Medical Abstracts

Keyword: lung cancer

1. Nature. 2019 Nov;575(7782):380-384. doi: 10.1038/s41586-019-1715-0. Epub 2019 Oct 30.

In vivo imaging of mitochondrial membrane potential in non-small-cell lung

cancer.

Momcilovic M(1), Jones A(2), Bailey ST(3), Waldmann CM(2), Li R(1), Lee

JT(2)(4)(5), Abdelhady G(1), Gomez A(6), Holloway T(2), Schmid E(7), Stout D(8),

Author information:

(1)Division of Pulmonary and Critical Care Medicine, Department of Medicine,

David Geffen School of Medicine at the University of California, Los Angeles, CA,

USA.

(2)Department of Molecular and Medical Pharmacology, David Geffen School of

Medicine at the University of California, Los Angeles, CA, USA.

(3)The Mouse Phase I Unit, Lineberger School of Medicine at the University of

North Carolina Chapel Hill, Chapel Hill, NC, USA.

Erratum in

Nature. 2020 Jan;577(7791):E7.

Comment in

Nature. 2019 Nov;575(7782):296-297.

Mitochondria are essential regulators of cellular energy and metabolism, and have

a crucial role in sustaining the growth and survival of cancer cells. A central

function of mitochondria is the synthesis of ATP by oxidative phosphorylation,

known as mitochondrial bioenergetics. Mitochondria maintain oxidative

phosphorylation by creating a membrane potential gradient that is generated by

the electron transport chain to drive the synthesis of ATP1. Mitochondria are

essential for tumour initiation and maintaining tumour cell growth in cell

culture and xenografts2,3. However, our understanding of oxidative mitochondrial

metabolism in cancer is limited because most studies have been performed in vitro

in cell culture models. This highlights a need for in vivo studies to better

understand how oxidative metabolism supports tumour growth. Here we measure

mitochondrial membrane potential in non-small-cell lung cancer in vivo using a

voltage-sensitive, positron emission tomography (PET) radiotracer known as

4-[18F]fluorobenzyl-triphenylphosphonium (18F-BnTP)4. By using PET imaging of

18F-BnTP, we profile mitochondrial membrane potential in autochthonous mouse

models of lung cancer, and find distinct functional mitochondrial heterogeneity

within subtypes of lung tumours. The use of 18F-BnTP PET imaging enabled us to

functionally profile mitochondrial membrane potential in live tumours.

DOI: 10.1038/s41586-019-1715-0

PMID: 31666695

2. Lancet. 2019 Nov 23;394(10212):1929-1939. doi: 10.1016/S0140-6736(19)32222-6.

Epub 2019 Oct 4.

Durvalumab plus platinum-etoposide versus platinum-etoposide in first-line

treatment of extensive-stage small-cell lung cancer (CASPIAN): a randomised,

controlled, open-label, phase 3 trial.

Paz-Ares L(1), Dvorkin M(2), Chen Y(3), Reinmuth N(4), Hotta K(5), Trukhin D(6),

Statsenko G(7), Hochmair MJ(8), Özgüro?lu M(9), Ji JH(10), Voitko O(11),

…

Author information:

(1)Department of Medical Oncology, Hospital Universitario 12 de Octubre,

H120-CNIO Lung Cancer Unit, Universidad Complutense and Ciberonc, Madrid, Spain.

Electronic address: lpazaresr@seom.org.

(2)BHI of Omsk Region Clinical Oncology Dispensary, Omsk, Russia.

(3)Cancer and Hematology Centers of Western Michigan, Grand Rapids, MI, USA.

…

Comment in

Lancet. 2019 Nov 23;394(10212):1884-1885.

BACKGROUND: Most patients with small-cell lung cancer (SCLC) have extensive-stage

disease at presentation, and prognosis remains poor. Recently, immunotherapy has

demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN

trial assessed durvalumab, with or without tremelimumab, in combination with

etoposide plus either cisplatin or carboplatin (platinum-etoposide) in

treatment-naive patients with ES-SCLC.

METHODS: This randomised, open-label, phase 3 trial was done at 209 sites across

23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO

performance status 0 or 1 and measurable disease as per Response Evaluation

Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a

1:1:1 ratio) to durvalumab plus platinum-etoposide; durvalumab plus tremelimumab

plus platinum-etoposide; or platinum-etoposide alone. All drugs were administered

intravenously. Platinum-etoposide consisted of etoposide 80-100 mg/m2 on days 1-3

of each cycle with investigator's choice of either carboplatin area under the

curve 5-6 mg/mL per min or cisplatin 75-80 mg/m2 (administered on day 1 of each

cycle). Patients received up to four cycles of platinum-etoposide plus durvalumab

1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance

durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles

of platinum-etoposide every 3 weeks plus prophylactic cranial irradiation

(investigator's discretion) in the platinum-etoposide group. The primary endpoint

was overall survival in the intention-to-treat population. We report results for

the durvalumab plus platinum-etoposide group versus the platinum-etoposide group

from a planned interim analysis. Safety was assessed in all patients who received

at least one dose of their assigned study treatment. This study is registered at

ClinicalTrials.gov, NCT03043872, and is ongoing.

FINDINGS: Patients were enrolled between March 27, 2017, and May 29, 2018. 268

patients were allocated to the durvalumab plus platinum-etoposide group and 269

to the platinum-etoposide group. Durvalumab plus platinum-etoposide was

associated with a significant improvement in overall survival, with a hazard

ratio of 0·73 (95% CI 0·59-0·91; p=0·0047]); median overall survival was 13·0

months (95% CI 11·5-14·8) in the durvalumab plus platinum-etoposide group versus

10·3 months (9·3-11·2) in the platinum-etoposide group, with 34% (26·9-41·0)

versus 25% (18·4-31·6) of patients alive at 18 months. Any-cause adverse events

of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab

plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide

group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients.

INTERPRETATION: First-line durvalumab plus platinum-etoposide significantly

improved overall survival in patients with ES-SCLC versus a clinically relevant

control group. Safety findings were consistent with the known safety profiles of

all drugs received.

FUNDING: AstraZeneca.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S0140-6736(19)32222-6

PMID: 31590988 [Indexed for MEDLINE]

3. N Engl J Med. 2019 Nov 21;381(21):2020-2031. doi: 10.1056/NEJMoa1910231. Epub

2019 Sep 28.

Nivolumab plus Ipilimumab in Advanced Non-Small-Cell Lung Cancer.

Hellmann MD(1), Paz-Ares L(1), Bernabe Caro R(1), Zurawski B(1), Kim SW(1),

…

Author information:

(1)From the Memorial Sloan Kettering Cancer Center, New York (M.D.H.); Hospital

Universitario Doce de Octubre, Centro Nacional de Investigaciones Oncológicas,

Universidad Complutense, and Centro de Investigación Biomédica en Red de Cáncer,

Madrid (L.P.-A.), Hospital Universitario Virgen Del Rocio, Seville (R.B.C.),…

Comment in

N Engl J Med. 2020 Feb 27;382(9):874.

N Engl J Med. 2020 Feb 27;382(9):874-875.

BACKGROUND: In an early-phase study involving patients with advanced

non-small-cell lung cancer (NSCLC), the response rate was better with nivolumab

plus ipilimumab than with nivolumab monotherapy, particularly among patients with

tumors that expressed programmed death ligand 1 (PD-L1). Data are needed to

assess the long-term benefit of nivolumab plus ipilimumab in patients with NSCLC.

METHODS: In this open-label, phase 3 trial, we randomly assigned patients with

stage IV or recurrent NSCLC and a PD-L1 expression level of 1% or more in a 1:1:1

ratio to receive nivolumab plus ipilimumab, nivolumab alone, or chemotherapy. The

patients who had a PD-L1 expression level of less than 1% were randomly assigned

in a 1:1:1 ratio to receive nivolumab plus ipilimumab, nivolumab plus

chemotherapy, or chemotherapy alone. All the patients had received no previous

chemotherapy. The primary end point reported here was overall survival with

nivolumab plus ipilimumab as compared with chemotherapy in patients with a PD-L1

expression level of 1% or more.

RESULTS: Among the patients with a PD-L1 expression level of 1% or more, the

median duration of overall survival was 17.1 months (95% confidence interval

[CI], 15.0 to 20.1) with nivolumab plus ipilimumab and 14.9 months (95% CI, 12.7

to 16.7) with chemotherapy (P = 0.007), with 2-year overall survival rates of

40.0% and 32.8%, respectively. The median duration of response was 23.2 months

with nivolumab plus ipilimumab and 6.2 months with chemotherapy. The overall

survival benefit was also observed in patients with a PD-L1 expression level of

less than 1%, with a median duration of 17.2 months (95% CI, 12.8 to 22.0) with

nivolumab plus ipilimumab and 12.2 months (95% CI, 9.2 to 14.3) with

chemotherapy. Among all the patients in the trial, the median duration of overall

survival was 17.1 months (95% CI, 15.2 to 19.9) with nivolumab plus ipilimumab

and 13.9 months (95% CI, 12.2 to 15.1) with chemotherapy. The percentage of

patients with grade 3 or 4 treatment-related adverse events in the overall

population was 32.8% with nivolumab plus ipilimumab and 36.0% with chemotherapy.

CONCLUSIONS: First-line treatment with nivolumab plus ipilimumab resulted in a

longer duration of overall survival than did chemotherapy in patients with NSCLC,

independent of the PD-L1 expression level. No new safety concerns emerged with

longer follow-up. (Funded by Bristol-Myers Squibb and Ono Pharmaceutical;

CheckMate 227 ClinicalTrials.gov number, NCT02477826.).

Copyright © 2019 Massachusetts Medical Society.

DOI: 10.1056/NEJMoa1910231

PMID: 31562796 [Indexed for MEDLINE]

4. Nat Commun. 2019 Nov 29;10(1):5444. doi: 10.1038/s41467-019-13334-8.

A high-throughput screen identifies that CDK7 activates glucose consumption in

lung cancer cells.

Ghezzi C(1)(2), Wong A(1)(2), Chen BY(1)(2), Ribalet B(3), Damoiseaux R(1)(2)(4),

Clark PM(5)(6)(7)(8).

Author information:

(1)Crump Institute for Molecular Imaging, University of California, Los Angeles,

CA, 90095, USA.

(2)Department of Molecular and Medical Pharmacology, University of California,

Los Angeles, CA, 90095, USA.

(3)Department of Physiology, University of California, Los Angeles, CA, 90095,

USA.

…

Elevated glucose consumption is fundamental to cancer, but selectively targeting

this pathway is challenging. We develop a high-throughput assay for measuring

glucose consumption and use it to screen non-small-cell lung cancer cell lines

against bioactive small molecules. We identify Milciclib that blocks glucose

consumption in H460 and H1975, but not in HCC827 or A549 cells, by decreasing

SLC2A1 (GLUT1) mRNA and protein levels and by inhibiting glucose transport.

Milciclib blocks glucose consumption by targeting cyclin-dependent kinase 7

(CDK7) similar to other CDK7 inhibitors including THZ1 and LDC4297. Enhanced

PIK3CA signaling leads to CDK7 phosphorylation, which promotes RNA Polymerase II

phosphorylation and transcription. Milciclib, THZ1, and LDC4297 lead to a

reduction in RNA Polymerase II phosphorylation on the SLC2A1 promoter. These data

indicate that our high-throughput assay can identify compounds that regulate

glucose consumption and that CDK7 is a key regulator of glucose consumption in

cells with an activated PI3K pathway.

DOI: 10.1038/s41467-019-13334-8

PMCID: PMC6884612

PMID: 31784510 [Indexed for MEDLINE]

5. Nat Commun. 2019 Nov 22;10(1):5324. doi: 10.1038/s41467-019-13331-x.

Causative role of PDLIM2 epigenetic repression in lung cancer and therapeutic

resistance.

Sun F(1)(2), Li L(1)(2), Yan P(1)(2)(3), Zhou J(1)(2), Shapiro SD(4), Xiao

G(5)(6), Qu Z(7)(8).

Author information:

(1)UPMC Hillman Cancer Center, Pittsburgh, PA, 15213, USA.

(2)Department of Microbiology and Molecular Genetics, University of Pittsburgh

School of Medicine, Pittsburgh, PA, 15213, USA.

(3)Chemical Biology Program, Memorial Sloan-Kettering Cancer Center, New York,

NY, USA.

Most cancers are resistant to anti-PD-1/PD-L1 and chemotherapy. Herein we

identify PDLIM2 as a tumor suppressor particularly important for lung cancer

therapeutic responses. While PDLIM2 is epigenetically repressed in human lung

cancer, associating with therapeutic resistance and poor prognosis, its global or

lung epithelial-specific deletion in mice causes increased lung cancer

development, chemoresistance, and complete resistance to anti-PD-1 and epigenetic

drugs. PDLIM2 epigenetic restoration or ectopic expression shows antitumor

activity, and synergizes with anti-PD-1, notably, with chemotherapy for complete

remission of most lung cancers. Mechanistically, through repressing NF-κB/RelA

and STAT3, PDLIM2 increases expression of genes involved in antigen presentation

and T-cell activation while repressing multidrug resistance genes and

cancer-related genes, thereby rendering cancer cells vulnerable to immune attacks

and therapies. We identify PDLIM2-independent PD-L1 induction by chemotherapeutic

and epigenetic drugs as another mechanism for their synergy with anti-PD-1. These

findings establish a rationale to use combination therapies for cancer treatment.

DOI: 10.1038/s41467-019-13331-x

PMCID: PMC6876573

PMID: 31757943 [Indexed for MEDLINE]

6. Genes Dev. 2019 Dec 1;33(23-24):1718-1738. doi: 10.1101/gad.328336.119. Epub 2019 Nov 14.

The KDM5A/RBP2 histone demethylase represses NOTCH signaling to sustain

neuroendocrine differentiation and promote small cell lung cancer tumorigenesis.

Oser MG(1)(2)(3), Sabet AH(1), Gao W(1)(3), Chakraborty AA(1)(3), Schinzel AC(1),

Jennings RB(1)(4), Fonseca R(1), Bonal DM(1)(5), Booker MA(6), Flaifel A(1)(4),

…

Author information:

(1)Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and

Women's Hospital, Harvard Medical School, Boston, Massachusetts 02215, USA.

(2)Lowe Center for Thoracic Oncology, Dana-Farber Cancer Institute, Boston,

Massachusetts 02215, USA.

(3)Department of Medicine, Brigham and Women's Hospital, Harvard Medical School,

Massachusetts 02115, USA.

More than 90% of small cell lung cancers (SCLCs) harbor loss-of-function

mutations in the tumor suppressor gene RB1 The canonical function of the RB1 gene

product, pRB, is to repress the E2F transcription factor family, but pRB also

functions to regulate cellular differentiation in part through its binding to the

histone demethylase KDM5A (also known as RBP2 or JARID1A). We show that KDM5A

promotes SCLC proliferation and SCLC's neuroendocrine differentiation phenotype

in part by sustaining expression of the neuroendocrine transcription factor

ASCL1. Mechanistically, we found that KDM5A sustains ASCL1 levels and

neuroendocrine differentiation by repressing NOTCH2 and NOTCH target genes. To

test the role of KDM5A in SCLC tumorigenesis in vivo, we developed a

CRISPR/Cas9-based mouse model of SCLC by delivering an adenovirus (or an

adeno-associated virus [AAV]) that expresses Cre recombinase and sgRNAs targeting

Rb1, Tp53, and Rbl2 into the lungs of Lox-Stop-Lox Cas9 mice. Coinclusion of a

KDM5A sgRNA decreased SCLC tumorigenesis and metastasis, and the SCLCs that

formed despite the absence of KDM5A had higher NOTCH activity compared to KDM5A

+/+ SCLCs. This work establishes a role for KDM5A in SCLC tumorigenesis and

suggests that KDM5 inhibitors should be explored as treatments for SCLC.

© 2019 Oser et al.; Published by Cold Spring Harbor Laboratory Press.

DOI: 10.1101/gad.328336.119

PMCID: PMC6942053 [Available on 2020-06-01]

PMID: 31727771 [Indexed for MEDLINE]

7. Nat Commun. 2019 Nov 12;10(1):5125. doi: 10.1038/s41467-019-12832-z.

ZEB1/NuRD complex suppresses TBC1D2b to stimulate E-cadherin internalization and

promote metastasis in lung cancer.

Manshouri R(1)(2), Coyaud E(3), Kundu ST(1)(2), Peng DH(1)(2), Stratton SA(4),

Alton K(4), Bajaj R(1)(2), Fradette JJ(1)(2), Minelli R(5), Peoples MD(5), Carugo

A(6), Chen F(7), Bristow C(6), Kovacs JJ(6), Barton MC(4), Heffernan T(6),

Creighton CJ(7), Raught B(3), Gibbons DL(8)(9).

Author information:

(1)Department of Thoracic/Head and Neck Medical Oncology, The University of Texas

MD Anderson Cancer Center, Houston, TX, 77030, USA.

(2)Department of Molecular and Cellular Oncology, The University of Texas MD

Anderson Cancer Center, Houston, TX, 77030, USA.

(3)Department of Medical Biophysics, Princess Margaret Cancer Centre, University

of Toronto, Toronto, ON, M5S 1A1, Canada.

…

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death

worldwide, due in part to the propensity of lung cancer to metastasize. Aberrant

epithelial-to-mesenchymal transition (EMT) is a proposed model for the initiation

of metastasis. During EMT cell-cell adhesion is reduced allowing cells to

dissociate and invade. Of the EMT-associated transcription factors, ZEB1 uniquely

promotes NSCLC disease progression. Here we apply two independent screens, BioID

and an Epigenome shRNA dropout screen, to define ZEB1 interactors that are

critical to metastatic NSCLC. We identify the NuRD complex as a ZEB1 co-repressor

and the Rab22 GTPase-activating protein TBC1D2b as a ZEB1/NuRD complex target. We

find that TBC1D2b suppresses E-cadherin internalization, thus hindering cancer

cell invasion and metastasis.

DOI: 10.1038/s41467-019-12832-z

PMCID: PMC6851102

PMID: 31719531 [Indexed for MEDLINE]

8. Nat Commun. 2019 Nov 6;10(1):5043. doi: 10.1038/s41467-019-12925-9.

Nestin regulates cellular redox homeostasis in lung cancer through the Keap1-Nrf2

feedback loop.

Wang J(1)(2), Lu Q(1)(2), Cai J(2)(3), Wang Y(1)(2), Lai X(4), Qiu Y(1)(2), Huang

Y(2)(5), Ke Q(1)(2), Zhang Y(1)(2), Guan Y(6), Wu H(2), Wang Y(2), Liu X(2), Shi

Y(2), Zhang K(7), Wang M(8), Peng Xiang A(9)(10)(11)(12)(13).

Author information:

(1)Program of Stem Cells and Regenerative Medicine, Affiliated Guangzhou Women

and Children's Hospital, Zhongshan School of Medicine, Sun Yat-Sen University,

Guangzhou, China.

(2)Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem

Cells and Tissue Engineering, Ministry of Education, Sun Yat-Sen University,

Guangzhou, China.

(3)Department of Hepatic Surgery and Liver Transplantation Center of the Third

Affiliated Hospital, Organ Transplantation Institute, Sun Yat-Sen University,

Guangzhou, China.

…

Abnormal cancer antioxidant capacity is considered as a potential mechanism of

tumor malignancy. Modulation of oxidative stress status is emerging as an

anti-cancer treatment. Our previous studies have found that Nestin-knockdown

cells were more sensitive to oxidative stress in non-small cell lung cancer

(NSCLC). However, the molecular mechanism by which Nestin protects cells from

oxidative damage remains unclear. Here, we identify a feedback loop between

Nestin and Nrf2 maintaining the redox homeostasis. Mechanistically, the ESGE

motif of Nestin interacts with the Kelch domain of Keap1 and competes with Nrf2

for Keap1 binding, leading to Nrf2 escaping from Keap1-mediated degradation,

subsequently promoting antioxidant enzyme generation. Interestingly, we also map

that the antioxidant response elements (AREs) in the Nestin promoter are

responsible for its induction via Nrf2. Taken together, our results indicate that

the Nestin-Keap1-Nrf2 axis regulates cellular redox homeostasis and confers

oxidative stress resistance in NSCLC.

DOI: 10.1038/s41467-019-12925-9

PMCID: PMC6834667

PMID: 31695040 [Indexed for MEDLINE]

9. Sci Transl Med. 2019 Nov 6;11(517). pii: eaaw7852. doi:

10.1126/scitranslmed.aaw7852.

Identification of DHODH as a therapeutic target in small cell lung cancer.

Li L(1), Ng SR(1)(2), Colón CI(1), Drapkin BJ(3), Hsu PP(1)(3)(4), Li Z(1)(2),

Nabel CS(1)(3)(4), Lewis CA(5), Romero R(1)(2), Mercer KL(1)(6), Bhutkar A(1),

Phat S(3), Myers DT(3), Muzumdar MD(1), Westcott PMK(1), Beytagh MC(1), Farago

AF(3)(7)(8), Vander Heiden MG(1)(2)(4), Dyson NJ(3)(8), Jacks T(9)(2)(6).

Author information:

(1)David H. Koch Institute for Integrative Cancer Research, Massachusetts

Institute of Technology, Cambridge, MA 02139, USA.

(2)Department of Biology, Massachusetts Institute of Technology, Cambridge, MA

02139, USA.

(3)Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA.

…

Small cell lung cancer (SCLC) is an aggressive lung cancer subtype with extremely

poor prognosis. No targetable genetic driver events have been identified, and the

treatment landscape for this disease has remained nearly unchanged for over 30

years. Here, we have taken a CRISPR-based screening approach to identify genetic

vulnerabilities in SCLC that may serve as potential therapeutic targets. We used

a single-guide RNA (sgRNA) library targeting ~5000 genes deemed to encode

"druggable" proteins to perform loss-of-function genetic screens in a panel of

cell lines derived from autochthonous genetically engineered mouse models (GEMMs)

of SCLC, lung adenocarcinoma (LUAD), and pancreatic ductal adenocarcinoma (PDAC).

Cross-cancer analyses allowed us to identify SCLC-selective vulnerabilities. In

particular, we observed enhanced sensitivity of SCLC cells toward disruption of

the pyrimidine biosynthesis pathway. Pharmacological inhibition of dihydroorotate

dehydrogenase (DHODH), a key enzyme in this pathway, reduced the viability of

SCLC cells in vitro and strongly suppressed SCLC tumor growth in human

patient-derived xenograft (PDX) models and in an autochthonous mouse model. These

results indicate that DHODH inhibition may be an approach to treat SCLC.

Copyright © 2019 The Authors, some rights reserved; exclusive licensee American

Association for the Advancement of Science. No claim to original U.S. Government

Works.

DOI: 10.1126/scitranslmed.aaw7852

PMID: 31694929

10. J Clin Oncol. 2020 Jan 10;38(2):115-123. doi: 10.1200/JCO.19.01488. Epub 2019 Nov 4.

Gefitinib Alone Versus Gefitinib Plus Chemotherapy for Non-Small-Cell Lung Cancer

With Mutated Epidermal Growth Factor Receptor: NEJ009 Study.

Hosomi Y(1), Morita S(2), Sugawara S(3), Kato T(4), Fukuhara T(5), Gemma A(6),

Takahashi K(7), Fujita Y(8), Harada T(9), Minato K(10), Takamura K(11), Hagiwara

K(12), Kobayashi K(13), Nukiwa T(14), Inoue A(15); North-East Japan Study Group.

Author information:

(1)Tokyo Metropolitan Komagome Hospital, Tokyo, Japan.

(2)Kyoto University Graduate School of Medicine, Kyoto, Japan.

(3)Sendai Kousei Hospital, Sendai, Japan.

…

PURPOSE: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor

combined with cytotoxic chemotherapy is highly effective for the treatment of

advanced non-small-cell lung cancer (NSCLC) with EGFR mutations; however, little

is known about the efficacy and safety of this combination compared with that of

standard therapy with EGFR- tyrosine kinase inhibitors alone.

METHODS: We randomly assigned 345 patients with newly diagnosed metastatic NSCLC

with EGFR mutations to gefitinib combined with carboplatin plus pemetrexed or

gefitinib alone. Progression-free survival (PFS), PFS2, and overall survival (OS)

were sequentially analyzed as primary end points according to a hierarchical

sequential testing method. Secondary end points were objective response rate

(ORR), safety, and quality of life.

RESULTS: The combination group demonstrated a better ORR and PFS than the

gefitinib group (ORR, 84% v 67% [P < .001]; PFS, 20.9 v 11.9 months; hazard ratio

for death or disease progression, 0.490 [P < .001]), although PFS2 was not

significantly different (20.9 v 18.0 months; P = .092). Median OS in the

combination group was also significantly longer than in the gefitinib group (50.9

v 38.8 months; hazard ratio for death, 0.722; P = .021). The rate of grade ≥ 3

treatment-related adverse events, such as hematologic toxicities, in the

combination group was higher than in the gefitinib group (65.3% v 31.0%); there

were no differences in quality of life. One treatment-related death was observed

in the combination group.

CONCLUSION: Compared with gefitinib alone, gefitinib combined with carboplatin

plus pemetrexed improved PFS in patients with untreated advanced NSCLC with EGFR

mutations with an acceptable toxicity profile, although its OS benefit requires

further validation.

DOI: 10.1200/JCO.19.01488

PMID: 31682542

11. Clin Cancer Res. 2019 Nov 26. doi: 10.1158/1078-0432.CCR-19-2541. [Epub ahead of print]

Release of Circulating Tumor Cells during Surgery for Non-Small Cell Lung Cancer:

Are They What They Appear to Be?

Tamminga M(1), de Wit S(2), van de Wauwer C(3), van den Bos H(4), Swennenhuis

JF(2), Klinkenberg TJ(3), Hiltermann TJN(5), Andree KC(2), Spierings DCJ(4),

Lansdorp PM(4)(6)(7), van den Berg A(8), Timens W(8), Terstappen LWMM(2), Groen

HJM(1).

Author information:

(1)Department of Pulmonary Diseases, University Medical Center Groningen,

University of Groningen, Groningen, the Netherlands. m.tamminga@umcg.nl

h.j.m.groen@umcg.nl.

(2)Department of Medical Cell BioPhysics, Faculty of Sciences and Technology,

University of Twente, Enschede, the Netherlands.

(3)Department of Cardiothoracic Surgery, University Medical Center Groningen,

University of Groningen, Groningen, the Netherlands.

…

PURPOSE: Tumor cells from patients with lung cancer are expelled from the primary

tumor into the blood, but difficult to detect in the peripheral circulation. We

studied the release of circulating tumor cells (CTCs) during surgery to test the

hypothesis that CTC counts are influenced by hemodynamic changes (caused by

surgical approach) and manipulation.

EXPERIMENTAL DESIGN: Patients undergoing video-assisted thoracic surgery (VATS)

or open surgery for (suspected) primary lung cancer were included. Blood samples

were taken before surgery (T0) from the radial artery (RA), from both the RA and

pulmonary vein (PV) when the PV was located (T1) and when either the pulmonary

artery (T2 open) or the PV (T2 VATS) was dissected. The CTCs were enumerated

using the CellSearch system. Single-cell whole-genome sequencing was performed on

isolated CTCs for aneuploidy.

RESULTS: CTCs were detected in 58 of 138 samples (42%) of 31 patients. CTCs were

more often detected in the PV (70%) compared with the RA (22%, P < 0.01) and in

higher counts (P < 0.01). After surgery, the RA but not the PV showed less often

CTCs (P = 0.02). Type of surgery did not influence CTC release. Only six of 496

isolated CTCs showed aneuploidy, despite matched primary tumor tissue being

aneuploid. Euploid so-called CTCs had a different morphology than aneuploid.

CONCLUSIONS: CTCs defined by CellSearch were identified more often and in higher

numbers in the PV compared with the RA, suggesting central clearance. The

majority of cells in the PV were normal epithelial cells and outnumbered CTCs.

Release of CTCs was not influenced by surgical approach.

©2019 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-19-2541

PMID: 31772122

12. Cancer. 2020 Jan 15;126(2):373-380. doi: 10.1002/cncr.32503. Epub 2019 Nov 26.

Epidermal growth factor receptor mutation analysis in tissue and plasma from the

AURA3 trial: Osimertinib versus platinum-pemetrexed for T790M mutation-positive

advanced non-small cell lung cancer.

Papadimitrakopoulou VA(1), Han JY(2), Ahn MJ(3), Ramalingam SS(4), Delmonte A(5),

Hsia TC(6), Laskin J(7), Kim SW(8), He Y(9), Tsai CM(10), Hida T(11), Maemondo

M(12), Kato T(13), Jenkins S(14), Patel S(14), Huang X(14), Laus G(15), Markovets

A(16), Thress KS(17), Wu YL(18), Mok T(19).

Author information:

(1)The University of Texas MD Anderson Cancer Center, Houston, Texas.

(2)Center for Lung Cancer, National Cancer Center, Goyang, Republic of Korea.

(3)Samsung Medical Center, School of Medicine, Sungkyunkwan University, Seoul,

Republic of Korea.

…

BACKGROUND: This study assesses different technologies for detecting epidermal

growth factor receptor (EGFR) mutations from circulating tumor DNA in patients

with EGFR T790M-positive advanced non-small cell lung cancer (NSCLC) from the

AURA3 study (NCT02151981), and it evaluates clinical responses to osimertinib and

platinum-pemetrexed according to the plasma T790M status.

METHODS: Tumor tissue biopsy samples were tested for T790M during screening with

the cobas EGFR Mutation Test (cobas tissue). Plasma samples were collected at

screening and at the baseline and were retrospectively analyzed for EGFR

mutations with the cobas EGFR Mutation Test v2 (cobas plasma), droplet digital

polymerase chain reaction (ddPCR; Biodesix), and next-generation sequencing (NGS;

Guardant360, Guardant Health).

RESULTS: With cobas tissue test results as a reference, the plasma T790M positive

percent agreement (PPA) was 51% (110 of 215 samples) by cobas plasma, 58% (110 of

189) by ddPCR, and 66% (136 of 207) by NGS. Plasma T790M detection was associated

with a larger median baseline tumor size (56 mm for T790M-positive vs 39 mm for

T790M-negative; P < .0001) and the presence of extrathoracic disease (58% for

M1b-positive vs 39% for M0-1a-positive; P = .002). Progression-free survival

(PFS) was prolonged in randomized patients (tissue T790M-positive) with a

T790M-negative cobas plasma result in comparison with those with a T790M-positive

plasma result in both osimertinib (median, 12.5 vs 8.3 months) and

platinum-pemetrexed groups (median, 5.6 vs 4.2 months).

CONCLUSIONS: PPA was similar between ddPCR and NGS assays; both were more

sensitive than cobas plasma. All 3 test platforms are suitable for routine

clinical practice. In patients with tissue T790M-positive NSCLC, an absence of

detectable plasma T790M at the baseline is associated with longer PFS, which may

be attributed to a lower disease burden.

© 2019 American Cancer Society.

DOI: 10.1002/cncr.32503

PMID: 31769875

13. Cell Cycle. 2020 Jan;19(1):97-108. doi: 10.1080/15384101.2019.1693189. Epub 2019 Nov 24.

Downregulation of lumican enhanced mitotic defects and aneuploidy in lung cancer

cells.

Yang CT(1)(2), Hsu PC(1), Chow SE(3)(4).

Author information:

(1)Department of Thoracic Medicine, Chang Gung Memorial Hospital, Taoyuan,

Taiwan.

(2)Department of Respiratory Therapy, College of Medicine, Chang Gung University,

Taoyuan, Taiwan.

(3)Department of Otolaryngology, Head and Neck Surgery, Chang Gung Memorial

Hospital, Taoyuan, Taiwan.

(4)Department of Nature Science, Center for General Studies, Chang Gung

University, Taoyuan, Taiwan.

Lumican is overexpressed in lung cancer cells and has been implicated in the

pathogenesis of tumorigenesis and regulation of cancer cell invasion. Lumican is

robustly associated with the binding of p120-catenin protein to modulate cell

metastasis. However, its role in cancer cell proliferation is still unclear. This

study investigated the effect of lumican on the cell division including mitosis

and cytokinesis in non-small lung cancer cells. We found that the downregulation

of lumican prolonged the doubling time of cells and retarded the cell growth in

H460 and A549 cells. Along with tubulin, lumican localized to the mitotic spindle

and centrosome during the metaphase-anaphase stage. The cell cycle was retained

in the G2/M phase after the downregulation of lumican. Interestingly, lumican was

found to play important roles in central spindle and midbody formation during

cytokinesis. Lumican interacted with the midbody-associated proteins such as

MKLP1, Aurora B, and ECT2. Notably, the downregulation of lumican decreased the

level of MKLP1 accompanied by the retention of midbody-residual that resulted in

multi-nucleated cells. Downregulation of lumican promoted the chromosome

missegregation and the increment of the bi-/multinucleated cells. The results of

this study indicated that lumican associated with tubulin is crucial for spindle

fiber formation and midbody assembly in cell division. Downregulation of lumican

displayed the defects in mitotic spindle assembly/dynamics and improper

kinetochore-microtubules attachment that led to increase aneuploidy. This

emerging property of lumican is suggested to tightly control chromosome

segregation during cell division in lung cancer cells.Abbreviations: ESCRT:

endosomal sorting complex required for transport; PRC1: protein regulator of

cytokinesis 1; Nci: negative control siRNA; Lumi: lumican siRNAs; MKLP1: mitotic

kinesin-like protein 1; H460LD and A549LD: H460 and A549 cell lines with less

expressed lumican.

DOI: 10.1080/15384101.2019.1693189

PMCID: PMC6927699 [Available on 2020-11-24]

PMID: 31760859

14. Oncotarget. 2019 Nov 5;10(60):6456-6465. doi: 10.18632/oncotarget.27290.

eCollection 2019 Nov 5.

Secretome of pleural effusions associated with non-small cell lung cancer (NSCLC)

and malignant mesothelioma: therapeutic implications.

Donnenberg AD(1)(2)(3), Luketich JD(2)(4), Donnenberg VS(2)(3)(4).

Author information:

(1)University of Pittsburgh School of Medicine, Department of Medicine,

Pittsburgh, PA, USA.

(2)UPMC Hillman Cancer Centers, Pittsburgh, PA, USA.

(3)McGowan Institute for Regenerative Medicine, Pittsburgh, PA, USA.

(4)University of Pittsburgh School of Medicine, Department of Cardiothoracic

Surgery, Pittsburgh, PA, USA.

INTRODUCTION: We compared the secretome of metastatic (non-small cell lung cancer

(NSCLC)) and primary (mesothelioma) malignant pleural effusions, benign effusions

and the published plasma profile of patients receiving chimeric antigen receptor

T cells (CAR-T), to determine factors unique to neoplasia in pleural effusion

(PE) and those accompanying an efficacious peripheral anti-tumor immune response.

MATERIALS AND METHODS: Cryopreserved cell-free PE fluid from 101 NSCLC patients,

8 mesothelioma and 13 with benign PE was assayed for a panel of 40

cytokines/chemokines using the Luminex system.

RESULTS: Profiles of benign and malignant PE were dominated by high

concentrations of sIL-6Rα, CCL2/MCP1, CXCL10/IP10, IL-6, TGFβ1, CCL22/MDC,

CXCL8/IL-8 and IL-10. Malignant PE contained significantly higher (p < 0.01,

Bonferroni-corrected) concentrations of MIP1β, CCL22/MDC, CX3CL1/fractalkine,

IFNα2, IFNγ, VEGF, IL-1α and FGF2. When grouped by function, mesothelioma PE had

lower effector cytokines than NSCLC PE. Comparing NSCLC PE and published plasma

levels of CAR-T recipients, both were dominated by sIL-6Rα and IL-6 but NSCLC PE

had more VEGF, FGF2 and TNFα, and less IL-2, IL-4, IL-13, IL-15, MIP1α and IFNγ.

CONCLUSIONS: An immunosuppressive, wound-healing environment characterizes both

benign and malignant PE. A dampened effector response (IFNα2, IFNγ, MIP1α, TNFα

and TNFβ) was detected in NSCLC PE, but not mesothelioma or benign PE. The data

indicate that immune effectors are present in NSCLC PE and suggest that the

IL-6/sIL-6Rα axis is a central driver of the immunosuppressive, tumor-supportive

pleural environment. A combination localized antibody-based immunotherapy with or

without cellular therapy may be justified in this uniformly fatal condition.

DOI: 10.18632/oncotarget.27290

PMCID: PMC6849644

PMID: 31741710

Conflict of interest statement: CONFLICTS OF INTEREST The authors have no

conflicts of interest to report.

15. Chest. 2019 Nov 15. pii: S0012-3692(19)34213-8. doi: 10.1016/ j.chest. 2019.10.042.

[Epub ahead of print]

Sensitivity of Radial Endobronchial Ultrasound-Guided Bronchoscopy for Lung

Cancer in Patients With Peripheral Pulmonary Lesions: An Updated Meta-analysis.

Sainz Zuñiga PV(1), Vakil E(2), Molina S(1), Bassett RL Jr(3), Ost DE(4).

Author information:

(1)School of Medicine and Health Sciences, Tecnologico de Monterrey, Monterrey,

NL, Mexico.

(2)Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer

Center, Houston, TX.

(3)Department of Biostatistics, The University of Texas MD Anderson Cancer

Center, Houston, TX.

(4)Department of Pulmonary Medicine, The University of Texas MD Anderson Cancer

Center, Houston, TX. Electronic address: dost@mdanderson.org.

BACKGROUND: Registry trials have found radial endobronchial ultrasound (r-EBUS)

sensitivity to vary between institutions, suggesting that in clinical practice,

r-EBUS sensitivity may be lower than reported in clinical trials. We performed a

meta-analysis to update the estimates of r-EBUS sensitivity and to explore

factors contributing to heterogeneity of results.

METHODS: A systematic review using PubMed was performed through July 2018 to

determine the sensitivity of r-EBUS for lung cancer, and to construct a summary

receiver operating characteristic curve. The DerSimonian and Laird method was

used to weight results. Subgroup analysis and meta-regression was used to

identify sources of heterogeneity. Study quality was assessed using the QUADAS

tool, and publication bias was tested using funnel plots.

RESULTS: Fifty-one studies with a total of 7,601 patients were included. r-EBUS

pooled sensitivity was 0.72 (95% CI, 0.70-0.75), and area under the sROC curve

was 0.96 (95% CI, 0.94-0.97). Significant heterogeneity was observed (I2 = 76%;

heterogeneity P < .01). We failed to demonstrate an association between

sensitivity and air bronchus sign, average nodule size, use of fluoroscopy,

virtual bronchoscopy, guide sheath, cancer prevalence, multicenter status, or

consecutive enrollment. Rapid onsite cytology was associated with increased

sensitivity (P = .01). The pooled pneumothorax rate was 0.7% (95% CI, 0.3%-1.1%).

Funnel plots were asymmetrical, demonstrating sample size-related effects and

possible publication bias.

CONCLUSIONS: r-EBUS has an excellent safety profile, but there is significant

between-study heterogeneity. Sample size-related effects and possibly publication

bias have led to overly optimistic estimates of the sensitivity of r-EBUS.

Copyright © 2019. Published by Elsevier Inc.

DOI: 10.1016/j.chest.2019.10.042

PMID: 31738928

16. Clin Cancer Res. 2019 Nov 15;25(22):6671-6682. doi:

10.1158/1078-0432.CCR-19-1176. Epub 2019 Aug 22.

Acquired Resistance Mutations to ALK Inhibitors Identified by Single Circulating

Tumor Cell Sequencing in ALK-Rearranged Non-Small-Cell Lung Cancer.

Pailler E(1)(2)(3), Faugeroux V(1)(2)(3), Oulhen M(1)(2), Mezquita L(4), Laporte

M(5), Honoré A(5), Lecluse Y(6), Queffelec P(1)(2), NgoCamus M(4), Nicotra C(4),

Remon J(4), Lacroix L(5), Planchard D(4), Friboulet L(2)(3), Besse B(#)(3)(4),

Farace F(#)(7)(2)(3).

Author information:

(1)Gustave Roussy, Université Paris-Saclay, "Rare Circulating Cells"

Translational Platform, CNRS UMS3655 - INSERM US23 AMMICA, Villejuif, France.

(2)INSERM, U981 "Identification of Molecular Predictors and New Targets for

Cancer Treatment," Villejuif, France.

(3)Univ Paris Sud, Université Paris-Saclay, Faculty of Medicine, Le

Kremlin-Bicêtre, France.

…

PURPOSE: Patients with anaplastic lymphoma kinase (ALK)-rearranged non-small-cell

lung cancer (NSCLC) inevitably develop resistance to ALK inhibitors. New

diagnostic strategies are needed to assess resistance mechanisms and provide

patients with the most effective therapy. We asked whether single circulating

tumor cell (CTC) sequencing can inform on resistance mutations to ALK inhibitors

and underlying tumor heterogeneity in ALK-rearranged NSCLC.

EXPERIMENTAL DESIGN: Resistance mutations were investigated in CTCs isolated at

the single-cell level from patients at disease progression on crizotinib (n = 14)

or lorlatinib (n = 3). Three strategies including filter laser-capture

microdissection, fluorescence activated cell sorting, and the DEPArray were used.

One hundred twenty-six CTC pools and 56 single CTCs were isolated and sequenced.

Hotspot regions over 48 cancer-related genes and 14 ALK mutations were examined

to identify ALK-independent and ALK-dependent resistance mechanisms.

RESULTS: Multiple mutations in various genes in ALK-independent pathways were

predominantly identified in CTCs of crizotinib-resistant patients. The RTK-KRAS

(EGFR, KRAS, BRAF genes) and TP53 pathways were recurrently mutated. In one

lorlatinib-resistant patient, two single CTCs out of 12 harbored ALK compound

mutations. CTC-1 harbored the ALK G1202R/F1174C compound mutation virtually

similar to ALK G1202R/F1174L present in the corresponding tumor biopsy. CTC-10

harbored a second ALK G1202R/T1151M compound mutation not detected in the tumor

biopsy. By copy-number analysis, CTC-1 and the tumor biopsy had similar profiles,

whereas CTC-10 harbored multiple copy-number alterations and whole-genome

duplication.

CONCLUSIONS: Our results highlight the genetic heterogeneity and clinical utility

of CTCs to identify therapeutic resistance mutations in ALK-rearranged patients.

Single CTC sequencing may be a unique tool to assess heterogeneous resistance

mechanisms and help clinicians for treatment personalization and resistance

options to ALK-targeted therapies.

©2019 American Association for Cancer Research.

DOI: 10.1158/1078-0432.CCR-19-1176

PMID: 31439588