Hee Kyung Ahn

Leptomeningeal metastases from breast cancer: intrinsic subtypes may affect unique clinical manifestations.

Leptomeningeal metastasis (LM) usually occurs late during the course of breast cancer. The aim of this study was to characterize the clinical features and outcomes of LM based on breast cancer subtypes in conjunction with brain parenchymal metastases. A retrospective study was performed of breast cancer patients with LM, who received palliative management at Samsung Medical Center between 1995 and 2008. Among the 272 metastatic breast cancer patients with central nervous system (CNS) involvement, 68 patients with LM were identified. The median age was 46xa0years (range, 24–72xa0years). The median survival duration from LM to death (LM-OS) was 4.5xa0months (range, 0.2–26.4xa0months). Patients surviving for 12 or more months were rarer among triple negative (TN) patients compared to other subtypes (21.7% for HRxa0+xa0ve vs. 27.8% for HER2xa0+xa0ve vs. 72.7% for TN, Pxa0=xa00.217). Death caused by CNS involvement appeared to be much more common in TN than in other subtypes (0% for HRxa0+xa0ve vs. 36% for HER2xa0+xa0ve vs. 64% for TN, Pxa0=xa00.060). Median survival time from distant metastasis was significantly different among the three groups (28.3 vs. 29.1 vs. 11.8xa0months, Pxa0<xa00.0001). However, median survival time from LM did not differ (4.1 vs. 5.9 vs. 3.8xa0months, Pxa0=xa00.226). Characteristic manifestations and treatment outcomes of LM may be affected by the unique biology of breast cancer intrinsic subtypes. The different roles of active combined treatment modalities including both systemic chemotherapy and local treatment modalities should be considered to improve outcomes.

Implications of Bone-Only Metastases in Breast Cancer: Favorable Preference with Excellent Outcomes of Hormone Receptor Positive Breast Cancer

Purpose The aim of the current study was to determine the incidence, clinical presentation, and treatment outcomes of bone-only metastases in patients with breast cancer and to analyze the impact of hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status on prognosis. Materials and Methods Between 1994 and 2007, of 968 patients with metastatic breast cancer who underwent palliative management at Samsung Medical Center, 565 (57%) relapsed with distant metastases. Of the 968, 146 (15%) had bone-only metastases during a median follow-up period of 75 months. Among the 146 patients with bone-only metastases, 122 (84%) were relapsed patients after curative surgery and 24 (26%) were initially metastatic cases. Results The median time from primary surgery to bone-only metastases of the 122 patients was 37 months (95% confidence interval [CI], 27 to 46 months). Bone-only metastases were more common in the HR-positive group than in the other subtypes (85% for HR+; 8.2% for HER2+; 6.8% for triple negative. Among all 146 patients, 75 (51%) were treated with hormone therapy. The median post-relapse progression-free survival was 15 months (95%CI, 13 to 17 months). The median overall survival was much longer in the HR+ patients than the HER2+ and triple negative breast cancer patients with marginal statistical significance (65 vs. 40 vs. 40 months, p=0.077). Conclusion Breast cancer patients with bone-only metastases had excellent clinical outcomes. Further study is now warranted to reveal the underlying biology that regulates the behavior of this indolent tumor, as it should identify favorable tumor characteristics in addition to favorable preferential metastatic site.

Favorable clinical outcomes of pemetrexed treatment in anaplastic lymphoma kinase positive non-small-cell lung cancer.

INTRODUCTIONnThe development of anaplastic lymphoma kinase (ALK) inhibitor has just followed the recent discovery of ALK rearrangement in lung cancer, therefore not much is yet known about the clinical course and treatment outcomes to chemotherapy in ALK-positive patients. The purpose of this study was to investigate the clinical characteristics and treatment outcomes in patients with ALK-positive NSCLC treated with conventional chemotherapy during pre-ALK inhibitor period.nnnPATIENTS AND METHODSnWe retrospectively screened 381 consecutive NSCLC patients without known epidermal growth factor receptor (EGFR) or KRAS mutation who were diagnosed between 2007 and 2008 at a single center, and identified ALK rearrangements by fluorescence in situ hybridization. Additional 44 ALK-positive patients who were identified since 2009 by central lab for participation on clinical trial were included for the analysis of clinical outcomes.nnnRESULTSnOf the 381 tumors screened, 21 (5.6%) showed ALK rearrangements, with twenty adenocarcinomas and one pleomorphic carcinoma. Of 65 ALK-positive patients including additional 44 ALK-positive patients, 32 patients received pemetrexed as a second- or further-line therapy, in whom the response rate was 34.4% (11/32), median progression-free survival (PFS) was 4.0 months (range: 0-22.0 months) and median overall survival (OS) was 50.8 months (95% confidence interval [CI]: 38.7-62.8).nnnCONCLUSIONSnThe prevalence of ALK rearrangement was 5.6% among EGFR and/or KRAS wild-type/unknown NSCLC population. Pemetrexed, given as a second- or further-line therapy, showed favorable clinical outcomes in ALK-positive NSCLC patients.

Successful treatment with crizotinib in mechanically ventilated patients with ALK positive non-small-cell lung cancer.

Lung cancer is the most common solid tumor in critically ill cancer patients admitted to intensive care units and is associated with a poor prognosis. Crizotinib is an anaplastic lymphoma kinase (ALK) inhibitor, which is active for advanced non-small cell lung cancer (NSCLC) patients harboring ALK rearrangements. We report three cases of NSCLC patients who required mechanical ventilation for respiratory failure and were successfully weaned from mechanical ventilation after treatment with ALK inhibitors. These responses were accompanied by minimal toxicities and an overt improvement in performance status. These results suggest that ALK inhibitors may be safe and effective in critically ill patients on mechanical ventilation for respiratory failure resulting from EML4-ALK translocated NSCLC progression.

Phase I trial of capecitabine plus everolimus (RAD001) in patients with previously treated metastatic gastric cancer

PurposeEverolimus is a novel inhibitor of the mammalian target of rapamycin pathway, which is aberrantly activated in cancer cell. We conducted a phase I study of capecitabine plus everolimus (RAD001) in refractory gastric cancer patients.MethodsPatients with metastatic gastric cancer and progression after prior chemotherapy were eligible. Four dose levels were planned as follows: Level 1, 5xa0mg bid/day of everolimus (D1-D21) and 500xa0mg/m2 bid/day of capecitabine (D1-14); Level 2, 5xa0mg bid/day of everolimus (D1-D21) and 750xa0mg/m2 bid/day of capecitabine (D1-14); Level 3, 5xa0mg bid/day of everolimus (D1-D21) and 1000xa0mg/m2 bid/day of capecitabine (D1-14); and Level 4, 10xa0mg bid/day of everolimus (D1-D21) and 1000xa0mg/m2 bid/day of capecitabine (D1-14). Treatment was repeated every 3xa0weeks until disease progression, patient refusal, or any serious adverse event.ResultsFifteen patients were enrolled in this study between November 2009 and April 2010. Fifteen patients were enrolled (median age, 50xa0years; men, 9). Six patients had received two previous chemotherapy regimens; six patients had three previous chemotherapy regimens before the study treatment. Thus, the majority of patients were heavily pretreated. The dose-limiting toxicities were grade 3 infection, grade 3 mucositis, and grade 3 hyperglycemia and hyponatremia. After a median follow-up duration of 5.6xa0months (range, 2.3–8.1xa0months), median PFS was 1.8xa0months (95% CI, 0.8–2.8xa0months). The maximum best change observed was a 28.7% decrease in sum of longest diameters when compared with baseline.ConclusionsThe combination of capecitabine and everolimus showed satisfactory toxicity profile and modest clinical benefit in patients with refractory gastric cancer. The recommended dose of capecitabine and everolimus was 650xa0mg/m2 twice daily and 5xa0mg twice daily, respectively.

Clinical impact of amphiregulin expression in patients with epidermal growth factor receptor (EGFR) wild-type nonsmall cell lung cancer treated with EGFR-tyrosine kinase inhibitors.

In patients with nonsmall cell lung cancer (NSCLC), several studies have demonstrated a positive correlation between somatic mutation in the epidermal growth factor receptor (EGFR) tyrosine kinase domain and clinical outcomes with the use of EGFR tyrosine kinase inhibitors (TKIs). However, some patients with wild‐type (WT) EGFR also responded to EGFR TKIs and remained stable. Recently, amphiregulin (AR) has been suggested as a predictive marker for EGFR TKIs in patients with WT EGFR‐positive NSCLC. The objective of the current study was to evaluate the association between AR expression and the efficacy of using EGFR TKIs in the treatment of patients with WT EGFR‐positive NSCLC.

Monosomal karyotype in acute myeloid leukemia predicts adverse treatment outcome and associates with high functional multidrug resistance activity.

Monosomal karyotype (MK) reflects highly unfavorable prognosis in patients with acute myeloid leukemia (AML). This study aimed to study the association of AML‐MK with multidrug resistance (MDR) functional activity. A total of 369 AML patients (excluding APL) between 1995 and 2008 at a single center were included retrospectively. Functional MDR activity was evaluated with rhodamine‐123 efflux activity with/without verapamil inhibition. MK was noted in 23 patients, only among whom classified into unfavorable cytogenetic risk group. Unfavorable cytogenetic subgroup with MK showed shorter OS (8.7 ± 5.9% vs. 23.5 ± 7.5% at 3 years, P = 0.030), EFS (8.7 ± 5.9% vs. 19.0 ± 6.9% at 3 years, P = 0.029), and a lower CR rate (34.8% vs. 65.7%, P = 0.031) compared with unfavorable subgroup without MK. Functional MDR activity was significantly higher in the unfavorable cytogenetic group with MK compared to all other cytogenetic risk groups taken as a whole (P = 0.026) and showed a trend toward statistical significance when compared with the unfavorable cytogenetic risk group without MK (P = 0.06). AML patients harboring MK showed a poor outcome in terms of lower CR rate and worse EFS/OS, and the presence of MK appeared to be associated with higher MDR functional activity of leukemic blasts. Am. J. Hematol., 2012.

Volume-based Metabolic Tumor Response to Neoadjuvant Chemotherapy Is Associated with an Increased Risk of Recurrence in Breast Cancer

PURPOSEnTo evaluate the prognostic value of a volume-based metabolic tumor response to neoadjuvant chemotherapy in patients with locally advanced breast cancer.nnnMATERIALS AND METHODSnThis study was approved by the institutional review board, with waivers of informed consent. One hundred sixty-seven patients (mean age, 44 years; range, 22-68 years) with clinical stage II or III breast cancer who underwent fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography scans at baseline and after completion of neoadjuvant chemotherapy between July 2006 and June 2013 were selected. The association between the metabolic response parameters and the disease-free survival was assessed by using a Cox proportional hazards regression model and time-dependent receiver operating characteristic curve analysis. Metabolic response parameters included the maximum standardized uptake value (SUVmax), the total metabolic tumor volume (MTVtotal), and the relative decrease in SUVmax and MTVtotal.nnnRESULTSnIn the Cox model, posttreatment SUVmax (P = .029) and MTVtotal (P = .028) and relative decreases in SUVmax (P = .032) and MTVtotal (P = .005) after neoadjuvant chemotherapy were significantly associated with disease-free survival after adjusting for pretreatment clinical stage, yp stage, and tumor subtype. In the time-dependent receiver operating characteristic curve analysis, MTVtotal after neoadjuvant chemotherapy had the highest association with outcome compared with the other parameters (P < .001). MTVtotal of up to 0.2 cm(3) after neoadjuvant chemotherapy was significantly associated with a favorable outcome in patients who did not achieve pathologic complete response after neoadjuvant chemotherapy.nnnCONCLUSIONnThe volume-based metabolic tumor response to neoadjuvant chemotherapy is associated with an increased risk of recurrence, regardless of tumor subtype and pathologic tumor response.

Retrospective analysis of extra-gastrointestinal stromal tumors.

AIMnTo investigate the clinicopathologic features of patients with extra-gastrointestinal stromal tumors (EGISTs) in South Korea.nnnMETHODSnA total of 51 patients with an EGIST were identified. The clinicopathologic features, including sex, age, location, tumor size, histology, mitotic rate, immunohistochemical features, genetic status and survival data, were analyzed.nnnRESULTSnThe median age was 55 years (range: 29-80 years), and male:female ratio was 1:1.04. The most common site was in the mesentery (n = 15) followed by the retroperitoneum (n = 13) and omentum (n = 8). The median tumor size was 9.0 cm (range: 2.6-30.0 cm) and the median mitotic rate was 5.0/50HPF. (1/50 - 185/50). KIT was analyzed in 16, which revealed 10 cases with wild-type KIT and 6 cases with an exon 11 mutation. Among 51 patients, 31 patients had undergone surgery, and 10 had unresectable disease and had taken palliative imatinib, which resulted in 22.7 mo of progression-free survival. Of the patients who had undergone surgery, 18 did not take adjuvant imatinib, and 8 of these were categorized as high risk according to the risk criteria. However, the relapse-free survival was not different (P = 0.157) between two groups.nnnCONCLUSIONnBecause the biologic behaviors of GISTs differ according to the location of the tumor, a more stratified strategy is required for managing EGISTs including incorporation of molecular features.

Epidermal growth factor receptor mutation and treatment outcome of mediastinoscopic N2 positive non-small cell lung cancer patients treated with neoadjuvant chemoradiotherapy followed by surgery

Epidermal growth factor receptor (EGFR) mutation in non-small cell lung cancer (NSCLC) is a strong predictive factor for a favorable response to EGFR tyrosine kinase inhibitors, however, its prognostic role in locally advanced stage is unclear. The aim of this study was to analyze the association of EGFR mutational status and clinical outcome after neoadjuvant chemoradiotherapy (CRT) followed by surgical resection in mediastinoscopically proven N2(+) NSCLC patients. We retrospectively identified 168 patients diagnosed between 1998 and 2006. EGFR mutational status was identified in 107 patients. Response and survival after neoadjuvant CRT followed by surgery were compared according to EGFR mutational status. 83 patients (77.6%) were found to have wild type EGFR, while exon 19 deletions or L858R missense mutations in the EGFR gene were detected in 19 patients. There was no significant difference in overall survival; however, the 5-year PFS rate in EGFR mutant patients (8.4%) were significantly lower than in the EGFR wild-type patients (33.6%; p=0.005). In multivariate analysis, EGFR mutation was a significant prognostic factor for a higher risk of distant recurrence/progression than the EGFR wild type (HR=7.183, p=0.005). In locally advanced mediastinoscopic N2-positive NSCLC, EGFR mutation was associated with more frequent distant relapses and worse 5-year PFS rate after neoadjuvant CRT followed by surgery, which might suggest that systemic control might be important in patients with the EGFR mutation. Therefore, the role of TKI for adjuvant EGFR TKI to decrease disease recurrence in distant sites should be further investigated.