Genomic, immunologic, and prognostic associations of TROP2 (TACSTD2) expression in solid tumors.

BACKGROUND: TROP2 (TACSTD2) expression is associated with decreased overall survival (OS) in some solid tumors, and the TROP2-targeting antibody-drug conjugate (ADC) sacituzumab govitecan has been approved in breast and urothelial carcinomas. We aimed to explore the multi-omic landscape associated with TACSTD2 gene expression in various solid tumors to identify patients most likely to benefit from this approach. METHODS: Breast (N = 11 246), colorectal (N = 15 425), hepatocellular (N = 433), pancreatic (N = 5488), and urothelial (N = 4125) tumors were stratified into quartiles by TACSTD2 gene expression, analyzed by next-generation DNA sequencing, whole transcriptome sequencing, and immunohistochemistry at Caris Life Sciences (Phoenix, AZ). Survival data were obtained from insurance claims, and Kaplan-Meier estimates were calculated for molecularly defined cohorts. RESULTS: Several pathogenic mutations were associated with TACSTD2-high tumors, including TP53 in breast, colorectal (CRC), pancreatic, and hepatocellular cancers; KRAS in pancreatic and CRC cancers; ARID1A and FGFR3 in urothelial cancer; and CTNNB1 in hepatocellular cancer. TACSTD2-low breast tumors were enriched for copy number amplifications in CCND1 and FGF/R family member genes. TACSTD2 high was generally associated with more immune cell infiltration and greater T-cell inflammation scores. Patients with TACSTD2-high breast, CRC, and pancreatic cancers demonstrated a significantly shorter OS than TACSTD2-low tumors. This was restricted to CRC with microsatellite stable tumors and patients with pancreatic cancer with KRAS-mutant tumors. Patients with breast cancer with TACSTD2-high tumors also experienced significantly worse OS following immune checkpoint inhibitors. CONCLUSIONS: TACSTD2 expression is associated with key driver alterations and a more active immune microenvironment, suggesting possible combinatorial strategies with TROP2-targeting ADCs plus immunotherapy in various solid tumors.

Activating point mutations in the MET kinase domain represent a unique molecular subset of lung cancer and other malignancies targetable with MET inhibitors.

Activating point mutations in the MET tyrosine kinase domain (TKD) are oncogenic in a subset of papillary renal cell carcinomas (PRCC). Here, using comprehensive genomic profiling among >600,000 patients, we identify activating MET TKD point mutations as putative oncogenic driver across diverse cancers, with a frequency of ~0.5%. The most common mutations in the MET TKD defined as oncogenic or likely oncogenic according to OncoKB resulted in amino acid substitutions at positions H1094, L1195, F1200, D1228, Y1230, M1250, and others. Preclinical modeling of these alterations confirmed their oncogenic potential, and also demonstrated differential patterns of sensitivity to type I and type II MET inhibitors. Two patients with metastatic lung adenocarcinoma harboring MET TKD mutations (H1094Y, F1200I) and no other known oncogenic drivers achieved confirmed partial responses to a type I MET inhibitor. Activating MET TKD mutations occur in multiple malignancies and may confer clinical sensitivity to currently available MET inhibitors.

Adagrasib Treatment After Sotorasib-Related Hepatotoxicity in Patients With KRASG12C-Mutated Non-Small Cell Lung Cancer: A Case Series and Literature Review.

PURPOSE: KRAS is the most commonly mutated driver oncogene in non-small cell lung cancer (NSCLC). Sotorasib and adagrasib, KRASG12C inhibitors, have been granted accelerated US approval; however, hepatotoxicity is a common side effect with higher rates in patients treated with sotorasib proximal to checkpoint inhibitor (CPI) therapy. The aim of this study was to assess the feasibility and safety of adagrasib after discontinuation of sotorasib because of treatment-related grade 3 hepatotoxicity through real-world and clinical cases. METHODS: Medical records from five patients treated in real-world settings were retrospectively reviewed. Patients had locally advanced or metastatic KRASG12C-mutated NSCLC and received adagrasib after sotorasib in the absence of extracranial disease progression. Additional data were collected for 12 patients with KRASG12C-mutated NSCLC enrolled in a phase Ib cohort of the KRYSTAL-1 study and previously treated with sotorasib. The end points associated with both drugs included timing and severity of hepatotoxicity, best overall response, and duration of therapy. RESULTS: All patients were treated with CPIs followed by sotorasib (initiated 0-64 days after CPI). All five real-world patients experienced hepatotoxicity with sotorasib that led to treatment discontinuation, whereas none experienced treatment-related hepatotoxicity with subsequent adagrasib treatment. Three patients from KRYSTAL-1 transitioned from sotorasib to adagrasib because of hepatotoxicity; one experienced grade 3 ALT elevation on adagrasib that resolved with therapy interruption and dose reduction. CONCLUSION: Adagrasib may have a distinct hepatotoxicity profile from sotorasib and is more easily combined with CPIs either sequentially or concurrently. These differences may be used to inform clinical decisions regarding an initial KRASG12C inhibitor for patients who recently discontinued a CPI or experience hepatotoxicity on sotorasib.

Tissue-specific thresholds of mutation burden associated with anti-PD-1/L1 therapy benefit and prognosis in microsatellite-stable cancers.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death protein 1 or its ligand (PD-1/L1) have expanded the treatment landscape against cancers but are effective in only a subset of patients. Tumor mutation burden (TMB) is postulated to be a generic determinant of ICI-dependent tumor rejection. Here we describe the association between TMB and survival outcomes among microsatellite-stable cancers in a real-world clinicogenomic cohort consisting of 70,698 patients distributed across 27 histologies. TMB was associated with survival benefit or detriment depending on tissue and treatment context, with eight cancer types demonstrating a specific association between TMB and improved outcomes upon treatment with anti-PD-1/L1 therapies. Survival benefits were noted over a broad range of TMB cutoffs across cancer types, and a dose-dependent relationship between TMB and outcomes was observed in a subset of cancers. These results have implications for the use of cancer-agnostic and universal TMB cutoffs to guide the use of anti-PD-1/L1 therapies, and they underline the importance of tissue context in the development of ICI biomarkers.

Influence of TP53 Comutation on the Tumor Immune Microenvironment and Clinical Outcomes With Immune Checkpoint Inhibitors in STK11-Mutant Non-Small-Cell Lung Cancer.

PURPOSE: Non-small-cell lung cancer (NSCLC) with STK11mut has inferior outcomes to immune checkpoint inhibitors (ICIs). Using multiomics, we evaluated whether a subtype of STK11mut NSCLC with a uniquely inflamed tumor immune microenvironment (TIME) harboring TP53 comutations could have favorable outcomes to ICIs. PATIENTS AND METHODS: NSCLC tumors (N = 16,896) were analyzed by next-generation sequencing (DNA-Seq/592 genes). A subset (n = 5,034) underwent gene expression profiling (RNA-Seq/whole transcriptome). Exome-level neoantigen load for STK11mut NSCLC was obtained from published pan-immune analysis. Tumor immune cell content was obtained from transcriptome profiles using the microenvironment cell population (MCP) counter. ICI data from POPLAR/OAK (n = 34) and the study by Rizvi et al (n = 49) were used to model progression-free survival (PFS), and a separate ICI-treated cohort (n = 53) from Dana-Farber Cancer Institute (DFCI) was used to assess time to treatment failure (TTF) and tumor RECIST response for STK11mutTP53mut versus STK11mutTP53wt NSCLC. RESULTS: Overall, 12.6% of NSCLC tumors had a STK11mut with the proportions of tumor mutational burden (TMB)-high (≥10 mut/Mb), PD-L1 ≥50%, and microsatellite instability-high being 38.3%, 11.8%, and 0.72%, respectively. Unsupervised hierarchical clustering of STK11mut (n = 463) for stimulator of interferon-gamma (STING) pathway genes identified a STING-high cluster, which was significantly enriched in TP53mut NSCLC (P < .01). Compared with STK11mutTP53wt, tumors with STK11mutTP53mut had higher CD8+T cells and natural killer cells (P < .01), higher TMB (P < .001) and neoantigen load (P < .001), and increased expression of MYC and HIF-1A (P < .01), along with higher expression (P < .01) of glycolysis/glutamine metabolism genes. Meta-analysis of data from OAK/POPLAR and the study by Rizvi et al showed a trend toward improved PFS in patients with STK11mutTP53mut. In the DFCI cohort, compared with the STK11mut TP53wt cohort, the STK11mutTP53mut tumors had higher objective response rates (42.9% v 16.7%; P = .04) and also had longer TTF (14.5 v 4.5 months, P adj = .054) with ICI. CONCLUSION: STK11mut NSCLC with TP53 comutation is a distinct subgroup with an immunologically active TIME and metabolic reprogramming. These properties should be exploited to guide patient selection for novel ICI-based combination approaches.

Characterization of MET Exon 14 Skipping Alterations (in NSCLC) and Identification of Potential Therapeutic Targets Using Whole Transcriptome Sequencing.

Introduction: Genomic alterations in the juxtamembrane exon 14 splice sites in NSCLC lead to increased MET stability and oncogenesis. We present the largest cohort study of MET Exon 14 (METex14) using whole transcriptome sequencing. Methods: A total of 21,582 NSCLC tumor samples underwent complete genomic profiling with next-generation sequencing of DNA (592 Gene Panel, NextSeq, whole exome sequencing, NovaSeq) and RNA (NovaSeq, whole transcriptome sequencing). Clinicopathologic information including programmed death-ligand 1 and tumor mutational burden were collected and RNA expression for mutation subtypes and MET amplification were quantified. Immunogenic signatures and potential pathways of invasion were characterized using single-sample gene set enrichment analysis and mRNA gene signatures. Results: A total of 533tumors (2.47%) with METex14 were identified. The most common alterations were point mutations (49.5%) at donor splice sites. Most alterations translated to increased MET expression, with MET co-amplification resulting in synergistic increase in expression (q < 0.05). Common coalterations were amplifications of MDM2 (19.0% versus 1.8% wild-type [WT]), HMGA2 (13.2% versus 0.98% WT), and CDK4 (10.0% versus 1.5% WT) (q < 0.05). High programmed death-ligand 1 > 50% (52.5% versus 27.3% WT, q < 0.0001) and lower proportion of high tumor mutational burden (>10 mutations per megabase, 8.3% versus 36.7% WT, p < 0.0001) were associated with METex14, which were also enriched in both immunogenic signatures and immunosuppressive checkpoints. Pathways associated with METex14 included angiogenesis and apical junction pathways (q < 0.05). Conclusions: METex14 splicing alterations and MET co-amplification translated to higher and synergistic MET expression at the transcriptomic level. High frequencies of MDM2 and CDK4 co-amplifications and association with multiple immunosuppressive checkpoints and angiogenic pathways provide insight into potential actionable targets for combination strategies in METex14 NSCLC.

Utilization and costs of epidermal growth factor receptor mutation testing and targeted therapy in Medicare patients with metastatic lung adenocarcinoma.

BACKGROUND: Guidelines in 2013 and 2014 recommended Epidermal Growth Factor Receptor (EGFR) testing for metastatic lung adenocarcinoma patients as the efficacy of targeted therapies depends on the mutations. However, adherence to these guidelines and the corresponding costs have not been well-studied. METHODS: We identified 2362 patients at least 65 years old newly diagnosed with metastatic lung adenocarcinoma from January 2013 to December 2015 using the SEER-Medicare database. We examined the utilization patterns of EGFR testing and targeted therapies including erlotinib and afatinib. We further examined the costs of both EGFR testing and targeted therapy in terms of Medicare costs and patient out-of-pocket (OOP) costs. RESULTS: The EGFR testing rate increased from 38% in 2013 to 51% and 49% in 2014 and 2015 respectively. The testing rate was 54% among the 394 patients who received erlotinib, and 52% among the 42 patients who received afatinib. The median Medicare and OOP costs for testing were $1483 and $293. In contrast, the costs for targeted therapy were substantially higher with median 30-day costs at $6114 and $240 for erlotinib and $6239 and $471 for afatinib. CONCLUSION: This population-based study suggests that testing guidelines improved the use of EGFR testing, although there was still a large proportion of patients receiving targeted therapy without testing. The costs of targeted therapy were substantially higher than the testing costs, highlighting the need to improve adherence to testing guidelines in order to improve clinical outcomes while reducing the economic burden for both Medicare and patients.

Multi-hallmark long noncoding RNA maps reveal non-small cell lung cancer vulnerabilities.

Long noncoding RNAs (lncRNAs) are widely dysregulated in cancer, yet their functional roles in cancer hallmarks remain unclear. We employ pooled CRISPR deletion to perturb 831 lncRNAs detected in KRAS-mutant non-small cell lung cancer (NSCLC) and measure their contribution to proliferation, chemoresistance, and migration across two cell backgrounds. Integrative analysis of these data outperforms conventional "dropout" screens in identifying cancer genes while prioritizing disease-relevant lncRNAs with pleiotropic and background-independent roles. Altogether, 80 high-confidence oncogenic lncRNAs are active in NSCLC, which tend to be amplified and overexpressed in tumors. A follow-up antisense oligonucleotide (ASO) screen shortlisted two candidates, Cancer Hallmarks in Lung LncRNA 1 (CHiLL1) and GCAWKR, whose knockdown consistently suppressed cancer hallmarks in two- and three-dimension tumor models. Molecular phenotyping reveals that CHiLL1 and GCAWKR control cellular-level phenotypes via distinct transcriptional networks. This work reveals a multi-dimensional functional lncRNA landscape underlying NSCLC that contains potential therapeutic vulnerabilities.

Impact of XPO1 mutations on survival outcomes in metastatic non-small cell lung cancer (NSCLC).

BACKGROUND: Nuclear protein transport is essential in guiding the traffic of important proteins and RNAs between the nucleus and cytoplasm. Export of proteins from the nucleus is mostly regulated by Exportin 1 (XPO1). In cancer, XPO1 is almost universally hyperactive and can promote the export of important tumor suppressors to the cytoplasm. Currently, there are no studies evaluating XPO1 amplifications and mutations in NSCLC and the impact on outcomes. METHODS: Tumor samples were analyzed using next-generation sequencing (NGS) (NextSeq, 592 Genes), immunohistochemistry (IHC), and whole transcriptome sequencing (WTS, NovaSeq) (Caris Life Sciences, Phoenix, AZ). Survival was extracted from insurance claims data and calculated from time of tissue collection to last contact using Kaplan-Meier estimate. RESULTS: Among 18,218 NSCLC tumors sequenced, 26 harbored XPO1 mutations and 24 had amplifications. XPO1 mutant tumors were more likely to have high TMB (79% vs. 52%, p = 0.007) and less likely to have high PD-L1 (32% vs. 68%, p = 0.03). KRAS co-mutations were seen in 19% (n = 5) and EGFR co-mutations were rare (n = 2). Among the 17,449 NSCLC tumors with clinical data, there were 24 XPO1 mutant. Comparison of survival between XPO1 mutant and WT showed a negative association with a hazard ratio (HR) of 1.932 (95% CI: 1.144-3.264 p = 0.012). XPO1 amplification was not associated with survival. CONCLUSIONS: XPO1 pathogenic mutations were associated with a poor survival in NSCLC. Although XPO1 mutations are rare in NSCLC, further studies to assess its associations with treatment responses are warranted.

Genomic and transcriptional alterations in first-line chemotherapy exert a potentially unfavorable influence on subsequent immunotherapy in NSCLC.

Background: Recent studies in non-small cell lung cancer (NSCLC) patients have demonstrated that first-line immunotherapy is associated with better therapeutic response than second-line treatment. So far, the mechanisms need to be explored. It prompted us to evaluate the association between first-line chemotherapy and subsequent immunotherapy in NSCLC as well as its underlying mechanisms at the genomic and transcriptomic level. Methods: We launched a prospective, observational clinical study, paired tumor biopsies before and after chemotherapy were collected from NSCLC patients without tyrosine kinase inhibitor (TKI)-related driver gene mutations. The analyses included genomic and transcriptional changes performed by next-generation sequencing (NGS)-based whole-exome sequencing (WES) and messager ribonucleic acid (mRNA) sequencing. Characteristic mutational alterations in 1574 genes were investigated based on mutational status, clinicopathological factors, and chemotherapy responses. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis, neoantigen prediction and intratumoral heterogeneity evaluation were also performed. Results: Samples and information from 32 NSCLC patients without TKI-related driver gene mutations were obtained. We found that the total number of single nucleotide variants (SNV)/insertion-deletion (INDEL) mutations did not change significantly after chemotherapy. The tumor mutation burden (TMB) decreased significantly after chemotherapy in smoking patients and the decreased TMB correlated with a better survival of smoking patients. The change in copy number variations (CNVs) exhibited a decreasing trend during chemotherapy. Subsequent analysis at mRNA level revealed a significant decrease in the expression levels of genes related to antigen processing and presentation as well as other factors relevant for response to immunotherapy. Pathway enrichment analysis confirmed that the immune-related signaling pathways or biological processes were decreased after first-line chemotherapy. Conclusions: Our study presents an explanation for the unsatisfactory results of immunotherapy when given after chemotherapy, and suggests that first-line chemotherapy is able to influence the tumor microenvironment and decrease the efficacy of subsequent immunotherapy. The study was registered at ClinicalTrials.gov, number NCT03764917, and has completed enrolment; patients are still in follow-up.

MET alterations and their impact on the future of non-small cell lung cancer (NSCLC) targeted therapies.

Introduction: The MET gene and its pathway normally plays a crucial role in cell homeostasis, motility, and apoptosis. However, when the MET gene is altered, there is an imbalance toward cell proliferation and invasion commonly seen in numerous different types of cancers. The heterogeneous group of MET alterations that includes MET amplification, MET exon 14 skipping mutation, and MET fusions has been difficult to diagnose and treat. Currently, treatments are focused on tyrosine kinase inhibitors but now there is emerging data on novel MET-targeted therapies including monoclonal antibodies and antibody-drug conjugates that have emerged.Areas covered: We introduce new emerging data on MET alterations in non-small cell lung cancer (NSCLC) that has contributed to advances in MET targeted therapeutics. We offer our perspective and examine new information on the mechanisms of the MET alterations in this review.Expert opinion: Given the trends currently involving the targeting of MET altered malignancies, there will most likely be a continued rapid expansion of testing, novel tyrosine kinase inhibitors and potent antibody approaches. Combination treatments will be necessary to optimize management of advanced and early disease.

Immune-Related Adverse Events (irAE) in Cancer Immune Checkpoint Inhibitors (ICI) and Survival Outcomes Correlation: To Rechallenge or Not?

INTRODUCTION: There is growing recognition of immune related adverse events (irAEs) from immune checkpoint therapies being correlated with treatment outcomes in certain malignancies. There are currently limited data or consensus to guide management of irAEs with regards to treatment rechallenge. METHODS: We conducted a retrospective analysis with an IRB-approved protocol of adult patients seen at the WVU Cancer Institute between 2011-2019 with a histopathologic diagnosis of active cancers and were treated with immune checkpoint inhibitors (ICI) therapy. RESULTS: Demographics were similar between the ICI interrupted irAE groups within cancer types. Overall, out of 548 patients who received ICI reviewed, there were 133 cases of ≥1 irAE found of any grade. Being treated with anti-CTLA-4 inhibitor ICI was associated with lower risk of death compared to anti-PD-1 ICI. The overall survival difference observed for irAE positive patients, between rechallenged (37.8 months, reinitiated with/without interruption; 38.6 months, reinitiated after interruption) and interrupted/non-reinitiated (i.e., discontinued) groups (24.9 months) was not statistically significant, with a numerical trend favoring the former. CONCLUSIONS: Our exploratory study did not identify significantly different survival outcomes among the Appalachian West Virginia adult cancer patients treated with ICI who developed irAE and had treatment reinitiated after interruption, when compared with those not reinitiated.

A Prospective Trial Evaluating the Safety and Systemic Response From the Concurrent Use of Radiation Therapy with Checkpoint Inhibitor Immunotherapy in Metastatic Non-Small Cell Lung Cancer.

INTRODUCTION/BACKGROUND: This study assessed the safety and systemic (abscopal) response from the addition of local stereotactic body radiation therapy (SBRT) to checkpoint inhibitor (CPI) immunotherapy in patients with metastatic non-small cell lung cancer. PATIENTS/METHODS: Thirty-five patients with at least 2 sites of measurable disease on PET/CT received standard-of-care CPI immunotherapy alone (n = 19), or in combination with 4 cycles doublet carboplatin/pemetrexed chemotherapy (n = 16), and 3 to 5 fractions SBRT to a single extracranial target lesion between cycles 1 to 2 of the systemic therapy. Adverse events were assessed using CTCAE version 5.0. Best systemic objective response rate (ORR) was assessed using iRECIST criteria, excluding any irradiated lesion(s). Additional SBRT to a different target lesion was offered to patients who continued on immunotherapy with unconfirmed progressive disease or mixed response. RESULTS: Fifteen patients (44%) experienced 22 grade 1 to 2 toxicities potentially attributable to radiation, most commonly pneumonitis (n = 9) and fatigue (n = 6), and no grade 3 to 5 radiation-induced toxicities. Patients undergoing combined CPI-chemotherapy received a lower median biologically effective dose of SBRT than those undergoing CPI monotherapy (43.2 vs. 60Gy), but had a higher rate of radiation-induced toxicity (56% vs. 32%, P < .01). The best systemic ORR was 53%, with 20.5% stable disease and 26.5% progressive disease. Fifteen patients underwent a subsequent course of SBRT based on their response, among which 3 (20%) had progression-free intervals of 12, 16, and 10 months thereafter. CONCLUSIONS: Addition of SBRT to CPI immunotherapy (with/without chemotherapy) is safe. The favorable systemic response observed warrants further assessment with a randomized trial.

Patterns of disease progression to checkpoint inhibitor immunotherapy in patients with stage IV non-small cell lung cancer.

INTRODUCTION: The purpose of this study was to assess patterns of disease progression for patients with metastatic non-small cell lung cancer (NSCLC) on checkpoint inhibitor immunotherapy. METHODS: This single centre, retrospective study included all patients diagnosed with Stage IV NSCLC from 2015 to 2019 who received at least 2 cycles of immunotherapy, with or without concurrent chemotherapy. Immune RECIST criteria were used to assess patterns of disease progression, and progression-free survival (PFS), excluding irradiated tumours. The chi-square and log-rank tests assessed for associations between baseline clinical characteristics and progressive disease in initial sites only (vs. new or combined sites), and PFS, respectively. RESULTS: Among 143 eligible patients with a median follow-up of 11 months, 97 (68%) developed disease progression. Of these, 67 patients (69.1%) progressed only at initial disease site(s), 10 patients (10.3%) progressed only at new disease site(s), and 20 patients (20.6%) progressed in both initial and new sites. Rates of disease progression based on tumour location were higher for liver (64%) and lung metastases (61%) than for other metastatic sites (33-36%) or the primary tumour (24%). Only higher PD-L1 expression (P = 0.002) and absence of lung metastasis (P = 0.048) at baseline were associated with improved PFS. No baseline characteristics significantly impacted the probability of initial disease site-only progression, though a trend was observed for untreated primary tumour (72% vs. 56%, P = 0.169). CONCLUSIONS: The dominant pattern of disease progression is in the initial sites of disease alone, suggesting a potential role for local radiation therapy as a complementary treatment modality to immunotherapy.

Y Chromosome LncRNA Are Involved in Radiation Response of Male Non-Small Cell Lung Cancer Cells.

Numerous studies have implicated changes in the Y chromosome in male cancers, yet few have investigated the biological importance of Y chromosome noncoding RNA. Here we identify a group of Y chromosome-expressed long noncoding RNA (lncRNA) that are involved in male non-small cell lung cancer (NSCLC) radiation sensitivity. Radiosensitive male NSCLC cell lines demonstrated a dose-dependent induction of linc-SPRY3-2/3/4 following irradiation, which was not observed in radioresistant male NSCLC cell lines. Cytogenetics revealed the loss of chromosome Y (LOY) in the radioresistant male NSCLC cell lines. Gain- and loss-of-function experiments indicated that linc-SPRY3-2/3/4 transcripts affect cell viability and apoptosis. Computational prediction of RNA binding proteins (RBP) motifs and UV-cross-linking and immunoprecipitation (CLIP) assays identified IGF2BP3, an RBP involved in mRNA stability, as a binding partner for linc-SPRY3-2/3/4 RNA. The presence of linc-SPRY3-2/3/4 reduced the half-life of known IGF2BP3 binding mRNA, such as the antiapoptotic HMGA2 mRNA, as well as the oncogenic c-MYC mRNA. Assessment of Y chromosome in NSCLC tissue microarrays and expression of linc-SPRY3-2/3/4 in NSCLC RNA-seq and microarray data revealed a negative correlation between the loss of the Y chromosome or linc-SPRY3-2/3/4 and overall survival. Thus, linc-SPRY3-2/3/4 expression and LOY could represent an important marker of radiotherapy in NSCLC. SIGNIFICANCE: This study describes previously unknown Y chromosome-expressed lncRNA regulators of radiation response in male NSCLC and show a correlation between loss of chromosome Y and radioresistance. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/19/4046/F1.large.jpg.

Emerging insights of tumor heterogeneity and drug resistance mechanisms in lung cancer targeted therapy.

The biggest hurdle to targeted cancer therapy is the inevitable emergence of drug resistance. Tumor cells employ different mechanisms to resist the targeting agent. Most commonly in EGFR-mutant non-small cell lung cancer, secondary resistance mutations on the target kinase domain emerge to diminish the binding affinity of first- and second-generation inhibitors. Other alternative resistance mechanisms include activating complementary bypass pathways and phenotypic transformation. Sequential monotherapies promise to temporarily address the problem of acquired drug resistance, but evidently are limited by the tumor cells' ability to adapt and evolve new resistance mechanisms to persist in the drug environment. Recent studies have nominated a model of drug resistance and tumor progression under targeted therapy as a result of a small subpopulation of cells being able to endure the drug (minimal residual disease cells) and eventually develop further mutations that allow them to regrow and become the dominant population in the therapy-resistant tumor. This subpopulation of cells appears to have developed through a subclonal event, resulting in driver mutations different from the driver mutation that is tumor-initiating in the most common ancestor. As such, an understanding of intratumoral heterogeneity-the driving force behind minimal residual disease-is vital for the identification of resistance drivers that results from branching evolution. Currently available methods allow for a more comprehensive and holistic analysis of tumor heterogeneity in that issues associated with spatial and temporal heterogeneity can now be properly addressed. This review provides some background regarding intratumoral heterogeneity and how it leads to incomplete molecular response to targeted therapies, and proposes the use of single-cell methods, sequential liquid biopsy, and multiregion sequencing to discover the link between intratumoral heterogeneity and early adaptive drug resistance. In summary, minimal residual disease as a result of intratumoral heterogeneity is the earliest form of acquired drug resistance. Emerging technologies such as liquid biopsy and single-cell methods allow for studying targetable drivers of minimal residual disease and contribute to preemptive combinatorial targeting of both drivers of the tumor and its minimal residual disease cells.

The Journey of an EGFR-Mutant Lung Adenocarcinoma through Erlotinib, Osimertinib and ABCP Immunotherapy Regimens: Sensitivity and Resistance.

Patients with epidermal growth factor receptor (EGFR) mutation positive non-small cell lung cancer (NSCLC) have several EGFR targeting tyrosine kinase inhibitors (TKIs) available in frontline management. However, the disease will inevitably progress over time due to acquired resistance. Longitudinal tumor profiling for genomics guided therapy is indicated upon disease progression. It is a common scenario yet, when after failure of EGFR-TKIs, potentially actionable genomic alterations are lacking. Management of such patient is challenging with very limited options available. Combination of chemotherapy, anti-vascular/anti-angiogenic and immune-checkpoint inhibitors may become a salvage option for such patients. Here we describe a case of TKI refractory EGFR-mutant NSCLC successfully treated with carboplatin, paclitaxel, atezolizumab and bevacizumab combination with remarkable prompt tumor response.

Primary pleural epithelioid sarcoma of the proximal type: a diagnostic and therapeutic challenge.

Epithelioid sarcoma (ES) is an uncommon soft tissue neoplasm first described in 1970. It is a unique soft tissue neoplasm of adolescents and younger adults which usually presents as a subcutaneous and deep dermal mass in the distal portions of the extremities. The proximal-type variant of this rare soft tissue neoplasm was only recently reported. The proximal form typically arise in proximal extremities and in the deep parts of pelvis, perineum and genital tract. The proximal type variant has distinct histological characteristics and aggressive clinical course as compared to the distal ES. Inactivation of INI1 has been reported in both distal and proximal variants and can help to make the diagnosis. Furthermore, the proximal variant has a possible association with malignant rhabdoid neoplasm. We describe here a case of primary pleural ES of the proximal type and highlight its diagnostic and therapeutic challenges.