2019年
No.12
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
1,139 cases. 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