Small Cell Lung Cancer Cases Research Articles

Characteristics and Outcomes of Small Cell Lung Cancer Detected by CT Screening

Previous studies with a limited number of patients have reported divergent findings on whether screening can detect small cell lung cancer (SCLC) at an earlier stage and whether there might be a survival benefit. This study examined the characteristics of SCLC detected by using low-dose CT (LDCT) screening in the National Lung Screening Trial, a randomized study of individuals at high risk for developing lung cancer comparing LDCT imaging vschest radiography. SCLC was denoted as screen detected if diagnosed≤ 1 year of a positive screen or after a longer period but with no time gap between diagnostic procedures of > 1 year; interval detected if diagnosed≤ 1 year of a negative screen; and nonscreen detected if the subject did not receive any screens or otherwise as postscreening. A total of 143 cases of SCLC were diagnosed, including 49 (34.2%) screen detected, 15 (10.5%) interval detected, and 79 (55.2%) nonscreened/postscreening. Of the screening phase-diagnosed cases (ie, screen or interval detected), a higher proportion of SCLC cases compared with NSCLC cases were interval detected (23%vs5%; P< .0001). A higher proportion of all SCLC cases compared with NSCLC cases were advanced stage (III/IV: 86%vs36%; P< .0001). The unfavorable SCLC stage distribution extended across screen-detected (80%stage III/IV), interval-detected (86%), and nonscreened/postscreening (90%) cancers. Among screen-detected SCLC, only 63.3%had≥ 1 noncalcified nodule in the cancer lobe compared with 85.4%of NSCLC cases (P< .0001). Even with very small LDCT screen-detected nodules, a high proportion of SCLC cases were late stage. There was no significant difference in survival between screen- and interval-detected or postscreening SCLC. "Early detection" with the use of LDCT imaging had no impact on SCLC outcomes. A successful screening modality should ideally detect SCLC earlier than when it can be detected on LDCT scans.

The role of immune microenvironment in small-cell lung cancer: Distribution of PD-L1 expression and prognostic role of FOXP3-positive tumour infiltrating lymphocytes

IntroductionThe prognosis of small-cell lung cancer (SCLC) is dismal and new effective therapies are needed. Immunotherapy looks promising, but no molecular predictive markers are currently available, and data on immune microenvironment are very limited. MethodsWe retrospectively analysed 104 SCLC cases. Immunohistochemistry evaluation of PD-L1 was performed both on tumour cells (TCs) and on tumour-infiltrating immune cells (TIICs) by using anti-PD-L1 22C3 antibody (DAKO) and categorised by using 1% as cut-off point. Tumour-infiltrating lymphocytes (TILs) were characterised by using anti-CD8 and anti-FOXP3 antibodies. Semi-quantitative score was used and categorised as positive versus negative/low. The relation of molecular markers with prognosis and with clinical variables was evaluated. ResultsThe analysis included 66 stage I–III patients (48 surgically resected, 18 treated with radical-intent chemoradiotherapy) and 38 metastatic cases. In the overall study population, PD-L1 was expressed on TCs and TIICs in 25% and 40% of cases, respectively. The proportion of PD-L1-positive cases was significantly higher in stage I–III versus metastatic patients (32% versus 13%, p: 0.034 for TCs; 51.5% versus 21% for TIICs, p: 0.002). CD8- and FOXP3-positive TILs were present in 59% and 72% of samples, respectively. The presence of FOXP3-TILs was associated with improved prognosis among non-metastatic patients, with a hazard ratio for survival of 0.32 (95% confidence interval [CI]: 0.16–0.7, p: 0.006) for univariate analysis, and 0.37 (95% CI: 0.17–0.81, p: 0.013) for multivariate analysis. ConclusionsImmune contexture of SCLC may differ according to stage. The presence of FOXP3-positive TILs is a potential prognostic marker for stage I–III SCLCs and warrants further investigation.

Clinical Activity of Pan-HER Inhibitors Against HER2-Mutant Lung Adenocarcinoma

IntroductionHER2 mutations are found in 2% to 4% of non–small-cell lung cancer cases and are usually mutually exclusive with other genetic alterations. We screened a large cohort of patients from multiple institutions in Korea, described the characteristics of HER2-mutant cases, and reported on several patients who were treated with pan-HER inhibitors. Patients and MethodsThe study population consisted of 360 patients diagnosed with adenocarcinoma from 4 institutions in Korea from June 2015 to September 2016. Tissue specimens from all participants were screened by direct sequencing, and next-generation sequencing was conducted only on specimens that were positive in direct sequencing. HER2-targeted therapy, either poziotinib or afatinib, was orally administrated. ResultsNext-generation sequencing was conducted in 129 patients, and finally 29 (8.1%) patients with HER2 mutation were identified. Most patients were female (58.6%), had never smoked (70.0%), and had stage IV non–small-cell lung cancer (55.2%). For all patients, the histologic type was adenocarcinoma, with no coexisting EGFR or ALK alterations. The most common type of HER2 mutation (48.3%) was c.2326_2327insTGT in exon 20. A partial response was observed in 2 patients who received poziotinib and 1 patient who received afatinib. The main toxicities of the pan-HER inhibitors were nausea, diarrhea, and mucositis. ConclusionHER2 mutation was estimated at a frequency of approximately 8.1% in Korean patients with adenocarcinoma in the absence of known driver mutations. Because some of the HER2-mutant cases responded to poziotinib or afatinib, further studies are warranted.

Clinicopathological characteristics of thyroid transcription factor 1–negative small cell lung cancers

Limitations in obtaining surgically resected or biopsy samples of small cell lung cancer (SCLC) tumors make comprehensive biological analyses difficult. The loss of thyroid transcription factor 1 (TTF-1) has been associated with the aggressive behavior of non-small cell lung cancer; however, clinicopathological features of TTF-1-negative SCLC remain unclear. This study aimed to elucidate the characteristics of TTF-1-negative SCLC. We studied the associations between the expression of TTF-1 and the clinicopathological factors associated with SCLC, including survival and expression of neuroendocrine markers (synaptophysin, chromogranin A, and CD56), neuroendocrine cell-specific transcription factors (ASCL1, BRN2), a proliferation marker (Ki-67 labeling index), and an oncogene (NF1B). Formalin-fixed and paraffin-embedded sections of SCLC tumors were subjected to immunohistochemistry and quantitative reverse-transcription polymerase chain reaction analyses. In a case-control cohort matched for basic clinical factors, expression of ProGRP, synaptophysin, chromogranin A, and ASCL1 was significantly decreased in TTF-1-negative SCLC samples. In contrast, there was no significant correlation between Ki-67 labeling index and TTF-1. In a larger serial case cohort, TTF-1-negative SCLC cases were older at diagnosis, but there was no significant difference in the overall survival of patients with TTF-1-negative and TTF-1-positive SCLC. In conclusion, TTF-1-negative SCLC showed decreased neuroendocrine differentiation, and significantly worse clinical outcomes were not observed.

Effects of DKK1 overexpression on bone metastasis of SBC-3 cells.

Among all malignancies, lung cancer is the leading cause of cancer-related deaths in China. Bone metastasis is one of the most common complications and one of the most important factors affecting the prognosis of lung cancer patients, which resulting in very poor therapeutic effects. Previously, we have demonstrated that the expression levels of Dickkopf1 (DKK1), a protein involved in cell regulation and proliferation, was dramatically higher in cells that have a tendency to metastasize and invade the bone tissue (SBC-5 cells) compared with cells that do not (SBC-3 cells). Downregulation of DKK1 in SBC-5 cells inhibited cell malignancy in vitro, and the formation of bone metastasis in vivo. However, whether upregulating DKK1 would be sufficient to induce aggressive tumor behavior (proliferation, migration, invasion and metastasis) in SBC-3 cells remained to be investigated. The present study aimed to examine the role of DKK1 in SBC-3 cells, as well as to investigate the SBC-3 ability to metastasize and invade the bone tissue. The results demonstrated that upregulation of DKK1 in SBC-3 cells enhanced cell proliferation, colony formation, cell migration and invasion in vitro, as well as bone metastasis in vivo. These results indicate that DKK1 may be an important regulator in the development of small cell lung cancer (SCLC), and targeting DKK1 may be an effective method for preventing and/or treating skeletal metastases in SCLC cases.

Spontaneous Regression of Small Cell Lung Cancer: A Case Report

Spontaneous regression (SR) is extremely rare in small cell lung cancer (SCLC). The present study reports a rare case of SCLC accompanied by partial SR in a 68-year-old man. The patient was scheduled to receive chemoradiotherapy for SCLC. Computed tomography (CT) simulation images for radiotherapy revealed partial regression of the primary tumor, while lymph node metastasis progression was observed. On 18F-fluorodeoxyglucose (FDG) positron emission tomography/CT, an abnormally high uptake of FDG was not observed in the primary exhibiting SR, while an extremely high uptake was identified in the lymph node metastases. The patient also presented with bilateral double vision, which suggested neurological paraneoplastic syndrome. He received chemoradiotherapy and a complete response was obtained. Until the last follow-up (58 months since the initiation of chemoradiotherapy), the patient was free from tumor progression.

Clinical characteristics and sequence complexity of anaplastic lymphoma kinase gene fusions in Chinese lung cancer patients

ObjectivesTo investigate the clinical characteristics of anaplastic lymphoma kinase (ALK) rearrangements and sequence complexity of the ALK fusion gene in Chinese lung cancer patients. MethodsWe prospectively screened ALK rearrangements in 1474 lung cancer specimens, including 1387 cases of non-small cell lung cancer (NSCLC), 54 cases of small cell lung cancer (SCLC), and 33 cases of cancer with lung metastasis from other organs by both standard polymerase chain reaction (PCR) and rapid amplification of cDNA ends (RACE)-coupled PCR. Fifteen cases of ALK-positive RACE-coupled PCR products were transformed into Escherichia coli for molecular cloning and sequenced for complexity analysis. ResultsThe overall frequency of ALK rearrangements was 5.1% (71/1387) in NSCLC. In 71 positive cases, the coexistence of epidermal growth factor receptor (EGFR) and ALK variations was found in 6 cases (8.5%), and the coexistence of different ALK variants was found in 2 cases (2.8%) (1 case with variants 1 and 9; the other case with variants 3 and 2) by PCR analysis. Furthermore, through sequence cloning analysis of 15 cases of non-selective ALK-positive samples, two cases with variants 1 and 3 harbored the coexistence of three subtypes (variant 1 subtypes: E13; A20, E13del63; A20 and E7E12E13; A20 and variant 3 subtypes: E6; A20, E6ins33; A20 and E3E6; A20). Variant 3a and 3b subtypes were always coexistent and had the same proportion of ALK variant 3 rearrangements. ALK rearrangement was associated with young age, female gender, never-smokers, those with adenocarcinoma, advanced stage, and EGFR mutations. No ALK fusion was detected in 54 cases of SCLC or 33 cases of cancer with lung metastasis from other organs. ConclusionsThe identification of novel ALK variants, the coexistence of EGFR mutations and ALK fusions, the coexistence of ALK variants, and the coexistence of subtypes reveal the diversity and sequence complexity of ALK fusions.

PC 02.01 Thoracic Radiation - YES

Small cell lung cancer (SCLC) accounts for 15%–20% of all lung cancers, and the overwhelming majority (>95%) are associated with tobacco exposure. The incidence of all types of lung cancer, including SCLC, has been declining in the United States with the onset of tobacco smoking cessation programs, although this trend took nearly 20 years to become evident among men. Overall survival (OS) rates for patients with lung cancer have also increased by about 5% since the advent of low-dose spiral computed tomography (CT) scanning to detect early lung cancer. The prognosis for patients with SCLC continues to be poor but has improved with the advent of smoking cessation campaigns, more effective chemotherapy agents and radiation planning and delivery techniques, and the use of prophylactic cranial irradiation (PCI) for those who experience a complete response to therapy. Consolidation with chest radiotherapy has improved OS among patients with extensive-stage SCLC who achieved a complete response to chemotherapy. SCLC often presents as bulky symptomatic masses, and mediastinal involvement is common with or without pleural effusion and extrathoracic disease. Extrathoracic spread (i.e., extensive-stage disease) is also quite common, being present in 80%-85% of cases at diagnosis. Brain metastases are present in approximately 20% of patients at diagnosis; roughly half of these metastases are symptomatic and the other half are detected by imaging. Predictors of poor prognosis include poor performance status, older age, and being male. The pathologic subtypes of the disease (small cell carcinoma and combined small cell carcinoma) all carry a similarly poor prognosis. Current guidelines of the U.S. National Comprehensive Cancer Network recommend the use of positron emission tomography (PET), CT scanning, or fused PET/CT scanning of the chest, liver, adrenals, bone, and other areas of concern in the diagnosis and staging of SCLC (NCCN guideline-SCLC 2017). Thoracic radiotherapy has also become important for improving OS among patients with SCLC who achieved a complete response to chemotherapy. In one prospectively randomized study of 498 patients with extensive-stage SCLC (WHO performance status score 0-2) who achieved complete response to chemotherapy, patients who received consolidation thoracic radiotherapy (30 Gy in 10 fractions) had significantly better 2-year OS rates than did those who did not receive thoracic radiotherapy (13% vs. 3%, P=0.004). Thoracic radiotherapy further improved thoracic-only failure rates (19.8% vs. 46% without, P=0.001) (Slotman B et al, Lancet Oncol 2015;385:36-42). However, many patients with extensive-stage SCLC do not respond to the standard etoposide/cisplatin chemotherapy (Fig 1). Those patients may need to receive molecular-targeted therapies or immunotherapy with the consolidating thoracic radiotherapy. Several histologic and immunohistochemical markers have been evaluated for diagnosing or monitoring treatment response in SCLC, including transcription thyroid factor-1 (positive in >85% of SCLC cases); cytokeratin 7; deletions in chromosome 3; Leu-7; chromogranin A; synaptophysin; myc amplification; and p53 mutations (present in ∼75% of cases). Deletions in tumor-suppressor genes are also relatively common and include fragile histidine triad (FHIT) (80%); RAS effector homologue (RASSF1) (>90%); TP53 (>75%); retinoblastoma-1 (RB1) (>90%); and retinoic acid receptor-beta (72%). However, to date no biomarkers have been validated for use in diagnosing SCLC. Moreover, mutations that are often present in non-small cell lung cancer (such as epidermal growth factor receptor [EGFR] mutations and anaplastic lymphoma kinase [ALK]) are rare in SCLC. Several clinicopathologic features have been linked with worse prognosis, including poor performance status, significant weight loss, high lactate dehydrogenase levels, large numbers of metastatic sites, and the presence of paraneoplastic syndromes. Because SCLC has the among the highest rates of somatic driver mutations, and because more than 95% of patients with SCLC are former or current smokers, immunotherapy seems a reasonable approach, as high mutation burdens correlate with good response to chemoradiotherapy and sensitivity to immunomodulators (Peifer M et al., Nat Genet 2012;44(10):1104-10). At MD Anderson Cancer Center, an ongoing phase I/II study of patients with extensive-stage SCLC has been proposed to the NRG as a prospective randomized study (PI J Welsh) (Fig 2). Use of thoracic radiotherapy to consolidate a site at which SCLC is quite likely to recur is reasonable, given that recurrence considerably reduces quality of their life as well as OS. In summary, in most cases SCLC presents as extensive-stage disease, for which outcomes are very poor. Consolidation with thoracic radiotherapy for patients who achieve a complete response to chemotherapy can improve 2-year OS rates. However, less toxic and more effective systemic treatment is also required to derive the greatest benefit from consolidation thoracic radiotherapy. thoracic radiotherapy extensive small-cell lung cancer, immunotherapyFig 2View Large Image Figure ViewerDownload Hi-res image Download (PPT)

RE: Proportion of Never-Smoker Non-Small Cell Lung Cancer Patients at Three Diverse Institutions.

Background: Approximately 10% to 15% of lung cancer cases in the United States occur in never smokers, but there has been much debate about whether this rate is increasing. To determine whether the proportion of never smokers among lung cancer cases is increasing, we conducted a retrospective study using registries from The University of Texas Southwestern Medical Center, Parkland Hospital, and Vanderbilt University. Methods: Registries were queried for demographic information from 1990 to 2013 including sex, age, stage, and self-reported smoking history. Ten thousand five hundred ninety-three non–small cell lung cancer (NSCLC) case patients and 1510 small cell lung cancer (SCLC) case patients were captured, and logistic regression analysis was performed. All statistical tests were two-sided. Results: The proportion of never-smoker NSCLC patients increased from 8.0% in the years 1990 to 1995 to 14.9% in 2011 to 2013 (P < .001). This increase was also observed using multivariable logistic regression after controlling for sex, stage at diagnosis, and race/ethnicity. The percentage of never smokers among SCLC case patients (1.5% in 1990–1995 to 2.5% in 2011–2013, P = .36) or squamous cell NSCLC case patients did not statistically significantly change during this period. Conclusions: This study demonstrates an increasing proportion of NSCLC patients who have never smoked in a large, diverse patient population between 1990 and 2013. Given that this increase appears independent of sex, stage, and race/ethnicity and also occurred in our county hospital, this trend is unlikely due to changes in referral patterns and suggests that the actual incidence of lung cancer in never smokers is increasing.

Human epididymis protein 4 may not be a reliable screening biomarker for detecting lung carcinoma patients.

Human epididymis protein 4 (HE4) acts as a protease inhibitor. It has been detected in the serum of patients with lung cancer patients and its utility for lung cancer screening was found in different studies. Nevertheless, little is known regarding the expression of HE4 in lung carcinoma subtypes. The aim of the present study was to investigate whether HE4 expression is a reliable marker for detecting any lung carcinoma subtypes, including small cell lung cancer (SCLC), non-small cell lung cancer (NSCLC) and adenocarcinoma (AC). In total, 141 lung carcinoma patients were enrolled in the study. Biopsy samples were obtained from bronchoscopic biopsy. The tumors were classified as SCLC (group 1, 54 cases) or NSCLC (group 2, 87 cases) based on histology and immunohistochemistry. The latter was sub-grouped as adenocarcinoma (group 2a, AC) and squamous cell carcinoma (group 2b, SCC). The immunohistochemical expression of HE4 was compared between the groups. The study revealed that the majority of the SCLC and SCC cases were devoid of HE4 (90.1 and 89.65%, respectively). Approximately 10% of cases had HE4 immune expression and the staining was focal and moderate throughout the tumor tissue. On the other hand, 78.8% of AC expressed HE4 and the staining was diffuse and strong. The overall HE4 expression in the lung cancer patients was 33.7%. In conclusion, the results of the present study have shown that HE4 is expressed in adenocarcinoma of the lung but it is not frequent in SCC and SCLC. The value of HE4 as a screening biomarker for lung cancer is limited but its presence exclusively in adenocarcinoma may provide new insight for targeted therapy.

Germline Genetic Variants and Lung Cancer Survival in African Americans

Background: African Americans have the highest lung cancer mortality in the United States. Genome-wide association studies (GWASs) of germline variants influencing lung cancer survival have not yet been conducted with African Americans. We examined five previously reported GWAS catalog variants and explored additional genome-wide associations among African American lung cancer cases.Methods: Incident non-small cell lung cancer cases (N = 286) in the Southern Community Cohort Study were genotyped on the Illumina HumanExome BeadChip. We used Cox proportional hazards models to estimate HRs and 95% confidence intervals (CIs) for overall mortality. Two independent African American studies (N = 316 and 298) were used for replication.Results: One previously reported variant, rs1878022 on 12q23.3, was significantly associated with mortality (HR = 0.70; 95% CI: 0.54-0.92). Replication findings were in the same direction, although attenuated (HR = 0.87 and 0.94). Meta-analysis had a HR of 0.83 (95% CI, 0.71-0.97). Analysis of common variants identified an association between chromosome 6q21.33 and mortality (HR = 0.46; 95% CI, 0.33-0.66).Conclusions: We identified an association between rs1878022 in CMKLR1 and lung cancer survival. However, our results in African Americans have a different direction of effect compared with a prior study in European Americans, suggesting a different genetic architecture or presence of gene-environment interactions. We also identified variants on chromosome 6 within the gene-rich HLA region, which has been previously implicated in lung cancer risk and survival.Impact: We found evidence that inherited genetic risk factors influence lung cancer survival in African Americans. Replication in additional populations is necessary to confirm potential genetic differences in lung cancer survival across populations. Cancer Epidemiol Biomarkers Prev; 26(8); 1288-95. ©2017 AACR.

Application of Serum ELAVL4 (HuD) Antigen Assay for Small Cell Lung Cancer Diagnosis.

The ELAVL4 (HuD) is a neuron-specific RNA-binding protein expressed in 100% of small cell lung cancer (SCLC) cells and over 50% of neuroblastoma cells. The aim of this study was to investigate the serum HuD concentration in SCLC patients and the possibility of its utilization as a biomarker of small cell lung cancer. Our study included 47 SCLC cases and 29 normal controls. Indirect competitive inhibition ELISA method was established to detect HuD antigen of serum samples. To design the ELISA system, purified antigen and real positive and negative serum samples were used, and checkerboard titration was performed. The value of current serum biomarkers (Pro-GRP, NSE, CYFRA21-1 and CEA) was obtained from a clinical laboratory. The HuD antigen concentration in the SCLCgroup was significantly higher than that in the normal group (p<0.01). The cut-off value, specificity and sensitivity were 60 ng/ml, 89.7% and 74.5%, respectively. The best linear range was 9.75~600 ng/ml. The sensitivity of the HuD-ELISA assay was much better than the current biomarkers-CEA, NSE and pro-GRP. Also,it was equal to or better than the combined use of two or three indicators. The high titres of HuD in SCLC patients and preferable consistency suggested that HuD may serve as a potential diagnostic criterium for SCLC and may serve as a marker of disease progression.

Prognostic factors and combined histologies in 205 resected small cell lung cancer (SCLC) patients.

e20009 Background: SCLC accounts for 15%-20% of all lung cancer, 2%-5% of them are combined SCLC. The objectives of this study were to evaluate the prognostic factors in a large series of resected SCLC patients, and to perform genetic analysis of combined forms. Methods: 205 SCLC cases were resected at Tianjin Cancer Hospital between 1/2005 and 12/2015. We analyzed: gender, age, type of resection, cigarette index (CI), tumor markers (CEA, SCC, NSE, Cyfra21-1), R resection type, number of resected lymph nodes (LNs), ratio of metastatic LNs, and pathological stage. All combined SCLC cases were identified by H&amp;E staining and confirmed by immunohistochemistry. The different components were microdissected using an automated dissection system (MillisectTM, Roche Diagnostics) and DNA was extracted and subjected to targeted exome sequencing. Results: The median follow-up time was 24 (2-121) months. Median survival time of all the patients was 24 months; 5-year survival rates were 51.4% overall, and 69.5%, 66.5%, 34.4%, and 0% for pathological stage I, II, III, and IV, respectively. Multivariate analysis indicated age, CI, complete resection, number of resected LNs and the ratio of metastatic LNs as independent prognostic factors. Twelve cases of combined SCLC were identified out of 170 with adequate histological material: 6/12 were combined with squamous cell carcinoma. 1-, 3-, 5-year survival rates were 73.3%, 0% and 0%. There were no significant differences between combined SCLC and pure SCLC with respect to gender, age, pathological stage, LN status and tumor markers. Three cases were successfully sequenced. Around 50% gene mutations were present in both components (10/24; 14/27; 4/5 respectively). TP53 mutations were present in all three cases. One case displayed amplification of 2 genes in both components. Interestingly, there were also gene mutations and amplifications that are unique to one of the components. Conclusions: In this large resected SCLC series we identified CI, complete resection, resected number of LNs and ratio of metastatic LNs to be prognostic. Combined SCLC had worse survival than pure SCLC. The histologically different components had a significant number of common as well as unique genetic alterations.

Phase 1/2 study of veliparib (V) combined with carboplatin (Cb) and etoposide (E) in patients (pts) with extensive-stage disease (ED) small cell lung cancer (SCLC) and other solid tumors: Phase 1 results.

8530 Background: The majority of SCLC cases are diagnosed as ED, for which there is a poor prognosis and no curative treatment (Tx). V, a potent PARP inhibitor, has been shown in preclinical studies to enhance the antitumor activity of platinum-based agents and E against SCLC. The presented phase 1 dose-escalation (NCT02289690) evaluated V combined with Cb/E. Methods: Pts (≥18 years) with ED SCLC or other advanced/metastatic solid tumors with ≤1 line of prior cytotoxic therapy and ECOG performance score 0/1 were included. This study followed a 3+3 design. V starting dose and schedule were 80 mg BID PO administered on days (D) –2 to 5 in combination with Cb AUC 5 mg/mL•min administered on D 1 and E 100 mg/m2 administered on D 1 to 3 via intravenous infusion in 21-D cycles. V schedules of D –2 to 12 and continuous dosing were also explored. Primary objectives were to establish the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) for V combined with Cb/E, and to evaluate the pharmacokinetic (PK) interaction between V and E. Results: Thirty-nine pts (n = 24 ED SCLC; n = 15 other solid tumors) with median age of 62 years (range 43–79) received study Tx. Most common adverse events (AEs; ≥40%) were nausea (54%), fatigue (51%), alopecia (46%), and anemia (44%); grade 3/4 AEs (≥30%) were decreased neutrophil count, neutropenia (31% each), and anemia (26%). Dose-limiting toxicity occurred in 1 pt (n = 1 grade 3 fatigue) at V 240 mg BID D –2 to 5. The MTD was not reached; RP2D for V was set at 240 mg BID on D –2 to 12 based on long-term tolerability. Continuous dosing of V 240 mg BID with Cb/E resulted in unacceptable Cb/E dose delays due to hematologic toxicity. Coadministration of V (80 to 240 mg BID) with Cb/E exhibited dose-proportional kinetics with no impact on the E PK. Confirmed responses: ED SCLC 63% (15/24 pts) across all dose levels and in 83% (5/6) at RP2D; other tumor types: 13% (2/15) across all dose levels. Conclusions: V + Cb/E had an acceptable safety profile in pts with ED SCLC, with an RP2D of 240 mg BID D –2 to 12. Coadministration of V with Cb/E had no effect on E PK. Responses were seen across all dose levels. A phase 2 study of V with Cb/E in ED SCLC is ongoing. Clinical trial information: NCT02289690.

Trends, practice patterns and underuse of surgery in the treatment of early stage small cell lung cancer

BackgroundPractice guidelines from the National Comprehensive Cancer Network and the American Society of Clinical Oncology recommend pathologic mediastinal staging and surgical resection for patients with clinically node-negative T1/T2 small cell lung cancer (SCLC), but the extent to which surgery is used is unknown. We sought to assess trends and practice patterns in the use of surgery for SCLC. MethodsT1 or T2N0M0 SCLC cases were identified in the National Cancer Database (NCDB), 2004–2013. Characteristics of patients undergoing resection were analyzed. Hierarchical logistic regression was used to identify individual and hospital-level predictors of receipt of surgery, adjusting for clinical, demographic and facility characteristics. Trends in resection rates were analyzed over the study period. Findings9740 patients were identified with clinical T1 or T2 N0M0 SCLC. Of these, 2210 underwent surgery (22.7%), with 1421 (64.3%) undergoing lobectomy, 739 (33.4%) sublobar resections and 50 (2.3%) pneumonectomies. After adjustment, Medicaid patients were less likely to receive surgery (OR0.65 95% CI 0.48–0.89, p=0.006), as were those with T2 tumors (OR0.25 CI0.22–0.29, p<0.0001). Academic facilities were more likely to resect eligible patients (OR 1.90 CI1.45–2.49, p<0.0001). Between 2004 and 2013, resection rates more than doubled from 9.1% to 21.7%. Overall, 68.7% of patients were not offered surgery despite having no identifiable contraindication. In patients not receiving surgery, only 7% underwent pathologic mediastinal staging. InterpretationRates of resection are increasing, but two thirds of potentially eligible patients fail to undergo surgery. Further study is required to address the lack of concordance between guidelines and practice.

Predictive and prognostic value of serum periostin in advanced non-small cell lung cancer patients receiving chemotherapy.

Periostin is an extracellular matrix protein involved in tumorigenesis and metastasis. However, the role of serum periostin as a surrogate marker for treatment efficacy is still unknown. In 122 advanced non-small cell lung cancer cases, 37 patients with benign lung disease and 40 healthy controls, serum periostin was measured by enzyme-linked immunosorbent assays. The associations of serum periostin levels with the clinic-pathological parameters, chemotherapy response, and clinical outcomes of non-small cell lung cancer patients were analyzed. Serum periostin levels were significantly higher in non-small cell lung cancer patients, and it was related significantly to bone metastasis ( p = 0.021). Serum periostin of 65 non-small cell lung cancer patients were detected before and after two cycles of chemotherapy. The patients with and without periostin response had significant difference in objective response to chemotherapy ( p = 0.001). For the 122 non-small cell lung cancer patients, the median progression-free survival was 5 months. In a multivariate analysis, performance status (hazard ratio, 1.71; 95% confidence interval, 1.10-2.67), baseline periostin (hazard ratio, 1.01; 95% confidence interval, 1.00-1.01), and periostin response (hazard ratio, 0.50; 95% confidence interval, 0.29-0.86) were significantly correlated with prognosis. In conclusion, serum periostin was elevated in advanced non-small cell lung cancer patients. Baseline periostin and periostin responses appeared to be reliable surrogate markers to predict chemotherapy response and survival in patients with advanced non-small cell lung cancer.

Survival improvement in patients with non-small cell lung cancer between 1983 and 2012: Analysis of the Surveillance, Epidemiology, and End Results database.

Non-small cell lung cancer is the most common malignancy in males; it constitutes the majority of lung cancer cases and requires massive medical resources. Despite improvements in managing non-small cell lung cancer, long-term survival remains very low. This study evaluated survival improvement in patients with non-small cell lung cancer in each decade between 1983 and 2012 to determine the impact of race, sex, age, and socioeconomic status on the survival rates in these patients. We extracted data on non-small cell lung cancer cases in each decade between 1983 and 2012 from the Surveillance, Epidemiology, and End Results registries. In total, 573,987 patients with non-small cell lung cancer were identified in 18 Surveillance, Epidemiology, and End Results registry regions during this period. The 12-month relative survival rates improved slightly across three decades, from 39.7% to 40.9% to 45.5%, with larger improvement in the last two decades. However, the 5-year-relative survival rates were very low, with 14.3%, 15.5%, and 18.4%, respectively, in three decades, indicating the urgency for novel comprehensive cancer care. In addition, our data demonstrated superiority in survival time among non-small cell lung cancer patients of lower socioeconomic status and White race. Although survival rates of non-small cell lung cancer patients have improved across the three decades, the 5-year-relative survival rates remain very poor. In addition, widening survival disparities among the race, the sex, and various socioeconomic status groups were confirmed. This study will help in predicting future tendencies of incidence and survival of non-small cell lung cancer, will contribute to better clinical trials by balancing survival disparities, and will eventually improve the clinical management of non-small cell lung cancer.

Changing epidemiology of elderly small cell lung cancer patients over the last 40 years; a SEER database analysis.

Small cell lung cancer (SCLC) is a distinct clinical and pathological entity within the spectrum of lung cancer. It was observed that the relative age distribution of the disease changed over years. Surveillance, epidemiology, and end results (SEER) database (1973-2013) was utilized to determine the incidence, presentation and treatment outcomes of elderly patients (>70 years) with SCLC. Join point regression analysis was then conducted to analyze age-adjusted trends in incidence for the elderly as well as the whole SCLC population. Survival analysis was conducted through Kaplan-Meier analysis. Clinicopathological characteristics and survival outcomes were compared between patients diagnosed at 70-79 years old and those older than 80 years old (octogenarian group). The proportion of elderly patients among all cases of SCLC increased from 23% in 1975 to 44% in 2010. Moreover, the proportion of elderly female patients among all cases of elderly SCLC increased from 25% in 1975 to 49% in 2010. When categorizing patients into four subgroups "70-74," "75-79," "80-84," and "85+", there was a trend toward a lower cancer-specific survival with increasing age (P < .0001). A limited improvement in 5 year survival was observed during the study period and it is less apparent as the age increases. The proportion of elderly patients among all cases of SCLC has increased over the past 40 years. Further studies are needed to better select appropriate treatments for this subset of patients.

Treatment of stage I non–small cell lung cancer: What's trending?

ObjectivesStage I non–small cell lung cancer traditionally is treated with lobectomy. Sublobar resection and stereotactic body radiation therapy provide alternative treatments for higher-risk groups. The purpose of this study was to determine the national treatment trends for stage I lung cancer. MethodsThe National Cancer Database was queried for patients with clinical stage I non–small cell lung cancer between 1998 and 2012. Patients were compared across treatment groups, and trends in treatment and disease were evaluated over the 15-year time period. ResultsThe National Cancer Database contained 369,931 patients with clinical stage I non–small cell lung cancer. After removing patients who received chemotherapy as a first course of treatment and patients with pathologic stage IV, 357,490 patients were analyzed. The first recorded cases of stereotactic body radiation therapy are in 2003 and rapidly increased to 6.6% (2063) of all patients treated in 2012. The number of diagnoses of stage I non–small cell lung cancer steadily increased over the 15-year period, whereas the rate of lobectomy decreased from 55% in 1998 to 50% in 2012 (P < .001). Most of the decrease in lobectomy can be explained by the increase in the rate of sublobar resection from 12% to 17% (P < .001). The percentage of untreated patients remained stable at approximately 7% (P = .283). ConclusionsAlthough the number of stage I non–small cell lung cancer cases continues to increase, lobectomy rates are decreasing while sublobar resection and stereotactic body radiation therapy rates are increasing. Although the increasing popularity of alternative therapies to lobectomy for treatment of stage I non–small cell lung cancer should allow more patients to undergo treatment, we did not observe this trend in the data.

Genomic Amplification of CD274 (PD-L1) in Small-Cell Lung Cancer

Purpose: Programmed death ligand-1 (PD-L1), encoded by the CD274 gene, is a target for immune checkpoint blockade; however, little is known about genomic CD274 alterations. A subset of small-cell lung cancer (SCLC) exhibits increased copy number of chromosome 9p24, on which CD274 resides; however, most SCLCs show low expression of PD-L1. We therefore examined whether CD274 is a target of recurrent genomic alterations.Experimental Design: We examined somatic copy number alterations in two patient cohorts by quantitative real-time PCR in 72 human SCLC cases (cohort 1) and SNP array analysis in 138 human SCLC cases (cohort 2). Whole-genome sequencing revealed the detailed genomic structure underlying focal amplification. PD-L1 expression in amplified cases from cohorts 1 and 2 was further examined by transcriptome sequencing and immunohistochemical (IHC) staining.Results: By examining somatic copy number alterations in two cohorts of primary human SCLC specimens, we observed 9p24 copy number gains (where CD274 resides) and focal, high-level amplification of CD274 We found evidence for genomic targeting of CD274, suggesting selection during oncogenic transformation. CD274 amplification was caused by genomic rearrangements not affecting the open reading frame, thus leading to massively increased CD274 transcripts and high level expression of PD-L1.Conclusions: A subset (4/210, 1.9%) of human SCLC patient cases exhibits massive expression of PD-L1 caused by focal amplification of CD274 Such tumors may be particularly susceptible to immune checkpoint blockade. Clin Cancer Res; 23(5); 1220-6. ©2016 AACR.