerase chain reaction. The fusion partner genes were identified as KIF5B (57%), CCDC6 (19%), and unknown (24%). CT imaging showed that 12 primary lesions (92%) were peripherally located and all were solid tumors without ground-glass, air bronchograms, or cavitation. The median size of the primary lesions was 30 mm (range, 12-63 mm). Of the 18 patients with CT images before initial chemotherapy, 12 (67%) showed an absence of lymphadenopathy. Distant metastasis included 13 with pleural dissemination (72%), 10 with lung metastasis (56%), 8 with bone metastasis (44%), and 2 with brain metastasis (11%). ConclusionAdvanced RET-rearranged NSCLC manifested as a relatively small and peripherally located solid primary lesion with or without small solitary lymphadenopathy. Pleural dissemination was frequently observed.

Beyond EGFR and ALK: targeting rare mutations in advanced non-small cell lung cancer.

Lung cancer remains the leading cause of cancer-related death in men and women, despite its constantly declining rates in incidence and mortality in the developed world. The past decade has witnessed an unprecedented rise in the development of molecular targeted therapies in various types of tumors. In non-small cell lung cancer (NSCLC), the greatest paradigm shift is the implementation of EGFR and ALK tyrosine kinase inhibitors in the first line and subsequent lines of therapy, with impressive results. Though less frequent than the molecular alterations in the aforementioned genes, a number of aberrations in potential oncogenic drivers has been discovered, namely mutations in the genes KRAS, BRAF, HER2, PI3KCA and DDR2, ROS1 and RET rearrangements and MET, HER2 and FGFR1 gene amplifications. A great number of clinical trials are currently underway, evaluating agents specifically designed to target these alterations, with mixed results so far. The greatest cumulative benefit offered by these trials is that, despite their success or failure in their objective goals, they have provided us with a better understanding of the complexity of the molecular intracellular processes, necessitating thus the accurate interpretation of the preclinical data in order to appropriately select the patients that may derive benefit from targeted treatment strategies.

Recurrent RET Gene Rearrangements in Intraductal Carcinomas of Salivary Gland.

Intraductal carcinoma (IC) is the World Health Organization designation for lesions previously called low-grade cribriform cystadenocarcinoma. The relationship of IC to salivary duct carcinoma (SDC) is controversial, but currently these are considered distinct entities. It is hypothesized that IC and SDC should have different genomic signatures that may be identifiable by next-generation sequencing. A total of 23 ICs were identified: 14 pure IC and 9 invasive carcinomas with an intraductal component. Five invasive carcinomas were subjected to next-generation paired-end RNA sequencing. Data analysis was performed using FusionSeq and Mutation detection algorithms (MuTect and VarScan) for variant callers. Gene fusion candidates were validated by fluorescence in situ hybridization and reverse transcription polymerase chain reaction, and mutations by Sanger sequencing. Among the 9 invasive carcinomas, all except 1 were apocrine SDCs with an intraductal component. The remaining case showed typical intercalated duct type IC with invasive adenocarcinoma. The 14 pure ICs had typical intercalated duct features (2 showed hybrid intercalated/apocrine features). RNA sequencing predicted a NCOA4-RET fusion, confirmed by reverse transcription polymerase chain reaction, in the intercalated duct type IC invasive component. Six additional cases of pure IC showed RET rearrangement by fluorescence in situ hybridization (7/15=47%). No apocrine carcinomas showed RET rearrangement. RNA sequencing and Sanger sequencing identified PIK3CA (p.E545K/p.H1047R) and/or HRAS (p.Q61R) hotspot mutations in 6 of 8 (75%) apocrine carcinomas. In conclusion, 2 distinctive types of intraductal lesions are emerging based on molecular analysis. Classic intercalated type ICs commonly harbor fusions involving RET and rarely show widespread invasion. Apocrine intraductal lesions are typically associated with widespread invasion with no pure examples and show similar PIK3CA and HRAS mutations to SDC.

The Impact of Smoking and TP53 Mutations in Lung Adenocarcinoma Patients with Targetable Mutations-The Lung Cancer Mutation Consortium (LCMC2).

Purpose: Multiplex genomic profiling is standard of care for patients with advanced lung adenocarcinomas. The Lung Cancer Mutation Consortium (LCMC) is a multi-institutional effort to identify and treat oncogenic driver events in patients with lung adenocarcinomas.Experimental Design: Sixteen U.S. institutions enrolled 1,367 patients with lung cancer in LCMC2; 904 were deemed eligible and had at least one of 14 cancer-related genes profiled using validated methods including genotyping, massively parallel sequencing, and IHC.Results: The use of targeted therapies in patients with EGFR, ERBB2, or BRAF p.V600E mutations, ALK, ROS1, or RET rearrangements, or MET amplification was associated with a survival increment of 1.5 years compared with those with such mutations not receiving targeted therapy, and 1.0 year compared with those lacking a targetable driver. Importantly, 60 patients with a history of smoking derived similar survival benefit from targeted therapy for alterations in EGFR/ALK/ROS1, when compared with 75 never smokers with the same alterations. In addition, coexisting TP53 mutations were associated with shorter survival among patients with EGFR, ALK, or ROS1 alterations.Conclusion: Patients with adenocarcinoma of the lung and an oncogenic driver mutation treated with effective targeted therapy have a longer survival, regardless of prior smoking history. Molecular testing should be performed on all individuals with lung adenocarcinomas irrespective of clinical characteristics. Routine use of massively parallel sequencing enables detection of both targetable driver alterations and tumor suppressor gene and other alterations that have potential significance for therapy selection and as predictive markers for the efficacy of treatment. Clin Cancer Res; 24(5); 1038-47. ©2017 AACR.

Expression and copy number gains of the RET gene in 631 early and mid stage non-small cell lung cancer cases.

BackgroundTo identify whether RET is a potential target for NSCLC treatment, we examined the status of the RET gene in 631 early and mid stage NSCLC cases from south central China.Methods RET expression was identified by Western blot. RET‐positive expression samples were verified by immunohistochemistry. RET gene mutation, copy number variation, and rearrangement were analyzed by DNA Sanger sequencing, TaqMan copy number assays, and reverse transcription‐PCR. ALK and ROS1 expression levels were tested by Western blot and EGFR mutation using Sanger sequencing.ResultsThe RET‐positive rate was 2.5% (16/631). RET‐positive expression was related to poorer tumor differentiation (P < 0.05). In the 16 RET‐positive samples, only two samples of moderately and poorly differentiated lung adenocarcinomas displayed RET rearrangement, both in RET‐KIF5B fusion partners. Neither ALK nor ROS1 translocation was found. The EGFR mutation rate in RET‐positive samples was significantly lower than in RET‐negative samples (P < 0.05).Conclusion RET‐positive expression in early and mid stage NSCLC cases from south central China is relatively low and is related to poorer tumor differentiation. RET gene alterations (copy number gain and rearrangement) exist in all RET‐positive samples. RET‐positive expression is a relatively independent factor in NSCLC patients, which indicates that the RET gene may be a novel target site for personalized treatment of NSCLC.

Efficacy of immune-checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC) patients harboring activating molecular alterations.

172 Background: Two revolutions recently occur in the treatment of advanced NSCLC: the development of targeted therapies and of ICI). Both strategies have been shown to outperform chemotherapy. Patients with molecular alterations are usually considered as poor candidate for immunotherapy. Here, we aimed to analyze the efficacy of immunotherapy in NSCLC patients with oncogenic addiction. Methods: We conducted a retrospective multicentric study, on patients treated with ICI and carrying an activating molecular abnormality: EGFR, ALK, KRAS, ROS1, HER2, BRAF, MET and RET. We have collected anonymized data, which were evaluated for clinical characteristics and outcome (progression free survival duration of ICI treatment and overall survival since initiation of ICI). Results: 209 patients were registered from 7 centers in France and Switzerland. 198 patients had adenocarcinoma (95.2%), 6 large cell carcinoma (2.9%), 161 were former or current smokers (81.3%), 99 were female (47.4%), median age at diagnosis was 59 yrs. (range 30-79). 33 patients had EGFR mutations (15.8%), 132 KRAS mutation (63.2%), 6 ALK rearrangement (2.9 %), 2 ROS1 rearrangement (1 %), 5 HER2 mutation (2.4 %), 12 BRAF mutations (5.7 %), 7 MET alteration (3.3 %), 3 RET rearrangements (1.4 %), and 9 had concomitant multiple molecular alterations (4.3%). After validated treatment 200 patients were treated with PD1 inhibitors (nivolumab, 97.5% and pembrolizumab, 2.5%), 4 with anti CTLA4 (tremelimumab), 5 with anti PDL1 (4 atezolizumab). The median PFS was 2.8 m. [95%CI 2.3;3.5] for the whole population 2.1 for EGFR [1.7;2.8], 3.5 for KRAS [2.5;4.9], 2.7 for BRAF [1.5;NR] and not estimable for other alterations. Median exposure to ICI was 1.89 m. [0;18.5]. The median overall survival for the whole population was 13.0 m. [9.4; 15.6], for EGFR 13.3 m. [4.7; NR], KRAS 11.3 m. [8.2; 16], BRAF 10.7 m. [1.5; NR] and not yet estimable for the other alterations. Conclusions: PFS (2.8 m.) and OS (13 m.) are very similar from the ones observed in pretreated unselected NSCLC patients. ICI is associated with better PFS in patients with KRAS mutation than in EGFR mutated patients. Analysis of outcome in other molecular subgroups is ongoing.

Coexistent genetic alterations involving ALK, RET, ROS1 or MET in 15 cases of lung adenocarcinoma

In lung cancer, targetable activating alterations in cancer genes, such as EGFR, ALK, RET, ROS1 and MET, are usually mutually exclusive. Rare lung cancer cases with coexistent alterations of EGFR and ALK or EGFR mutations with RET or ROS1 rearrangements have been reported. In this study, we report 15 patients (3 men and 12 women; 14 Caucasians and 1 African American) with ages ranging from 43 to 81 years (median 60 years) with lung adenocarcinoma in which coexistent alterations of two cancer-associated genes, including ALK, ROS1, or RET rearrangement or MET amplification were present. The combination of alterations detected by fluorescence in situ hybridization included ALK combined with ROS1 (n=4), ALK with MET (n=3), ALK with RET (n=1); RET with MET (n=4), RET with ROS1 (n=2), and ROS1 combined with MET (n=1). The frequencies of involvement were similar for all 4 genes, 53% for both ALK and MET (n=8), 47% for both RET and ROS1 (n=7). Activating gene mutations were also detected by next-generation sequencing for TP53 (n=6), EGFR (n=5), KRAS (n=3) and STK11 (n=2). Nine patients reported a smoking history (8 heavy and 1 light) and 6 patients were non-smokers. These findings suggest the need for assessing a panel of genes in lung cancer. Since targetable agents are available for each of these activating alterations, treatment with more than one targeted agent may be beneficial for this rare group of patients.

Abstract B049: Characterizing and targeting RET fusions-positive metastatic colorectal cancer (mCRC)

Abstract Background: RET fusions occur in &amp;lt;1% of CRCs and represent new therapeutic targets, as indicated by earlier promising case reports of patients (pts) treated with multitargeted tyrosine kinase inhibitors (TKIs). Although ALK, ROS1, and NTRK fusions identify a peculiar subtype of mCRCs that may be targeted by selective inhibitors such as entrectinib, the clinical, molecular, and therapeutic landscape of RET rearranged mCRC still needs to be unveiled. Methods: Pts with mCRC harboring RET fusions were identified worldwide taking advantage of 1) previously published molecular case reports; 2) Italian and Korean screening collaboration; 3) Ignyta’s phase 1/1b trial of RXDX-105, a novel selective and potent RET-inhibitor with VEGFR-sparing activity; and 4) Foundation Medicine Database. Clinical and molecular characteristics of RET-rearranged cases were compared with nonrearranged ones screened at 3 referral centers in Milan, Pisa, and Seoul. Results: 24 RET rearranged (12 NCOA4-RET, 8 CCDC6-RET, 2 TRIM24-RET, 1 novel TNIP1-RET, and 1 novel SNRNP70-RET) and 236 not rearranged mCRCs pts were included. Rearrangements were more frequent in older pts (p=0.027), with right-sided primary tumors (p&amp;lt;0.028), RAS wild-type (p&amp;lt;0.001), BRAF wild-type (p&amp;lt;0.001), and MSI-high (p&amp;lt;0.001). All RET fusions were found in RAS and BRAF wild-type tumors, whereas MSI-high status and right-sided primary tumor were found in the 47% and 55% of RET-positive cases, respectively. At a median follow-up of 31.5 months, pts bearing RET-rearranged tumors had a shorter overall survival (OS) when compared to nonrearranged (HR: 16.4, 95%CI: 5.64-47.39; p&amp;lt;0.001). In the multivariable model including other significant variables (primary tumor resection and location, RAS, BRAF, and MMR status), RET rearrangements retained significant association with shorter OS (HR: 3,69, 95% CI 1.62 - 8.44; p=0.002), as well as primary tumor resection (p=0.036). Primary-tumor location and MSI status were not independent prognostic factors, instead. While multitargeted TKIs (i.e., regorafenib/sunitinib) conferred only short-lasting clinical benefit, a patient achieved a long-lasting and ongoing (16+ months) complete response to RXDX-105. NGS molecular data and preclinical experiments with unselective/selective inhibitors in RET fusion positive PDX will be presented. Conclusions: RET rearrangements define a new and rare molecular subtype of mCRCs associated with unfavorable prognosis and specific clinicopathologic and molecular features. The present findings in RET-rearranged mCRC resemble those previously reported for ALK, ROS1, and NTRK positive ones. Above all, since sensitivity to available treatment options including anti-EGFRs may be very limited, RET fusions should be regarded as novel therapeutic targets, particularly regarding the development of specific inhibitors, such as RXDX-105. Citation Format: Federica Morano, Alexa Schrock, Jeeyun Lee, Petros Nikolinakos, Alexander Drilon, Jason Christiansen, Vi Chiu, Alberto Zaniboni, Daniele Rossini, Seung Tae Kim, Massimo Milione, Rupal Patel, Vincet Miller, Salvatore Corallo, Maria Di Bartolomeo, Jeffrey Ross, Andrea Bertotti, Alberto Bardelli, Federica Di Nicolantonio, Siraj Ali, Livio Trusolino, Alfredo Falcone, Filippo de Braud, Chiara Cremolini, Filippo Pietrantonio. Characterizing and targeting RET fusions-positive metastatic colorectal cancer (mCRC) [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr B049.

NCOA4-RET fusion in colorectal cancer: Therapeutic challenge using patient-derived tumor cell lines.

The RET fusion is considered as the potential novel target in solid tumors. However, RET fusion is not well yet identified in colorectal cancer (CRC), and the effect of RET kinase inhibitor is also not evaluated in CRC with RET fusion. We established patient-derived tumor cells (PDCs) with RET fusion from recurrent brain metastatic lesion that newly appeared during the surveillance for stage III CRC patient. To investigate therapeutic options to CRC patient with a RET fusion, we performed cell viability assays using the PDCs. NCOA4-RET fusion was detected by FusionPlex using the resected brain metastatic tissue of CRC patient with solitary brain metastasis and then reconfirmed by fluorescence in situ hybridization (FISH) test. We also confirmed the RET fusions by a qPCR in matched PDCs. We tested whether the PDCs from RET fusion colon cancer were sensitive to carbozantinib, sorafenib, vandetanib, and PD0331992. Cell viability assays showed that carbozantinib, sorafenib, and PD0332991 did not suppress cell viability. Only, vandetanib revealed the significant inhibitory effect in MTT proliferation assay. Next, we analyzed regulation of targeted downstream pathways upon exposure to vandetanib by immunoblot assay. In colon cancer PDCs with NCOA4-RET fusion, vandetanib potently inhibited AKT and ERK phosphorylation. This study shows that vandetanib might be one of useful treatment strategies for CRC patient with NCOA4-RET fusion. Therefore, inhibition of the RET kinase is a promising targeted therapy for cancer patients whose tumors harbor a RET rearrangement.

Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes.

This corrects the article DOI: 10.1038/nrclinonc.2017.175.

Targeting RET-driven cancers: lessons from evolving preclinical and clinical landscapes.

The gene encoding the receptor-tyrosine kinase RET was first discovered more than three decades ago, and activating RET rearrangements and mutations have since been identified as actionable drivers of oncogenesis. Several multikinase inhibitors with activity against RET have been explored in the clinic, and confirmed responses to targeted therapy with these agents have been observed in patients with RET-rearranged lung cancers or RET-mutant thyroid cancers. Nevertheless, response rates to RET-directed therapy are modest compared with those achieved using targeted therapies matched to other oncogenic drivers of solid tumours, such as sensitizing EGFR or BRAFV600E mutations, or ALK or ROS1 rearrangements. To date, no RET-directed targeted therapeutic has received regulatory approval for the treatment of molecularly defined populations of patients with RET-mutant or RET-rearranged solid tumours. In this Review, we discuss how emerging data have informed the debate over whether the limited success of multikinase inhibitors with activity against RET can be attributed to the tractability of RET as a drug target or to the lack, until 2017, of highly specific inhibitors of this oncoprotein in the clinic. We emphasize that novel approaches to targeting RET-dependent tumours are necessary to improve the clinical efficacy of single-agent multikinase inhibition and, thus, hasten approvals of RET-directed targeted therapies.

Clinical and Translational Implications of RET Rearrangements in Non-Small Cell Lung Cancer.

Since the discovery in 2012 of rearranged during transfection proto-oncogene gene (RET) rearrangements in NSCLC, at least 12 different fusion variants have been identified, with kinesin family member 5B gene (KIF5B)-RET being the most frequent and the best characterized. Unlike ALK receptor tyrosine kinase gene (ALK) and ROS1 rearrangements, RET fusion genes cannot be adequately detected by immunohistochemistry (IHC), although fluorescence in situ hybridization and reverse transcriptase polymerase chain reaction are fully complementary diagnostic tools. In large retrospective studies, RET rearrangements correlate with adenocarcinoma histologic subtype, never-smoking status, younger age, more advanced disease stage, potentially higher chemosensitivity (in particular, to pemetrexed-based regimens), and coexistence of other genomic alterations. To date, several preclinical models, clinical trials, and retrospective studies have investigated multitarget inhibitors with anti-rearranged during transfection proto-oncogene (RET) activity in patients with RET-rearranged lung cancer. In the clinical setting, the benefit in terms of response (16%-47%) and progression-free survival (2-7 months) is clearly not comparable to that seen with other targeted agents in oncogene-addicted NSCLC. Furthermore, multikinase agents showed high rates of severe toxicities, leading to frequent dose reduction and drug discontinuation. To date, no definitive conclusions about a potentially different impact of anti-RET therapies according to RET fusion variants have been drawn on account of discordant data coming mostly from small subgroup analyses. Importantly, the absence of a striking clinical benefit in RET oncogene-addicted NSCLC underscores theclear need for development of more selective andpotentRET inhibitors and for better characterization of concomitant genomic alterations and mechanisms of resistance to RET inhibition in patients with lung cancer.

P3.03-007 LCMC2: Expanded Profiling of Lung Adenocarcinomas Identifies ROS1 and RET Rearrangements and TP53 Mutations as a Negative Prognostic Factor

The Lung Cancers Mutation Consortium (LCMC) is a multi-institutional effort where 16 sites identify oncogenic drivers and pool data to assess the impact of targeted therapies in patients with lung adenocarcinomas. We now report the results of the second patient cohort (LCMC2) with an expanded multiplex molecular panel to include RET and ROS1 and tumor suppressors.

P1.02-044 Relationship between RET Rearrangement and Thymidylate Synthase mRNA Expression in Non-Small Cell Lung Cancer Tissues

P1.02-044 Relationship between RET Rearrangement and Thymidylate Synthase mRNA Expression in Non-Small Cell Lung Cancer Tissues

P3.03-004 The Frequency and Clinical Implication of ALK, ROS1, RET and NTRK1 Gene Rearrangements in Adenosquamous Lung Carcinoma Patients

P3.03-004 The Frequency and Clinical Implication of ALK, ROS1, RET and NTRK1 Gene Rearrangements in Adenosquamous Lung Carcinoma Patients

Molecular diagnostics of lung cancer in the clinic.

According to current practice guidelines, all patients with advanced non-small cell lung cancer (NSCLC) should undergo predictive biomarker testing. For squamous cell carcinoma patients, PD-L1 immunohistochemistry is indicated to select patients for immunotherapy in the first line. For lung adenocarcinoma, all patients with advanced disease should undergo testing for epidermal growth factor receptor (EGFR) mutations, ALK and ROS1 rearrangements, and PD-L1 expression to predict response to EGFR, ALK, or ROS1 targeted inhibitors or immunotherapy, respectively. Besides these, a number of other biomarkers are under clinical investigation as predictors of response to targeted therapies, including BRAF, ERBB2, MET splice mutations and amplification, and RET rearrangements. Successful testing for this complex array of molecular targets demands careful coordination between proceduralists, pathologists and molecular laboratories to ensure proper tumor tissue handling following biopsy as well as judicious use of diagnostic immunohistochemistry. Even so, sample failure rates due to inadequate tumor tissue are high in practice, particularly when using sequential testing methods. Use of next generation sequencing (NGS) in clinical practice can enable detection of multiple targets and multiple alteration types (mutation, gene copy change, and rearrangement) simultaneously even with small amounts of input nucleic acids, thus increasing molecular testing success rates. In patients with an established lung cancer diagnosis but with prohibitively limited amounts of tumor tissue or who are experiencing relapse, analyses of circulating tumor DNA (ctDNA) from the plasma can serve as an alternate testing substrate, however the more limited clinical sensitivity of this approach must be taken into account. This review will explore the indications for and pitfalls of routine NGS and plasma genotyping in the clinic, including the intersection of these technologies.

Beyond ALK and ROS1: RET, NTRK, EGFR and BRAF gene rearrangements in non-small cell lung cancer.

The discovery of gene rearrangements involving the receptor tyrosine kinase genes ALK and ROS1 has revolutionized management of the subset of non-small cell lung cancers characterized by these alterations. The oncogenic fusion proteins expressed in these tumors drive cancer cell growth and survival, and targeted inhibition of this signaling can lead to dramatic and durable responses in patients. While the best characterized gene fusions in non-small cell lung cancer (NSCLC) involve ALK and ROS1, fusions involving other kinases including RET, NTRK, EGFR and BRAF are now established as additional targetable drivers. Here we review data supporting the roles of these fusions as oncogenic drivers, and the potential for targeting these fusions for improved clinical outcomes. These discoveries should encourage multiplexed molecular profiling of lung cancers using next-generation platforms which identify these gene fusions in order to expand treatment options for patients.

Next Generation Sequencing and Clinical Outcomes of Lung Adenocarcinomas Treated With Stereotactic Body Radiation Therapy

Genetic aberrations in lung adenocarcinomas (LAC) are well characterized and clinical outcomes have been influenced by the development of targeted therapies for driver mutations. However, little is known regarding the impact of genetic alterations on the efficacy of radiation therapy. We sought to determine the frequency and association of genomic mutations with clinical outcomes for early-stage LAC treated with stereotactic body radiotherapy (SBRT). Under an IRB approved protocol, the records of 242 consecutive early-stage lung cancer patients treated with SBRT at 4 academic sites were reviewed. Inclusion criteria included LAC histology with adequate tumor sample for successful use of SNaPshot or TruSight mutation testing panel and FISH lung cancer panel. Univariable (UVA) analyses were performed to identify characteristics associated with local recurrence (LR), regional recurrence (RR), and metastatic recurrence (MR). Additionally, Kaplan-Meier analysis (KM) was performed to compare clinical endpoints. Ninety-eight LACs (40.5%) were identified, of which 45 patients (46.0%) had genetic testing performed. The following aberrations were seen: KRAS (20.0%), ALK rearrangement (8.9%), Her2 (6.7%), BRAF (2.2%), SMAD4 (4.4%), EGFR (15.6%), MET amplification (17.8%), STK11 (2.2%), RET rearrangement (2.2%), p53 (15.6%), and PTEN (2.2%). Notably no patients had mutations of AKT1, IDH-1, IDH-2, NRAS, P13KCA, or ROS1 rearrangement. Median follow-up was 10.6 months (1.1 months – 36.0 months), median total delivered radiation dose was 50 Gy (48 Gy – 60 Gy), median radiation dose per fraction was 10 Gy (7.5 Gy – 20 Gy), and median number of fractions of 5 (3-8). KRAS mutation was associated with worse LR (HR = 3.64, 95% CI 1.05-12.65, P < 0.05). MET amplification was associated with worse RR (HR = 4.64, 95% CI 1.54-14.03, P < 0.01) and MR (HR = 3.73, 95% CI 1.24-11.23, P = 0.02). On KM, 1-year local control rates for KRAS mutated patients was 63.5% compared to 96.0% for KRAS wild-type patients (P = 0.02). 1-year regional control and metastatic control for MET amplified patients was 38.1% and 68.6% compared to 87.5% and 85.4% for MET wild-type patients respectively (both P < 0.01). Our series is the first to quantify genetic mutations in early-stage LAC patients undergoing SBRT. We found that KRAS mutation was associated with worse LR and MET amplification was associated with worse RR and MR. These results need to be further validated in a prospective setting.

PD-L1 expression and CD8+ tumor-infiltrating lymphocytes are associated with ALK rearrangement and clinicopathological features in inflammatory myofibroblastic tumors.

BackgroundInflammatory myofibroblastic tumors (IMTs) are rare mesenchymal neoplasms that are composed of myofibroblastic cells accompanied by inflammatory infiltrate. We investigated the immune profiles of IMTs, including PD-L1 expression and proportion of CD8+ tumor-infiltrating lymphocytes (TILs), as well as its clinicopathological characteristics according to ALK gene rearrangementstatus.MethodsTwenty-eight IMTs from 25 patients were retrieved from our pathology files (2005–2015), and their clinicopathological parameters and outcomes were analyzed. Immunohistochemistry (IHC) was performed using whole-tissue sections to detect PD-L1 and CD8 expression, and fluorescent in situ hybridization (FISH) analysis and IHC were performed using tissue microarrays to identify rearrangements in the ALK, ROS1, and RET genes.ResultsALK rearrangement was observed in 11 cases (44.0%), and all cases exhibited diffuse cytoplasmic ALK expression during IHC. ROS1 or RET rearrangement was not detected using IHC or FISH. IMTs harboring ALK rearrangement (ALK-positive) were located in the lungs (n = 7), genitourinary tract (n = 2), and mesentery (n = 1). The mean patient age was 33.2 years for ALK-positive IMTs and 53.1 years for ALK-negative IMTs. All patients with ALK-positive IMTs survived without recurrence or metastasis. IMTs with metastasis and/or recurrence were ALK-negative and exhibited elevated PD-L1 expression (positive tumor cells: 70.0% vs. 21.3%, P = 0.023; H-score: 107.5 vs. 26.3, P = 0.005). In addition, ALK-negative IMTs had a more CD8+ TILs, compared to ALK-positive IMTs (23.3% vs. 8.9%, P = 0.027).ConclusionALK-positive IMTs are characterized by younger age, well-defined margins, frequent involvement of the lung, and fewer CD8+ TILs. Greater PD-L1 expression was observed in IMTs with tumor necrosis and metastasis/recurrence, which were also negative for ALK rearrangement. These results suggest that immune checkpoint inhibitors may be a novel option for treating patients with advanced IMT.

The importance of RET -directed therapy in patients with RET- rearranged non-small cell lung cancer

Non-small cell lung cancer (NSCLC) has been recognized as a heterogeneous set of diseases according to oncogenic gene alterations level, such as sensitizing EGFR mutations, ALK rearrangements, or ROS1 rearrangements (1). Specific molecularly targeted therapies are effective in NSCLC patients harboring sensitizing EGFR mutations, ALK or ROS1 rearrangements, with response rates of approximately 60% and median progression-free survival of over 10 months (2-4). RET is a proto-oncogene that codes for a transmembrane protein belonging to the receptor tyrosine kinases family (5). In 2012, RET rearrangements were identified as new oncogenic alterations occurring in 1% to 2% of patients with NSCLC (6-9). It is reported that RET rearrangements has tumor-driving activity in vitro and in vivo . RET can partner with different genes in NSCLC, and KIF5B is the most common fusion partner in NSCLC. To date, several other genes including CCDC6, NCOA, TRIM33, CUX1, KIAA1468, KIAA1217, and FRMD4A, have been identified as other fusion partners of RET in NSCLC patients. RET rearrangements tend to be found in younger patients, female, never or former light smokers, and in patients with lung adenocarcinomas (10). A few case reports reported that cabozantinib and vandetanib, which are multi-targeted tyrosine kinase inhibitor exhibiting RET kinase activity, have antitumor activity in patients with RET -rearranged NSCLC (11-13).