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高分SCI文摘

2019年

No.12

来源:tushuguan 发布时间:2019-08-27 浏览次数:
字号: + - 14

Medical Abstracts

Keyword: lung cancer

1. Lancet Oncol. 2019 Aug;20(8):1098-1108. doi: 10.1016/S1470-2045(19)30329-8. Epub 2019 Jun 26.

5-year overall survival in patients with lung cancer eligible or ineligible for

screening according to US Preventive Services Task Force criteria: a prospective,

observational cohort study.

Luo YH(1), Luo L(2), Wampfler JA(3), Wang Y(4), Liu D(5), Chen YM(6), Adjei

AA(7), Midthun DE(8), Yang P(9).

Author information:

(1)Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic,

MN, USA; Division of Medical Oncology, Department of Health Sciences Research,

Mayo Clinic, MN, USA; Department of Chest Medicine, Taipei Veterans General

Hospital, Taipei, Taiwan; School of Medicine, National Yang-Ming University,

Taipei, Taiwan; Institute of Clinical Medicine, National Yang-Ming University,

Taipei, Taiwan.

(2)Department of Science and Education, Guizhou Province People's Hospital,

Guiyang, Guizhou, China.

(3)Division of Biomedical Statistics and Informatics, Department of Health

Sciences Research, Mayo Clinic, MN, USA.

...

BACKGROUND: The US Preventive Services Task Force (USPSTF) recommends lung cancer

screening among individuals aged 55-80 years with a 30 pack-year cigarette

smoking history and, if they are former smokers, those who quit within the past

15 years. Our previous report found that two-thirds of newly diagnosed patients

with lung cancer do not meet these criteria; they are reported to be either

long-term quitters (15 years since quitting) or from a younger age group (age

50-54 years). We aimed to assess survival outcomes in these two subgroups.

METHODS: For this prospective, observational cohort study we identified and

followed up patients aged 50-80 years with lung cancer, with a smoking history of

30 pack-years or more, and included both current smokers and former smokers who

quit within the past 30 years. We identified patients from two cohorts in the

USA: a hospital cohort (Mayo Clinic, Rochester, MN) and a community cohort

(Olmsted County, MN). Patients were divided into those meeting USPSTF criteria

(USPSTF group) versus those not meeting USPSTF criteria (long-term quitters or

the younger age group). The main outcome was overall survival at 5 years after

diagnosis. 5-year overall survival was analysed with and without matching age and

pack-years smoked for long-term quitters. The USPSTF group was subdivided into

two age subgroups (55-69 years and 70-80 years) for multivariable regression

analysis.

FINDINGS: Between Jan 1, 1997, and Dec 31, 2017, 8739 patients with lung cancer

were identified and followed up. Median follow-up was 6·5 (IQR 3·8-10·0) years,

and median overall survival was 16·9 months (95% CI 16·2-17·5). 5-year overall

survival was 27% (95% CI 25-30) in long-term quitters, 22% (19-25) in the younger

age group, and 23% (22-24) in the USPSTF group. In both cohorts, 5-year overall

survival did not differ significantly between long-term quitters and the USPSTF

group (hospital cohort: hazard ratio [HR] 1·02 [95% CI 0·94-1·10]; p=0·72;

community cohort: 0·97 [0·75-1·26]; p=0·82); matched analysis showed similar

results in both cohorts. 5-year overall survival also did not differ

significantly between the younger age group and the USPSTF group in both cohorts

(hospital cohort: HR 1·16 [95% CI 0·98-1·38], p=0·08; community cohort: 1·16

[0·74-1·82]; p=0·52); multivariable regression analyses stratified by age group

yielded similar findings.

INTERPRETATION: Patients with lung cancer who quit 15 or more years before

diagnosis and those who are up to 5 years younger than the age cutoff recommended

for screening, but otherwise meet USPSTF criteria, have a similar risk of death

to those individuals who meet all USPSTF criteria. Individuals in both subgroups

could benefit from screening, as expansion of USPSTF screening criteria to

include these subgroups could enable earlier detection of lung cancer and

improved survival outcomes.

FUNDING: National Institutes of Health and the Mayo Clinic Foundation.

Copyright © 2019 Elsevier Ltd. All rights reserved.

DOI: 10.1016/S1470-2045(19)30329-8

PMCID: PMC6669095 [Available on 2020-08-01]

PMID: 31255490

2. Nat Med. 2019 Jun;25(6):954-961. doi: 10.1038/s41591-019-0447-x. Epub 2019 May 20.

End-to-end lung cancer screening with three-dimensional deep learning on low-dose

chest computed tomography.

Ardila D(1), Kiraly AP(1), Bharadwaj S(1), Choi B(1), Reicher JJ(2), Peng L(1),

Tse D(3), Etemadi M(4), Ye W(1), Corrado G(1), Naidich DP(5), Shetty S(1).

Author information:

(1)Google AI, Mountain View, CA, USA.

(2)Stanford Health Care and Palo Alto Veterans Affairs, Palo Alto, CA, USA.

(3)Google AI, Mountain View, CA, USA. tsed@google.com.

(4)Northwestern Medicine, Chicago, IL, USA.

(5)New York University-Langone Medical Center, Center for Biological Imaging, New

York City, NY, USA.

Erratum in

Nat Med. 2019 Aug;25(8):1319.

With an estimated 160,000 deaths in 2018, lung cancer is the most common cause of

cancer death in the United States1. Lung cancer screening using low-dose computed

tomography has been shown to reduce mortality by 20-43% and is now included in US

screening guidelines1-6. Existing challenges include inter-grader variability and

high false-positive and false-negative rates7-10. We propose a deep learning

algorithm that uses a patient's current and prior computed tomography volumes to

predict the risk of lung cancer. Our model achieves a state-of-the-art

performance (94.4% area under the curve) on 6,716 National Lung Cancer Screening

Trial cases, and performs similarly on an independent clinical validation set of

1,139cases. We conducted two reader studies. When prior computed tomography

imaging was not available, our model outperformed all six radiologists with

absolute reductions of 11% in false positives and 5% in false negatives. Where

prior computed tomography imaging was available, the model performance was on-par

with the same radiologists. This creates an opportunity to optimize the screening

process via computer assistance and automation. While the vast majority of

patients remain unscreened, we show the potential for deep learning models to

increase the accuracy, consistency and adoption of lung cancer screening

worldwide.

DOI: 10.1038/s41591-019-0447-x

PMID: 31110349 [Indexed for MEDLINE]

3. Cell. 2019 Jul 11;178(2):330-345.e22. doi: 10.1016/j.cell.2019.06.005. Epub 2019 Jun 27.

BACH1 Stabilization by Antioxidants Stimulates Lung Cancer Metastasis.

Wiel C(1), Le Gal K(2), Ibrahim MX(3), Jahangir CA(4), Kashif M(4), Yao H(4),

Ziegler DV(3), Xu X(4), Ghosh T(5), Mondal T(5), Kanduri C(5), Lindahl P(6),

Sayin VI(7), Bergo MO(8).

Author information:

(1)Department of Biosciences and Nutrition, Karolinska Institutet, 141 83

Huddinge, Sweden; Sahlgrenska Cancer Center, Department of Molecular and Clinical

Medicine, Institute of Medicine, University of Gothenburg, 405 30 Gothenburg,

Sweden.

(2)Sahlgrenska Cancer Center, Department of Surgery, Institute of Clinical

Sciences, University of Gothenburg, 405 30 Gothenburg, Sweden; Wallenberg Centre

for Molecular and Translational Medicine, University of Gothenburg, 405 30

Gothenburg, Sweden.

(3)Sahlgrenska Cancer Center, Department of Molecular and Clinical Medicine,

Institute of Medicine, University of Gothenburg, 405 30 Gothenburg, Sweden.

...

For tumors to progress efficiently, cancer cells must overcome barriers of

oxidative stress. Although dietary antioxidant supplementation or activation of

endogenous antioxidants by NRF2 reduces oxidative stress and promotes early lung

tumor progression, little is known about its effect on lung cancer metastasis.

Here, we show that long-term supplementation with the antioxidants

N-acetylcysteine and vitamin E promotes KRAS-driven lung cancer metastasis. The

antioxidants stimulate metastasis by reducing levels of free heme and stabilizing

the transcription factor BACH1. BACH1 activates transcription of Hexokinase 2 and

Gapdh and increases glucose uptake, glycolysis rates, and lactate secretion,

thereby stimulating glycolysis-dependent metastasis of mouse and human lung

cancer cells. Targeting BACH1 normalized glycolysis and prevented

antioxidant-induced metastasis, while increasing endogenous BACH1 expression

stimulated glycolysis and promoted metastasis, also in the absence of

antioxidants. We conclude that BACH1 stimulates glycolysis-dependent lung cancer

metastasis and that BACH1 is activated under conditions of reduced oxidative

stress.

Copyright © 2019 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cell.2019.06.005

PMID: 31257027

4. Cell. 2019 Jul 11;178(2):316-329.e18. doi: 10.1016/j.cell.2019.06.003. Epub 2019 Jun 27.

Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of

Bach1.

Lignitto L(1), LeBoeuf SE(2), Homer H(1), Jiang S(1), Askenazi M(3), Karakousi

TR(2), Pass HI(4), Bhutkar AJ(5), Tsirigos A(2), Ueberheide B(1), Sayin VI(2),

Papagiannakopoulos T(6), Pagano M(7).

Author information:

(1)Department of Biochemistry and Molecular Pharmacology, New York University

School of Medicine, New York, NY 10016, USA; Perlmutter NYU Cancer Center, New

York University School of Medicine, New York, NY 10016, USA.

(2)Perlmutter NYU Cancer Center, New York University School of Medicine, New

York, NY 10016, USA; Department of Pathology, New York University School of

Medicine, New York, NY 10016, USA.

(3)Department of Biochemistry and Molecular Pharmacology, New York University

School of Medicine, New York, NY 10016, USA; Biomedical Hosting LLC, 33 Lewis

Avenue, Arlington, MA 02474, USA.

...

Approximately 30% of human lung cancers acquire mutations in either Keap1 or

Nfe2l2, resulting in the stabilization of Nrf2, the Nfe2l2 gene product, which

controls oxidative homeostasis. Here, we show that heme triggers the degradation

of Bach1, a pro-metastatic transcription factor, by promoting its interaction

with the ubiquitin ligase Fbxo22. Nrf2 accumulation in lung cancers causes the

stabilization of Bach1 by inducing Ho1, the enzyme catabolizing heme. In mouse

models of lung cancers, loss of Keap1 or Fbxo22 induces metastasis in a

Bach1-dependent manner. Pharmacological inhibition of Ho1 suppresses metastasis

in a Fbxo22-dependent manner. Human metastatic lung cancer display high levels of

Ho1 and Bach1. Bach1 transcriptional signature is associated with poor survival

and metastasis in lung cancer patients. We propose that Nrf2 activates a

metastatic program by inhibiting the heme- and Fbxo22-mediated degradation of

Bach1, and that Ho1 inhibitors represent an effective therapeutic strategy to

prevent lung cancer metastasis.

Copyright © 2019 Elsevier Inc. All rights reserved.

DOI: 10.1016/j.cell.2019.06.003

PMCID: PMC6625921 [Available on 2020-07-11]

PMID: 31257023

5. Nature. 2019 Jul;571(7763):127-131. doi: 10.1038/s41586-019-1340-y. Epub 2019 Jun 26.

UDP-glucose accelerates SNAI1 mRNA decay and impairs lung cancer metastasis.

Wang X(1)(2)(3), Liu R(1)(2), Zhu W(1), Chu H(4), Yu H(1)(2), Wei P(5), Wu X(6),

Zhu H(7), Gao H(1)(2), Liang J(1)(2), Li G(8), Yang W(9)(10).

Author information:

(1)State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular

Cell Science, Innovation Center for Cell Signaling Network, Shanghai Institute of

Biochemistry and Cell Biology, Chinese Academy of Sciences, University of the

Chinese Academy of Sciences, Shanghai, China.

(2)Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of

Biochemistry and Cell Biology, Chinese Academy of Sciences, University of the

Chinese Academy of Sciences, Shanghai, China.

(3)Precise Genome Engineering Center, School of Life Sciences, Guangzhou

University, Guangzhou, China.

...

Comment in

Nature. 2019 Jul;571(7763):39-40.

Cancer metastasis is the primary cause of morbidity and mortality, and accounts

for up to 95% of cancer-related deaths1. Cancer cells often reprogram their

metabolism to efficiently support cell proliferation and survival2,3. However,

whether and how those metabolic alterations contribute to the migration of tumour

cells remain largely unknown. UDP-glucose 6-dehydrogenase (UGDH) is a key enzyme

in the uronic acid pathway, and converts UDP-glucose to UDP-glucuronic acid4.

Here we show that, after activation of EGFR, UGDH is phosphorylated at tyrosine

473 in human lung cancer cells. Phosphorylated UGDH interacts with Hu antigen R

(HuR) and converts UDP-glucose to UDP-glucuronic acid, which attenuates the

UDP-glucose-mediated inhibition of the association of HuR with SNAI1 mRNA and

therefore enhances the stability of SNAI1 mRNA. Increased production of SNAIL

initiates the epithelial-mesenchymal transition, thus promoting the migration of

tumour cells and lung cancer metastasis. In addition, phosphorylation of UGDH at

tyrosine 473 correlates with metastatic recurrence and poor prognosis of patients

with lung cancer. Our findings reveal a tumour-suppressive role of UDP-glucose in

lung cancer metastasis and uncover a mechanism by which UGDH promotes tumour

metastasis by increasing the stability of SNAI1 mRNA.

DOI: 10.1038/s41586-019-1340-y

PMID: 31243371

6. Autophagy. 2019 Jun 28:1-13. doi: 10.1080/15548627.2019.1634945. [Epub ahead of print]

Circular RNA circHIPK3 modulates autophagy via MIR124-3p-STAT3-PRKAA/AMPKα

signaling in STK11 mutant lung cancer.

Chen X(1)(2), Mao R(3), Su W(4), Yang X(5), Geng Q(5), Guo C(2), Wang Z(2), Wang

J(1), Kresty LA(2), Beer DG(2), Chang AC(2), Chen G(6).

Author information:

(1)a Department of Thoracic Surgery , Peking University People's Hospital ,

Beijing , China.

(2)b Section of Thoracic Surgery, Department of Surgery , Rogel Cancer Center,

University of Michigan , Ann Arbor , USA.

(3)c Cancer Center , Xinjiang Medical University , Urumqi , China.

(4)d Department of Oncology , Affiliated Hospital of Guangdong Medical University

, Zhanjiang , China.

(5)e The First Affiliated Hospital , Xian Jiaotong University , Xi'an , China.

(6)f School of Medicine , Southern University of Science and Technology ,

Shenzhen , China.

The role of circular RNA in cancer is emerging. A newly reported circular RNA

HIPK3 (circHIPK3) is critical in cell proliferation of various cancer types,

although its role in non-small cell lung cancer (NSCLC), has yet to be

elucidated. Our results provided evidence that silencing of circHIPK3

significantly impaired cell proliferation, migration, invasion and induced

macroautophagy/autophagy. Mechanistically, we uncovered that autophagy was

induced upon loss of circHIPK3 via the MIR124-3p-STAT3-PRKAA/AMPKa axis in STK11

mutant lung cancer cell lines (A549 and H838). STAT3 abrogation as well as

transfection with a MIR124-3p mimic, recapitulated the induction of autophagy. We

also demonstrated antagonistic regulation on autophagy between circHIPK3 and

linear HIPK3 (linHIPK3). We therefore propose that the ratio between circHIPK3

and linHIPK3 (C:L ratio) may reflect autophagy levels in cancer cells. We

observed that a high C:L ratio (>0.49) was an indicator of poor survival,

especially in advanced-stage NSCLC patients. These results support that circHIPK3

is a key autophagy regulator in a subset of lung cancer and has potential

clinical use as a prognostic factor. The circular RNA HIPK3 (circHIPK3) functions

as an oncogene and autophagy regulator may potential use as a prognostic marker

and therapeutic target in lung cancer. Abbreviations 3-MA: 3-methyladenine; AMPK:

AMP-activated protein kinase; ATG7: autophagy related 7; Baf-A: bafilomycin A1;

BECN1: beclin 1; circHIPK3: circular HIPK3; CQ: chloroquine; GAPDH:

glyceraldehyde-3-phosphate dehydrogenase; GFP: green fluorescent protein; HIPK3:

homeodomain interacting protein kinase 3; IL6R: interleukin 6 receptor;

MAP1LC3B/LC3B: microtubule associated protein 1 light chain 3 beta; NSCLC:

non-small cell lung cancer; RFP: red fluorescent protein; RPS6KB1/S6K: ribosomal

protein S6 kinase B1; SQSTM1/p62: sequestosome 1; STAT3: signal transducer and

activator of transcription 3; STK11: serine/threonine kinase 11.

DOI: 10.1080/15548627.2019.1634945

PMID: 31232177

7. J Exp Med. 2019 Jun 21. pii: jem.20190249. doi: 10.1084/jem.20190249. [Epub ahead of print]

Single-cell transcriptomic analysis of tissue-resident memory T cells in human

lung cancer.

Clarke J(1)(2), Panwar B(1), Madrigal A(1), Singh D(1), Gujar R(1), Wood O(2),

Chee SJ(2)(3), Eschweiler S(1), King EV(2)(4), Awad AS(3)(5), Hanley CJ(2),

McCann KJ(2), Bhattacharyya S(1), Woo E(3), Alzetani A(3), Seumois G(1), Thomas

GJ(2), Ganesan AP(1), Friedmann PS(5), Sanchez-Elsner T(5), Ay F(1), Ottensmeier

CH(#)(6), Vijayanand P(#)(7)(5)(8).

Author information:

(1)La Jolla Institute for Immunology, La Jolla, CA.

(2)National Institute for Health Research and Cancer Research UK Southampton

Experimental Cancer Medicine Center, National Institute for Health Research

Southampton Biomedical Research Center, Cancer Sciences Unit, Faculty of

Medicine, University of Southampton, Southampton, UK.

(3)Southampton University Hospitals National Health Service Foundation Trust,

Southampton, UK.

...

High numbers of tissue-resident memory T (TRM) cells are associated with better

clinical outcomes in cancer patients. However, the molecular characteristics that

drive their efficient immune response to tumors are poorly understood. Here,

single-cell and bulk transcriptomic analysis of TRM and non-TRM cells present in

tumor and normal lung tissue from patients with lung cancer revealed that

PD-1-expressing TRM cells in tumors were clonally expanded and enriched for

transcripts linked to cell proliferation and cytotoxicity when compared with

PD-1-expressing non-TRM cells. This feature was more prominent in the TRM cell

subset coexpressing PD-1 and TIM-3, and it was validated by functional assays ex

vivo and also reflected in their chromatin accessibility profile. This

PD-1+TIM-3+ TRM cell subset was enriched in responders to PD-1 inhibitors and in

tumors with a greater magnitude of CTL responses. These data highlight that not

all CTLs expressing PD-1 are dysfunctional; on the contrary, TRM cells with PD-1

expression were enriched for features suggestive of superior functionality.

© 2019 Clarke et al.

DOI: 10.1084/jem.20190249

PMID: 31227543

8. J Clin Oncol. 2019 Aug 1;37(22):1927-1934. doi: 10.1200/JCO.19.00189. Epub 2019 Jun 17.

Immune Checkpoint Inhibitor Outcomes for Patients With Non-Small-Cell Lung Cancer

Receiving Baseline Corticosteroids for Palliative Versus Nonpalliative

Indications.

Ricciuti B(1), Dahlberg SE(1), Adeni A(1), Sholl LM(2), Nishino M(2), Awad MM(1).

Author information:

(1)1Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA.

(2)2Brigham and Women's Hospital, Boston, MA.

PURPOSE: Baseline use of corticosteroids is associated with poor outcomes in

patients with non-small-cell lung cancer (NSCLC) treated with programmed cell

death-1 axis inhibition. To approach the question of causation versus correlation

for this association, we examined outcomes in patients treated with immunotherapy

depending on whether corticosteroids were administered for cancer-related

palliative reasons or cancer-unrelated indications.

PATIENTS AND METHODS: Clinical outcomes in patients with NSCLC treated with

immunotherapy who received 10 mg prednisone were compared with outcomes in

patients who received 0 to < 10 mg of prednisone.

RESULTS: Of 650 patients, the 93 patients (14.3%) who received 10 mg of

prednisone at the time of immunotherapy initiation had shorter median

progression-free survival (mPFS) and median overall survival (mOS) times than

patients who received 0 to < 10 mg of prednisone (mPFS, 2.0 v 3.4 months,

respectively; P = .01; mOS, 4.9 v 11.2 months, respectively; P < .001). When

analyzed by reason for corticosteroid administration, mPFS and mOS were

significantly shorter only among patients who received 10 mg prednisone for

palliative indications compared with patients who received 10 mg prednisone for

cancer-unrelated reasons and with patients receiving 0 to < 10 mg of prednisone

(mPFS, 1.4 v 4.6 v 3.4 months, respectively; log-rank P < .001 across the three

groups; mOS, 2.2 v 10.7 v 11.2 months, respectively; log-rank P < .001 across the

three groups). There was no significant difference in mPFS or mOS in patients

receiving 10 mg of prednisone for cancer-unrelated indications compared with

patients receiving 0 to < 10 mg of prednisone.

CONCLUSION: Although patients with NSCLC treated with 10 mg of prednisone at

the time of immunotherapy initiation have worse outcomes than patients who

received 0 to < 10 mg of prednisone, this difference seems to be driven by a

poor-prognosis subgroup of patients who receive corticosteroids for palliative

indications.

DOI: 10.1200/JCO.19.00189

PMID: 31206316

9. J Am Coll Cardiol. 2019 Jun 18;73(23):2976-2987. doi: 10.1016/j.jacc.2019.03.500.

Cardiac Radiation Dose, Cardiac Disease, and Mortality in Patients With

Lung Cancer.

Atkins KM(1), Rawal B(2), Chaunzwa TL(3), Lamba N(4), Bitterman DS(1), Williams

CL(5), Kozono DE(5), Baldini EH(5), Chen AB(5), Nguyen PL(5), D'Amico AV(5),

Nohria A(6), Hoffmann U(7), Aerts HJWL(8), Mak RH(9).

Author information:

(1)Harvard Radiation Oncology Program, Dana-Farber Cancer Institute and Brigham

and Women's Hospital, Boston, Massachusetts.

(2)Department of Biostatistics and Computational Biology, Dana-Farber Cancer

Institute, Harvard Medical School, Boston, Massachusetts.

(3)Yale School of Medicine, New Haven, Connecticut; Department of Radiation

Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Boston,

Massachusetts.

...

BACKGROUND: Radiotherapy-associated cardiac toxicity studies in patients with

locally advanced non-small cell lung cancer (NSCLC) have been limited by small

sample size and nonvalidated cardiac endpoints.

OBJECTIVES: The purpose of this analysis was to ascertain whether cardiac

radiation dose is a predictor of major adverse cardiac events (MACE) and

all-cause mortality (ACM).

METHODS: This retrospective analysis included 748 consecutive locally advanced

NSCLC patients treated with thoracic radiotherapy. Fine and Gray and Cox

regressions were used to identify predictors for MACE and ACM, adjusting for lung

cancer and cardiovascular prognostic factors, including pre-existing coronary

heart disease (CHD).

RESULTS: After a median follow-up of 20.4 months, 77 patients developed 1 MACE

(2-year cumulative incidence, 5.8%; 95% confidence interval [CI]: 4.3% to 7.7%),

and 533 died. Mean radiation dose delivered to the heart (mean heart dose) was

associated with a significantly increased risk of MACE (adjusted hazard ratio

[HR]: 1.05/Gy; 95% CI: 1.02 to 1.08/Gy; p < 0.001) and ACM (adjusted HR: 1.02/Gy;

95% CI: 1.00 to 1.03/Gy; p = 0.007). Mean heart dose (10 Gy vs. <10 Gy) was

associated with a significantly increased risk of ACM in CHD-negative patients

(178 vs. 118 deaths; HR: 1.34; 95% CI: 1.06 to 1.69; p = 0.014) with 2-year

estimates of 52.2% (95% CI: 46.1% to 58.5%) versus 40.0% (95% CI: 33.5% to

47.4%); but not among CHD-positive patients (112 vs. 82 deaths; HR: 0.94; 95% CI:

0.70 to 1.25; p = 0.66) with 2-year estimates of 54.6% (95% CI: 46.8% to 62.7%)

versus 50.8% (95% CI: 41.5% to 60.9%), respectively (p for interaction = 0.028).

CONCLUSIONS: Despite the competing risk of cancer-specific death in locally

advanced NSCLC patients, cardiac radiation dose exposure is a modifiable cardiac

risk factor for MACE and ACM, supporting the need for early recognition and

treatment of cardiovascular events and more stringent avoidance of high cardiac

radiotherapy dose.

Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.

DOI: 10.1016/j.jacc.2019.03.500

PMID: 31196455

10. J Clin Oncol. 2019 Jun 13:JCO1900075. doi: 10.1200/JCO.19.00075. [Epub ahead of print]

Erlotinib Versus Gemcitabine Plus Cisplatin as Neoadjuvant Treatment of Stage

IIIA-N2 EGFR-Mutant Non-Small-Cell Lung Cancer (EMERGING-CTONG 1103): A

Randomized Phase II Study.

Zhong WZ(1), Chen KN(2), Chen C(3), Gu CD(4), Wang J(5), Yang XN(1), Mao WM(6),

Wang Q(7), Qiao GB(1)(8), Cheng Y(9), Xu L(10), Wang CL(11), Chen MW(12), Kang

X(2), Yan W(2), Yan HH(1), Liao RQ(1), Yang JJ(1), Zhang XC(1), Zhou Q(1), Wu

YL(1).

Author information:

(1)1 Guangdong Provincial People's Hospital and Guangdong Academy of Medical

Sciences, Guangzhou, People's Republic of China.

(2)2 Peking University Cancer Hospital and Institute, Beijing, People's Republic

of China.

(3)3 Fujian Medical University Union Hospital, Fuzhou, People's Republic of

China.

...

PURPOSE: To assess the benefits of epidermal growth factor receptor (EGFR)

tyrosine kinase inhibitors as neoadjuvant/adjuvant therapies in locally advanced

EGFR mutation-positive non-small-cell lung cancer.

PATIENTS AND METHODS: This was a multicenter (17 centers in China), open-label,

phase II, randomized controlled trial of erlotinib versus gemcitabine plus

cisplatin (GC chemotherapy) as neoadjuvant/adjuvant therapy in patients with

stage IIIA-N2 non-small-cell lung cancer with EGFR mutations in exon 19 or 21

(EMERGING). Patients received erlotinib 150 mg/d (neoadjuvant therapy, 42 days;

adjuvant therapy, up to 12 months) or gemcitabine 1,250 mg/m2 plus cisplatin 75

mg/m2 (neoadjuvant therapy, two cycles; adjuvant therapy, up to two cycles).

Assessments were performed at 6 weeks and every 3 months postsurgery. The primary

end point was objective response rate (ORR) by Response Evaluation Criteria in

Solid Tumors (RECIST) version 1.1; secondary end points were pathologic complete

response, progression-free survival (PFS), overall survival, safety, and

tolerability.

RESULTS: Of 386 patients screened, 72 were randomly assigned to treatment

(intention-to-treat population), and 71 were included in the safety analysis (one

patient withdrew before treatment). The ORR for neoadjuvant erlotinib versus GC

chemotherapy was 54.1% versus 34.3% (odds ratio, 2.26; 95% CI, 0.87 to 5.84; P =

.092). No pathologic complete response was identified in either arm. Three (9.7%)

of 31 patients and zero of 23 patients in the erlotinib and GC chemotherapy arms,

respectively, had a major pathologic response. Median PFS was significantly

longer with erlotinib (21.5 months) versus GC chemotherapy (11.4 months; hazard

ratio, 0.39; 95% CI, 0.23 to 0.67; P < .001). Observed adverse events reflected

those most commonly seen with the two treatments.

CONCLUSION: The primary end point of ORR with 42 days of neoadjuvant erlotinib

was not met, but the secondary end point PFS was significantly improved.

DOI: 10.1200/JCO.19.00075

PMID: 31194613

11. Am J Respir Crit Care Med. 2019 Jun 5. doi: 10.1164/rccm.201807-1292OC. [Epub

ahead of print]

YES1 Drives Lung Cancer Growth and Progression and Predicts Sensitivity to

Dasatinib.

Garmendia I(1), Pajares MJ(1), Hermida-Prado F(2), Ajona D(1), Bértolo C(1),

Sainz C(3), Lavín A(1), Remírez AB(1), Valencia K(1), Moreno H(4), Ferrer I(5),

Behrens C(6), Cuadrado M(7), Paz-Ares L(5), Bustelo XR(7), Gil-Bazo I(8), Alameda

D(1), Lecanda F(1), Calvo A(9), Felip E(10), Sánchez-Céspedes M(11), Wistuba

II(12), Granda-Diaz R(2), Rodrigo JP(2), García-Pedrero JM(2), Pio R(13),

Montuenga LM(14), Agorreta J(1).

Author information:

(1)CIMA, Program in Solid Tumors, Pamplona, Spain.

(2)Hospital Universitario Central de Asturias, 16474, Oviedo, Asturias, Spain.

(3)Centro para la Investigación Médica Aplicada, Biomarcadores y Tumores Sólidos,

Pamplona, Navarra, Spain.

...

RATIONALE: the characterization of new genetic alterations is essential to assign

effective personalized therapies in non-small cell lung cancer (NSCLC).

Furthermore, finding stratification biomarkers is essential for successful

personalized therapies. Molecular alterations of YES1, a member of the SRC family

kinases (SFKs), can be found in a significant subset of lung cancer patients.

OBJECTIVES: to evaluate YES1 genetic alteration as a therapeutic target and

predictive biomarker of response to dasatinib in NSCLC.

METHODS: functional significance was evaluated by in vivo models of NSCLC and

metastasis and patient-derived xenografts (PDX). The efficacy of pharmacological

and genetic (CRISPR/Cas9) YES1 abrogation was also evaluated. In vitro functional

assays for signaling, survival and invasion, were also performed. The association

between YES1 alterations and prognosis was evaluated in clinical samples.

MEASUREMENTS AND MAIN RESULTS: we demonstrated that YES1 is essential for NSCLC

carcinogenesis. Furthermore, YES1 overexpression induced metastatic spread in

preclinical in vivo models. YES1 genetic depletion by CRISPR/Cas9 technology

significantly reduced tumor growth and metastasis. YES1 effects were mainly

driven by mTOR signaling. Interestingly, cell lines and PDX models with YES1 gene

amplifications presented a high sensitivity to dasatinib, a SFK inhibitor,

pointing out YES1 status as a stratification biomarker for dasatinib response.

Moreover, high YES1 protein expression was an independent predictor for poor

prognosis in lung cancer patients.

CONCLUSIONS: YES1 is a promising therapeutic target in lung cancer. Our results

provide support for the clinical evaluation of dasatinib treatment in a selected

subset of patients using YES1 status as predictive biomarker for therapy.

DOI: 10.1164/rccm.201807-1292OC

PMID: 31166114

12. J Clin Oncol. 2019 Jun 2:JCO1900934. doi: 10.1200/JCO.19.00934. [Epub ahead of print]

Five-Year Overall Survival for Patients With Advanced Non?Small-Cell Lung Cancer

Treated With Pembrolizumab: Results From the Phase I KEYNOTE-001 Study.

Garon EB(1), Hellmann MD(2), Rizvi NA(3), Carcereny E(4), Leighl NB(5), Ahn

MJ(6), Eder JP(7), Balmanoukian AS(8), Aggarwal C(9), Horn L(10), Patnaik A(11),

Gubens M(12), Ramalingam SS(13), Felip E(14), Goldman JW(1), Scalzo C(15), Jensen

E(15), Kush DA(15), Hui R(16).

Author information:

(1)1University of California, Los Angeles, Los Angeles, CA.

(2)2Memorial Sloan Kettering Cancer Center, New York, NY.

(3)3Columbia University Medical Center, New York, NY.

...

PURPOSE: Pembrolizumab monotherapy has demonstrated durable antitumor activity in

advanced programmed death ligand 1 (PD-L1) -expressing non?small-cell lung cancer

(NSCLC). We report 5-year outcomes from the phase Ib KEYNOTE-001 study. These

data provide the longest efficacy and safety follow-up for patients with NSCLC

treated with pembrolizumab monotherapy.

PATIENTS AND METHODS: Eligible patients had confirmed locally advanced/metastatic

NSCLC and provided a contemporaneous tumor sample for PD-L1 evaluation by

immunohistochemistry using the 22C3 antibody. Patients received intravenous

pembrolizumab 2 mg/kg every 3 weeks or 10 mg/kg every 2 or 3 weeks. Investigators

assessed response per immune-related response criteria. The primary efficacy end

point was objective response rate. Overall survival (OS) and duration of response

were secondary end points.

RESULTS: We enrolled 101 treatment-naive and 449 previously treated patients.

Median follow-up was 60.6 months (range, 51.8 to 77.9 months). At data

cutoff-November 5, 2018-450 patients (82%) had died. Median OS was 22.3 months

(95% CI, 17.1 to 32.3 months) in treatment-naive patients and 10.5 months (95%

CI, 8.6 to 13.2 months) in previously treated patients. Estimated 5-year OS was

23.2% for treatment-naive patients and 15.5% for previously treated patients. In

patients with a PD-L1 tumor proportion score of 50% or greater, 5-year OS was

29.6% and 25.0% in treatment-naive and previously treated patients, respectively.

Compared with analysis at 3 years, only three new-onset treatment-related grade 3

adverse events occurred (hypertension, glucose intolerance, and hypersensitivity

reaction, all resolved). No late-onset grade 4 or 5 treatment-related adverse

events occurred.

CONCLUSION: Pembrolizumab monotherapy provided durable antitumor activity and

high 5-year OS rates in patients with treatment-naive or previously treated

advanced NSCLC. Of note, the 5-year OS rate exceeded 25% among patients with a

PD-L1 tumor proportion score of 50% or greater. Pembrolizumab had a tolerable

long-term safety profile with little evidence of late-onset or new toxicity.

DOI: 10.1200/JCO.19.00934

PMID: 31154919

13. J Clin Oncol. 2019 Jun 20;37(18):1558-1565. doi: 10.1200/JCO.19.00201. Epub 2019 May 8.

Local Consolidative Therapy Vs. Maintenance Therapy or Observation for Patients

With Oligometastatic Non-Small-Cell Lung Cancer: Long-Term Results of a

Multi-Institutional, Phase II, Randomized Study.

Gomez DR(1), Tang C(1), Zhang J(1), Blumenschein GR Jr(1), Hernandez M(1), Lee

JJ(1), Ye R(1), Palma DA(2), Louie AV(2), Camidge DR(3), Doebele RC(3), Skoulidis

F(1), Gaspar LE(3), Welsh JW(1), Gibbons DL(1), Karam JA(1), Kavanagh BD(3), Tsao

AS(1), Sepesi B(1), Swisher SG(1), Heymach JV(1).

Author information:

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

(2)2 London Health Sciences Center, London, Ontario, Canada.

(3)3 University of Colorado School of Medicine, Aurora, CO.

PURPOSE: Our previously published findings reported that local consolidative

therapy (LCT) with radiotherapy or surgery improved progression-free survival

(PFS) and delayed new disease in patients with oligometastatic non-small-cell

lung cancer (NSCLC) that did not progress after front-line systemic therapy.

Herein, we present the longer-term overall survival (OS) results accompanied by

additional secondary end points.

PATIENTS AND METHODS: This multicenter, randomized, phase II trial enrolled

patients with stage IV NSCLC, three or fewer metastases, and no progression at 3

or more months after front-line systemic therapy. Patients were randomly assigned

(1:1) to maintenance therapy or observation (MT/O) or to LCT to all active

disease sites. The primary end point was PFS; secondary end points were OS,

toxicity, and the appearance of new lesions. All analyses were two sided, and P

values less than .10 were deemed significant.

RESULTS: The Data Safety and Monitoring Board recommended early trial closure

after 49 patients were randomly assigned because of a significant PFS benefit in

the LCT arm. With an updated median follow-up time of 38.8 months (range, 28.3 to

61.4 months), the PFS benefit was durable (median, 14.2 months [95% CI, 7.4 to

23.1 months] with LCT v 4.4 months [95% CI, 2.2 to 8.3 months] with MT/O; P =

.022). We also found an OS benefit in the LCT arm (median, 41.2 months [95% CI,

18.9 months to not reached] with LCT v 17.0 months [95% CI, 10.1 to 39.8 months]

with MT/O; P = .017). No additional grade 3 or greater toxicities were observed.

Survival after progression was longer in the LCT group (37.6 months with LCT v

9.4 months with MT/O; P = .034). Of the 20 patients who experienced progression

in the MT/O arm, nine received LCT to all lesions after progression, and the

median OS was 17 months (95% CI, 7.8 months to not reached).

CONCLUSION: In patients with oligometastatic NSCLC that did not progress after

front-line systemic therapy, LCT prolonged PFS and OS relative to MT/O.

DOI: 10.1200/JCO.19.00201

PMCID: PMC6599408 [Available on 2020-06-20]

PMID: 31067138

14. J Exp Med. 2019 Jun 3;216(6):1377-1395. doi: 10.1084/jem.20181394. Epub 2019 Apr 23.

Lamin B1 loss promotes lung cancer development and metastasis by epigenetic

derepression of RET.

Jia Y(1)(2), Vong JS(1), Asafova A(1), Garvalov BK(3)(4), Caputo L(1), Cordero

J(1)(2), Singh A(1)(2), Boettger T(1), Günther S(1), Fink L(5), Acker T(4),

Barreto G(1), Seeger W(1)(6), Braun T(1), Savai R(1)(6), Dobreva G(7)(2)(8).

Author information:

(1)Max Planck Institute for Heart and Lung Research, Member of the German Center

for Lung Research, Bad Nauheim, Germany.

(2)Anatomy and Developmental Biology, Centre for Biomedicine and Medical

Technology Mannheim (CBTM) and European Center for Angioscience (ECAS), Medical

Faculty Mannheim, Heidelberg University, Mannheim, Germany.

(3)Microvascular Biology and Pathobiology, European Center for Angioscience

(ECAS), Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany.

...

Although abnormal nuclear structure is an important criterion for cancer

diagnostics, remarkably little is known about its relationship to tumor

development. Here we report that loss of lamin B1, a determinant of nuclear

architecture, plays a key role in lung cancer. We found that lamin B1 levels were

reduced in lung cancer patients. Lamin B1 silencing in lung epithelial cells

promoted epithelial-mesenchymal transition, cell migration, tumor growth, and

metastasis. Mechanistically, we show that lamin B1 recruits the polycomb

repressive complex 2 (PRC2) to alter the H3K27me3 landscape and repress genes

involved in cell migration and signaling. In particular, epigenetic derepression

of the RET proto-oncogene by loss of PRC2 recruitment, and activation of the

RET/p38 signaling axis, play a crucial role in mediating the malignant phenotype

upon lamin B1 disruption. Importantly, loss of a single lamin B1 allele induced

spontaneous lung tumor formation and RET activation. Thus, lamin B1 acts as a

tumor suppressor in lung cancer, linking aberrant nuclear structure and

epigenetic patterning with malignancy.

© 2019 Jia et al.

DOI: 10.1084/jem.20181394

PMCID: PMC6547854

PMID: 31015297

15. J Clin Oncol. 2019 Jun 1;37(16):1370-1379. doi: 10.1200/JCO.18.02236. Epub 2019 Mar 20.

ALK Resistance Mutations and Efficacy of Lorlatinib in Advanced Anaplastic

Lymphoma Kinase-Positive Non-Small-Cell Lung Cancer.

Shaw AT(1), Solomon BJ(2), Besse B(3), Bauer TM(4), Lin CC(5), Soo RA(6), Riely

GJ(7), Ou SI(8), Clancy JS(9), Li S(10), Abbattista A(11), Thurm H(10), Satouchi

M(12), Camidge DR(13), Kao S(14), Chiari R(15), Gadgeel SM(16), Felip E(17),

Martini JF(10).

Author information:

(1)1 Massachusetts General Hospital, Boston, MA.

(2)2 Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.

(3)3 Gustave Roussy Cancer Campus, Villejuif, France.

...

PURPOSE: Lorlatinib is a potent, brain-penetrant, third-generation anaplastic

lymphoma kinase (ALK)/ROS1 tyrosine kinase inhibitor (TKI) with robust clinical

activity in advanced ALK-positive non-small-cell lung cancer, including in

patients who have failed prior ALK TKIs. Molecular determinants of response to

lorlatinib have not been established, but preclinical data suggest that ALK

resistance mutations may represent a biomarker of response in previously treated

patients.

PATIENTS AND METHODS: Baseline plasma and tumor tissue samples were collected

from 198 patients with ALK-positive non-small-cell lung cancer from the

registrational phase II study of lorlatinib. We analyzed plasma DNA for ALK

mutations using Guardant360. Tumor tissue DNA was analyzed using an ALK

mutation-focused next-generation sequencing assay. Objective response rate,

duration of response, and progression-free survival were evaluated according to

ALK mutation status.

RESULTS: Approximately one quarter of patients had ALK mutations detected by

plasma or tissue genotyping. In patients with crizotinib-resistant disease, the

efficacy of lorlatinib was comparable among patients with and without ALK

mutations using plasma or tissue genotyping. In contrast, in patients who had

failed 1 or more second-generation ALK TKIs, objective response rate was higher

among patients with ALK mutations (62% v 32% [plasma]; 69% v 27% [tissue]).

Progression-free survival was similar in patients with and without ALK mutations

on the basis of plasma genotyping (median, 7.3 months v 5.5 months; hazard ratio,

0.81) but significantly longer in patients with ALK mutations identified by

tissue genotyping (median, 11.0 months v 5.4 months; hazard ratio, 0.47).

CONCLUSION: In patients who have failed 1 or more second-generation ALK TKIs,

lorlatinib shows greater efficacy in patients with ALK mutations compared with

patients without ALK mutations. Tumor genotyping for ALK mutations after failure

of a second-generation TKI may identify patients who are more likely to derive

clinical benefit from lorlatinib.

DOI: 10.1200/JCO.18.02236

PMCID: PMC6544460 [Available on 2020-06-01]

PMID: 30892989

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