Publications by authors named "John V Heymach"

303 Publications

Enhanced vulnerability of LKB1-deficient NSCLC to disruption of ATP pools and redox homeostasis by 8-Cl-Ado.

Mol Cancer Res 2021 Oct 15. Epub 2021 Oct 15.

Thoracic and Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center

Loss of function somatic mutations of STK11, a tumor suppressor gene encoding LKB1 that contributes to the altered metabolic phenotype of cancer cells, is the second most common event in lung adenocarcinomas and often co-occurs with activating KRAS mutations. Tumor cells lacking LKB1 display an aggressive phenotype, with uncontrolled cell growth and higher energetic and redox stress due to its failure to balance ATP and NADPH levels in response to cellular stimulus. The identification of effective therapeutic regimens for LKB1-deficient non-small cell lung cancer (NSCLC) patients remains a major clinical need. Here, we report that LKB1-deficient NSCLC tumor cells displayed reduced basal levels of ATP and to a lesser extent other nucleotides, and markedly enhanced sensitivity to 8-Cl-adenosine (8-Cl-Ado), an energy-depleting nucleoside analogue. Treatment with 8-Cl-Ado depleted intracellular ATP levels, raised redox stress and induced cell death leading to a compensatory suppression of mTOR signaling in LKB1-intact, but not LKB1-deficient, cells. Proteomic analysis revealed that the MAPK/MEK/ERK and PI3K/AKT pathways were activated in response to 8-Cl-Ado treatment and targeting these pathways enhanced the anti-tumor efficacy of 8-Cl-Ado. Implications: Together, our findings demonstrate that LKB1-deficient tumor cells are selectively sensitive to 8-Cl-Ado and suggest that therapeutic approaches targeting vulnerable energy stores combined with signaling pathway inhibitors merit further investigation for this patient population.
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http://dx.doi.org/10.1158/1541-7786.MCR-21-0448DOI Listing
October 2021

Poziotinib for Patients With Exon 20 Mutant Non-Small-Cell Lung Cancer: Results From a Phase II Trial.

J Clin Oncol 2021 Sep 22:JCO2101113. Epub 2021 Sep 22.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: Targeted therapies against non-small-cell lung cancer (NSCLC) harboring mutations remain an unmet need. In this study, we assessed the efficacy and safety of poziotinib in patients with exon 20 mutant advanced NSCLC in a single-arm, open-label, phase II study.

Patients And Methods: Patients with advanced exon 20 mutant NSCLC were enrolled to receive poziotinib at a dose of 16 mg/d for 28-day cycles. The primary end point was objective response rate per RECIST version 1.1. Confirmatory scans were performed at least 28 days from initial radiologic response.

Results: Thirty patients received poziotinib treatment. At baseline, 90% of patients received prior platinum-based chemotherapy and 53% had two lines or more prior systemic therapies. As of data cutoff on March 1, 2021, the confirmed objective response rate was 27% (95% CI, 12 to 46). Responses were observed across exon 20 mutation subtypes. The median duration of response was 5.0 months (95% CI, 4.0 to not estimable). The median progression-free survival was 5.5 months (95% CI, 4.0 to 7.0). The median overall survival was 15 months (95% CI, 9.0 to not estimable). The most common grade 3 treatment-related adverse events were skin rash (47%) and diarrhea (20%). There was one possible treatment-related death because of pneumonitis.

Conclusion: Poziotinib showed promising antitumor activity in patients with exon 20 mutant NSCLC including patients who had previously received platinum-based chemotherapy.
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http://dx.doi.org/10.1200/JCO.21.01113DOI Listing
September 2021

Stereotactic ablative radiotherapy for operable stage I non-small-cell lung cancer (revised STARS): long-term results of a single-arm, prospective trial with prespecified comparison to surgery.

Lancet Oncol 2021 10 13;22(10):1448-1457. Epub 2021 Sep 13.

Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Background: A previous pooled analysis of the STARS and ROSEL trials showed higher survival after stereotactic ablative radiotherapy (SABR) than with surgery for operable early-stage non-small-cell lung cancer (NSCLC), but that analysis had notable limitations. This study reports long-term results of the revised STARS trial, in which the SABR group was re-accrued with a larger sample size, along with a protocol-specified propensity-matched comparison with a prospectively registered, contemporary institutional cohort of patients who underwent video-assisted thoracoscopic surgical lobectomy with mediastinal lymph node dissection (VATS L-MLND).

Methods: This single-arm prospective trial was done at the University of Texas MD Anderson Cancer Center (Houston, TX, USA) and enrolled patients aged 18 years or older with a Zubrod performance status of 0-2, newly diagnosed and histologically confirmed NSCLC with N0M0 disease (squamous cell, adenocarcinoma, large cell, or NSCLC not otherwise specified), and a tumour diameter of 3 cm or less. This trial did not include patients from the previous pooled analysis. SABR dosing was 54 Gy in three fractions (for peripheral lesions) or 50 Gy in four fractions (for central tumours; simultaneous integrated boost to gross tumour totalling 60 Gy). The primary endpoint was the 3-year overall survival. For the propensity-matching analysis, we used a surgical cohort from the MD Anderson Department of Thoracic and Cardiovascular Surgery's prospectively registered, institutional review board-approved database of all patients with clinical stage I NSCLC who underwent VATS L-MLND during the period of enrolment in this trial. Non-inferiority could be claimed if the 3-year overall survival rate after SABR was lower than that after VATS L-MLND by 12% or less and the upper bound of the 95% CI of the hazard ratio (HR) was less than 1·965. Propensity matching consisted of determining a propensity score using a multivariable logistic regression model including several covariates (age, tumour size, histology, performance status, and the interaction of age and sex); based on the propensity scores, one patient in the SABR group was randomly matched with one patient in the VATS L-MLND group using a 5:1 digit greedy match algorithm. This study is registered with ClinicalTrials.gov, NCT02357992.

Findings: Between Sept 1, 2015, and Jan 31, 2017, 80 patients were enrolled and included in efficacy and safety analyses. Median follow-up time was 5·1 years (IQR 3·9-5·8). Overall survival was 91% (95% CI 85-98) at 3 years and 87% (79-95) at 5 years. SABR was tolerated well, with no grade 4-5 toxicity and one (1%) case each of grade 3 dyspnoea, grade 2 pneumonitis, and grade 2 lung fibrosis. No serious adverse events were recorded. Overall survival in the propensity-matched VATS L-MLND cohort was 91% (95% CI 85-98) at 3 years and 84% (76-93) at 5 years. Non-inferiority was claimed since the 3-year overall survival after SABR was not lower than that observed in the VATS L-MLND group. There was no significant difference in overall survival between the two patient cohorts (hazard ratio 0·86 [95% CI 0·45-1·65], p=0·65) from a multivariable analysis.

Interpretation: Long-term survival after SABR is non-inferior to VATS L-MLND for operable stage IA NSCLC. SABR remains promising for such cases but multidisciplinary management is strongly recommended.

Funding: Varian Medical Systems and US National Cancer Institute (National Institutes of Health).
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http://dx.doi.org/10.1016/S1470-2045(21)00401-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8521627PMC
October 2021

Structure-based classification predicts drug response in EGFR-mutant NSCLC.

Nature 2021 Sep 15;597(7878):732-737. Epub 2021 Sep 15.

Department of Biostatistics, MD Anderson Cancer Center, Houston, TX, USA.

Epidermal growth factor receptor (EGFR) mutations typically occur in exons 18-21 and are established driver mutations in non-small cell lung cancer (NSCLC). Targeted therapies are approved for patients with 'classical' mutations and a small number of other mutations. However, effective therapies have not been identified for additional EGFR mutations. Furthermore, the frequency and effects of atypical EGFR mutations on drug sensitivity are unknown. Here we characterize the mutational landscape in 16,715 patients with EGFR-mutant NSCLC, and establish the structure-function relationship of EGFR mutations on drug sensitivity. We found that EGFR mutations can be separated into four distinct subgroups on the basis of sensitivity and structural changes that retrospectively predict patient outcomes following treatment with EGFR inhibitors better than traditional exon-based groups. Together, these data delineate a structure-based approach for defining functional groups of EGFR mutations that can effectively guide treatment and clinical trial choices for patients with EGFR-mutant NSCLC and suggest that a structure-function-based approach may improve the prediction of drug sensitivity to targeted therapies in oncogenes with diverse mutations.
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http://dx.doi.org/10.1038/s41586-021-03898-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8481125PMC
September 2021

Inhibition of nonsense-mediated decay rescues p53β/γ isoform expression and activates the p53 pathway in MDM2-overexpressing and select p53-mutant cancers.

J Biol Chem 2021 Sep 2:101163. Epub 2021 Sep 2.

Department of Thoracic Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Inactivation of p53 is present in almost every tumor and hence, p53-reactivation strategies are an important aspect of cancer therapy. Common mechanisms for p53 loss in cancer include expression of p53 negative regulators such as MDM2, which mediate the degradation of wild-type (WT) p53 (p53α), and inactivating mutations in the TP53 gene. Currently, approaches to overcome p53 deficiency in these cancers are limited. Here, using non-small cell lung cancer (NSCLC) and glioblastoma multiforme (GBM) cell line models, we show that two alternatively-spliced, functional truncated isoforms of p53 (p53β and p53γ, comprising exons 1 to 9β or 9γ, respectively) and which lack the C-terminal MDM2 binding domain have markedly reduced susceptibility to MDM2-mediated degradation but are highly susceptible to nonsense mediated decay (NMD), a regulator of aberrant mRNA stability. In cancer cells harboring MDM2 overexpression or TP53 mutations downstream of exon 9, NMD inhibition markedly upregulates p53β and p53γ, and restores activation of the p53 pathway. Consistent with p53 pathway activation, NMD inhibition induces tumor suppressive activities such as apoptosis, reduced cell viability and enhanced tumor radiosensitivity, in a relatively p53-dependent manner. In addition, NMD inhibition also inhibits tumor growth in a MDM2 overexpressing xenograft tumor model. These results identify NMD inhibition as a novel therapeutic strategy for restoration of p53 function in p53-deficient tumors bearing MDM2 overexpression or p53 mutations downstream of exon 9, subgroups which comprise approximately 6% of all cancers.
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http://dx.doi.org/10.1016/j.jbc.2021.101163DOI Listing
September 2021

Nodal immune flare mimics nodal disease progression following neoadjuvant immune checkpoint inhibitors in non-small cell lung cancer.

Nat Commun 2021 08 19;12(1):5045. Epub 2021 Aug 19.

Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Radiographic imaging is the standard approach for evaluating the disease involvement of lymph nodes in patients with operable NSCLC although the impact of neoadjuvant immune checkpoint inhibitors (ICIs) on lymph nodes has not yet been characterized. Herein, we present an ad hoc analysis of the NEOSTAR trial (NCT03158129) where we observed a phenomenon we refer to as "nodal immune flare" (NIF) in which patients treated with neoadjuvant ICIs demonstrate radiologically abnormal nodes post-therapy that upon pathological evaluation are devoid of cancer and demonstrate de novo non-caseating granulomas. Abnormal lymph nodes are analyzed by computed tomography and F-fluorodeoxyglucose positron emission tomography/computer tomography to evaluate the size and the maximum standard uptake value post- and pre-therapy in NEOSTAR and an independent neoadjuvant chemotherapy cohort. NIF occurs in 16% (7/44) of patients treated with ICIs but in 0% (0/28) of patients after neoadjuvant chemotherapy. NIF is associated with an inflamed nodal immune microenvironment and with fecal abundance of genera belonging to the family Coriobacteriaceae of phylum Actinobacteria, but not with tumor responses or treatment-related toxicity. Our findings suggest that this apparent radiological cancer progression in lymph nodes may occur due to an inflammatory response after neoadjuvant immunotherapy, and such cases should be evaluated by pathological examination to distinguish NIF from true nodal progression and to ensure appropriate clinical treatment planning.
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http://dx.doi.org/10.1038/s41467-021-25188-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8376947PMC
August 2021

ARTEMIS highlights VEGF inhibitors as effective partners for EGFR TKIs in EGFR mutant NSCLC.

Cancer Cell 2021 Sep 12;39(9):1178-1180. Epub 2021 Aug 12.

Department of Thoracic Head and Neck Medical Oncology, Division of Cancer Medicine, University of Texas M.D. Anderson Cancer Center, Houston, TX, USA. Electronic address:

The randomized ARTEMIS study demonstrates that adding the VEGF inhibitor bevacizumab to the EGFR inhibitor erlotinib improves progression-free survival in EGFR mutant non-small-cell lung cancer by more than 6 months, with even greater benefits seen in patients with brain metastases and EGFR L858R mutation. This provides further evidence for the tailored use of VEGF/EGFR combinations.
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http://dx.doi.org/10.1016/j.ccell.2021.07.017DOI Listing
September 2021

Clinical Outcomes in Non-Small-Cell Lung Cancer Patients Treated With EGFR-Tyrosine Kinase Inhibitors and Other Targeted Therapies Based on Tumor Versus Plasma Genomic Profiling.

JCO Precis Oncol 2021 Aug 5;5. Epub 2021 Aug 5.

University of Texas MD Anderson Cancer Center, Houston, TX.

Purpose: To compare clinical outcomes in a cohort of patients with advanced non-small-cell lung cancer (NSCLC) with targetable genomic alterations detected using plasma-based circulating tumor DNA (ctDNA) or tumor-based next-generation sequencing (NGS) assays treated with US Food and Drug Administration-approved therapies at a large academic research cancer center.

Methods: A retrospective review from our MD Anderson GEMINI database identified 2,224 blood samples sent for ctDNA NGS testing from 1971 consecutive patients with a diagnosis of advanced NSCLC. Clinical, treatment, and outcome information were collected, reviewed, and analyzed.

Results: Overall, 27% of the ctDNA tests identified at least one targetable mutation and 73% of targetable mutations were -sensitizing mutations. Among patients treated with first-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) therapies, there were no significant differences in progression-free survival of 379 days and 352 days ( value = .41) with treatment based on tissue (n = 40) or ctDNA (n = 40), respectively. Additionally, there were no differences in progression-free survival or objective response rate among those with low (n = 8, 0.01%-0.99%) versus high (n = 16, ≥ 1%) levels of ctDNA of the targetable mutation as measured by variant allele frequency (VAF). Overall, there was excellent testing concordance (n = 217 tests) of > 97%, sensitivity of 91.7%, and specificity of 99.7% between blood-based ctDNA NGS and tissue-based NGS assays.

Conclusion: There were no significant differences in clinical outcomes among patients treated with approved EGFR-TKIs whose mutations were identified using either tumor- or plasma-based comprehensive profiling and those with very low VAF as compared with high VAF, supporting the use of plasma-based profiling to guide initial TKI use in patients with metastatic EGFR-mutant NSCLC.
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http://dx.doi.org/10.1200/PO.20.00532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8345916PMC
August 2021

Oncogene-specific differences in tumor mutational burden, PD-L1 expression, and outcomes from immunotherapy in non-small cell lung cancer.

J Immunother Cancer 2021 Aug;9(8)

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

Background: Non-small cell lung cancer (NSCLC) patients bearing targetable oncogene alterations typically derive limited benefit from immune checkpoint blockade (ICB), which has been attributed to low tumor mutation burden (TMB) and/or PD-L1 levels. We investigated oncogene-specific differences in these markers and clinical outcome.

Methods: Three cohorts of NSCLC patients with oncogene alterations (n=4189 total) were analyzed. Two clinical cohorts of advanced NSCLC patients treated with ICB monotherapy [MD Anderson (MDACC; n=172) and Flatiron Health-Foundation Medicine Clinico-Genomic Database (CGDB; n=894 patients)] were analyzed for clinical outcome. The FMI biomarker cohort (n=4017) was used to assess the association of oncogene alterations with TMB and PD-L1 expression.

Results: High PD-L1 expression (PD-L1 ≥50%) rate was 19%-20% in classic , exon 20 and -mutant tumors, and 34%-55% in tumors with , V600E, , , or alterations. Compared with mutant tumors, non-V600E group had higher TMB (9.6 vs 7.8 mutations/Mb, p=0.003), while all other oncogene groups had lower TMB (p<0.001). In the two clinical cohorts treated with ICB, molecular groups with , , , , , or alterations had short progression-free survival (PFS; 1.8-3.7 months), while V600E group was associated with greater clinical benefit from ICB (CGDB cohort: PFS 9.8 months vs 3.7 months, HR 0.66, p=0.099; MDACC cohort: response rate 62% vs 24%; PFS 7.4 vs 2.8 months, HR 0.36, p=0.026). G12C and non-G12C subgroups had similar clinical benefit from ICB in both cohorts. In a multivariable analysis, V600E mutation (HR 0.58, p=0.041), PD-L1 expression (HR 0.57, p=0.022), and high TMB (HR 0.66, p<0.001) were associated with longer PFS.

Conclusions: High TMB and PD-L1 expression are predictive for benefit from ICB treatment in oncogene-driven NSCLCs. NSCLC harboring mutations demonstrated superior benefit from ICB that may be attributed to higher TMB and higher PD-L1 expression in these tumors. Meanwhile and mutations and , , , and fusions define NSCLC subsets with minimal benefit from ICB despite high PD-L1 expression in NSCLC harboring oncogene fusions. These findings indicate a TMB/PD-L1-independent impact on sensitivity to ICB for certain oncogene alterations.
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http://dx.doi.org/10.1136/jitc-2021-002891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8356172PMC
August 2021

Estrogen Promotes Resistance to Bevacizumab in Murine Models of NSCLC.

J Thorac Oncol 2021 Jul 24. Epub 2021 Jul 24.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Introduction: Subgroup analyses from clinical studies have suggested that among patients with metastatic NSCLC receiving chemotherapy, females may derive less benefit from the addition of the vascular endothelial growth factor (VEGF) monoclonal antibody bevacizumab (BV) than males. This has raised the question of whether estrogen may affect the response to antiangiogenic therapy.

Methods: To address this, we investigated the effects of estrogen on tumor growth, angiogenesis, and the response to BV in human xenograft models of NSCLC.

Results: We observed that estrogen induced marked resistance to BV, which was accompanied by a 2.3-fold increase in tumor vascular pericyte coverage (p = 0.01) and an up-regulation of proangiogenic factors, VEGF and platelet-derived growth factor-BB. We also investigated the role of infiltrating myeloid cells, a population that has been associated with resistance to anti-VEGF therapies. We observed that estrogen induced a greater than twofold increase (p = 0.001) in the recruitment of tumor-infiltrating myeloid cells and concomitant increases in the myeloid recruitment factors, G-CSF and CXCL1. Blockade of the estrogen receptor pathway using fulvestrant resensitized tumors to VEGF targeting as evidenced by reduced tumor vasculature and an increase in overall survival in our NSCLC xenograft models.

Conclusions: Collectively, these data provide evidence that estrogen may promote resistance to VEGF-targeted therapies, potentially by enhancing pericyte coverage and myeloid recruitment, and suggest that estrogen receptor blockade merits further investigation as an approach to enhance the effects of antiangiogenic therapy.
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http://dx.doi.org/10.1016/j.jtho.2021.07.007DOI Listing
July 2021

Lung Cancer Models Reveal Severe Acute Respiratory Syndrome Coronavirus 2-Induced Epithelial-to-Mesenchymal Transition Contributes to Coronavirus Disease 2019 Pathophysiology.

J Thorac Oncol 2021 Jul 16. Epub 2021 Jul 16.

Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Introduction: Coronavirus disease 2019 is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which enters host cells through the cell surface proteins ACE2 and TMPRSS2.

Methods: Using a variety of normal and malignant models and tissues from the aerodigestive and respiratory tracts, we investigated the expression and regulation of ACE2 and TMPRSS2.

Results: We find that ACE2 expression is restricted to a select population of epithelial cells. Notably, infection with SARS-CoV-2 in cancer cell lines, bronchial organoids, and patient nasal epithelium induces metabolic and transcriptional changes consistent with epithelial-to-mesenchymal transition (EMT), including up-regulation of ZEB1 and AXL, resulting in an increased EMT score. In addition, a transcriptional loss of genes associated with tight junction function occurs with SARS-CoV-2 infection. The SARS-CoV-2 receptor, ACE2, is repressed by EMT through the transforming growth factor-β, ZEB1 overexpression, and onset of EGFR tyrosine kinase inhibitor resistance. This suggests a novel model of SARS-CoV-2 pathogenesis in which infected cells shift toward an increasingly mesenchymal state, associated with a loss of tight junction components with acute respiratory distress syndrome-protective effects. AXL inhibition and ZEB1 reduction, as with bemcentinib, offer a potential strategy to reverse this effect.

Conclusions: These observations highlight the use of aerodigestive and, especially, lung cancer model systems in exploring the pathogenesis of SARS-CoV-2 and other respiratory viruses and offer important insights into the potential mechanisms underlying the morbidity and mortality of coronavirus disease 2019 in healthy patients and patients with cancer alike.
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http://dx.doi.org/10.1016/j.jtho.2021.07.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8282443PMC
July 2021

High-dose irradiation in combination with non-ablative low-dose radiation to treat metastatic disease after progression on immunotherapy: Results of a phase II trial.

Radiother Oncol 2021 Sep 5;162:60-67. Epub 2021 Jul 5.

Translational Molecular Pathology, The University of Texas MD Anderson Cancer Center, Houston, USA.

Aim: To report early findings from a phase II trial of high-dose radiotherapy (HD-RT) with or without low-dose RT (LD-RT) for metastatic cancer.

Methods: Eligible patients had metastatic disease that progressed on immunotherapy within 6 months. Patients were given either HD-RT (20-70 Gy total; 3-12.5 Gy/f), or HD-RT + LD-RT (0.5-2 Gy/f up to 1-10 Gy total) to separate lesions, with continued immunotherapy. Radiographic response was assessed per RECIST 1.1 and Immune-Related Response Criteria (irRC). Primary endpoints: (1) 4-month disease control (DCR, complete/partial response [CR/PR] or stable disease [SD]) or an overall response (ORR, CR/PR) at any point in ≥10% of patients, per RECIST 1.1; (2) dose-limiting toxicity within 3 months not exceeding 30%. Secondary endpoint was lesion-specific response.

Results: Seventy-four patients (NSCLC, n = 38; melanoma n = 21) were analyzed (39 HD-RT and 35 HD-RT + LD-RT). The median follow-up time was 13.6 months. The primary endpoint was met for 72 evaluable patients, with a 4-month DCR of 42% (47% [16/34] vs. 37% [14/38] in HD-RT + LD-RT vs. HD-RT, P = 0.38), and 19% ORR at any time (26% [9/34] vs. 13% [5/38] in HD-RT + LD-RT vs. HD-RT, P = 0.27). Three patients had toxicity ≥grade 3. LD-RT lesion response (53%) was improved compared to nonirradiated lesions in HD-RT + LD-RT (23%, P = 0.002) and HD-RT (11%, P < 0.001). T- and NK cell infiltration was enhanced in lesions treated with LD-RT.

Conclusions: HD-RT plus LD-RT safely improved lesion-specific response in patients with immune resistant solid tumors by promoting infiltration of effector immune cells into the tumor microenvironment.
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http://dx.doi.org/10.1016/j.radonc.2021.06.037DOI Listing
September 2021

Immune evolution from preneoplasia to invasive lung adenocarcinomas and underlying molecular features.

Nat Commun 2021 05 11;12(1):2722. Epub 2021 May 11.

Department of Thoracic/Head and Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The mechanism by which anti-cancer immunity shapes early carcinogenesis of lung adenocarcinoma (ADC) is unknown. In this study, we characterize the immune contexture of invasive lung ADC and its precursors by transcriptomic immune profiling, T cell receptor (TCR) sequencing and multiplex immunofluorescence (mIF). Our results demonstrate that anti-tumor immunity evolved as a continuum from lung preneoplasia, to preinvasive ADC, minimally-invasive ADC and frankly invasive lung ADC with a gradually less effective and more intensively regulated immune response including down-regulation of immune-activation pathways, up-regulation of immunosuppressive pathways, lower infiltration of cytotoxic T cells (CTLs) and anti-tumor helper T cells (Th), higher infiltration of regulatory T cells (Tregs), decreased T cell clonality, and lower frequencies of top T cell clones in later-stages. Driver mutations, chromosomal copy number aberrations (CNAs) and aberrant DNA methylation may collectively impinge host immune responses and facilitate immune evasion, promoting the outgrowth of fit subclones in preneoplasia into dominant clones in invasive ADC.
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http://dx.doi.org/10.1038/s41467-021-22890-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8113327PMC
May 2021

Resolving the Spatial and Cellular Architecture of Lung Adenocarcinoma by Multiregion Single-Cell Sequencing.

Cancer Discov 2021 Oct 10;11(10):2506-2523. Epub 2021 May 10.

Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Little is known of the geospatial architecture of individual cell populations in lung adenocarcinoma (LUAD) evolution. Here, we perform single-cell RNA sequencing of 186,916 cells from five early-stage LUADs and 14 multiregion normal lung tissues of defined spatial proximities from the tumors. We show that cellular lineages, states, and transcriptomic features geospatially evolve across normal regions to LUADs. LUADs also exhibit pronounced intratumor cell heterogeneity within single sites and transcriptional lineage-plasticity programs. T regulatory cell phenotypes are increased in normal tissues with proximity to LUAD, in contrast to diminished signatures and fractions of cytotoxic CD8 T cells, antigen-presenting macrophages, and inflammatory dendritic cells. We further find that the LUAD ligand-receptor interactome harbors increased expression of epithelial , which mediates protumor phenotypes. These data provide a spatial atlas of LUAD evolution, and a resource for identification of targets for its treatment. SIGNIFICANCE: The geospatial ecosystem of the peripheral lung and early-stage LUAD is not known. Our multiregion single-cell sequencing analyses unravel cell populations, states, and phenotypes in the spatial and ecologic evolution of LUAD from the lung that comprise high-potential targets for early interception..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1285DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8487926PMC
October 2021

Short Communication: Interim toxicity analysis for patients with limited stage small cell lung cancer (LSCLC) treated on CALGB 30610 (Alliance) / RTOG 0538.

Lung Cancer 2021 06 18;156:68-71. Epub 2021 Apr 18.

University of Chicago Comprehensive Cancer Center, Chicago, IL, United States.

Introduction: The CALGB 30610/RTOG 0538 randomized trial was designed to test whether high-dose thoracic radiotherapy (TRT) would improve survival compared with 45 Gy twice-daily (BID) TRT in limited stage small cell lung cancer (LSCLC). Two piloted experimental TRT regimens were of interest to study, 70 Gy daily (QD) and 61.2 Gy concomitant boost (CB). Driven by concerns about adequate patient accrual, a study design was employed that eliminated one experimental TRT arm based on early interim toxicity and tolerability, with the study then continuing as a traditional 2-arm phase III study.

Methods: Patients with LSCLC were assigned to receive four cycles of cisplatin and etoposide chemotherapy with one of 3 TRT regimens starting with either the first or second cycle of chemotherapy. The interim endpoint was the cumulative highest toxicity calculated from a scoring system based on treatment-related grade 3 and higher toxicity and the ability to complete therapy in the experimental arms.

Results: The final interim analysis was performed after 70 patients accrued to each experimental cohort, and a difference in treatment related toxicity scoring was not found (p = 0.739). Severe esophageal toxicity was comparable in both cohorts. Pulmonary toxicity was low overall, though 4 patients (5.7 %) on the 61.2 Gy arm developed grade 4 dyspnea, which was not observed in the 70 Gy arm. A protocol mandated decision was made to discontinue the 61.2 Gy arm following review of toxicity with the Data and Safety Monitoring Board.

Conclusion: A randomized trial design using a planned early interim toxicity analysis to discriminate between experimental treatment arms is feasible in a phase III setting. Refinement of the design could increase the likelihood of detecting clinically meaningful differences in toxicity in future studies.
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http://dx.doi.org/10.1016/j.lungcan.2021.04.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8418826PMC
June 2021

Evaluation of Pathologic Response in Lymph Nodes of Patients With Lung Cancer Receiving Neoadjuvant Chemotherapy.

J Thorac Oncol 2021 08 20;16(8):1289-1297. Epub 2021 Apr 20.

Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Introduction: Major pathologic response (MPR), defined as residual viable tumor of less than or equal to 10%, currently serves as a surrogate end point for survival for patients with resectable NSCLC after neoadjuvant chemotherapy. However, the significance of pathologic response in lymph nodes harboring metastatic tumors in such patients remains uncertain. Therefore, we studied the effect of neoadjuvant chemotherapy on resected positive lymph nodes and determined if the degree of pathologic response in the lymph nodes alone (LN-MPR) or in combination with that of the primary tumor (PT-MPR) was able to predict the outcome.

Methods: A total of 75 patients with NSCLC who underwent neoadjuvant chemotherapy and completed surgical resection were included in this study. Tissue specimens were retrospectively evaluated by two pathologists blinded to the patients' treatments and outcomes. Specimens were reviewed for the degree of pathologic response in the primary tumor and in any involved lymph nodes. The prognostic performance of LN-MPR alone or in combination with PT-MPR with respect to overall survival (OS) was evaluated using the Kaplan-Meier method and Cox regression model.

Results: LN-MPR was significantly predictive of long-term OS after neoadjuvant chemotherapy. A combination of PT-MPR with LN-MPR was significantly associated with outcome and allowed stratification of patients into three prognostic groups (p = 0.001).

Conclusions: LN-MPR in isolation is a reliable predictor of OS in patients with NSCLC receiving neoadjuvant chemotherapy. A combination of LN-MPR with PT-MPR seems to correlate well with the outcome and can be used to predict prognosis in this patient population.
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http://dx.doi.org/10.1016/j.jtho.2021.03.029DOI Listing
August 2021

Single-Cell Expression Landscape of SARS-CoV-2 Receptor and Host Proteases in Normal and Malignant Lung Tissues from Pulmonary Adenocarcinoma Patients.

Cancers (Basel) 2021 Mar 12;13(6). Epub 2021 Mar 12.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.

The novel coronavirus SARS-CoV-2 is the causative agent of the COVID-19 pandemic. Severely symptomatic COVID-19 is associated with lung inflammation, pneumonia, and respiratory failure, thereby raising concerns of elevated risk of COVID-19-associated mortality among lung cancer patients. Angiotensin-converting enzyme 2 (ACE2) is the major receptor for SARS-CoV-2 entry into lung cells. The single-cell expression landscape of and other SARS-CoV-2-related genes in pulmonary tissues of lung cancer patients remains unknown. We sought to delineate single-cell expression profiles of and other SARS-CoV-2-related genes in pulmonary tissues of lung adenocarcinoma (LUAD) patients. We examined the expression levels and cellular distribution of and SARS-CoV-2-priming proteases and in 5 LUADs and 14 matched normal tissues by single-cell RNA-sequencing (scRNA-seq) analysis. scRNA-seq of 186,916 cells revealed epithelial-specific expression of , , and . Analysis of 70,030 LUAD- and normal-derived epithelial cells showed that levels were highest in normal alveolar type 2 (AT2) cells and that was expressed in 65% of normal AT2 cells. Conversely, the expression of was highest and most frequently detected (75%) in lung cells with malignant features. -positive cells co-expressed genes implicated in lung pathobiology, including COPD-associated , and the scavengers and . Notably, the viral scavenger was significantly positively correlated with expression in AT2 cells. We describe normal and tumor lung epithelial populations that express SARS-CoV-2 receptor and proteases, as well as major host defense genes, thus comprising potential treatment targets for COVID-19 particularly among lung cancer patients.
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http://dx.doi.org/10.3390/cancers13061250DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7998226PMC
March 2021

Global analysis of shared T cell specificities in human non-small cell lung cancer enables HLA inference and antigen discovery.

Immunity 2021 03;54(3):586-602.e8

Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA 94305, USA.

To identify disease-relevant T cell receptors (TCRs) with shared antigen specificity, we analyzed 778,938 TCRβ chain sequences from 178 non-small cell lung cancer patients using the GLIPH2 (grouping of lymphocyte interactions with paratope hotspots 2) algorithm. We identified over 66,000 shared specificity groups, of which 435 were clonally expanded and enriched in tumors compared to adjacent lung. The antigenic epitopes of one such tumor-enriched specificity group were identified using a yeast peptide-HLA A02:01 display library. These included a peptide from the epithelial protein TMEM161A, which is overexpressed in tumors and cross-reactive epitopes from Epstein-Barr virus and E. coli. Our findings suggest that this cross-reactivity may underlie the presence of virus-specific T cells in tumor infiltrates and that pathogen cross-reactivity may be a feature of multiple cancers. The approach and analytical pipelines generated in this work, as well as the specificity groups defined here, present a resource for understanding the T cell response in cancer.
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http://dx.doi.org/10.1016/j.immuni.2021.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7960510PMC
March 2021

Current and future treatment options for exon 14 skipping alterations in non-small cell lung cancer.

Ther Adv Med Oncol 2021 15;13:1758835921992976. Epub 2021 Feb 15.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.

It has been over three decades since the hepatocyte growth factor (HGF) ligand and its receptor MET proto-oncogene (MET) pathway was established as promoting cancer growth and metastasis. exon 14 skipping () alterations occur in 3-4% of all non-small cell lung cancer (NSCLC) patients, typically in elderly patients (older than 70 years), and result in constitutive activation of the MET receptor by altering a region required for receptor degradation. Multi-kinase inhibitor of MET, such as crizotinib, and more recently selective MET inhibitors, such as capmatinib and tepotinib, have demonstrated clinical efficacy and safety in NSCLC patients in clinical trials. These results have led to the approval of MET inhibitors by regulatory agencies across the globe. The success also fueled the excitement of further development of therapeutic strategies to target in lung cancers. This article provides an overview of the clinical development program targeting in NSCLC, including small molecular tyrosine kinase inhibitors and anti-MET antibodies. Furthermore, combination therapy immune checkpoint inhibitors or other targeted therapies are also under development in various patient populations, with acquired resistance immune or targeted therapy. Clinical trials in different development stages are ongoing and more drugs targeted to c-MET will be available for NSCLC patients with skipping mutations in the future.
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http://dx.doi.org/10.1177/1758835921992976DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7890719PMC
February 2021

Controversies and challenges in the pathologic examination of lung resection specimens after neoadjuvant treatment.

Lung Cancer 2021 04 17;154:76-83. Epub 2021 Feb 17.

Department of Cardiovascular and Thoracic Surgery, The University of Texas MD Anderson Cancer Center, Houston, USA.

New therapy approaches in the treatment of surgically resectable non-small cell lung cancer (NSCLC) challenge the traditional handling and examination of pathology specimens. The increasingly common use of neoadjuvant therapies before surgical resection, due to advantages in novel drug administration, tolerance, and measurement of radiographic and pathologic response compared to adjuvant treatment, has the potential to alter the microscopic tumor appearance and its biology. Currently, many clinical trials use pathologic response as a surrogate endpoint of clinical efficacy, since the extent of residual viable tumor appears to correlate with outcome in patients treated with neoadjuvant chemotherapy. Consequently, pathologic assessment of the extent of residual viable tumor is of paramount importance. However, high level evidence-based guidelines on how to process and evaluate such specimens are lacking. Moreover, while pathologic response has been shown to be associated with survival after chemotherapy, its significance after immunotherapy remains to be determined. Additionally, many clinical trials do not routinely include pathologists in trial design, which may lead to non-standardized evaluation of pathologic response. Although recently, several algorithms have been proposed to address these issues, none of them represents evidence-based recommendations or is universally applied. Therefore, controversies and challenges continue to exist, raising concerns about the validity, reproducibility, and comparability of the results of many neoadjuvant clinical trials. Herein, we discuss the current difficulties in pathologic specimen evaluation following neoadjuvant therapy in NSCLC and propose potential approaches to overcome these challenges.
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http://dx.doi.org/10.1016/j.lungcan.2021.02.014DOI Listing
April 2021

Neoadjuvant nivolumab or nivolumab plus ipilimumab in operable non-small cell lung cancer: the phase 2 randomized NEOSTAR trial.

Nat Med 2021 03 18;27(3):504-514. Epub 2021 Feb 18.

Thoracic/Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA.

Ipilimumab improves clinical outcomes when combined with nivolumab in metastatic non-small cell lung cancer (NSCLC), but its efficacy and impact on the immune microenvironment in operable NSCLC remain unclear. We report the results of the phase 2 randomized NEOSTAR trial (NCT03158129) of neoadjuvant nivolumab or nivolumab + ipilimumab followed by surgery in 44 patients with operable NSCLC, using major pathologic response (MPR) as the primary endpoint. The MPR rate for each treatment arm was tested against historical controls of neoadjuvant chemotherapy. The nivolumab + ipilimumab arm met the prespecified primary endpoint threshold of 6 MPRs in 21 patients, achieving a 38% MPR rate (8/21). We observed a 22% MPR rate (5/23) in the nivolumab arm. In 37 patients resected on trial, nivolumab and nivolumab + ipilimumab produced MPR rates of 24% (5/21) and 50% (8/16), respectively. Compared with nivolumab, nivolumab + ipilimumab resulted in higher pathologic complete response rates (10% versus 38%), less viable tumor (median 50% versus 9%), and greater frequencies of effector, tissue-resident memory and effector memory T cells. Increased abundance of gut Ruminococcus and Akkermansia spp. was associated with MPR to dual therapy. Our data indicate that neoadjuvant nivolumab + ipilimumab-based therapy enhances pathologic responses, tumor immune infiltrates and immunologic memory, and merits further investigation in operable NSCLC.
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http://dx.doi.org/10.1038/s41591-020-01224-2DOI Listing
March 2021

Single-cell analyses reveal increased intratumoral heterogeneity after the onset of therapy resistance in small-cell lung cancer.

Nat Cancer 2020 Apr 17;1:423-436. Epub 2020 Feb 17.

Department of Thoracic/Head & Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.

The natural history of small cell lung cancer (SCLC) includes rapid evolution from chemosensitivity to chemoresistance, although mechanisms underlying this evolution remain obscure due to scarcity of post-relapse tissue samples. We generated circulating tumor cell (CTC)-derived xenografts (CDXs) from SCLC patients to study intratumoral heterogeneity (ITH) via single-cell RNAseq of chemo-sensitive and -resistant CDXs and patient CTCs. We found globally increased ITH including heterogeneous expression of therapeutic targets and potential resistance pathways, such as EMT, between cellular subpopulations following treatment-resistance. Similarly, serial profiling of patient CTCs directly from blood confirmed increased ITH post-relapse. These data suggest that treatment-resistance in SCLC is characterized by coexisting subpopulations of cells with heterogeneous gene expression leading to multiple, concurrent resistance mechanisms. These findings emphasize the need for clinical efforts to focus on rational combination therapies for treatment-naïve SCLC tumors to maximize initial responses and counteract the emergence of ITH and diverse resistance mechanisms.
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http://dx.doi.org/10.1038/s43018-019-0020-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7842382PMC
April 2020

Evolution of DNA methylome from precancerous lesions to invasive lung adenocarcinomas.

Nat Commun 2021 01 29;12(1):687. Epub 2021 Jan 29.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.

The evolution of DNA methylome and methylation intra-tumor heterogeneity (ITH) during early carcinogenesis of lung adenocarcinoma has not been systematically studied. We perform reduced representation bisulfite sequencing of invasive lung adenocarcinoma and its precursors, atypical adenomatous hyperplasia, adenocarcinoma in situ and minimally invasive adenocarcinoma. We observe gradual increase of methylation aberrations and significantly higher level of methylation ITH in later-stage lesions. The phylogenetic patterns inferred from methylation aberrations resemble those based on somatic mutations suggesting parallel methylation and genetic evolution. De-convolution reveal higher ratio of T regulatory cells (Tregs) versus CD8 + T cells in later-stage diseases, implying progressive immunosuppression with neoplastic progression. Furthermore, increased global hypomethylation is associated with higher mutation burden, copy number variation burden and AI burden as well as higher Treg/CD8 ratio, highlighting the potential impact of methylation on chromosomal instability, mutagenesis and tumor immune microenvironment during early carcinogenesis of lung adenocarcinomas.
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http://dx.doi.org/10.1038/s41467-021-20907-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7846738PMC
January 2021

Patterns of transcription factor programs and immune pathway activation define four major subtypes of SCLC with distinct therapeutic vulnerabilities.

Cancer Cell 2021 03 21;39(3):346-360.e7. Epub 2021 Jan 21.

Department of Thoracic/Head & Neck Medical Oncology, the University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address:

Despite molecular and clinical heterogeneity, small cell lung cancer (SCLC) is treated as a single entity with predictably poor results. Using tumor expression data and non-negative matrix factorization, we identify four SCLC subtypes defined largely by differential expression of transcription factors ASCL1, NEUROD1, and POU2F3 or low expression of all three transcription factor signatures accompanied by an Inflamed gene signature (SCLC-A, N, P, and I, respectively). SCLC-I experiences the greatest benefit from the addition of immunotherapy to chemotherapy, while the other subtypes each have distinct vulnerabilities, including to inhibitors of PARP, Aurora kinases, or BCL-2. Cisplatin treatment of SCLC-A patient-derived xenografts induces intratumoral shifts toward SCLC-I, supporting subtype switching as a mechanism of acquired platinum resistance. We propose that matching baseline tumor subtype to therapy, as well as manipulating subtype switching on therapy, may enhance depth and duration of response for SCLC patients.
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http://dx.doi.org/10.1016/j.ccell.2020.12.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143037PMC
March 2021

KRT-232 and navitoclax enhance trametinib's anti-Cancer activity in non-small cell lung cancer patient-derived xenografts with KRAS mutations.

Am J Cancer Res 2020 1;10(12):4464-4475. Epub 2020 Dec 1.

Department of Thoracic and Cardiovascular Surgery, The University of Texas MD Anderson Cancer Center Houston, Texas, USA.

Activating mutations of the KRAS gene are one of the major genomic alterations associated with tumorigenesis of non-small cell lung cancer (NSCLC). Thus far, treatment of KRAS-mutant NSCLC remains an unmet medical need. We determined the treatment responses of 13 KRAS mutant and 14 KRAS wild type NSCLC patient-derived xenografts (PDXs) to agents that target known NSCLC vulnerabilities: the MEK inhibitor trametinib, the MDM2 inhibitor KRT-232, and the BCL-X/BCL-2 inhibitor navitoclax. The results showed that the tumor regression rate after single agent therapy with KRT-232, trametinib and navitoclax was 11%, 10% and 0%, respectively. Combination therapies of trametinib plus KRT-232 and trametinib plus navitoclax led to improved partial response rates over single-agent activity in a subset of PDX models. Tumor regression was observed in 23% and 50% of PDXs after treatment with trametinib plus KRT-232 and trametinib plus navitoclax, respectively. The disease control rates in KRAS-mutant PDXs tested were 90%-100% after treatment with trametinib plus KRT-232 or plus navitoclax. A correlation analysis of treatment responses and genomic and proteomic biomarkers revealed that sensitivity to KRT-232 was significantly associated with TP53 wild-type or STK11 mutant genotypes (P<0.05). The levels of several proteins, including GSK3b, Nrf2, LKB1/pS334, and SMYD3, were significantly associated with sensitivity to trametinib plus navitoclax. Thus, the combination of trametinib plus KRT-232 or navitoclax resulted in improved efficacy compared with the agents alone in a subgroup of NSCLC PDX model with KRAS mutations. Expanded clinical trials of these targeted drug combinations in NSCLC are warranted.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7783771PMC
December 2020

New Verse for a Familiar Song: Small Molecule Inhibitors for MET exon 14 Skipping Non-Small Cell Lung Cancer.

Oncologist 2020 10 27;25(10):822-825. Epub 2020 Aug 27.

Department of Thoracic Head and Neck Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, Texas, USA.

MET exon 14 skipping alterations (METex14) represent one of the newest discovered driver oncogene alterations for non-small cell lung cancer (NSCLC), which serve to define a distinct elderly patient population. New challenges in detection and treatment have emerged. In the last 15 years, the successes of tumor molecular profiling and therapeutic stratification in patients with advanced-stage disease have made NSCLC a poster child in the era of precision medicine. Each of the oncogenic drivers defines a distinct patient population. The selection of treatments based on oncogenic drivers such as EGFR, ALK, and ROS1, among others, has been transformative in terms of the duration and quality of life for patients with NSCLC receiving effective inhibitors. METex14 have emerged as one of the newest additions of driver oncogenes for NSCLC.
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http://dx.doi.org/10.1634/theoncologist.2020-0760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7543381PMC
October 2020

Characterization of the Immune Landscape of EGFR-Mutant NSCLC Identifies CD73/Adenosine Pathway as a Potential Therapeutic Target.

J Thorac Oncol 2021 04 31;16(4):583-600. Epub 2020 Dec 31.

Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas.

Introduction: Lung adenocarcinomas harboring EGFR mutations do not respond to immune checkpoint blockade therapy and their EGFR wildtype counterpart. The mechanisms underlying this lack of clinical response have been investigated but remain incompletely understood.

Methods: We analyzed three cohorts of resected lung adenocarcinomas (Profiling of Resistance Patterns of Oncogenic Signaling Pathways in Evaluation of Cancer of Thorax, Immune Genomic Profiling of NSCLC, and The Cancer Genome Atlas) and compared tumor immune microenvironment of EGFR-mutant tumors to EGFR wildtype tumors, to identify actionable regulators to target and potentially enhance the treatment response.

Results: EGFR-mutant NSCLC exhibited low programmed death-ligand 1, low tumor mutational burden, decreased number of cytotoxic T cells, and low T cell receptor clonality, consistent with an immune-inert phenotype, though T cell expansion ex vivo was preserved. In an analysis of 75 immune checkpoint genes, the top up-regulated genes in the EGFR-mutant tumors (NT5E and ADORA1) belonged to the CD73/adenosine pathway. Single-cell analysis revealed that the tumor cell population expressed CD73, both in the treatment-naive and resistant tumors. Using coculture systems with EGFR-mutant NSCLC cells, T regulatory cell proportion was decreased with CD73 knockdown. In an immune-competent mouse model of EGFR-mutant lung cancer, the CD73/adenosine pathway was markedly up-regulated and CD73 blockade significantly inhibited tumor growth.

Conclusions: Our work revealed that EGFR-mutant NSCLC has an immune-inert phenotype. We identified the CD73/adenosine pathway as a potential therapeutic target for EGFR-mutant NSCLC.
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http://dx.doi.org/10.1016/j.jtho.2020.12.010DOI Listing
April 2021

Genotype-Specific Differences in Circulating Tumor DNA Levels in Advanced NSCLC.

J Thorac Oncol 2021 04 31;16(4):601-609. Epub 2020 Dec 31.

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas. Electronic address:

Introduction: Plasma-based circulating tumor DNA (ctDNA) is an established biomarker for molecular profiling with emerging applications in disease monitoring in multiple tumor types, including, NSCLC. However, determinants of ctDNA shedding and correlation with tumor burden are incompletely understood, particularly in advanced-stage disease.

Methods: We retrospectively analyzed ctDNA-based and tissue-based genomic data and imaging from 144 patients with NSCLC. Tumor burden was quantified with computed tomography (CT) and brain magnetic resonance imaging for the overall cohort and 18F-fludeoxyglucose positron emission tomography-CT in a subset of patients.

Results: There was a moderate but statistically significant correlation between ctDNA variant allele frequency and multiple imaging measures of tumor burden such as CT volume (rho = 0.34, p ≤ 0.0001) and metabolic tumor volume (rho = 0.36, p = 0.003). This correlation was strongest in KRAS-mutant tumors (rho = 0.56, p ≤ 0.001), followed by TP53 mutants (rho = 0.43, p ≤ 0.0001), and weakest in EGFR-mutated (EGFR+) tumors (rho = 0.24, p = 0.077). EGFR+ tumors with EGFR copy number gain had significantly higher variant allele frequency than EGFR+ without copy number gain (p ≤ 0.00001). In multivariable analysis, TP53 and EGFR mutations, visceral metastasis, and tumor burden were independent predictors of increased ctDNA shedding.

Conclusions: Levels of detectable ctDNA were affected not only by tumor burden but also by tumor genotype. The genotype-specific differences observed may be due to variations in DNA shedding and cellular turnover. These findings have implications for the emerging use of ctDNA in NSCLC disease monitoring and early detection.
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http://dx.doi.org/10.1016/j.jtho.2020.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012216PMC
April 2021
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