Overall Survival In Small Cell Lung Cancer Research Articles

JCES01.24 Molecular Mechanism of Transformation from Adenocarcinoma to Small-Cell Lung Cancer after EGFR-TKI

In patients with advanced non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations, EGFR-tyrosine kinase inhibitors (TKIs) are recommended as first-line treatment due to favorable clinical efficacy. However, acquired resistance inevitably develops after median progression-free survival (PFS) of 9-14 months. Among the mechanisms of acquired resistance, small-cell lung cancer (SCLC) transformation was reported to account for nearly 5%. However, the molecular details underlying this histological change and resistance to EGFR-TKI therapy remain unclear. 15 out of 233 (6.4%) patients were confirmed to develop SCLC transformation after failure to EGFR-TKI. We analyzed the clinical parameters of these patients by using chi-square test and Kaplan-Meier analysis. To explore gene alterations that might contribute to SCLC transformation, next generation sequencing (NGS) was performed on four pairs of matched pre- and post-transformation tumor tissue samples. We further performed NGS on 11 matched circulating tumor DNA (ctDNA) to explore the potential mechanism of resistance to EGFR-TKI. The median age of SCLC transformed patients was 53 years. 93.3% (14/15) patients harbored EGFR exon19 deletion. The median PFS and overall survival (OS) of SCLC-transformed patients treated with EGFR-TKI compared to those without transformation were 11.7 versus 11.9 months (P=0.473) and 29.4 versus 24.3 months (P=0.664), respectively. All 4 patients developed loss of heterozygosity of TP53/RB1 after transformation. Besides, increased copy number of five proto-oncogenes were identified in post-transformation tissue samples. Three patients developed EGFR T790M mutation in the post-transformation ctDNA rather than their tissue samples. SCLC transformation was commonly seen in patients harboring EGFR exon 19 deletion. The clinical outcomes of TKI and OS in SCLC transformed patients were similar to non-transformed patients. The loss of heterozygosity of TP53 and RB1along with increased copy number of proto-oncogenes may lead to the SCLC transformation. The mechanisms of acquired resistance to TKI during SCLC transformation might be the emergence of classic drug resistance mutations, which was undetectable due to the intra-tumor heterogeneity.

P3.02b-116 Molecular Mechanism of Transformation from Adenocarcinoma to Small-Cell Lung Cancer after EGFR-TKI: Topic: EGFR RES

In patients with advanced non–small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) activating mutations, EGFR-tyrosine kinase inhibitors (TKIs) are recommended as first-line treatment due to favorable clinical efficacy. However, acquired resistance inevitably develops after median progression-free survival (PFS) of 9-14 months. Among the mechanisms of acquired resistance, small-cell lung cancer (SCLC) transformation was reported to account for nearly 5%. However, the molecular details underlying this histological change and resistance to EGFR-TKI therapy remain unclear. 15 out of 233 (6.4%) patients were confirmed to develop SCLC transformation after failure to EGFR-TKI. We analyzed the clinical parameters of these patients by using chi-square test and Kaplan-Meier analysis. To explore gene alterations that might contribute to SCLC transformation, next generation sequencing (NGS) was performed on four pairs of matched pre- and post-transformation tumor tissue samples. We further performed NGS on 11 matched circulating tumor DNA (ctDNA) to explore the potential mechanism of resistance to EGFR-TKI. The median age of SCLC transformed patients was 53 years. 93.3% (14/15) patients harbored EGFR exon19 deletion. The median PFS and overall survival (OS) of SCLC-transformed patients treated with EGFR-TKI compared to those without transformation were 11.7 versus 11.9 months (P=0.473) and 29.4 versus 24.3 months (P=0.664), respectively. All 4 patients developed loss of heterozygosity of TP53/RB1 after transformation. Besides, increased copy number of five proto-oncogenes were identified in post-transformation tissue samples. Three patients developed EGFR T790M mutation in the post-transformation ctDNA rather than their tissue samples. SCLC transformation was commonly seen in patients harboring EGFR exon 19 deletion. The clinical outcomes of TKI and OS in SCLC transformed patients were similar to non-transformed patients. The loss of heterozygosity of TP53 and RB1 along with increased copy number of proto-oncogenes may lead to the SCLC transformation. The mechanisms of acquired resistance to TKI during SCLC transformation might be the emergence of classic drug resistance mutations, which was undetectable due to the intra-tumor heterogeneity.

Syndrome of Inappropriate Antidiuretic Hormone Secretion: A Poor Prognosis in Small-cell Lung Cancer

Small cell lung cancer (SCLC) is frequently associated with syndrome of inappropriate antidiuretic hormone (SIADH) secretion. In this study we investigated the prognostic value of SIADH in Chinese patients with SCLC. We prospectively studied a total of 385 patients with SCLC diagnosed in our institution. The relationship between the SIADH and treatment outcomes including progression-free survival (PFS) and overall survival (OS) were analyzed. Univariate analysis and Cox multivariate analyses were used for statistical analyses. PFS and OS curves were drawn using Kaplan-Meier method. The median PFS and OS in patients with SIADH was 6.7months (95% confidence interval [CI]: 4.3-9.1) and 11.6months (95% CI: 7.4-15.7), respectively. The corresponding PFS and OS in SCLC without SIADH was 9.2months (95% CI: 8.6-9.8) and 19.2months (95% CI: 16.5-21.9), respectively; the difference between groups was statistically significant (p=0.007 and p=0.000, respectively). The association of SIADH with poor PFS (p=0.000) and OS (p=0.002) retained its statistical significance after adjusting for potential confounding variables. In addition, PFS (p=0.000) and OS (p=0.000) of SIAHD patients with plasma sodium <125mmol/L or without plasma sodium recovery to normal level are both shorter than in patients without SIADH. OS in SIAHD patients with plasma sodium recovery time to normal level is also shorter than patients without SIADH (p=0.03). SIADH is a common occurrence in patients with SCLC and is associated with poor prognosis for SCLC in Chinese patients.

Prognostic value of serum IL-17 and VEGF levels in small cell lung cancer.

To explore the prognostic value of serum interleukin-17 (IL-17) and vascular endothelial growth factor (VEGF) levels in patients with small cell lung cancer (SCLC). IL-17 and VEGF levels were determined by a commercially available ELISA method. Serum IL-17 and VEGF levels were higher in the SCLC group than the control group (p&lt;0.001 and p&lt;0.0001, respectively). In addition, there was a significant correlation between IL-17 and VEGF. The level of IL-17 showed significant correlations with tumor stage and tumor metastasis, while serum VEGF levels were significantly associated only with tumor metastasis. Univariate and multivariate analysis indicated that an elevated IL-17 level was an independent prognostic factor for shorter overall survival in SCLC. IL-17 may play an important role in tumor dissemination in SCLC patients and measurement of IL-17 could have useful prognostic value for worse overall survival in patients with SCLC.

Circulating tumor cells (CTC) in small cell lung cancer (SCLC), a promising prognostic factor.

7630 Background: Prognostic models for SCLC are using performance score (PS), laboratory tests or disease stage assessed by imaging tests. Even the recently introduced TNM system show that increasing from stage 1A (T1N0M0, 5 year survival 38%) to stage IV (metastasized, 5 year survival 1%) still provides us with a poor prognostic assessment. In this study we evaluated the use of CTC as a prognostic marker for Overall Survival (OS) in SCLC. Methods: In an ongoing study, patients (pts) with pathological proven SCLC were treated with firstline cisplatin /etoposide for a maximum of 4 cycles. Prior to the start, prior to the second cycle and at the end of chemotherapy 20 mL of whole blood was drawn and within 72 hours analyzed for circulating cells using CellTracks technology at a central laboratory (Veridex, Enschede, the Netherlands). Pts were staged as limited or extensive disease (IASLC 2009). Clinical data and CTC characteristics were analyzed in a blinded fashion. Pts were stratified into unfavorable and favorable prognostic groups based on CTC levels ≥ 2 or < 2 CTCs/7.5 mL, respectively. OS was analyzed in a Cox regression analysis using as covariates disease stage, PS and CTC before therapy or CTC decrease of at least 50% after the first cycle of chemotherapy. Results: A total of 41 pts with pathologically proven SCLC were included. Median (range) age was 66 yrs (47-84), male/female 26/15, PS 0/1/2/3 is 14/22/2/3, stage LD/ED 17/24, median (range) number of CTC is 9.5 (0-9909), 30 pts had ≥ 2 CTC at baseline. 33 pts were evaluable for CTC after one cycle of chemotherapy and 26 showed a decrease in CTCs of 50% or more. Median (range) OS was 240 days (219- 377). The predefined favorable prognostic group (baseline < 2 CTC count) was the most important prognostic factor (HR 3.3) after correction for age, sex, PS and stage. A decrease of at least 50% in CTC after one cycle of chemotherapy was the strongest prognostic factor (HR 0.015, 95%CI, 0.02-0.125, p < 0.0001) after correcting for baseline CTC, age, sex, PS and stage. Conclusions: Baseline CTCs and early decrease in CTCs in firstline chemotherapy are an independent predictive factor for OS in SCLC. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Veridex/Immunicon Veridex LLC Veridex LLC

PDGFR-Β expression in small cell lung cancer patients

Platelet derived growth factor (PDGF) and PDGFR-beta are expressed and have been found to have prognostic value in several human cancers. Data in non-small-cell cancer cell lines have suggested that PDGFR is a therapeutic target for drug development. In the current study PDGFR-beta expression and prognostic value in small cell lung cancer (SCLC) was investigated. Paraffin-embedded tissue blocks from 53 patients with limited and extensive stage SCLC were obtained for immunohistochemical staining. Tumors from each patient were sampled 3 times and stained with PDGFR-beta specific antibody. Patients were divided into low and high staining groups based on intensity. There was high intensity PDGFR-beta staining in 20 patients with SCLC. Another 29 expressed low intensity PDGFR-beta staining, with only 4 patients showing no PDGFR-beta staining. There was no statistically significant difference in 5 year overall survival between patients with low levels of PDGFR-beta staining vs. those with high level staining SCLC tumors (p = 0.538). The present study found that the majority of SCLC patients express, at least, a low level of PDGF-beta. However, the level of PDGFR-beta expression was not a statistically significant predictor of 5 year overall survival in SCLC.