Monthly Pubmed Review of the Most Relevant Research on Lung Cancer
Literature Review, August 2017
Glucose metabolism-targeted therapy and withaferin A are effective for epidermal growth factor receptor tyrosine kinase inhibitor-induced drug-tolerant persisters. Kunimasa K1, Nagano T1, Shimono Y2, et al. Cancer Sci. 2017 Jul;108(7):1368-1377. doi: 10.1111/cas.13266. Epub 2017 Jun 19. In pathway-targeted cancer drug therapies, the relatively rapid emergence of drug-tolerant persisters (DTPs) substantially limits the overall therapeutic benefit. However, little is known about the roles of DTPs in drug resistance. In this study, we investigated the features of epidermal growth factor receptor- tyrosine kinase inhibitor-induced DTPs and explored a new treatment strategy to overcome the emergence of these DTPs. We used two EGFR-mutated lung adenocarcinoma cell lines, PC9 and II-18. They were treated with 2 μM gefitinib for 6, 12, or 24 days or 6 months. We analyzed the mRNA expression of the stem cell-related markers by quantitative RT-PCR and the expression of the cellular senescence- associated proteins. Then we sorted DTPs according to the expression pattern of CD133 and analyzed the features of sorted cells. Finally, we tried to ablate DTPs by glucose metabolism targeting therapies and a stem-like cell targeting drug, withaferin A. Drug-tolerant persisters were composed of at least two types of cells, one with the properties of cancer stem-like cells (CSCs) and the other with the properties of therapy-induced senescent (TIS) cells. The CD133high cell population had CSC properties and the CD133low cell population had TIS properties. The CD133low cell population containing TIS cells showed a senescence-associated secretory phenotype that supported the emergence of the CD133high cell population containing CSCs. Glucose metabolism inhibitors effectively eliminated the CD133low cell population. Withaferin A effectively eliminated the CD133high cell population. The combination of phloretin and withaferin A effectively suppressed gefitinib-resistant tumor growth.
Spatial distribution of EGFR and KRAS mutation frequencies correlates with histological growth patterns of lung adenocarcinomas. Dietz S1,2,3, Harms A2,4, Endris V4, et al. Int J Cancer. 2017 Jul
12. doi: 10.1002/ijc.30881. [Epub ahead of print]
Multiregional analysis provided first indications for morphological and molecular heterogeneity in lung adenocarcinomas (ADCs), but comprehensive morpho-molecular comparisons are still lacking. The purpose of our study was to investigate the spatial distribution of EGFR and KRAS alterations systematically throughout whole tumor cross-sections in correlation with the tumor cell content and the histopathological patterns. Central sections of 19 ADCs were subdivided into 467 segments of 5 mm × 5 mm. We determined the predominant histological growth pattern and the allele frequencies of driver gene mutations by digital PCR in every segment. We further quantified the absolute cell counts and proportions of tumor and non-neoplastic cells in all segments to normalize the mutant allele frequencies. Driver gene mutations could be detected in >99% of the tumor containing segments, with high levels of inter- and intratumor heterogeneity regarding the mutant allele frequency (range: 0.04-19.36). Different patterns for the distribution of the variant allele frequency within a tumor were recognizable. While some cases showed ubiquitously low or high levels, others revealed regions with focally elevated frequencies.
Differences between KRAS and EGFR alterations were not significant. The great majority of the analyzed tumor sections (16/19) exhibited two or more morphological growth patterns. Mutant allele frequencies were significantly higher in segments with a predominant solid pattern compared to all other histologies (p < 0.01). Our data indicate that driver gene mutations are present with high levels of inter- and intratumor heterogeneity throughout the whole tumor, with a correlation between the allele frequencies and histological growth patterns.
Jin H1, Jiang AY2, Wang H3, Cao Y4, Wu Y5, Jiang XF1.
Non small cell lung cancer (NSCLC) is among the leading causes of cancer associated mortality worldwide. In clinical practice, therapeutic strategies based on drug combinations are often used for the treatment of various types of cancer. The present study aimed to investigate the effects of the combination of dihydroartemisinin (DHA) and gefitinib on NSCLC. Cell Counting kit 8 assay was used to evaluate cell viability. Transwell assays were performed to investigate cellular migration and invasion, and cellular apoptosis was evaluated using the terminal deoxynucleotidyl transferase dUTP nick end labeling assay.
Flow cytometry was used to investigate cell cycle distribution and the expression levels of target proteins were determined using western blot analysis. The results of the present study demonstrated that DHA (5, 10, 20, 50 and 100 µM) reduced cancer cell viability in a dose dependent manner in the NCI H1975 human NSCLC cell line and significantly enhanced gefitinib induced apoptosis. Furthermore, DHA and gefitinib co administration induced cell cycle arrest in G2/M phase, which was associated with a marked decline in the protein expression levels of G2/M regulatory proteins, including cyclin B1 and cyclin dependent kinase 1. The addition of DHA appeared to potentiate the inhibitory actions of gefitinib on the migratory and invasive capabilities of NCI H1975 cells. DHA and gefitinib co administration also downregulated the expression levels of phosphorylated (p) Akt, p mechanistic target of rapamycin, p signal transducer and activator of transcription 3 and B cell lymphoma 2 (Bcl 2), and upregulated the expression of Bcl 2 associated X protein. In conclusion, the present results suggested that the combination of DHA and gefitinib may have potential as a novel and more effective therapeutic strategy for the treatment of patients with NSCLC.
Impact of EBUS-TBNA on PET-CT Imaging of Mediastinal Nodes. Sivapalan P1, Naur TMH, Colella S, Richter Larsen K, Konge L, Frost Clementsen P. J Bronchology Interv Pulmonol. 2017 Jul;24(3):188- 192. doi: 10.1097/LBR.0000000000000373.
BACKGROUND: Positron emission tomography-computed tomography (PET-CT) with fluorine-18- fluorodeoxyglucose has a high sensitivity in detecting malignancy in patients suspected of lung cancer but a low specificity as inflammatory reactions can also result in metabolic activity. Furthermore, it is assumed that invasive pulmonary procedures with biopsies from benign lesions can induce metabolic activity resulting in false-positive results. However, this hypothesis lacks solid evidence. We aimed to evaluate how often endobronchial ultrasound (EBUS) with biopsies from benign lesions are followed by false-positive results. METHODS: Patients with suspected or proven lung cancer admitted for invasive pulmonary procedures in a 6-year period were retrospectively reviewed. Patients who had at least 1 nonmalignant mediastinal lymph node (MLN) biopsied 1 to 13 days before PET-CT were included. The number of false-positive and true-negative results shortly after EBUS biopsy of nonmalignant MLN was reviewed. RESULTS: Of 1025 patients, 216 patients were referred for PET-CT 1 to 13 days after biopsy. Of these, 107 patients had at least 1 MLN biopsied. From a total of 198 biopsied MLNs, we found 62% without metabolic activity (benign) and 38% with metabolic activity. In 5% the metabolic activity could be explained by an infection or inflammatory disorder, in 15% no cytologic follow-up was available, in 1% malignancy was confirmed at follow-up, and in 3% the patients were not possible to follow-up. In the remaining 14%, no other reasonable explanation for the metabolic activity was found other than the biopsy. CONCLUSIONS: EBUS with biopsy do not necessarily result in PET activity. Therefore, PET- positive results should always be taken seriously, even when PET is performed shortly after biopsies.
Conventional real-time PCR-based detection of T790M using tumor tissue or blood in patients with EGFR TKI-resistant NSCLC. Wu YL1,2, Tong RZ1, Zhang Y1, et al. Onco Targets Ther. 2017 Jul 5;10:3307-3312. doi: 10.2147/OTT.S136823. eCollection 2017.
Blood biopsy has many advantages over tissue biopsy for diagnosing acquired T790M mutation in patients with non-small-cell lung cancer, such as being less risky and painful. New techniques with high sensitivity (eg, droplet digital PCR) show promising results during blood biopsy, but the positive rates of identification are still quite unclear. Whether there are other factors, except technology, affecting the results of blood biopsy is unclear. In this study, we used conventional amplification refractory mutation system to detect tumor tissue or blood for T790M mutation in patients clinically resistant to tyrosine kinase inhibitors. A total of 45 patients treated at West China Hospital between 2014 and 2016 were analyzed. The positive rate of T790M mutation was 70.8% based on tissue biopsy and 37.5% based on blood biopsy. Of the 24 patients whose epidermal growth factor receptor gene was genotyped through tissue and blood biopsy, 10 (41.7%) were concordant for T790M mutation status (κ=0.006). Of the 17 patients positive for T790M by tissue biopsy, 7 (41.2%) were positive for T790M by blood biopsy, and 3 of these 7 were only weakly positive. Of the 7 patients negative for T790M by tissue biopsy, 2 (28.6%) were positive by blood biopsy. Our T790M detection rate is higher than that reported by other studies using digital droplet PCR. These results suggest that other factors (eg, clinical features), intrinsically connected with circulating tumor DNA level, also affect the results of blood biopsy, and thus cannot be controlled through technological optimization.
The role of endobronchial ultrasound elastography in the diagnosis of mediastinal and hilar lymph nodes. Gu Y1, Shi H2, Su C3, et al. Oncotarget. 2017 Jul 6. doi: 10.18632/oncotarget.19031. [Epub ahead of print]
Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has been widely used for diagnosis and mediastinal lymph nodes staging in patients with suspicious lung cancer. Ultrasound elastography is a novel sonographical technique that can evaluate tissue compressibility. The aim of the present study was to investigate the diagnostic yield of elastography for differentiating malignant and benign mediastinal lymph nodes. Conventional EBUS B-mode features, including size, shape, border distinction, echogenicity, central hilar structure with central blood vessel and coagulation necrosis were also evaluated. The ultrasonic features were compared with the pathological results from EBUS-TBNA. 133 lymph nodes in 60 patients were assessed. Elastography displayed the highest area under the curve (AUC) (type 3 versus type 1: AUC, 0.825; 95% confidence interval [CI], 0.707-0.910) with an impressive sensitivity (100%) and an acceptable specificity (65%). The combined model covering the four positive criteria (elastography, heterogeneity, size, and shape) showed that the odds ratio for malignance is 9.44 with a 95% CI of 3.99 to 22.32 (p <0.0001). The combined model was superior to elastography alone (AUC, 0.851; sensitivity, 89.89%; specificity, 72.73%; p <0.0001). This prospective study showed that elastography is a feasible technique for classifying mediastinal lymph nodes, especially in combination with conventional EBUS imaging.
Influence of the Learning Effect on the Diagnostic Yield of Endobronchial Ultrasound-guided Transbronchial Needle Aspiration of Mediastinal and Hilar Lymph Nodes. Fuso L1, Varone F, Magnini D, Pecoriello A, Montemurro G, Angeletti G, Valente S. J Bronchology Interv Pulmonol. 2017 Jul;24(3):193-199. doi: 10.1097/LBR.0000000000000372.
BACKGROUND: The diagnostic yield of conventional transbronchial needle aspiration (TBNA) is characterized by a learning effect. The aim of this retrospective study was to verify whether a learning curve similarly affected the yield of endobronchial ultrasound-guided (EBUS)-TBNA. To this end, we evaluated the sensitivity and diagnostic accuracy of EBUS-TBNA during the first 3 years of activity. METHODS: EBUS-TBNA was performed by 2 operators with no previous experience in this technique. Cytologic samples were obtained from mediastinal and hilar lymph nodes enlarged at a chest computed tomography scan and/or with increased fluorodeoxyglucose uptake at computed tomography/positron emission tomography scan in patients with suspected lung cancer. The cytologic diagnosis of EBUS- TBNA samples has been compared with the final diagnosis obtained from further diagnostic procedures, surgery, or clinical-radiologic follow-up. RESULTS: From October 2012 to October 2015, we collected 408 EBUS-TBNA cytologic samples from 313 patients: 223 samples were positive for metastatic involvement and 185 were nonmetastatic. The latter included 137 true-negative and 48 false-negative results. The final diagnosis comprised 271 metastatic and 137 nonmetastatic lymph nodes. The overall sensitivity for cancer was 82% and diagnostic accuracy was 88%. Sensitivity and accuracy per year were as follows: first year, 78% and 82% in 90 nodal samples; second year, 83% and 89% in 144 nodal samples; third year, 85% and 91% in 174 nodal samples. CONCLUSIONS: EBUS-TBNA can be considered as a reliable tool even if performed by operators without previous experience in this procedure, and the diagnostic yield continues to increase progressively over a long time.
Comparison of Bayesian penalized likelihood reconstruction versus OS-EM for characterization of small pulmonary nodules in oncologic PET/CT. Howard BA1, Morgan R2,3, Thorpe MP2, Turkington TG2, Oldan J4, James OG2, Borges-Neto S2. Ann Nucl Med. 2017 Jul 8. doi: 10.1007/s12149-017-1192-1. [Epub ahead of print]
OBJECTIVE: To determine whether the recently introduced Bayesian penalized likelihood PET reconstruction (Q.Clear) increases the visual conspicuity and SUVmax of small pulmonary nodules near the PET resolution limit, relative to ordered subset expectation maximization (OS-EM). METHODS: In this institutional review board-approved and HIPAA-compliant study, 29 FDG PET/CT scans performed on a five-ring GE Discovery IQ were retrospectively selected for pulmonary nodules described in the radiologist’s report as “too small to characterize”, or small lung nodules in patients at high risk for lung cancer. Thirty-two pulmonary nodules were assessed, with mean CT diameter of 8 mm (range 2-18). PET images were reconstructed with OS-EM and Q.Clear with noise penalty strength β values of 150, 250, and 350. Lesion visual conspicuity was scored by three readers on a 3-point scale, and lesion SUVmax and background liver and blood pool SUVmean and SUVstdev were recorded. Comparison was made by linear mixed model with modified Bonferroni post hoc testing; significance cutoff was p < 0.05.
RESULTS: Q.Clear improved lesion visual conspicuity compared to OS-EM at β = 150 (p < 0.01), but not 250 or 350. Lesion SUVmax was increased compared to OS-EM at β = 150 and 250 (p < 0.01), but not 350. CONCLUSION: In a cohort of small pulmonary nodules with size near an 8 mm PET full-width half maximum, Q.Clear significantly increased lesion visual conspicuity and SUVmax compared to our standard non- time-of-flight OS-EM reconstruction, but only with low noise penalization. Q.Clear with β= 150 may be advantageous when evaluation of small pulmonary nodules is of primary concern.
Validation of the Disease-Specific GPA for Patients With 1 to 3 Synchronous Brain Metastases in Newly Diagnosed NSCLC. Woody NM1, Greer MD2, Reddy CA3, et al. Clin Lung Cancer. 2017 Jul 6. pii: S1525-7304(17)30198-5. doi: 10.1016/j.cllc.2017.06.011. [Epub ahead of print]
BACKGROUND: The disease-specific graded prognostic assessment (DS-GPA) for brain metastases is a powerful prognostic tool but has not been validated for patients with synchronous brain metastases (SBM) in newly diagnosed non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: We identified patients with newly diagnosed NSCLC with 1 to 3 SBM treated with stereotactic radiosurgery (SRS) between 1997 and 2012. We included patients whose brain metastases were treated with SRS alone or combined SRS and whole-brain radiotherapy (WBRT). Patients were stratified according to NSCLC DS- GPA to evaluate the accuracy of survival estimates. RESULTS: One hundred sixty-four patients were treated with either SRS alone (n = 85; 52%) or SRS and WBRT (n = 79; 48%). Median overall survival (OS) stratified according to DS-GPA of 0 to 1, 1.5 to 2, 2.5 to 3, and 3.5 to 4 were 2.8, 6.7, 9.8, and 13.2 months, respectively, consistent with OS reported for brain metastases in NSCLC DS-GPA (3.0, 6.5, 11.3, and 14.8 months, respectively). No difference in median progression-free survival or OS was noted with combined use of SRS and WBRT: 6.0 versus 6.1 months (P = .81) and 8.5 versus 9.1 months (P =.093), respectively. In multivariable analysis, Karnofsky performance status (hazard ratio [HR], 0.98; P =.008), extracranial metastases (HR, 0.498; P = .0003), squamous histology (HR, 1.81; P = .02), and number of brain metastases (2 vs. 1; HR, 1.504; P = .04, and 3 vs. 1; HR, 1.66; P = .05) were significant predictors of OS. CONCLUSION: The DS-GPA accurately estimates the prognosis of patients with SBM in newly diagnosed NSCLC. Patients with synchronous brain metastasis in newly diagnosed NSCLC should be carefully stratified for consideration of aggressive therapy.
Copyright © 2017 Elsevier Inc. All rights reserved.
Evaluation of Appropriate Mediastinal Staging among Endobronchial Ultrasound Bronchoscopists. Miller RJ1, Mudambi L1, Vial MR1, Hernandez M2, Eapen GA1. Ann Am Thorac Soc. 2017 Jul;14(7):1162-1168. doi: 10.1513/AnnalsATS.201606-487OC.
RATIONALE: Endobronchial ultrasound (EBUS) has transformed mediastinal staging in lung cancer. A systematic approach, beginning with lymph nodes contralateral to the primary tumor (N3), is considered superior to selective sampling of radiographically abnormal nodes. However, the extent to which this recommendation is followed in practice remains unknown. OBJECTIVES: To assess the frequency with which pulmonologists, pulmonary fellows, and interventional pulmonologists endoscopically stage lung cancer appropriately. METHODS: Bronchoscopists currently performing EBUS were surveyed about their practice patterns, procedural volume, and self-confidence in EBUS skills; they then performed a proctored simulated staging EBUS. The primary outcome was the proportion of participants who appropriately initiated ultrasonographic evaluation with the N3 nodal stations in a simulated patient undergoing EBUS for mediastinal staging. RESULTS: Sixty physicians (22 interventional pulmonologists, 18 general pulmonologists, and 20 pulmonary fellows) participated in the study. The rates of appropriate staging by study group were 95.5% (21 of 22) for interventional pulmonologists, 44.4% (8 of 18) for general pulmonologists, and 30.0% (6 of 20) for pulmonary fellows (P < 0.001).
Increased procedural volume correlated with appropriate staging practices (P < 0.001). Within each group, we assessed the concordance between self-confidence in EBUS and simulation performance. Among interventional pulmonologists, the concordance was 95.4%, followed by 61.1% for general pulmonologists and 40.0% for pulmonary fellows. CONCLUSIONS: General pulmonologists and pulmonary fellows were less likely than interventional pulmonologists to perform appropriate EBUS staging. In addition, the lack of concordance between self-confidence and appropriate staging performance among noninterventionists signals a need for improved dissemination of guidelines for EBUS-guided mediastinal staging.
A novel molecular diagnostics platform for somatic and germline precision oncology.
Cabanillas R1, Diñeiro M1, Castillo D2, et al. Mol Genet Genomic Med. 2017 Apr 23;5(4):336-359. doi: 10.1002/mgg3.291. eCollection 2017 Jul.
BACKGROUND: Next-generation sequencing (NGS) opens new options in clinical oncology, from therapy selection to genetic counseling. However, realization of this potential not only requires succeeding in the bioinformatics and interpretation of the results, but also in their integration into the clinical practice. We have developed a novel NGS diagnostic platform aimed at detecting (1) somatic genomic alterations associated with the response to approved targeted cancer therapies and (2) germline mutations predisposing to hereditary malignancies. METHODS: Next-generation sequencing libraries enriched in the exons of 215 cancer genes (97 for therapy selection and 148 for predisposition, with 30 informative for both applications), as well as selected introns from 17 genes involved in drug-related rearrangements, were prepared from 39 tumors (paraffin-embedded tissues/cytologies), 36 germline samples (blood) and 10 cell lines using hybrid capture. Analysis of NGS results was performed with specifically developed bioinformatics pipelines. RESULTS: The platform detects single-nucleotide variants (SNVs) and insertions/deletions (indels) with sensitivity and specificity >99.5% (allelic frequency ≥0.1), as well as copy-number variants (CNVs) and rearrangements. Somatic testing identified tailored approved targeted drugs in 35/39 tumors (89.74%), showing a diagnostic yield comparable to that of leading commercial platforms. A somatic EGFR p.E746_S752delinsA mutation in a mediastinal metastasis from a breast cancer prompted its anatomopathologic reassessment, its definite reclassification as a lung cancer and its treatment with gefitinib (partial response sustained for 15 months). Testing of 36 germline samples identified two pathogenic mutations (in CDKN2A and BRCA2). We propose a strategy for interpretation and reporting of results adaptable to the aim of the request, the availability of tumor and/or normal samples and the scope of the informed consent. CONCLUSION: With an adequate methodology, it is possible to translate to the clinical practice the latest advances in precision oncology, integrating under the same platform the identification of somatic and germline genomic alterations.
Lung cancer screening with low-dose spiral computed tomography: evidence from a pooled analysis of two Italian randomized trials. Infante M1, Sestini S, Galeone C, et al. Eur J Cancer Prev. 2017 Jul;26(4):324-329. doi: 10.1097/CEJ.0000000000000264.
The benefits and harms of lung cancer (LC) screening with low-dose computed tomography (LDCT) are debatable. Positive results from the US National Lung Screening Trial were not evident in the European trials, possibly due to their smaller sample sizes. To address this issue, we conducted a patient-level pooled analysis of two Italian randomized controlled trials. Data from DANTE and MILD trials were combined for a total of 3640 individuals in the LDCT arm and 2909 in the control arm. LC and overall mortality were analyzed using multivariate hazard ratios (HRs) and log-rank tests stratified by study. The median follow-up was 8.2 years, with a total of 30 480 person-years in the LDCT arm and 22 157 in the control arm. A total of 192 patients developed LC in the LDCT arm and 105 in the control arm. Half of the LC cases in the LDCT arm had stage IA or IB cancer, as compared with 21% in the control arm.
Overall mortality rates/100 000 person-years were 925 in the LDCT arm and 1074 in the control arm, and LC mortality rates were 299 and 357, respectively. The multivariate pooled overall mortality HR was 0.89 (95% confidence interval: 0.74-1.06) and the LC mortality HR was 0.83 (95% confidence interval: 0.61-1.12) for the LDCT arm as compared with the control arm. The present pooled analysis shows a nonsignificant 11% reduction in overall mortality in individuals undergoing LDCT screening as compared with the control arm. A pooled analysis of all European trials would be a useful contribution to assess the real benefit of LDCT screening.
Presence of Even a Small Ground-Glass Component in Lung Adenocarcinoma Predicts Better Survival. Berry MF1, Gao R2, Kunder CA3, Backhus L2, Khuong A2, Kadoch M4, Leung A4, Shrager J2. Clin Lung Cancer. 2017 Jul 8. pii: S1525-7304(17)30207-3. doi: 10.1016/j.cllc.2017.06.020. [Epub ahead of print]
BACKGROUND: While lepidic-predominant lung adenocarcinomas are known to have better outcomes than similarly sized solid tumors, the impact of smaller noninvasive foci within predominantly solid tumors is less clearly characterized. We tested the hypothesis that lung adenocarcinomas with even a small ground-glass opacity (GGO) component have a better prognosis than otherwise similar pure solid (PS) adenocarcinomas. PATIENTS AND METHODS: The maximum total and solid-component diameters were determined by preoperative computed tomography in patients who underwent lobar or sublobar resection of clinical N0 adenocarcinomas without induction therapy between May 2003 and August 2013. Survival between patients with PS tumors (0% GGO) or tumors with a minor ground-glass (MGG) component (1%-25% GGO) was compared by Kaplan-Meier and Cox analyses. RESULTS: A total of 123 patients met the inclusion criteria, comprising 54 PS (44%) and 69 MGG (56%) whose mean ground-glass component was 18 ± 7%. The solid component tumor diameter was not significantly different between the groups (2.3 ± 1.2 cm vs. 2.5 ± 1.3 cm, P = .2). Upstaging to pN1-2 was more common for the PS group (13% [7/54] vs. 3% [2/69], P = .04), but the distribution of pathologic stage was not significantly different between the groups (PS 76% stage I [41/54] vs. MGG 80% stage I [55/69], P =.1). Having a MGG component was associated with markedly better survival in both univariate analysis (MGG 5-year overall survival 86.7% vs. PS 64.5%, P = .001) and multivariable survival analysis (hazard ratio, 0.30, P = .01). CONCLUSION: Patients with resected cN0 lung adenocarcinoma who have even a small GGO component have markedly better survival than patients with PS tumors, which may have implications for both treatment and surveillance strategies.
Molecular Profiling of Malignant Pleural Effusion in Metastatic Non-Small-Cell Lung Carcinoma. The Effect of Preanalytical Factors. Carter J1, Miller JA1, Feller-Kopman D2, Ettinger D3, Sidransky D3, Maleki Z1. Ann Am Thorac Soc. 2017 Jul;14(7):1169-1176. doi: 10.1513/AnnalsATS.201609- 709OC.
RATIONALE: Non-small-cell lung cancer (NSCLC)-associated malignant pleural effusions (MPEs) are sometimes the only available specimens for molecular analysis. OBJECTIVES: This study evaluates diagnostic yield of NSCLC-associated MPE, its adequacy for molecular profiling and the potential influence of MPE volume/cellularity on the analytic sensitivity of our assays. METHODS: Molecular results of 50 NSCLC-associated MPE cases during a 5-year period were evaluated. Molecular profiling was performed on cell blocks and consisted of fluorescent in situ hybridization (FISH) for ALK gene rearrangements and the following sequencing platforms: Sanger sequencing (for EGFR) and high- throughput pyrosequencing (for KRAS and BRAF) during the first 4 years of the study period, and targeted next-generation sequencing performed thereafter. RESULTS: A total of 50 NSCLC-associated MPE cases were identified where molecular testing was requested. Of these, 17 cases were excluded: 14 cases (28%) due to inadequate tumor cellularity and 3 cases due to unavailability of the slides to review. A total of 27 out of 50 MPE cases (54%) underwent at least EGFR and KRAS sequencing and FISH for ALK rearrangement. Of the 27 cases with molecular testing results available, a genetic abnormality was detected in 16 cases (59%). The most common genetic aberrations identified involved EGFR ( 9 ) and KRAS ( 7 ). Six cases had ALK FISH only, of which one showed rearrangement. MPE volume was not associated with overall cellularity or tumor cellularity (P = 0.360). CONCLUSIONS: Molecular profiling of MPE is a viable alternative to testing solid tissue in NSCLC. This study shows successful detection of genetic aberrations in 59% of samples with minimal risk of false negative.
Shared Gene Expression Alterations in Nasal and Bronchial Epithelium for Lung Cancer Detection. AEGIS Study Team. Collaborators: (14) Perez-Rogers JF1,2, Gerrein J1,2, Anderlind C2, Liu G2, Zhang S2, Alekseyev Y3, Smith KP4, Whitney D2,4, Evan Johnson W2, Elashoff DA5, Dubinett SM6, Brody J2, Spira A2, Lenburg ME2. J Natl Cancer Inst. 2017 Jul 1;109(7). doi: 10.1093/jnci/djw327.
BACKGROUND: We previously derived and validated a bronchial epithelial gene expression biomarker to detect lung cancer in current and former smokers. Given that bronchial and nasal epithelial gene expression are similarly altered by cigarette smoke exposure, we sought to determine if cancer-associated gene expression might also be detectable in the more readily accessible nasal epithelium. METHODS: Nasal epithelial brushings were prospectively collected from current and former smokers undergoing diagnostic evaluation for pulmonary lesions suspicious for lung cancer in the AEGIS-1 (n = 375) and AEGIS-2 (n = 130) clinical trials and gene expression profiled using microarrays. All statistical tests were two-sided. RESULTS: We identified 535 genes that were differentially expressed in the nasal epithelium of AEGIS-1 patients diagnosed with lung cancer vs those with benign disease after one year of follow-up ( P < .001). Using bronchial gene expression data from the AEGIS-1 patients, we found statistically significant concordant cancer-associated gene expression alterations between the two airway sites ( P
< .001). Differentially expressed genes in the nose were enriched for genes associated with the regulation of apoptosis and immune system signaling. A nasal lung cancer classifier derived in the AEGIS-1 cohort that combined clinical factors (age, smoking status, time since quit, mass size) and nasal gene expression (30 genes) had statistically significantly higher area under the curve (0.81; 95% confidence interval [CI] = 0.74 to 0.89, P = .01) and sensitivity (0.91; 95% CI = 0.81 to 0.97, P = .03) than a clinical-factor only model in independent samples from the AEGIS-2 cohort. CONCLUSIONS: These results support that the airway epithelial field of lung cancer-associated injury in ever smokers extends to the nose and demonstrates the potential of using nasal gene expression as a noninvasive biomarker for lung cancer detection.
Pneumotoxicity associated with immune checkpoint inhibitor therapies. Shannon VR1. Curr Opin Pulm Med. 2017 Jul;23(4):305-316. doi: 10.1097/MCP.0000000000000382.
PURPOSE OF REVIEW: Immune checkpoint inhibitor therapies represent a new paradigm in cancer therapeutics, in which the targets are not the cancer cells, but the body’s own immune system. Harnessing the immune system to better fight cancer has generated a unique spectrum of immune-related adverse events (IrAEs) that effect virtually every major organ system. Although lung involvement is less common than other forms of IrAEs, its consequences are potentially lethal. This review focuses on the evolving spectrum of lung toxicities associated with the two major classes of immune checkpoint inhibitor therapies, cytotoxic T-cell ligand-4, and programed cell death-1 (PDL-1). RECENT FINDINGS: Lung injury was not reported in the earliest clinical trials of immune checkpoint inhibitors. More recent studies, however, have described unique radiographic and clinical toxicity profiles that differ significantly from lung injury patterns associated with conventional cytotoxic therapies. The pathophysiologic mechanisms of immune-related lung injury, its radiographic and clinical disease spectrum, associated risk factors, and optimal treatment strategies remain poorly understood. SUMMARY: Adverse immune-mediated lung events are increasingly recognized as unique and potentially life-threatening sequelae of checkpoint inhibitor therapies. Early recognition of symptoms and radiographic abnormalities is essential to proper management and successful outcome.
Development and Validation of an Individualized Immune Prognostic Signature in Early-Stage Nonsquamous Non-Small Cell Lung Cancer. Li B1, Cui Y2, Diehn M3, Li R4. JAMA Oncol. 2017 Jul
6. doi: 10.1001/jamaoncol.2017.1609. [Epub ahead of print]
The prevalence of early-stage non-small cell lung cancer (NSCLC) is expected to increase with recent implementation of annual screening programs. Reliable prognostic biomarkers are needed to identify patients at a high risk for recurrence to guide adjuvant therapy.
OBJECTIVE: To develop a robust, individualized immune signature that can estimate prognosis in patients with early-stage nonsquamous NSCLC. DESIGN, SETTING, AND PARTICIPANTS: This retrospective study analyzed the gene expression profiles of frozen tumor tissue samples from 19 public NSCLC cohorts, including 18 microarray data sets and 1 RNA-Seq data set for The Cancer Genome Atlas (TCGA) lung adenocarcinoma cohort. Only patients with nonsquamous NSCLC with clinical annotation were included. Samples were from 2414 patients with nonsquamous NSCLC, divided into a meta-training cohort (729 patients), meta-testing cohort (716 patients), and 3 independent validation cohorts (439, 323, and 207 patients). All patients underwent surgery with a negative surgical margin, received no adjuvant or neoadjuvant therapy, and had publicly available gene expression data and survival information. Data were collected from July 22 through September 8, 2016. MAIN OUTCOMES AND MEASURES: Overall survival. RESULTS: Of 2414 patients (1205 men [50%], 1111 women [46%], and 98 of unknown sex [4%]; median age [range], 64 [15-90] years), a prognostic immune signature of 25 gene pairs consisting of 40 unique genes was constructed using the meta-training data set. In the meta-testing and validation cohorts, the immune signature significantly stratified patients into high- vs low-risk groups in terms of overall survival across and within subpopulations with stage I, IA, IB, or II disease and remained as an independent prognostic factor in multivariate analyses (hazard ratio range, 1.72 [95% CI, 1.26-2.33; P < .001] to 2.36 [95% CI, 1.47-3.79; P < .001]) after adjusting for clinical and pathologic factors. Several biological processes, including chemotaxis, were enriched among genes in the immune signature. The percentage of neutrophil infiltration (5.6% vs 1.8%) and necrosis (4.6% vs 1.5%) was significantly higher in the high-risk immune group compared with the low-risk groups in TCGA data set (P < .003). The immune signature achieved a higher accuracy (mean concordance index [C-index], 0.64) than 2 commercialized multigene signatures (mean C-index, 0.53 and 0.61) for estimation of survival in comparable validation cohorts. When integrated with clinical characteristics such as age and stage, the composite clinical and immune signature showed improved prognostic accuracy in all validation data sets relative to molecular signatures alone (mean C-index, 0.70 vs 0.63) and another commercialized clinical- molecular signature (mean C-index, 0.68 vs 0.65). CONCLUSIONS AND RELEVANCE: The proposed clinical-immune signature is a promising biomarker for estimating overall survival in nonsquamous NSCLC, including early-stage disease. Prospective studies are needed to test the clinical utility of the biomarker in individualized management of nonsquamous NSCLC.
Crizotinib Versus Chemotherapy in Asian Patients with Advanced ALK-positive Non-small Cell Lung Cancer. Nishio M1, Kim DW2, Wu YL3, et al. Cancer Res Treat. 2017 Jul 6. doi: 10.4143/crt.2017.280. [Epub ahead of print]
PURPOSE: Crizotinib has demonstrated superior progression-free survival (PFS) and objective response rates (ORRs) versus chemotherapy in previously treated and untreated patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC). We report the safety and efficacy of crizotinib in Asian subpopulations of two global phase III trials. MATERIALS AND METHODS: This analysis evaluated previously treated and untreated patients in two randomized, open-label phase III trials of crizotinib versus chemotherapy in ALK-positive advanced NSCLC in second-line (PROFILE 1007) and first-line settings (PROFILE 1014). Efficacy and safety were analyzed by race in the intention- to-treat and “as-treated” populations for efficacy and safety endpoints, respectively. RESULTS: In previously treated (n=157) and untreated (n=157) Asian patients, PFS was statistically significantly longer with crizotinib versus chemotherapy (hazard ratio for PFS, 0.526; 95% confidence interval, 0.363-0.762 [p<0.001] and 0.442; 95% confidence interval, 0.302-0.648 [p<0.001], respectively). Similar antitumor activity was seen in the non-Asian and overall populations. ORRs were statistically significantly higher with crizotinib versus chemotherapy in both Asian and non-Asian previously treated and untreated patients (p<0.05). The most common treatment-emergent adverse events (any grade) with crizotinib were vision disorder, diarrhea, and nausea, which were observed at a comparable incidence across Asian and
non-Asian populations, irrespective of previous treatment status. Most adverse events were mild to moderate in severity. CONCLUSION: These data, currently the only analysis showing Asian and non- Asian populations in the same study, support the efficacy and safety of crizotinib in Asian patients with previously treated or untreated ALK-positive advanced NSCLC.
Hair Repigmentation During Immunotherapy Treatment With an Anti-Programmed Cell Death 1 and Anti-Programmed Cell Death Ligand 1 Agent for Lung Cancer. Rivera N1, Boada A1, Bielsa MI1, Fernández-Figueras MT2, Carcereny E3, Moran MT3, Ferrándiz C1. JAMA Dermatol. 2017 Jul 12. doi: 10.1001/jamadermatol.2017.2106. [Epub ahead of print]
IMPORTANCE: New targeted therapies for cancer have been released in recent years, opening new horizons in the treatment of patients with cancer. However, their related adverse events (AE) are not fully characterized. Hair repigmentation (HR) is a nondescribed effect secondary to anti-programmed cell death 1 (anti-PD-1) and anti-programmed cell death ligand 1 (anti-PD-L1 ) therapy for treatment of lung cancer (LC), in opposition to the vitiligo reactions that develop during melanoma treatment. OBJECTIVE: To describe a new adverse event occurring during anti-PD-1/anti-PD-L1 therapy for LC. DESIGN, SETTING, AND PARTICIPANTS: A case series from a descriptive observation of 14 patients with HR after anti-PD-1/anti-PD-L1 treatment, recruited between September and December, 2016, who were followed up to detect whether they developed cutaneous AE at the time HR was detected. The patients had all been treated in the dermatology department at Hospital Universitari Germans Trias i Pujol, Badalona, Spain. MAIN OUTCOMES AND MEASURES: Clinical observation of HR during anti-PD- 1/anti-PD-L1 therapy for LC, proved by comparing old pictures provided by the patients and recent pictures taken during the follow-up. RESULTS: Fourteen patients (13 men and 1 woman; mean age, 64.9 years) receiving anti-PD-1 or anti-PD-L1 therapy for non-small-cell lung cancer (NSCLC) presented hair repigmentation during follow-up. This hair repigmentation consisted in a diffuse darkening of the hair in 13 of 14 patients, or in black patches between white hairs in 1. Thirteen of 14 patients presented a good clinical response to the treatment, with at least stable disease, and only 1 had to stop the therapy after only 4 cycles of treatment owing to a life-threatening progression of the disease. CONCLUSIONS AND RELEVANCE: We present to our knowledge the first report of hair repigmentation owing to anti-PD- 1/anti-PD-L1 therapy for lung cancer in a series of 14 patients. Hair repigmentation may be a good response marker in patients receiving anti-PD1/anti-PD-L1 therapy for LC.
Tumor response dynamics of advanced non-small-cell lung cancer patients treated with PD-1 inhibitors: Imaging markers for treatment outcome. Nishino M1, Dahlberg SE2, Adeni AE3, Lydon C4, Hatabu H5, Janne PA3, Hodi FS3, Awad MM6. Clin Cancer Res. 2017 Jul 5. pii: clincanres.1434.2017. doi: 10.1158/1078-0432.CCR-17-1434. [Epub ahead of print]
PURPOSE: We evaluated tumor burden dynamics in advanced non-small-cell lung cancer (NSCLC) patients treated with commercial PD-1 inhibitors to identify imaging markers associated with improved overall survival (OS). <p>Experimental Design: The study included 160 advanced NSCLC patients treated with commercial nivolumab or pembrolizumab monotherapy as a part of clinical care. Tumor burden dynamics were studied for the association with OS.</p> <p>Results: Tumor burden change at best overall response (BOR) ranged from -100% to +278% (median: +3.5%). Response rate (RR) was 18% (29/160). Current and former smokers had a higher RR than never smokers (p=0.04). Durable disease control for at least 6 months was noted in 26 patients (16%), which included 10 patients with stable disease as BOR. Using a landmark analysis, patients with <20% tumor burden increase from baseline within 8 weeks of therapy had longer OS than patients with ≥20% increase (median OS:12.4 vs. 4.6 months, p<0.001). Patients with <20% tumor burden increase throughout therapy had significantly reduced hazards of death (HR=0.24, Cox p<0.0001) after adjusting for smoking (HR=0.86, p=0.61) and baseline tumor burden (HR=1.55, p=0.062), even though some patients met criteria for RECIST
progression while on therapy. One patient (0.6%) had atypical response pattern consistent with pseudoprogression.</p> Conclusions: Objective response or durable disease control was noted in 24% of advanced NSCLC patients treated with commercial PD-1 inhibitors. A tumor burden increase of <20% from baseline during therapy was associated with longer OS, proposing a practical marker of treatment benefit. Pseudoprogression is rare in NSCLCs treated with PD-1 inhibitors.
Mild pulmonary emphysema a risk factor for interstitial lung disease when using cetuximab for squamous cell carcinoma of the head and neck. Okamoto I1, Tsukahara K1, Sato H1, Motohashi R1, Yunaiyama D2, Shimizu A1. Acta Otolaryngol. 2017 Jul 25:1-4. doi: 10.1080/00016489.2017.1355566. [Epub ahead of print]
BACKGROUND: Interstitial lung disease (ILD) is an occasionally fatal adverse event associated with cetuximab (Cmab) therapy. Our objective was to clarify to what degree pulmonary emphysema is a risk factor in the treatment of head and neck cancer with Cmab through a retrospective analysis. METHODS: Subjects were 116 patients who were administered Cmab for head and neck squamous cell carcinoma.
The degree of pulmonary emphysema before initiating treatment with Cmab was visually assessed retrospectively, with scoring according to the Goddard classification used in Japanese chronic obstructive pulmonary disease (COPD) guidelines for chest computed tomography (CT). Scoring was conducted by two diagnostic radiologists and mean scores were used. Cutoffs for the development and nondevelopment of ILD were examined by receiver operating characteristic (ROC) analysis and Fisher’s exact test. Values of p < .05 were considered to indicate a significant difference. RESULTS: Among the 116 patients, 11 (9.5%) developed ILD, and 105 (90.5%) did not. In ROC analysis, the optimal Goddard score cut-off of
<3.0 offered 55% sensitivity and 81% specificity (p = .015). With a cutoff of <3.0, even very mild pulmonary emphysema would represent a risk factor for ILD when using Cmab.
Yang JC1, Ou SI2, De Petris L3, Gadgeel S4, Gandhi L5, Kim DW6, Barlesi F7, Govindan R8, Dingemans AC9, Crino L10, Lena H11, et al. J Thorac Oncol. 2017 Jul 5. pii: S1556-0864(17)30570-1. doi: 10.1016/j.jtho.2017.06.070. [Epub ahead of print]
INTRODUCTION: Alectinib demonstrated clinical efficacy and an acceptable safety profile in two phase II studies (NP28761 and NP28673). Here we report pooled efficacy and safety data after 15 and 18 months’ longer follow-up than the respective primary analyses. MATERIALS AND METHODS: Enrolled patients had ALK-positive NSCLC and had progressed on, or were intolerant to, crizotinib.
Patients received oral alectinib 600 mg twice daily. The primary endpoint in both studies was objective response rate (ORR) assessed by an independent review committee (IRC) using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). Secondary endpoints included disease control rate (DCR); duration of response (DOR); progression-free survival (PFS); overall survival (OS); and safety.
RESULTS: The pooled dataset included 225 patients (n=138 NP28673; n=87 NP28761). The response- evaluable (RE) population included 189 patients (84%; n=122 NP28673; n=67 NP28761). In the RE population, ORR by IRC was 51.3% (95% confidence interval [CI], 44.0-58.6; all partial responses), DCR was 78.8% (95% CI, 72.3-84.4), and median DOR was 14.9 months (95% CI, 11.1-20.4) after 58% of events. Median PFS by IRC was 8.3 months (95% CI, 7.0-11.3) and median OS was 26.0 months (95% CI, 21.4-not estimable). Grade ≥3 adverse events (AEs) occurred in 40% of patients, 6% withdrew treatment due to AEs and 33% had AEs leading to dose interruptions/modification. CONCLUSION: This pooled data analysis confirmed the robust systemic efficacy of alectinib in ALK-positive NSCLC with a durable response rate. Alectinib also had an acceptable safety profile with a longer duration of follow-up.
Spotlight on ceritinib in the treatment of ALK+ NSCLC: design, development and place in therapy. Santarpia M1, Daffinà MG1, D’Aveni A1, et al. Drug Des Devel Ther. 2017 Jul 5;11:2047-2063. doi: 10.2147/DDDT.S113500. eCollection 2017.
The identification of echinoderm microtubule-associated protein-like 4 (EML4) and anaplastic lymphoma kinase (ALK) fusion gene in non-small cell lung cancer (NSCLC) has radically changed the treatment of a subset of patients harboring this oncogenic driver. Crizotinib was the first ALK tyrosine kinase inhibitor to receive fast approval and is currently indicated as the first-line therapy for advanced, ALK-positive NSCLC patients. However, despite crizotinib’s efficacy, patients almost invariably progress, with the central nervous system being one of the most common sites of relapse. Different mechanisms of acquired resistance have been identified, including secondary ALK mutations, ALK copy number alterations and activation of bypass tracks. Different highly potent and brain-penetrant next-generation ALK inhibitors have been developed and tested in NSCLC patients with ALK rearrangements. Ceritinib, a structurally distinct and selective ALK inhibitor, showed 20 times higher potency than crizotinib in inhibiting ALK and had activity against the most common crizotinib-resistant mutations, including L1196M and G1269A, in preclinical models. In Phase I and II studies, ceritinib demonstrated pronounced activity in both crizotinib-naïve and crizotinib-refractory patients, with responses observed regardless of the presence of ALK resistance mutations. Ceritinib was the first ALK inhibitor to be approved for the treatment of crizotinib-refractory, ALK-rearranged NSCLC, and recent results from a Phase III study have demonstrated superior efficacy compared to standard chemotherapy in the first- and second-line setting.
We provide an extensive overview of ceritinib from the design of the compound through preclinical data until efficacy and toxicity results from Phase I-III clinical studies. We review the molecular alterations associated with resistance to ceritinib and highlight the importance of obtaining tumor biopsy at progression to tailor therapy based upon the underlying resistance mechanism. We finally provide an outlook on novel rational therapeutic combinations.
Efficacy of alectinib in central nervous system metastases in crizotinib-resistant ALK-positive non- small-cell lung cancer: Comparison of RECIST 1.1 and RANO-HGG criteria. Gandhi L1, Ou SI2, Shaw AT3, et al. Eur J Cancer. 2017 Jul 10;82:27-33. doi: 10.1016/j.ejca.2017.05.019. [Epub ahead of print]
BACKGROUND: Central nervous system (CNS) progression is common in patients with anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer (NSCLC) receiving crizotinib. Next- generation ALK inhibitors have shown activity against CNS metastases, but accurate assessment of response and progression is vital. Data from two phase II studies in crizotinib-refractory ALK+ NSCLC were pooled to examine the CNS efficacy of alectinib, a CNS-active ALK inhibitor, using Response Evaluation Criteria in Solid Tumours (RECIST version 1.1) and Response Assessment in Neuro- Oncology high-grade glioma (RANO-HGG) criteria. METHODS: Both studies enrolled patients aged
≥18 years who had previously received crizotinib. NP28761 was conducted in North America and NP28673 was a global study. All patients received 600 mg oral alectinib twice daily and had baseline CNS imaging. CNS response for those with baseline CNS metastases was determined by an independent review committee. RESULTS: Baseline measurable CNS disease was identified in 50 patients by RECIST and 43 by RANO-HGG. CNS objective response rate was 64.0% by RECIST (95% confidence interval [CI]: 49.2-77.1; 11 CNS complete responses [CCRs]) and 53.5% by RANO-HGG (95% CI: 37.7- 68.8; eight CCRs). CNS responses were durable, with consistent estimates of median duration of 10.8 months with RECIST and 11.1 months with RANO-HGG. Of the 39 patients with measurable CNS disease by both RECIST and RANO-HGG, only three (8%) had CNS progression according to one criteria but not the other (92% concordance rate). CONCLUSION: Alectinib demonstrated promising efficacy in the CNS for ALK+ NSCLC patients pretreated with crizotinib, regardless of the assessment criteria used.
Neoadjuvant chemotherapy by bronchial arterial infusion in patients with unresectable stage III squamous cell lung cancer. Zhu J1, Zhang HP1, Jiang S2, Ni J1. Ther Adv Respir Dis. 2017 Aug;11(8):301-309. doi: 10.1177/1753465817717169. Epub 2017 Jul 4.
BACKGROUND: We investigated the effects of neoadjuvant chemotherapy administered via bronchial arterial infusion (BAI) on unresectable stage III lung squamous cell carcinoma (SCC). METHODS: This was a single-arm retrospective study of chemotherapy with gemcitabine plus cisplatin (GP) administered via BAI to patients with unresectable lung SCC. Data regarding the post-treatment response rate, downstage rate, and surgery rate, as well as progression-free survival (PFS), overall survival (OS), quality of life, and post-BAI side effects were collected. RESULTS: A total of 36 patients were enrolled in this study between August 2010 and May 2014. The response rate was 72.2%, and the downstage rate was 22.2%. Among the patients who were downstaged, 16 (44.4%) patients were because of their T stage, and 5 (13.9%) patients were downstaged due to to their N stage. The surgery rate was 52.8%, the 1-year survival rate was 75.4%, and the 2-year survival rate was 52.1%. The median PFS was 14.0 months [95% confidence interval (CI): 8.6-19.4], and the median OS was 25.0 months (95% CI: 19.1-30.9). The quality of life was significantly improved, and the chemotherapy was well tolerated. CONCLUSIONS: Compared with intravenous neoadjuvant chemotherapy, BAI chemotherapy significantly improved the surgery rate, prolonged PFS and OS, and improved the quality of life in patients with unresectable stage III lung SCC.