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Thymic epithelial tumors (TETs) are rare but are the most common tumors of the anterior mediastinum. Platinum-based combination chemotherapy is the standard of care for such tumors and is associated with a 50% to 90% objective response rate (ORR) in metastatic disease. Nevertheless, there is no standard chemotherapeutic option after failure of platinum-based combination chemotherapy. Genetic alterations associated with the cell cycle, including pRB, p16This is a phase 2, multicenter, open-label, single-arm study of palbociclib monotherapy in patients with recurrent or metastatic advanced TETs who failed one or more cytotoxic chemotherapies. The patients received 125 mg of oral palbociclib daily for 21 days, followed by a 7-day break. The primary end point was progression-free survival (PFS). The secondary end points were ORR, duration of response, overall survival, and safety.Between August 2017 and October 2019, a total of 48 patients were enrolled. The median number of previous chemotherapies was one (range: one to four), and 21 (43.7%) of 48 patients received thymectomy. By the WHO classification, the patients were type A (n = 1), type B1 (n = 2), type B2 (n = 8), type B3 (n = 13), thymic carcinoma (n = 23), and unknown (n = 1). With a median follow-up of 14.5 months (range: 0.8-38.2), the median number of cycles of palbociclib monotherapy was 10 (range: 1-40). The ORR was 12.5% (four partial responses in thymoma and two partial responses in thymic carcinoma). The PFS at 6 months was 60.2%, and the median PFS was 11.0 months (95% confidence interval: 4.6-17.4). The median overall survival was 26.4 months (95% confidence interval: 17.4-35.4). The most common treatment-related adverse events of any grade were neutropenia (62.5%), anemia (37.5%), and thrombocytopenia (29.1%), and the most common grade 3/4 treatment-related hematologic adverse event was neutropenia (41.7%). Neutropenia above grade 3 was reversible, and there were no cases with neutropenic fever.Palbociclib monotherapy was well tolerated and had encouraging efficacy in patients with TETs who failed platinum-based combination chemotherapy.

Decitabine is widely accepted as the treatment options for elderly acute myeloid leukemia (AML) patients. However, the efficacy has yet been assessed in Asian population. We retrospectively analyzed the outcomes of 80 Korean elderly AML patients who were treated with decitabine. The median age was 74 years (range, 64 to 86 years) and 6 (7.5%), 48 (60.0%), and 25 (31.3%) patients were categorized to favorable, intermediate, and poor risk group, respectively. The median OS was 10.2 months (95% CI 5.0-15.4). Given that decitabine treatment demonstrated improved clinical outcomes, it could be considered as one of the first-line treatment for Korean elderly AML patients.

Background/Aims Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare hematologic malignancy that typically presents in the form of skin manifestations with or without lymph node and bone marrow involvement. Given its rarity and recent recognition as a distinct pathological entity, no standard of treatment exists for this aggressive disease and its prognosis is particularly dismal. Methods We retrospectively analyzed clinical features and treatment outcomes of patients who were diagnosed with BPDCN between 2000 and 2014. Results Ten patients had a median age at diagnosis of 41 years (range, 18 to 79), and seven patients were male. Sites of disease involvement were the skin (n = 7), lymph node (n = 5), bone marrow (n = 2), liver (n = 2), spleen (n = 2), and soft tissue (n = 1). Intensified chemotherapy regimens such as hyperCVAD regimen (cyclophosphamide, vincristine, doxorubicin, dexamethasone, methotrexate, cytarabine), and VPDL (vincristine, methylprednisolone, daunorubicin, L-asparaginase) were used as a first-line treatment. Although all patients treated with intensified chemotherapy showed an objective response (five patients with complete response) with median progression-free survival of 11.2 months (range 6.2 to 19.4), complete remission was not sustained for more than 2 years in any case. The response was relatively long-lived compared with previously reported CHOP (doxorubicin, cyclophosphamide, vincristine, prednisone)-like regimens, but the above regimens do not result in long-term remission. Conclusions All patients treated with hyperCVAD or VPDL showed an objective response, but the duration of response was relatively short. Thus, the development of more effective induction as well as consolidation treatment strategy should be warranted to improve this rare disease entity.

Purpose The purpose of this study was to assess the tumor characteristics and long-term clinical outcomes of adjuvant treatments after surgery with a curative aim for patients with breast cancer who are 65 years and older. Materials and Methods Patients with breast cancer who underwent curative surgery from 2000 to 2009 were analyzed (n=4,388). Tumor characteristics and survival outcome were compared by dividing the patients into two age groups (< 65 and ≥ 65 years old). The Kaplan-Meier method was used for comparison of survival rates by log-rank test, and a Cox regression model was used to examine the effect of variables. Results Among 4,388 patients with invasive breast cancer, 317 patients (7.2%) were 65 years or older and the median age of all patients was 47 years (range, 18 to 91 years). Tumor characteristics were similar between the two age groups, but the older patients were treated less often with adjuvant treatments. During a median follow-up period of 122 months, recurrence-free survival (RFS) was equivalent for patients 65 years and older compared to younger patients, but significantly worse in overall survival (OS) and breast cancer–specific survival (BCSS) (5-year OS, 94.3% vs. 90.5%; p < 0.001 and 5-year BCSS, 94.7% vs. 91.8%; p=0.031). In the multivariate model, age ≥ 65 years old was identified as an independent risk factor for OS and RFS. Conclusion Elderly breast cancer appeared to have worse outcomes with very low prevalence in Korea, despite similar tumor characteristics. More active adjuvant therapies would have a role for aggressive subtypes for fit, elderly patients.

Monocarboxylate transporters (MCTs) play a major role in up-regulation of glycolysis and adaptation to acidosis. However, the role of MCTs in gastric cancer (GC) is not fully understood. We investigated the potential utilization of a new cancer therapy for GC. We characterized the expression patterns of the MCT isoforms 1, 2, and 4 and investigated the role of MCT in GC through in vitro and in vivo tests using siRNA targeting MCTs. In GC cell lines, MCT1, 2, and 4 were up-regulated with different expression levels; MCT1 and MCT4 were more widely expressed in GC cell lines compared with MCT2. Inhibition of MCTs by siRNA or AR-C155858 reduced cell viability and lactate uptake in GC cell lines. The effect of inhibition of MCTs on tumor growth was also confirmed in xenograft models. Furthermore, MCT inhibition in GC cells increased the sensitivity of cells to radiotherapy or chemotherapy. Compared with normal gastric tissue, no significant alterations of expression levels in tumors were identified for MCT1 and MCT2, whereas a significant increase in MCT4 expression was observed. Most importantly, MCT4 was highly overexpressed in malignant cells of acsites and its silencing resulted in reduced tumor cell proliferation and lactate uptake in malignant ascites. Our study suggests that MCT4 is a clinically relevant target in GC with peritoneal carcinomatosis.

The macrophage inflammatory protein 1α (MIP-1α) is anticipated to have a role in extranodal natural killer (NK)/T-cell lymphoma (ENKTL) because the expression of MIP-1α is related to Epstein-Barr virus (EBV) latency in EBV-related non-Hodgkin lymphoma cells. Thus, we measured the serum level of MIP-1α in 69 patients with ENKTL using frozen serum samples that were archived at diagnosis. As serum level of MIP-1α was not detectable in 19 patients (range: 0-24.37 pg/mL), patients were dichotomized into positive (n = 50) and negative (n = 19) MIP-1α groups according to the presence of detectable level of MIP-1α in serum. MIP-1α-positive group showed a significantly poor overall survival (OS) in comparison with the MIP-1α-negative group (p = 0.004). In the subgroup analysis, the positivity of MIP-1α was significantly associated with OS in patients with stage IIIE/IV and a detectable level of EBV DNA (p = 0.002 and 0.032, respectively). Multivariate analysis also showed that the positivity of MIP-1α was independently associated with worse OS together with bone marrow involvement (p = 0.002). An in vitro study with patient-derived ENKTL tumour cells showed the expression of CCR1 and CCR5 on the surface of tumour cells (28% and 14%, respectively) , and the addition of MIP-1α to the culture media of tumour cells increased cell growth supporting the negative impact of MIP-1α on the prognosis of ENKTL patients. In conclusion, serum levels of MIP-1α could predict survival outcomes in patients with ENKTL. Therefore, MIP-1α should be considered for prognostication and a potential therapeutic target. Copyright © 2016 John Wiley & Sons, Ltd.

PURPOSE Limited treatment options exist for patients with thymic epithelial tumor (TET) whose disease progresses after platinum-based chemotherapy. We conducted a phase II study of pembrolizumab in patients with TET to evaluate its efficacy and safety. METHODS Patients with histologically confirmed TET whose disease progressed after at least one line of platinum-based chemotherapy were eligible for the study. Patients were excluded if they had an active autoimmune disease requiring systemic treatment within the past year or documented history of clinically severe autoimmune disease. Patients received 200 mg of pembrolizumab intravenously every 3 weeks until tumor progression or unacceptable toxicity. The primary objective of response rate was assessed every 9 weeks by investigators. RESULTS Of 33 patients enrolled, 26 had thymic carcinoma and seven had thymoma. Of seven thymoma, two (28.6%; 95% CI, 8.2% to 64.1%) had partial response, and five (71.6%) had stable disease. Of 26 thymic carcinoma, five (19.2%; 95% CI, 8.5% to 37.9%) had partial response and 14 (53.8%) had stable disease. The median progression-free survival was 6.1 months for both groups. The most common adverse events of any grade included dyspnea (11; 33.3%), chest wall pain (10; 30.3%), anorexia (seven; 21.2%), and fatigue (seven; 21.2%). Five (71.4%) of seven patients with thymoma and four (15.4%) of 26 patients with thymic carcinoma reported grade ≥ 3 immune-related adverse events, including hepatitis (four; 12.1%), myocarditis (three; 9.1%), myasthenia gravis (two; 6.1%), thyroiditis (one; 3.0%), antineutrophil cytoplasmic antibody–associated rapidly progressive glomerulonephritis (one; 3.0%), colitis (one; 3.0%), and subacute myoclonus (one; 3.0%). CONCLUSIONS Pembrolizumab showed encouraging antitumor activity in patients with advanced TET. Given the high incidence of autoimmunity, additional studies are needed to identify those who can benefit from pembrolizumab without immune-related adverse events.

Background We conducted a prospective phase II study of cisplatin plus cremophor EL-free paclitaxel (Genexol-PM) in patients with unresectable thymic epithelial tumors to determine the efficacy and tolerability of the combination therapy. Methods Patients were treated with cisplatin (70 mg/m 2 ) and Genexol-PM (230 mg/m 2 ) on day 1 of a 3-week cycle as first-line palliative chemotherapy. The primary end point of this study was objective response rate, and the secondary end points included toxicity, progression-free survival (PFS), overall survival, correlation between early 18F-fluorodeoxyglucose positron emission tomography/computed tomography response and PFS, and correlation between baseline flurododeoxyglucose uptake and histology. Results Forty-two patients with unresectable thymoma ( n = 14) or thymic carcinoma ( n = 28) were enrolled between May 2012 and October 2014. The median age was 59 years (range: 25–77) and 30 patients (71%) were male, and 39 patients (93%) had an ECOG PS of 1. The median number of treatment cycles was six (range: 1–6). For 40 assessable patients, the objective response rate was 62.5% (95% confidence interval [CI]: 47.6–77.4) with rates of 46% (95% CI: 23.3–76.9) for advanced thymoma ( n = 13) and 70% (95% CI: 52.0–82.1) for thymic carcinoma ( n = 27). With a median follow-up of 15.5 months, the median PFS for all 42 patients was 9.8 months (11.4 months for thymoma versus 8.1 months for thymic carcinoma). The 2-year overall survival was 77.9% for thymoma and 65.9% for thymic carcinoma. There were no treatment-related deaths. The most common grade 3 and 4 treatment-related adverse event was neutropenia in 11 patients (26%). Eight patients (19%) experienced grade 2 hypersensitivity reactions. There was no correlation between early positron emission tomography response and PFS, but tumor histology (thymoma versus thymic carcinoma) was correlated with SUV max before chemotherapy. Conclusions These data suggest that combination of cisplatin and Genexol-PM is highly effective and tolerable for the treatment of unresectable thymic epithelial tumors.

Background: The purpose of this randomised phase III trial was to evaluate whether the addition of simvastatin, a synthetic 3-hydroxy-3methyglutaryl coenzyme A reductase inhibitor, to XELIRI/FOLFIRI chemotherapy regimens confers a clinical benefit to patients with previously treated metastatic colorectal cancer. Methods: We undertook a double-blind, placebo-controlled phase III trial of 269 patients previously treated for metastatic colorectal cancer and enrolled in 5 centres in South Korea. Patients were randomly assigned (1 : 1) to one of the following groups: FOLFIRI/XELIRI plus simvastatin (40 mg) or FOLFIRI/XELIRI plus placebo. The FOLFIRI regimen consisted of irinotecan at 180 mg m−2 as a 90-min infusion, leucovorin at 200 mg m−2 as a 2-h infusion, and a bolus injection of 5-FU 400 mg m−2 followed by a 46-h continuous infusion of 5-FU at 2400 mg m−2. The XELIRI regimen consisted of irinotecan at 250 mg m−2 as a 90-min infusion with capecitabine 1000 mg m−2 twice daily for 14 days. The primary end point was progression-free survival (PFS). Secondary end points included response rate, duration of response, overall survival (OS), time to progression, and toxicity. Results: Between April 2010 and July 2013, 269 patients were enrolled and assigned to treatment groups (134 simvastatin, 135 placebo). The median PFS was 5.9 months (95% CI, 4.5–7.3) in the XELIRI/FOLFIRI plus simvastatin group and 7.0 months (95% CI, 5.4–8.6) in the XELIRI/FOLFIRI plus placebo group (P=0.937). No significant difference was observed between the two groups with respect to OS (median, 15.9 months (simvastatin) vs 19.9 months (placebo), P=0.826). Grade ⩾3 nausea and anorexia were noted slightly more often in patients in the simvastatin arm compared with with the placebo arm (4.5% vs 0.7%, 3.0% vs 0%, respectively). Conclusions: The addition of 40 mg simvastatin to the XELIRI/FOLFIRI regimens did not improve PFS in patients with previously treated metastatic colorectal cancer nor did it increase toxicity.

// Ji Yun Lee 1, * , Kyunghee Park 2, * , Sung Hee Lim 1 , Hae Su Kim 1 , Kwai Han Yoo 1 , Ki Sun Jung 1 , Haa-Na Song 1 , Mineui Hong 3 , In-Gu Do 3 , TaeJin Ahn 2 , Se Kyung Lee 4 , Soo Youn Bae 4 , Seok Won Kim 4 , Jeong Eon Lee 4 , Seok Jin Nam 4 , Duk-Hwan Kim 5 , Hae Hyun Jung 6 , Ji-Yeon Kim 1 , Jin Seok Ahn 1 , Young-Hyuck Im 1 , Yeon Hee Park 1 1 Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 2 Samsung Genomic Institute, Samsung Biological Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 3 Center of Companion Diagnostics, Innovative Cancer Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 4 Department of Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea 5 Department of Molecular Cell Biology, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Suwon, Korea 6 Biomedical Research Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea * These authors have contributed equally to this work Correspondence to: Yeon Hee Park, e-mail: yhparkhmo@skku.edu Keywords: breast cancer, brain metastasis, gene, mutation, mechanism Received: August 27, 2015 Accepted: October 06, 2015 Published: October 20, 2015 ABSTRACT Although breast cancer is the second most common cause of brain metastasis with a notable increase of incidence, genes that mediate breast cancer brain metastasis (BCBM) are not fully understood. To study the molecular nature of brain metastasis, we performed gene expression profiling of brain metastasis and matched primary breast cancer (BC). We used the Ion AmpliSeq Cancer Panel v2 covering 2,855 mutations from 50 cancer genes to analyze 18 primary BC and 42 BCBM including 15 matched pairs. The most common BCBM subtypes were triple-negative (42.9%) and basal-like (36.6%). In a total of 42 BCBM samples, 32 (76.2%) harbored at least one mutation (median 1, range 0–7 mutations). Frequently detected somatic mutations included TP53 (59.5%), MLH1 (14.3%), PIK3CA (14.3%), and KIT (7.1%). We compared BCBM with patient-matched primary BC specimens. There were no significant differences in mutation profiles between the two groups. Notably, gene expression in BCBM such as TP53, PIK3CA, KIT, MLH1, and RB1 also seemed to be present in primary breast cancers. The TP53 mutation frequency was higher in BCBM than in primary BC (59.5% vs 38.9%, respectively). In conclusion, we found actionable gene alterations in BCBM that were maintained in primary BC. Further studies with functional testing and a delineation of the role of these genes in specific steps of the metastatic process should lead to a better understanding of the biology of metastasis and its susceptibility to treatment.

Purpose Oropharyngeal squamous cell carcinoma (OSCC) has been recognized as an immunosuppressive disease. Various mechanisms have been proposed for immune escape, including dysregulation of immune checkpoints such as the PD-1:PD-L1 pathway. We investigated the expression of programmed cell death-ligand 1 (PD-L1) in HPV-negative and HPV-positive OSCC to determine its prevalence and prognostic relevance. Materials and Methods Using immunohistochemistry, 133 cases of OSCC were evaluated for expression of PD-L1. Formalin-fixed paraffin-embedded tumor samples were stained with monoclonal antibody (clone 5H1) to PD-L1. PD-L1 positivity was defined as membrane staining in ≥20% of tumor cells. Correlations between PD-L1 expression and HPV status and survival parameters were analyzed. Results Of the 133 patients, 68% showed PD-L1 expression, and 67% of patients were positive for p16 expression by immunohistochemistry. No significant difference in PD-L1 expression was observed between HPV(-) and HPV(+) tumors (61% vs. 71%, p=0.274). No significant difference in age, gender, smoking history, location of tumor origin, or stage was observed according to PD-L1 status. With a median follow-up period of 44 months, older age (≥65) (p=0.017) and T3-4 stage (p

T790M mutation is most common resistant mechanism to epidermal growth factor receptor gene (EGFR) tyrosin kinase inhibitor (TKI). Several third-generation EGFR-mutant selective TKI, such as AZD9291 (AstraZeneca), Rociletinib (Clovis), or HM61713 (Hanmi) have been developed. Acquired resistant C797S mutation was known to be one of the resistance mechanisms of AZD9291, which has not been reported for HM61713 yet. This is the first case report of C797S mutation as resistance mechanism of HM61713.

Background The aim of this retrospective study was to evaluate the clinical outcomes of reduced dose, biweekly docetaxel chemotherapy for Korean patients with castrate-resistant prostate cancer (CRPC). Methods We retrospectively reviewed the medical records of 48 patients with metastatic CRPC who were treated with a biweekly regimen (intravenous docetaxel 40 mg/m2 on day 1 plus prednisolone 5 mg twice daily) between 2012 and 2015 at Samsung Medical Center (Seoul, Korea). Prior to the adoption of a biweekly regimen in Oct 2013, our institutional standard chemotherapy was docetaxel 75 mg/m2 every 3 weeks for patients with CRPC (n = 24). After Oct 2013, all chemotherapy-naïve patients with CRPC received a 40 mg/m2 biweekly regimen (n = 24). The primary end point was a PSA response, defined as a greater than 50% decline in PSA level from baseline. Results The baseline characteristics of the patients in the two treatment groups were similar. The most common cause of treatment discontinuation was disease progression, which was exhibited by 17 patients (71%) in the 3-weekly group and 20 (75%) in the biweekly group. PSA responses were observed in 12 (50%) and 11 (46%) patients in the 3-weekly and biweekly groups, respectively (p = 0.683). Time to treatment failure (TTTF, 4.5 vs 3.9 months) and time-to-progression (TTP, 5.0 vs 4.2 months) were not significantly different between the 3-weekly and biweekly groups. Conclusions Within the limitations of a retrospective study, the biweekly reduced dose docetaxel regimen was active and well-tolerated in Korean patients with metastatic CRPC.

Purpose Papillary thyroid carcinomas (PTCs) frequently involve genetic alterations. The objective of this study was to investigate genetic alterations and further explore the relationships between these genetic alterations and clinicopathological characteristics in a high-recurrence risk (node positive, N1) PTC group. Materials and methods Tumor tissue blocks were obtained from 240 surgically resected patients with histologically confirmed stage III/IV (pT3/4 or N1) PTCs. We screened gene fusions using NanoString's nCounter technology and mutational analysis was performed by direct DNA sequencing. Data describing the clinicopathological characteristics and clinical courses were retrospectively collected. Results Of the 240 PTC patients, 207 (86.3%) had at least one genetic alteration, including BRAF mutation in 190 patients (79.2%), PIK3CA mutation in 25 patients (10.4%), NTRK1/3 fusion in six patients (2.5%), and RET fusion in 24 patients (10.0%). Concomitant presence of more than two genetic alterations was seen in 36 patients (15%). PTCs harboring BRAF mutation were associated with RET wild-type expression (p=0.001). RET fusion genes have been found to occur with significantly higher frequency in N1b stage patients (p=0.003) or groups of patients aged 45 years or older (p=0.031); however, no significant correlation was found between other genetic alterations. There was no trend toward favorable recurrence-free survival or overall survival among patients lacking genetic alterations. Conclusion In the selected high-recurrence risk PTC group, most patients had more than one genetic alteration. However, these known alterations could not entirely account for clinicopathological features of high-recurrence risk PTC.

Objective We conducted this study to investigate the value of early metabolic responses assessed by 18 F-fluorodeoxyglucose positron emission tomography/computed tomography ( 18 F-FDG PET/CT) in predicting prognosis and monitoring treatment response in patients with unresectable thymic epithelial tumors (TETs). Patients and methods Study subjects were selected from the prospective dataset of a phase II clinical trial for cisplatin plus Cremorphor EL-free paclitaxel. A total of thirty patients with unresectable TETs who underwent baseline and early post treatment scan after two cycles of chemotherapy were enrolled (22 Male; mean age 55.0±15.0years). Metabolic parameters including metabolic tumor volume (MTV) and total lesion glycolysis (TLG) of the tumor lesions were measured. Results Multivariate analysis using Cox proportional hazards regression model showed that percent decrease of MTV (HR=0.995 by 1% decrease, P =0.037) and TLG (HR=0.996 by 1% decrease, P =0.044) were significant predictors of progression-free survival (PFS). Receiver operating characteristic curve identified an 88.0% decrease in MTV and a 92.0% decrease in TLG as the optimal cut-off value for disease progression. Responders with ≥88% of ΔMTV and ≥92% of Δ TLG had significantly longer PFS than non-responders ( P =0.012, 0.026, respectively). Conclusion The percent decrease in MTV and TLG of tumor lesions measured by early post treatment FDG PET/CT significantly associated with disease progression in this study. Early metabolic response based on these volumetric parameters has the potential to monitor treatment response and predict prognosis in patients with unresectable TETs.

Objectives Pleural metastases of thymic epithelial tumors (TETs) are relatively common, and this unique growth pattern makes the use of RECIST (response evaluation criteria in solid tumors) response criteria difficult. To standardize tumor measurement in TETs, the International Thymic Malignancy Interest Group (ITMIG) has proposed newly developed criteria. We compared evaluation of objective response between ITMIG modified criteria and RECIST 1.1 in patients with TET treated with systemic chemotherapy. Patients and methods We retrospectively evaluated the tumor response of 40 patients with unresectable TET who were enrolled in a phase II clinical trial using ITMIG modified criteria, and compared the findings with prospectively evaluated tumor response assessed by RECIST 1.1. Agreement analyses for the response at each time point, including overall response and declaring progression, were performed and the time to progression (TTP) was also assessed using the two different measurements. Results The overall response rate assessed by the two methods did not differ significantly, with kappa value of 0.897. Agreement analysis for declaring progression of disease (PD) at the date of RECIST 1.1-designated PD showed 95% concordance rate with ITMIG modified criteria ( p = 1.000, kappa index = 0.875). The median TTP according to RECIST 1.1 and ITMIG modified criteria was 8.4 and 7.9 months ( p = 0.983), respectively. Validation with another cohort of 27 TET patients treated with neoadjuvant chemotherapy also showed a 96% concordance rate in overall response between the two different criteria. Conclusions ITMIG modified criteria showed a high concordance rate with RECIST 1.1 criteria in response assessment of TETs. Given the rarity of TETs, further evaluation of ITMIG modified criteria in a larger number of patients will be required before their implementation in clinical trials.

Purpose The purpose of this study was to investigate the clinicopathologic features and prognostic factors affecting outcome in patients with isolated locoregional recurrence of breast cancer (ILRR). Methods We retrospectively analyzed the medical records of 104 patients who were diagnosed with ILRR and underwent curative surgery from January 2000 to December 2010 at Samsung Medical Center. Results Among 104 patients, 43 (41%) underwent total mastectomy and 61 (59%) underwent breast-conserving surgery for primary breast cancer. The median time from initial operation to ILRR was 35.7 months (4.5–132.3 months). After diagnosis of ILRR, 45 (43%) patients were treated with mastectomy, 41 (39%) with excision of recurred lesion, and 18 (17%) with node dissection. During a median follow-up of 8.9 years, the 5-year overall survival was 77% and 5-year distant metastasis-free survival (DMFS) was 54%. On multivariate analysis, younger age (< 35 years), higher stage, early onset of elapse (≤ 24 months), lymph node recurrences, and subtype of triple negative breast cancer (TNBC) were found to be independently associated with DMFS. Patients in the no chemotherapy group showed a longer DMFS after surgery for ILRR than those treated with chemotherapy (median 101.5 vs. 48.0 months, p = 0.072) but without statistical significance. Conclusion Our analysis showed that younger age (< 35 years), higher stage, early onset of relapse (≤ 24 months), lymph node recurrence, and subtype of TNBC are the worst prognostic factors for ILRR.

BACKGROUND:Metastatic breast cancer (MBC) remains a devastating and incurable disease. Over the past decade, the implementation of clinical trials both with and without molecular targeted therapeutics has impacted the daily clinical treatment of patients with MBC. In this study, we determine whether including MBC patients in clinical trials affects clinical outcomes. METHODS:We retrospectively reviewed data for a total of 863 patients diagnosed with initial or recurrent (after receiving adjuvant systemic treatments following surgery) metastatic disease between January 2000 and December 2013. Data were obtained from the breast cancer database of Samsung Medical Center. RESULTS:Among the 806 patients selected for inclusion, 188 (23%) had participated in clinical trials. A total of 185 clinical trials were conducted from 2000 to 2014. When compared with earlier periods (n = 10 for 2000-2004), clinical trial enrollment significantly increased over time (n = 103 for 2005-2009, P = 0.024; n = 110 for 2010-2014, P = 0.046). Multivariate analyses revealed that biologic subtype, distant recurrence free interval (DRFI), and clinical trial enrollment were independent predictors of overall survival. Patients who participated in clinical trials showed improved survival, with a hazard ratio of 0.75 (95% CI, 0.59-0.95), which was associated with a 25% reduction in the risk of death. However, subgroup analysis showed that this improved survival benefit was not maintained in patients with triple negative breast cancer (TNBC). CONCLUSIONS:Although not conclusive, we could speculate that there were differences in the use of newer agents or regimens over time, and these differences appear to be associated with improved survival.

Purpose: In this phase Ib/II study, we aimed to assess the safety and efficacy of afatinib plus nimotuzumab (N) in advanced non–small cell lung cancer (NSCLC) patients with acquired resistance to gefitinib or erlotinib. Experimental Design: In phase Ib stage, patients received afatinib (40 mg or 30 mg once daily) plus nimotuzumab (100 mg or 200 mg once weekly) for 28-day cycles to determine the recommended phase II dose (RPIID). The safety and efficacy of RPIID dose was evaluated in phase II stage. Results: In total, 50 patients were enrolled (13 to phase Ib and 37 to phase II). In the first dose-finding cohort (afatinib 40 mg plus nimotuzumab 100 mg), one patient experienced dose-limiting toxicity (DLT) of grade 3 diarrhea and in the subsequent cohort (afatinib 40 mg plus nimotuzumab 200 mg), two DLTs (grade 3 diarrhea and grade 3 neutropenia) occurred in 2 of 6 patients. Accordingly, RPIID was determined as afatinib 40 mg plus nimotuzumab 100 mg. In 44 patients treated with RPIID, 7 (16%) patients had grade 3 toxicities; skin rash (7%), diarrhea (5%), acne (2%), and fatigue (2%). The overall response rate was 23% and the median duration of response was 4.3 months (range, 0.7–16.2 months). The median progression-free survival and overall survival were 4.0 months [95% confidence interval (CI), 2.3–5.7 months] and 11.7 months (95% CI, 9.4–14.0 months), respectively. Conclusions: Combination treatment of afatinib and nimotuzumab demonstrated an acceptable safety profile and encouraging antitumor activity in advanced NSCLC patients with acquired resistance to gefitinib or erlotinib. Larger phase III trial is warranted to confirm its efficacy and safety. Clin Cancer Res; 22(9); 2139–45. ©2015 AACR.

Secondary central nervous system (CNS) involvement is a fatal complication of diffuse large B-cell lymphoma (DLBCL). We evaluated the efficacy and feasibility of high-dose chemotherapy containing busulfan and thiotepa followed by autologous stem cell transplantation (HDC-ASCT) in DLBCL with secondary CNS involvement. Thirty-one patients with secondary CNS involvement including CNS involvement at diagnosis (n = 9), isolated CNS relapse (n = 14), and CNS involvement with systemic disease progression or relapse (n = 8) were selected and analyzed from our prospective cohorts. Of these, 12 patients, including seven with isolated CNS relapse, successfully completed HDC-ASCT without engraftment failure or transplantation-related mortality. After ASCT, six patients were alive; however, three patients experienced post-transplantation relapse. With a median follow-up of 29 months after secondary CNS involvement, the median overall survival of 31 patients was 9 months (95% CI 5–12 months). The survival outcomes of patients who had undergone HDC-ASCT were significantly better than those of patients who did not (p < 0.01). Accordingly, patients with isolated CNS relapse tended to have a longer survival outcome than other cases. Our results suggest that HDC-ASCT may provide survival benefits in DLBCL patients with secondary CNS involvement, especially in case of isolated CNS relapse.

Background: Multiple myeloma is a heterogeneous disease with certain genetic features associated with worse outcomes. The benefit of Bortezomib for high risk genetic patient subgroups remains unclear in an Asian population. We performed a retrospective analysis to compare bortezomib-based induction versus thalidomide-based induction in Asian patients who were treated with upfront autologous transplant. Methods: We retrospectively analyzed outcomes of 240 patients who received autologous transplant in two centers in Singapore (n=167) and one center in Korea (n=73) after bortezomib-based (n=120) versus thalidomide-based induction (n=120) between 2006 and 2014. Patients were staged according to International Staging System (ISS), and responses were defined according to International Myeloma Working Group criteria. Early relapse was defined as relapse within 12 months post-transplant. High risk cytogenetics included the presence of 17p13 deletion, t(14;16), or t(4;14) by FISH. Results: Baseline characteristics (age, gender, ISS, cytogenetics) were not significantly different between groups receiving bortezomib versus thalidomide induction. Bortezomib induction was associated with improved rates of complete response (CR) post-induction (40% vs 25%, p=0.013) and post-transplant (52% vs 48%, p=0.038). Median overall survival (OS) was prolonged with bortezomib (53 months vs 27 months, p=0.027). Multivariate analysis adjusted for baseline characteristics showed bortezomib reduced the risk of early relapse (HR 0.23, 95% CI 0.09-0.57, p=0.001), and improved overall survival (OS) (HR 0.2, 95% CI 041-0.93, p=0.021). Factors independently associated with poorer OS were high risk cytogenetics (HR 1.77, p=0.011), failure to achieve very good partial response (VGPR) or better post-induction (HR 1.70, p=0.005), early relapse (HR 6.20, p Conclusion: Our results suggest that despite upfront autologous stem cell transplantation, patients benefit from bortezomib versus thalidomide induction. Furthermore, bortezomib may be beneficial in overcoming the adverse prognostic effect of high-risk cytogenetics. Disclosures Durie: Janssen: Consultancy; Takeda: Consultancy; Amgen: Consultancy.

e638 Background: The aim of this retrospective study was to evaluate clinical outcomes of biweekly 40 mg/m2 docetaxel plus prednisolone, as compared with standard 3-weekly regimen in Korean patients with castration-resistant prostate cancer (CRPC). Methods: We retrospectively reviewed the medical records of 48 patients with metastatic CRPC who were consecutively treated with docetaxel plus prednisolone as first-line chemotherapy between Jan 2012 and Dec 2014 at Samsung Medical Center (Seoul, Korea). Prior to the adoption of a biweekly regimen in Oct 2013, our institutional standard chemotherapy was docetaxel 75 mg/m2 every 3 weeks for patients with CRPC (n = 24). After Oct 2013, all chemotherapy-naïve CRPC patients received 40 mg/m2 biweekly regimen (n = 24). The primary end point was the PSA response, defined as a greater than 50% decline in PSA levels from baseline. Results: The baseline characteristics of the patients were similar in the two treatment groups. The most common cause of treatment discontinuation was disease progression: 17 (71%) in 3-weekly group and 20 (82%) in biweekly group. PSA responses were observed in 12 (50%) and 11 (46%) patients in the 3-weekly and biweekly groups, respectively. Time-to-failure (TTF, 4.5 versus 3.9 months) and time-to-progression (TTP, 5.0 versus 4.2 months) were statistically similar between the 3-weekly and biweekly groups, respectively. In 3-weekly group, the most commonly observed toxic effects were anemia and neutropenia. Whereas, in biweekly group, fatigue and nail changes were the most commonly observed toxic effects. Conclusions: Within the limitation of a retrospective study, biweekly reduced dose docetaxel regimen is active and well-tolerated in Korean patients with metastatic CRPC.

e14003 Background: Human papillomavirus (HPV) associated oropharyngeal squamous cell carcinoma of head and neck is an immunosuppressive malignancy. In head and neck squamous cell carcinoma (HNSCC),...

3576 Background: The purpose of this randomized phase III trial was to evaluate the addition of synthetic 3-hydroxy-3methyglutaryl coenzyme A (HMG-CoA) reductase inhibitor, simvastatin to XELIRI/FO...