[Show abstract][Hide abstract]ABSTRACT: Standard therapy for limited stage small cell lung cancer (SCLC) (AJCC stages I-III) is concurrent chemoradiation (CRT) with cisplatin/etoposide (EP) but carboplatin/etoposide (EC) is often used in clinical practice. Though a growing proportion of this disease is diagnosed in older patients, there are limited studies of older patients comparing cisplatin to carboplatin. This study compared survival outcomes of elderly patients with limited stage SCLC treated with concurrent EC or EP and radiation.
No preview · Article · Jan 2016 · Practical Radiation Oncology
[Show abstract][Hide abstract]ABSTRACT: Background:
Genomic studies in small cell lung cancer (SCLC) lag far behind those performed in non-small cell lung cancer (NSCLC). To date, most SCLC studies have evaluated patients with surgically resectable disease. Here we sought to evaluate the genomic mutation spectrum of 'every-day' SCLC patient tumors with extensive stage disease (ES-SCLC) and to correlate mutations with the main clinical outcomes of response to chemotherapy, progression-free (PFS) and overall (OS) survival.
Patients and methods:
A total of 50 SCLC patient tumors were examined in this study; targeted exome sequencing was obtained on 42 patients and whole-exome sequencing on 8 patients. Mutated genes were correlated with clinical outcomes using Kaplan-Meier methods (PFS, OS) and logistic regression (chemo-response). RB1 protein expression was detected by either western blotting of cultured cell lysates or IHC of tumor specimens.
In all, 39 patients had ES-SCLC; 15 patients had either primary refractory/ resistant disease and 21 patients had sensitive disease. The two most frequently mutated genes were TP53 (86%) and RB1 (58%); other frequently mutated genes (>10% patients) were involved in epigenetic regulation as well as the mTOR pathway. We identified a number of low frequency, targetable mutations, including RICTOR, FGFR1, KIT, PTCH1 and RET. Using multivariate analysis, RB1 was the only significant factor (p=0.038) in predicting response to first line chemotherapy, with an odds ratio of 5.58 comparing mutant RB1 to wild-type. Patients with mutant RB1 had both better OS (11.7 vs. 9.1 months p=0.04) and PFS (11.2 vs. 8.6 months, p =0.06) compared to patients with wild-type RB1. Interestingly, about 25% of SCLC cell lines and tumor specimens expressed RB1 protein, possibly representing the subgroup with wild-type RB1.
We found that SCLC tumors harboring no mutation in RB1 had a poor response to chemotherapy.
Full-text · Article · Jan 2016 · Annals of Oncology
[Show abstract][Hide abstract]ABSTRACT: Small cell lung cancer (SCLC) has an annual mortality approaching that of breast and prostate cancer. Although sensitive to initial chemotherapy, SCLC rapidly develops resistance, leading to less effective second-line therapies. SCLC cells often overexpress Bcl-2, which protects cells from apoptosis both by sequestering pro-apoptotic family members and by modulating inositol 1,4,5-trisphosphate receptor (IP3R)-mediated calcium signaling. BH3-mimetic agents such as ABT-263 disrupt the former activity but have limited activity in SCLC patients. Here we report for the first time that Bcl-2-IP3 receptor disruptor-2 (BIRD-2), a decoy peptide that binds to the BH4 domain of Bcl-2 and prevents Bcl-2 interaction with IP3Rs, induces cell death in a wide range of SCLC lines, including ABT-263-resistant lines. BIRD-2-induced death of SCLC cells appears to be a form of caspase-independent apoptosis mediated by calpain activation. By targeting different regions of the Bcl-2 protein and different mechanisms of action, BIRD-2 and ABT-263 induce cell death synergistically. Based on these findings, we propose that targeting the Bcl-2-IP3R interaction be pursued as a novel therapeutic strategy for SCLC, either by developing BIRD-2 itself as a therapeutic agent or by developing small-molecule inhibitors that mimic BIRD-2.
Full-text · Article · Dec 2015 · Cell Death & Disease
[Show abstract][Hide abstract]ABSTRACT: Background. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)therapy isclearly beneficial in patients with advanced EGFR-mutated non-small cell lung cancer (NSCLC). However, acquired resistance develops uniformly and the benefit of continuation of EGFRTKI therapy beyond progression remains unclear. Materials and Methods. This was a randomized phase II study of chemotherapy (arm A: pemetrexed or docetaxel) versus chemotherapy plus erlotinib (ERL) (arm B) in patients with progressive NSCLC following clinical benefit from erlotinib. In arm B, chemotherapy was given with erlotinib at an oral daily dose of 150 mg on days 2-19 of each cycle to minimize negative pharmacodynamic interactions. The primary endpoint was that continuation of erlotinib in this patient population could extend progression-free survival (PFS) by 50%. Results. A total of 46 patients were randomized (arm A: 24; arm B: 22). Patient characteristics were well balanced except there were more female patients in arm A (p =.075). The median PFS of patients in arm A was 5.5 months and for those in arm B, 4.4 months (p =.699). The response rates were 13% and 16% in arms A and B, respectively (p =.79). EGFR status data were available for 39 of the 46 patients and no significant difference in PFS was seen for continuing ERL beyond progression in mutation-positive patients. Substantially more toxicity was seen in arm Bthanarm A. Conclusion. There was added toxicity but no benefit with the continuation of ERL beyond progression along with chemotherapy as compared with chemotherapy alone.