Ki Sun Jung

Mutational profiling of brain metastasis from breast cancer: matched pair analysis of targeted sequencing between brain metastasis and primary breast cancer

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.

A Phase Ib/II Study of Afatinib in Combination with Nimotuzumab in Non-Small Cell Lung Cancer Patients with Acquired Resistance to Gefitinib or Erlotinib

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.

MCT4 as a potential therapeutic target for metastatic gastric cancer with peritoneal carcinomatosis

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.

Clinical features and outcomes of systemic amyloidosis with gastrointestinal involvement: a single-center experience

Background/Aims The gastrointestinal (GI) tract often becomes involved in patients with systemic amyloidosis. As few GI amyloidosis data have been reported, we describe the clinical features and outcomes of patients with pathologically proven GI amyloidosis. Methods We identified 155 patients diagnosed with systemic amyloidosis between April 1995 and April 2013. Twenty-four patients (15.5%) were diagnosed with GI amyloidosis using associated symptoms, and the diagnoses were confirmed by direct biopsy. Results Among the 24 patients, 20 (83.3%) had amyloidosis light chain (AL), three (12.5%) had amyloid A, and one (4.2%) had transthyretin-related type amyloidosis. Their median age was 57 years (range, 37 to 72), and 10 patients were female (41.7%). The most common symptoms of GI amyloidosis were diarrhea (11 patients, 45.8%), followed by anorexia (nine patients, 37.5%), weight loss, and nausea and/or vomiting (seven patients, 29.2%). The histologically confirmed GI tract site in AL amyloidosis was the stomach in 11 patients (55.0%), the colon in nine (45.0%), the rectum in seven (35.0%), and the small bowel in one (5.0%). Patients with GI involvement had a greater frequency of organ involvement (p = 0.014). Median overall survival (OS) in patients with GI involvement was shorter (7.95 months; range, 0.3 to 40.54) than in those without GI involvement (15.84 months; range, 0.0 to 114.53; p = 0.069) in a univariate analysis. A multivariate analysis of prognostic factors for AL amyloidosis revealed that GI involvement was not a significant predictor of OS (p = 0.447). Conclusions The prognosis of patients with AL amyloidosis and GI involvement was poorer than those without GI involvement, and they presented with more organ involvement and more advanced disease than those without organ involvement.

Clinicopathologic Features and Long-Term Outcomes of Elderly Breast Cancer Patients: Experiences at a Single Institution in Korea

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.

A case of Fanconi syndrome accompanied by crystal depositions in tubular cells in a patient with multiple myeloma

Fanconi syndrome (FS) is a rare condition that is characterized by defects in the proximal tubular function. A 48-year-old woman was admitted for evaluation of proteinuria. The patient showed normal anion gap acidosis, normoglycemic glycosuria, hypophosphatemia, and hypouricemia. Thus, her condition was compatible with FS. The M peak was found behind the beta globulin region in urine protein electrophoresis. Upon bone marrow examination, we found that 24% of cells were CD138+ plasma cells with kappa restriction. From a kidney biopsy, we found crystalline inclusions within proximal tubular epithelial cells. Thereafter, she was diagnosed with FS accompanied by multiple myeloma. The patient received chemotherapy and autologous stem cell transplantation, and obtained very good partial hematologic response. However, proximal tubular dysfunction was persistent until 1 year after autologous stem cell transplantation. In short, we report a case of FS accompanied by multiple myeloma, demonstrating crystalline inclusion in proximal tubular cells on kidney biopsy.

Weekly docetaxel and gemcitabine in previously treated metastatic esophageal squamous cell carcinoma

AIM To assess the efficacy and safety of weekly docetaxel plus a fixed-dose rate (FDR) of gemcitabine in metastatic esophageal squamous cell carcinoma (SCC). METHODS A multi-center, open-label, prospective phase II study was designed. Thirty-three esophageal SCC patients with documented progression after fluoropyrimidine/platinum-based first-line chemotherapy were enrolled and treated with docetaxel 35 mg/m(2) and gemcitabine 1000 mg/m(2) iv at a FDR (10 mg/m(2) per minute) on days 1 and 8. Treatment was repeated every twenty-one days until disease progression, unacceptable toxicity, or consent withdrawal. The primary endpoint was response rate (RR), and secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS). RESULTS Combination of weekly docetaxel and FDR gemcitabine was well tolerated: the most common treatment-related adverse events were anemia (97%), fatigue (64%) and neutropenia (55%). One patient with multiple lung and lymph node metastases died of respiratory failure after receiving four cycles of chemotherapy, and the possibility of drug-induced pneumonitis could not be completely excluded. Disease control (objective response plus stable disease) in the ITT population was achieved in 88% of patients, and the overall RR was 30% (95%CI: 15%-46%). The median PFS and OS were 4.0 (95%CI: 3.4-4.6) and 8.8 mo (95%CI: 7.8-9.8 mo), respectively. CONCLUSION A combination of weekly docetaxel and FDR gemcitabine showed promising antitumor activity and tolerability in previously treated, metastatic esophageal SCC.

Pilot study of sirolimus in patients with PIK3CA mutant/amplified refractory solid cancer

In patients with refractory cancer, the effect of additional chemotherapy is very limited. Targeted agents for molecular pathways associated with cancer cell progression and survival have emerged as attractive options in several cancer types. The current pilot study assessed the efficacy and safety of sirolimus in patients with refractory cancer with PIK3CA mutation/amplification. Refractory cancer patients with PIK3CA mutation/amplification were enrolled, irrespective of tumor-types. Enrolled patients received a daily dose of 1 mg sirolimus and one cycle defined as 28 days. An assessment of the efficacy and safety of sirolimus was performed. Overall, 4 patients were enrolled between October 2014 and April 2015. The median of 2.5 cycles of sirolimus was administered. Three patients had advanced gastric cancer and one had advanced cholangiocarcinoma. The overall response rate was 0%, three patients (75%) had stable disease following one cycle and one patient (25%) received sirolimus for 4 cycles without disease progression. The median progression free survival was 1.9 months [95% confidence interval (CI), 0.3–3.5 months], and the median overall survival was 3.6 months (95% CI, 0.4–6.8 months). Grade 3 or greater hematologic/non-hematologic toxicity was not observed. Grade 1 nausea was reported in one patient each. There were no treatment-associated mortalities. Sirolimus had modest efficacy and a tolerable toxicity-profile in patients with refractory cancer with PIK3CA mutation/amplification.

680PPHASE II STUDY OF A COMBINATION CHEMOTHERAPY WITH WEEKLY DOCETAXEL AND GEMCITABINE IN PREVIOUSLY TREATED METASTATIC ESOPHAGEAL SQUAMOUS CELL CANCER

ABSTRACT Aim: This multicenter, phase II study was conducted to assess the efficacy and safety of weekly docetaxel plus fixed-dose rate (FDR) gemcitabine as second-line chemotherapy in patients with metastatic esophageal squamous cell carcinoma (SCC). Methods: Esophageal SCC patients with documented progression after fluoropyrimidine-based first-line chemotherapy were treated with docetaxel 35 mg/m2 and gemcitabine 1,000 mg/m2 iv at FDR (10 mg/m2/min) on days 1 and 8. Treatment was repeated every 21 days until disease progression, unacceptable toxicity, or consent withdrawal. Primary endpoint was response rate (RR), and secondary endpoints were safety, progression-free survival (PFS) and overall survival (OS). Results: A total of 33 patients were registered onto this prospective study. Combination or weekly docetaxel and FDR gemcitabine was well tolerated: the most common treatment-related adverse events were anemia (97%), fatigue (64%) and neutropenia (55%). Grade 3 or 4 neutropenia was developed in 13 patients (39%) and three episodes of febrile neutropenia were observed. One patient with lung and extensive lymph node metastases died of respiratory failure after receiving fourth cycles of chemotherapy, and the possibility of drug-induced pneumonitis could not be completely excluded. The overall RR was 30% with one complete and 9 partial responses. Stable disease was documented in 19 patients (58%). The median PFS and OS were 6 (95% CI 5-8) and 9 (95% CI 7-11) months, respectively. Conclusions: The weekly combination of docetaxel and FDR gemcitabine showed a promising antitumor activity and tolerability in previously treated, metastatic esophageal SCC. Disclosure: All authors have declared no conflicts of interest.

Early progression (within 12 months) after autologous stem-cell transplantation in patients with multiple myeloma

Background: Autologous stem cell transplantation (ASCT) has become the standard of care for eligible patients with newly diagnosed multiple myeloma (MM). Although, attaining best pre-transplant response is important for long-term disease control, early progressive disease after ASCT is not fully understood in a subset ofMMpatients. The aim of this study is was to evaluate risk factors and clinical features of patients with early progression of disease after ASCT. Methods: We retrospectively reviewed 330 patients diagnosed with MM based on the International Myeloma Working Group diagnostic criteria and underwent ASCT between October 1998 and February 2015. Patients who progressed within 12months after ASCT were classified as the study group.Univariate andmultivariate analyses were performed on the recognized baseline parameters, and treatment related factors were also evaluated.Results: Among 324 patients, 103 (32%) progressed within 12 months after stem cell transplantation. Multivariate logistic regression analyses revealed that azotemia (Cr 2.0mg/dL) (RR1⁄43.2) and non-hyperdiploidy (RR1⁄42.6) were independently associated with early progressive disease (P<0.05). During a median 2.8 years of follow-up, the median overall survival of patients who progressed within 12 months after ASCT was significant poor (29.1months, 95% CI, 22.3-35.9) compared to those who did not progress within 12 months (94.5months, 95% CI, 78.5-110.5, p < 0.001). Conclusions: Early progression of disease after ASCT is associated with a poor prognosis in MM patients. PreASCT response ( PR versus < PR) did not affect early disease progression after stem cell transplantation. Patients with nonhyperdiploidy and azotemia may experience a limited benefit from ASCT. Further tailored therapy is needed for these patients.