Sun Min Lim

Fibroblast Growth Factor Receptor 1 Gene Amplification Is Associated With Poor Survival and Cigarette Smoking Dosage in Patients With Resected Squamous Cell Lung Cancer

PURPOSE To investigate the frequency and the prognostic role of fibroblast growth factor receptor 1 (FGFR1) amplification in patients with surgically resected squamous cell carcinoma of the lung (SCCL) and the association between smoking and FGFR1 amplification. PATIENTS AND METHODS Gene copy number of FGFR1 was investigated in microarrayed tumors from 262 patients with SCCL who had tumor tissue as well as smoking and survival data available. Gene copy number was evaluated by fluorescent in situ hybridization, and an FGFR1-amplified tumor (FGFR1 amp(+)) was prespecified as a tumor with nine or more copies of FGFR1. RESULTS Among 262 patients, the frequency of FGFR1 amp(+) was 13.0%. Patients with FGFR1 amp(+) had significantly shorter disease-free survival (DFS; 26.9 v 94.6 months; P < .001) as well as shorter overall survival (OS; 51.2 v 115.0 months; P = .002) than those without FGFR1 amp(+). Multivariate modeling confirmed that patients with FGFR1 amp(+) had a significantly greater risk of recurrence and death than those without FGFR1 amp(+) after adjusting for sex, smoking status, pathologic stage, and adjuvant chemotherapy (DFS: adjusted hazard ratio [AHR], 2.24; 95% CI, 1.45 to 3.45; P < .001; OS: AHR, 1.83; 95% CI, 1.15 to 2.89; P = .01). The frequency of FGFR1 amp(+) was significantly higher in current smokers than in former smokers and never-smokers (28.9% v 2.5% v 0%; P(trend) < .001). As the smoking dosage increased, so did the incidence of FGFR1 amp(+) (P(trend) = .002). CONCLUSION FGFR1 amplification is an independent negative prognostic factor in surgically resected SCCL and is associated with cigarette smoking in a dose-dependent manner. FGFR1 amplification is a relevant therapeutic target in Asian patients with SCCL.

A multicenter, phase II trial of everolimus in locally advanced or metastatic thyroid cancer of all histologic subtypes

BACKGROUND This phase II study investigated the efficacy and safety of everolimus, an inhibitor of mammalian target of rapamycin (mTOR), in locally advanced or metastatic thyroid cancer. PATIENTS AND METHODS Patients with thyroid cancer of any histology that was resistant or not appropriate for (131)I received everolimus 10 mg daily orally until unacceptable toxicity or disease progression. The primary end point was disease control rate [partial response (PR) + stable response ≥12 weeks]. Secondary end points included response rates, clinical benefit (PD + durable stable disease (SD)], progression-free survival (PFS), overall survival, duration of response, and safety. RESULTS Thirty-eight of 40 enrolled patients were evaluable for efficacy. The disease control rate was 81% and two (5%) patients achieved objective response; their duration of response was 21+ and 24+ weeks. Stable disease (SD) and progressive disease was reported in 76% and 17% of patients, respectively. Seventeen (45%) patients showed durable SD (≥24 weeks) and clinical benefit was reported in 19 (50%) patients. Median PFS was 47 weeks [95% confidence interval (CI) 14.9-78.5]. Calcitonin, CEA, and thyroglobulin concentrations were ≥50% lower than baseline in three (30%) and four (44%) patients with medullary thyroid cancer and five (33%) patients with PTC, respectively. The most common treatment-related adverse events were mucositis (84%), anorexia (44%), and aspartate transaminase/alanine transaminase elevation (26%). CONCLUSIONS Everolimus had a limited activity with low response rate in locally advanced or metastatic thyroid cancer. Reasonable clinical benefit rate and safety profile may warrant further investigation. CLINICALTRIALSGOV NUMBER NCT01164176.

The frequency and impact of ROS1 rearrangement on clinical outcomes in never smokers with lung adenocarcinoma

BACKGROUND To determine the frequency and predictive impact of ROS1 rearrangements on treatment outcomes in never-smoking patients with lung adenocarcinoma. PATIENTS AND METHODS We concurrently analyzed ROS1 and ALK rearrangements and mutations in the epidermal growth factor receptor (EGFR), and KRAS in 208 never smokers with lung adenocarcinoma. ROS1 and ALK rearrangements were identified by fluorescent in situ hybridization. RESULTS Of 208 tumors screened, 7 (3.4%) were ROS1 rearranged, and 15 (7.2%) were ALK-rearranged. CD74-ROS1 fusions were identified in two patients using reverse transcriptase-polymerase chain reaction. The frequency of ROS1 rearrangement was 5.7% (6 of 105) among EGFR/KRAS/ALK-negative patients. Patients with ROS1 rearrangement had a higher objective response rate (ORR; 60.0% versus 8.5%; P = 0.01) and a longer median progression-free survival (PFS; not reached versus 3.3 months; P = 0.008) to pemetrexed than those without ROS1/ALK rearrangement. The PFS to EGFR-tyrosine kinase inhibitors in patients harboring ROS1 rearrangement was shorter than those without ROS1/ALK rearrangement (2.5 versus 7.8 months; P = 0.01). CONCLUSIONS The frequency of ROS1 rearrangements in clinically selected patients is higher than that reported for unselected patients, suggesting that ROS1 rearrangement is a druggable target in East-Asian never smokers with lung adenocarcinoma. Given the different treatment outcomes to conventional therapies and availability of ROS1 inhibitors, identification of ROS1 rearrangement can lead to successful treatment in ROS1-rearranged lung adenocarcinomas.

Screening of ROS1 rearrangements in lung adenocarcinoma by immunohistochemistry and comparison with ALK rearrangements.

ROS1 rearrangement is a predictive biomarker for response to the tyrosine kinase inhibitor, crizotinib. We investigated the usefulness of ROS1 immunohistochemistry (IHC) for the detection of patients who harbor ROS1 rearrangements in two separate cohorts. We also compared ROS1 IHC with ALK IHC in terms of diagnostic performance to predict each gene rearrangement. In a retrospective cohort, IHC was performed in 219 cases of lung adenocarcinoma with already known genetic alterations. In a prospective cohort, we performed IHC for 111 consecutive cases of lung adenocarcinoma and confirmed the results by subsequent FISH. In the retrospective cohort, all 8 ROS1-rearranged tumors were immunoreactive, and 14 of 211 ROS1-wild cases were immunoreactive (sensitivity 100% and specificity 93.4%). In the prospective cohort, all IHC-negative cases were FISH-negative, and 5 of 34 ROS1 immunoreactive cases were ROS1-rearranged (sensitivity 100% and specificity 72.6%). In ROS1-wild tumors, ROS1 protein was more expressed in the tumors of ever-smokers than in those of never-smokers (p = 0.003). ALK IHC showed 100% sensitivity and 98.1 to 100% specificity in both patient cohorts. In conclusion, ROS1 IHC is highly sensitive, but less specific compared with ALK IHC for detection of the corresponding rearrangement. ROS1 IHC-reactive tumors, especially when the tumor is stained with moderate to strong intensity or a diffuse pattern, are recommended to undergo FISH to confirm the gene rearrangement.

Comparison of two inflammation-based prognostic scores in patients with unresectable advanced gastric cancer

Objectives: The objective of this study was to compare the usefulness of two inflammation-based prognostic scores, neutrophil to lymphocyte ratio (NLR) and modified Glasgow Prognostic Score (mGPS), assessed at diagnosis in stage IV advanced gastric cancer (AGC). Methods: We retrospectively reviewed the medical records of 104 patients with newly diagnosed metastatic AGC treated with palliative chemotherapy. Results: In the univariate analysis, the following variables were associated with shorter overall survival (OS): poor or undifferentiated histology (p = 0.013), more than 1 metastasis (p = 0.004), the presence of lymph node metastasis (p = 0.003), the presence of bone metastasis (p = 0.019), a lower albumin level (p < 0.001), elevated C-reactive protein (p < 0.001), a high absolute neutrophil count (p = 0.016), NLR ≥3 (p < 0.001) and higher mGPS (p < 0.001 and p = 0.007, respectively). In the multivariate analysis, high NLR and mGPS were independent prognostic factors for shorter OS (p = 0.037, p < 0.001 and p = 0.010, respectively), along with lymph node metastasis (p = 0.005) and histological subtype (p = 0.048). Conclusion: This study suggests that the inflammatory markers, NLR and mGPS, are independent prognostic factors for OS in patients with unresectable AGC treated with palliative chemotherapy.

Treatment Outcome of Patients with Anaplastic Thyroid Cancer: A Single Center Experience.

Purpose Anaplastic thyroid cancer is known to have a poor prognosis due to its aggressive and rapid metastasis with median survival of less than 6 months. Multimodal treatment involving surgery and chemoradiotherapy has been used to improve the survival of patients. Here, we retrospectively review of treatment outcome of 13 consecutive patients who were treated at a single center. Materials and Methods We retrospectively reviewed medical records of 13 anaplastic thyroid cancer patients who received multidisciplinary treatment between 2006 and 2010. Kaplan-Meier survival curve was used to analyze progression-free survival and overall survival of patients. Results The median patient age at diagnosis was 69 years, and six patients had stage IVc diseases. Eight patients received primary surgery followed by radiotherapy or concurrent chemoradiotherapy (CCRT). Five patients received weekly doxorubicin-based definitive CCRT, but only one patients condition remained stable, while the rest experienced rapid disease progression. The median progression-free survival was 2.8 months (95% CI, 1.2-4.4 months), and the median overall survival was 3.8 months (95% CI, 3.0-4.6 months). Conclusion Patients with anaplastic thyroid cancer showed poor prognosis despite multimodality treatment. Therefore, identification of novel therapeutic targets is warranted to take an effective mode of treatment.

Open-label, multicenter, phase II Study of ceritinib in patients with non–small-cell lung cancer harboring ROS1 rearrangement

Purpose ROS1 rearrangement is a distinct molecular subset of non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of ceritinib in patients with ROS1-rearranged NSCLC. Patients and Methods We enrolled 32 patients with advanced NSCLC who tested positive for ROS1 rearrangement by fluorescent in situ hybridization. Ceritinib 750 mg was administered once daily. The primary end point was objective response rate. The secondary end points were disease control rate; duration of response; progression-free survival; overall survival; toxicity; and concordance among fluorescent in situ hybridization, immunohistochemistry, and next-generation sequencing. Results Between June 7, 2013, and February 1, 2016, 404 patients underwent ROS1 prescreening, and 32 patients with ROS1 rearrangement were enrolled. All patients except two were crizotinib-naïve. At the time of data cutoff, the median follow-up was 14.0 months, and 18 patients (56%) had discontinued treatment. Of the 32 patients enrolled, 28 were evaluable for response by independent radiologic review. Objective response rate was 62% (95% CI, 45% to 77%), with one complete response and 19 partial responses; duration of response was 21.0 months (95% CI, 17 to 25 months); and disease control rate was 81% (95% CI, 65% to 91%). The median progression-free survival was 9.3 months (95% CI, 0 to 22 months) for all patients and 19.3 months (95% CI, 1 to 37 months) for crizotinib-naïve patients. The median overall survival was 24 months (95% CI, 5 to 43 months). Of the eight patients with brain metastases, intracranial disease control was reported in five (63%; 95% CI, 31% to 86%). The most common adverse events (majority, grade 1 or 2) for all treated patients were diarrhea (78%), nausea (59%), and anorexia (56%). Conclusion Ceritinib demonstrated potent clinical activity in patients with ROS1-rearranged NSCLC who were heavily treated previously with multiple lines of chemotherapy.

Prediction for response duration to epidermal growth factor receptor-tyrosine kinase inhibitors in EGFR mutated never smoker lung adenocarcinoma

OBJECTIVES Among non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations, ∼ 20-30% exhibit de novo resistance to EGFR-tyrosine kinase inhibitor (TKI). The aim of this study was to examine whether mutations in the EGFR-downstream genes may be associated with de novo resistance to EGFR-TKIs in EGFR mutation-positive patients. MATERIALS AND METHODS Sixty-eight never-smoker adenocarcinoma patients with an activating EGFR mutation were included in the mutational analysis and 55 patients treated with EGFR-TKIs were analyzed for the treatment outcomes to EGFR-TKIs. We concurrently analyzed mutations in PIK3CA, PTEN, AKT and STK11, which are all EGFR-downstream genes. Mutations in PIK3CA, PTEN, AKT, and STK11 were analyzed by polymerase chain reaction-based sequencing. RESULTS PIK3CA mutations were detected in 4.4% (3/68) of patients, PTEN mutations in 16.1% (11/68), AKT mutations in 5.9% (4/68), and STK11 mutations in 13.2% (9/68). One patient with an activating exon 21 L858R mutation concomitantly had an exon 20 T790M mutation in EGFR. The proportion of patients who had mutations in EGFR-downstream genes was 32.4% (22/68). When we analyzed the treatment outcome of 55 patients treated with EGFR-TKI, the presence of mutations in EGFR-downstream genes correlated with a poor overall response rate to EGFR-TKIs (63.6 vs.14.5% in patients with mutation in EGFR-downstream gene, P<0.0001), shorter median progression-free survival (12.0 vs. 3.0 months, P=0.060), and shorter median overall survival (18.9 vs. 25.0 months, P=0.048). CONCLUSION Mutations in the EGFR-downstream genes may confer resistance to EGFR-TKIs and result in poor treatment outcomes in never-smoker adenocarcinoma patients with activating EGFR mutations.

Clinical and prognostic implications of ALK and ROS1 rearrangements in never-smokers with surgically resected lung adenocarcinoma

OBJECTIVES The aim of this study is to evaluate the prevalence and prognostic significance of anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) rearrangement in never-smokers with surgically resected lung adenocarcinoma. METHODS We retrospectively analyzed 162 consecutive never-smokers who underwent curative resection for stage IB to IIIA lung adenocarcinoma at a single institution. We concurrently analyzed mutations in the epidermal growth factor receptor (EGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) genes, and investigated ALK rearrangements by fluorescence in situ hybridization assay. ROS1 rearrangement was also determined in all triple (EGFR/KRAS/ALK)-negative tumors. RESULTS Of 162 never smokers with lung adenocarcinoma, 14 (8.6%) and 5 (3.1%) had ALK and ROS1 rearrangements, respectively. Nineteen of the 74 (25.7%) EGFR and KRAS mutation-negative patients were fusion-positive (ALK or ROS1 fusion). Fusion-positive patients tended to have shorter median disease-free survival (DFS) than fusion-negative patients (28.0 vs. 33.9 months; p=0.128). In multivariate analysis, fusion-positive patients had significantly poorer DFS than fusion-negative patients after adjustment for age, sex, T stage, N stage, and adjuvant chemotherapy use (p=0.022; hazard ratio, 2.11; 95% confidence interval, 1.19-4.30). The first recurrence sites were not significantly different between fusion-positive and fusion-negative patients in this study. CONCLUSION This study shows significantly poorer DFS of ALK or ROS1 fusion-positive lung adenocarcinoma in never-smokers after curative surgery.

Next-generation sequencing reveals somatic mutations that confer exceptional response to everolimus

Background Given the modest responses to everolimus, a mTOR inhibitor, in multiple tumor types, there is a pressing need to identify predictive biomarkers for this drug. Using targeted ultra-deep sequencing, we aimed to explore genomic alterations that confer extreme sensitivity to everolimus. Results We collected formalin-fixed paraffin-embedded tumor/normal pairs from 39 patients (22 with exceptional clinical benefit, 17 with no clinical benefit) who were treated with everolimus across various tumor types (13 gastric cancers, 15 renal cell carcinomas, 2 thyroid cancers, 2 head and neck cancer, and 7 sarcomas). Ion AmpliSeqTM Comprehensive Cancer Panel was used to identify alterations across all exons of 409 target genes. Tumors were sequenced to a median coverage of 552x. Cancer genomes are characterized by 219 somatic single-nucleotide variants (181 missense, 9 nonsense, 7 splice-site) and 22 frameshift insertions/deletions, with a median of 2.1 mutations per Mb (0 to 12.4 mutations per Mb). Overall, genomic alterations with activating effect on mTOR signaling were identified in 10 of 22 (45%) patients with clinical benefit and these include MTOR, TSC1, TSC2, NF1, PIK3CA and PIK3CG mutations. Recurrently mutated genes in chromatin remodeling genes (BAP1; n = 2, 12%) and receptor tyrosine kinase signaling (FGFR4; n = 2, 12%) were noted only in patients without clinical benefit. Conclusions Regardless of different cancer types, mTOR-pathway-activating mutations confer sensitivity to everolimus. Targeted sequencing of mTOR pathway genes facilitates identification of potential candidates for mTOR inhibitors.