Significant Difference In Relapse-free Survival Research Articles

Differing Clinical Courses and Prognoses in Patients With Gastric Neuroendocrine Tumors Based on the 2010-WHO Classification Scheme.

The aim of this study is to test the prognostic accuracy of the 2010-WHO classification for postsurgery survival in nonmetastatic gastric neuroendocrine tumor (NET) cases. Whether the 2010-WHO classification of NETs can predict relapse after surgical resection has not yet been established.We selected 175 nonmetastatic gastric NET patients at Asan Medical Center, Seoul, Korea between 1996 and 2013. All tumors were classified using the WHO-2010 scheme.Among 175 patients with gastric NETs, we diagnosed 39 cases as WHO grade 1, 13 cases as grade 2, 66 cases as grade 3 (neuroendocrine carcinomas; NECs), and 57 cases as mixed with adenocarcinoma. Patients with grade 3 had a lower relapse-free survival (RFS) and overall survival (OS) than those with WHO grade 1/2 and had a lower OS than patients with mixed type tumors. Patients with grade 1/2 had a better OS than patients with mixed type. There was no significant difference in RFS and OS between small and large cell type lesions. Among WHO grade 1/2 patients with ≤1 cm sized lesions, none exhibited lympho-vascular, perineural, mucosal, or submucosal invasion, and we detected no lymph node metastases or recurrences.Our findings strongly suggest that WHO grade 3 behaves more aggressively than adenocarcinoma. Additionally, the survival of cases with large and small cell NEC was similar. Among WHO grade 1/2 patients who had ≤1 cm lesions, none exhibited lympho-vascular, perineural, mucosal, or submucosal invasion and all could be treated by endoscopic resection or minimally invasive surgery without node dissection.

Growth rate of chemotherapy-naïve lung metastasis from colorectal cancer could be a predictor of early relapse after lung resection.

The aim of this study was to elucidate a potential risk factor for early relapse after pulmonary metastasectomy of colorectal cancer and to propose an optimal treatment strategy for lung metastasis with an aggressive nature. Seventy patients who underwent pulmonary metastasectomy for diachronically measurable pulmonary lesions were retrospectively analyzed. We calculated the tumor doubling time (TDT) as the growth rate of lung metastasis and divided the study population into two groups: Rapid (TDT ≤ 100 days) and Slow (TDT > 100 days). The patients consisted of 47 males and 23 females, with a mean age of 63 years. Forty-two patients had a relapse after pulmonary metastasectomy with a median follow-up duration of 24 months. There was a significant difference in relapse-free survival between the Rapid and Slow groups (p = 0.047). Using a multivariate analysis, no preoperative chemotherapy and a high level of serum carcinoembryonic antigen were proven to be significant risk factors for relapse after metastasectomy. Meanwhile, multivariate analyses among 37 patients without preoperative chemotherapy indicated that TDT was the sole significant factor for relapse-free survival. In addition, eight of nine patients with relapse within 12 months were placed into the Rapid group. Although this was a preliminary study with a small number of patients, it suggested that lung metastases demonstrating a TDT of 100 days or less have a high risk of early relapse after metastasectomy.

The value of cytoplasmic Y-box-binding protein 1 as a prognostic marker for breast cancer in Korean.

BackgroundThe human Y-box-binding protein 1 (YB-1) is a member of the DNA/RNA-binding family of proteins that regulates transcription and translation of genes. Previous studies suggest that YB-1 may have an oncogenic role in various cancers. In this study, we evaluate the prognostic value of cytoplasmic YB-1 with respect to breast cancer.MethodsImmunohistochemical staining study was performed with YB-1 using tissue block from 233 patients with invasive ductal carcinoma. Patients were divided into two groups according to expression of cytoplasmic YB-1 in tumor cell (high versus low). The relationship between the expression of YB-1, clinicopathological characteristics and breast cancer prognosis was analyzed.ResultsHormone receptor negativity, worse histologic and nuclear grade, high tumor stage, lymphovascular invasion and high Ki67 (≥14 %) were related with the increased expression of cytoplasmic YB-1 in tumor cell (p < 0.05). Although there was no significant difference in relapse-free survival (RFS) between the two groups (p = 0.412), difference in overall survival (OS) was statistically significant (p = 0.035). In multivariate analysis for OS, YB-1 was an independent prognostic factor (p = 0.043).ConclusionThis suggests that the increased expression of cytoplasmic YB-1 in tumor cells can be regarded as an independent prognostic factor for breast cancer, related to poor prognostics. Expression of cytoplasmic YB-1 in cancer cell could be used as an independent prognostic marker for predicting OS in breast cancer.

Prognostic signature of early lung adenocarcinoma based on the expression of ribonucleic acid metabolism–related genes

ObjectiveThe current staging system for lung cancer is not sufficient to accurately identify those patients with early-stage tumors who would benefit from postsurgery chemotherapy. The objective of this study was to validate a prognostic signature based on the expression of 5 RNA (ribonucleic acid) metabolism-related genes. MethodsFive lung cancer microarray datasets, 3 from adenocarcinomas and 2 from squamous cell carcinomas, were analyzed. Kaplan-Meier survival curves and Cox proportional hazards models were used to evaluate the relationship between the classifier and recurrence and survival. ResultsStatistically significant differences in relapse-free survival and overall survival were observed when lung adenocarcinoma patients were divided into 3 risk groups. The prognostic information provided by the signature was independent from other demographic and disease variables, including stage. Significant differences in survival were observed between low- and high-risk groups in stage-IB patients: 5-year survival rates ranged from 83% to 100% in the low-risk groups, and from 30% to 71% in the high-risk groups, depending on the dataset. The RNA metabolism score additionally displayed an association with the benefit of adjuvant chemotherapy (P < .001), suggesting that those patients in the low-risk group are not good candidates for this treatment. ConclusionsThe RNA metabolism signature is a prognostic marker that may be useful for predicting survival and optimizing the benefit of adjuvant chemotherapy in patients with lung adenocarcinoma.

Flow cytometric maturity score as a novel prognostic parameter in patients with acute myeloid leukemia.

The European LeukemiaNet (ELN) classification is widely accepted for risk stratification of patients with acute myeloid leukemia (AML). In order to establish immunophenotypic features that predict prognosis, the expression of single AML blast cell antigens has been evaluated with partly conflicting results; however, the influence of immunophenotypic blast maturity is largely unknown. In our study, 300 AML patients diagnosed at our institution between January 2003 and April 2012 were analyzed. A flow cytometric maturity score was developed in order to distinguish "mature" AML (AML-ma) from "immature" AML (AML-im) by quantitative expression levels of early progenitor cell antigens (CD34, CD117, and TdT). AML-ma showed significantly longer relapse-free survival (RFS) and overall survival (OS) than AML-im (p < 0.001). Interestingly, statistically significant differences in RFS and OS were maintained within the "intermediate-risk" group according to ELN (RFS, 7.0 years (AML-ma) vs. 3.3 years (AML-im); p = 0.002; OS, 5.1 years (AML-ma) vs. 3.0 years (AML-im); p = 0.022). Our novel flow cytometric score easily determines AML blast maturity and can predict clinical outcome. It remains to be clarified whether these results simply reflect an accumulation of favorable molecular phenotypes in the AML-ma subgroup or whether they rely on biological differences such as a higher proportion of leukemia stem cells and/or a higher degree of genetic instability within the AML-im subgroup.

Role of allogeneic stem cell transplantation in adult patients with Ph-negative acute lymphoblastic leukemia

AbstractBecause a pediatric-inspired Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL) protocol yielded a markedly improved outcome in adults with Philadelphia chromosome–negative ALL, we aimed to reassess the role of allogeneic stem cell transplantation (SCT) in patients treated in the GRAALL-2003 and GRAALL-2005 trials. In all, 522 patients age 15 to 55 years old and presenting with at least 1 conventional high-risk factor were candidates for SCT in first complete remission. Among these, 282 (54%) received a transplant in first complete remission. At 3 years, posttransplant cumulative incidences of relapse, nonrelapse mortality, and relapse-free survival (RFS) were estimated at 19.5%, 15.5%, and 64.7%, respectively. Time-dependent analysis did not reveal a significant difference in RFS between SCT and no-SCT cohorts. However, SCT was associated with longer RFS in patients with postinduction minimal residual disease (MRD) ≥10−3 (hazard ratio, 0.40) but not in good MRD responders. In B-cell precursor ALL, SCT also benefitted patients with focal IKZF1 gene deletion (hazard ratio, 0.42). This article shows that poor early MRD response, in contrast to conventional ALL risk factors, is an excellent tool to identify patients who may benefit from allogeneic SCT in the context of intensified adult ALL therapy. Trial GRAALL-2003 was registered at www.clinicaltrials.gov as #NCT00222027; GRAALL-2005 was registered as #NCT00327678.

Leukemia cell mobilization with G-CSF plus plerixafor during busulfan-fludarabine conditioning for allogeneic stem cell transplantation.

We hypothesized that during conditioning chemotherapy for allogeneic stem cell transplant (allo-SCT), disruption of stromal-leukemia interactions using granulocyte-colony stimulating factor (G-CSF) in combination with the CXCR4-specific inhibitor plerixafor, may promote release of leukemic cells from the niche and increase tumor elimination. In a phase 1/2 investigation, we treated 45 AML/MDS/CML patients (34 AML, 7 MDS, and 4 CML) with G-CSF (10 μg/kg daily for 6 days starting on day −9) plus plerixafor (doses of 0, 80, 160 or 240 μg/kg daily for 4 days starting on day −7) along with the busulfan-fludarabine (Bu-Flu) conditioning regimen. In the phase 1 part, we determined that G-CSF plus plerixafor is safe in this setting. We compared clinical effects and outcomes of AML/MDS study patients (n = 40) to 164 patients from a historical data set who received Bu-Flu alone prior to allo-SCT by stratifying on cytogenetics and disease status to correct for bias. Study patients had increased myeloid chimerism and lower rates of GvHD. There was no significant difference in relapse free survival or overall survival. The G-CSF plus plerixafor combination increased circulating white blood cells, CD34+ cells, and CXCR4+ cells, and preferentially mobilized FISH+ leukemic cells. ClinicalTrials.gov identifier is NCT00822770.

Prognostic importance of expression of the Wilms’ tumor 1 gene in newly diagnosed acute promyelocytic leukemia

Wilms’ tumor 1 gene (WT1) is known to be highly expressed in acute promyelocytic leukemia (APL) but information on its impact on prognosis is lacking. WT1 expression was analyzed in bone marrow samples of 79 patients with APL at initial diagnosis. Patients had a differing outcome according to their level of WT1 expression. In patients who achieved a complete remission (CR), low or high WT1 expression was significantly associated with inferior overall survival (OS) compared to intermediate WT1 expression (49% for WT1high vs. 63% for WT1low vs. 93% for WT1int; p = 0.008). Moreover, there were significant differences in relapse-free survival (RFS) between the three expression groups (42% for WT1high vs. 63% for WT1low vs. 83% for WT1int; p = 0.047). In multivariable analysis WT1 expression showed an independent prognostic impact on OS of responders to induction therapy. In conclusion, the level of WT1 expression can add prognostic information in APL risk stratification.

An Optimized Risk Stratification Model in Acute Promyelocytic Leukemia Identifies Patients with an Exceptionally Good Prognosis Regarding the Incidence of Relapse

Introduction: Risk stratification in acute promyelocytic leukemia (APL) is based on the easily accessible Sanz-Score, which combines leukocyte and platelet counts at initial diagnosis. This score showed significant differences in relapse-free survival (RFS) of APL patients in various studies and is currently used to determine whether a patient can be treated with ATRA and ATO alone or needs additional chemotherapy. However, to make therapeutic decisions based on a risk stratification system derived from the endpoint RFS bears the drawback that relapses are rare in APL and most events are deaths in complete remission (CR), which can be therapy related (e.g. toxicity). The cumulative incidence of relapse (CIR) therefore seems to be a better parameter for decision making with regard to therapy intensity. In this study, we optimized a risk score combining data on gene expression of BAALC (brain and acute leukemia, cytoplasmic), ERG (ets’ related gene) and WT1 (Wilms’ tumor 1) to retrospectively predict the CIR of APL patients.Methods: Data on BAALC, ERG and WT1 expression levels of 79 patients with newly diagnosed APL were obtained from bone marrow mononuclear cells using quantitative real-time RT-PCR in preceding studies. The following gene expression levels were identified as negative risk factors: BAALC expression ≥25th percentile (BAALChigh), ERG expression >75th percentile (ERGhigh) and WT1 expression ≤25th percentile or ≥75th percentile (WT1low or high). As ERGhigh was the only independent predictor for relapse in multivariate analysis with a hazard ratio (HR) of 11.6, its predictive weight was regarded superior, respectively . Cut-off analyses were performed to determine the optimal ERG expression level cut-off for risk of relapse. Accordingly, the new cut-off for high ERG expression was set at ≥62nd percentile (optimized ERGhigh: optERGhigh; Sensitivity: 1.0, Specificity: 0.71). A combined risk score was developed as follows: For the presence of one of the mentioned risk factors, one scoring point was assigned to a respective patient, i.e. a maximum of 3 points (one point for BAALChigh, optERGhigh and WT1low or high, respectively) and a minimum of 0 points (i.e. presenting with none of the aforementioned risk factors) could be allocated to one patient. Accordingly, patients were divided into two risk groups: 34 patients scored 0-1 points and 45 patients scored 2-3 points. CIR, overall survival (OS) and RFS were calculated using the Kaplan-Meier method and a log-rank test was used to compare differences between the two risk groups (p<0.05).Results: Patients with 2-3 points had a CIR of 18% at 10 years of follow-up whereas none of the patients with 0-1 points suffered a relapse (CIR: 0%; p=0.02; Fig. 1). All relapses occurred between 8.4 months and 3.5 years after first CR. Moreover, OS and RFS also differed significantly between the two risk groups: OS was 53% for patients with 2-3 points vs. 85% for patients with 0-1 points (p=0.004); RFS was 49% vs. 93%, respectively (p<0.0001). In multivariate analysis the optimized combined risk score was the strongest independent risk factor for every endpoint.Conclusion: The combination of expression levels of BAALC, ERG and WT1 into a risk score identified a group of patients at high risk for relapse which could benefit from close monitoring resulting possibly in an early intervention when molecular relapse is detected. On the other hand, it identified a low risk group with very good outcome and no APL-related events after patients had achieved first CR. A molecular risk score focusing on relapse risk might be a promising approach to guide therapeutic decisions in the future. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Postoperative Radiotherapy Alone Versus Chemoradiotherapy in Stage I-II Endometrial Carcinoma: An Investigational and Propensity Score Matching Analysis.

PurposeThe purpose of this study was to compare the results of postoperative adjuvant radiotherapy (RT) and concurrent chemoradiotherapy (CRT) in stage I-II endometrial carcinoma.Materials and MethodsWe analyzed a total of 64 patients with surgically staged I-II endometrial carcinoma who were treated with postoperative adjuvant RT or concurrent CRT between March 1999 and July 2013. Thirty-two patients who received postoperative RT alone were matched with those who received postoperative CRT (n=32) in accordance to age, stage, and tumor histology. Overall survival and relapse-free survival, as well as toxicity of the RT and CRT arms were evaluated and compared.ResultsThe 5-year overall survival rate was 90.0% for the RT arm and 91.6% for the CRT arm. There was no significant difference in overall survival between the two treatment arms (p=0.798). The 5-year relapse-free survival rate was 87.2% in the RT arm and 88.0% in the CRT arm. Again, no significant difference in relapse-free survival was seen between the two arms (p=0.913). In a multivariate analysis, tumor histology was an independent prognostic factor for relapse-free survival (hazard ratio, 3.67; 95% of CI, 2.34 to 7.65; p=0.045). Acute grade 3 or 4 hematologic toxicities in the CRT arm were significantly higher than in the RT alone arm (6.2% vs. 31.2%, p=0.010).ConclusionAdjuvant pelvic concurrent chemoradioherapy did not show superior results in overall survival and relapse-free survival compared to RT alone in stage I-II endometrial carcinoma.

Primary concomitant EGFR T790M mutation predicted worse prognosis in non-small cell lung cancer patients.

PurposeWe performed this analysis to improve the understanding of the clinicopathological characteristics and clinical outcome of non-small cell lung cancer (NSCLC) patients harboring the primary epidermal growth factor receptor (EGFR) T790M mutation along with activating EGFR mutation.MethodsResected tumors from 1903 NSCLC patients were analyzed for mutation in EGFR, as well as KRAS (Kirsten rat sarcoma viral oncogene homolog), BRAF (v-raf murine sarcoma viral oncogene homolog B), HER2 (human epidermal growth factor 2), PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha), and EML4 (echinoderm microtubule associated protein like 4)–ALK (anaplastic lymphoma receptor tyrosine kinase) fusion. Fluorescence in situ hybridization was performed to define EGFR and c-MET (met proto-oncogene gene amplification. Expression of PIK3CA and p-Akt (phosphorylated protein kinase B) were tested using immunohistochemistry. Clinical and pathological data, including sex, age at diagnosis, stage, tumor differentiation, smoking history, histological subtype, relapse-free and overall survival, were further analyzed.ResultsIn all, 16 NSCLC patients were found to harbor primary EGFR T790M mutation, including 14 adenocarcinomas and two adenosquamous carcinomas, accounting for 2.04% of all the EGFR mutant cases and 0.84% of the total. No c-MET amplification was found to coexist with primary EGFR T790M. Fewer EGFR copy-number variations were found in samples harboring EGFR T790M mutations compared with those in patients with exon 19 deletions and L858R. Overall survival was significantly shorter for patients harboring EGFR T790M mutation than it was for patients with exon 19 deletions (logrank P=0.008). When taking patients harboring EGFR L858R or exon 19 deletions as one group, the overall survival was also significantly longer than that in patients with T790M mutation (logrank P=0.012). There was no significant difference in relapse-free survival among three subgroups of patients.ConclusionOur study described the clinicopathological and molecular characteristics of NSCLC patients harboring primary EGFR T790M mutations. Its value of being a predictor for worse prognosis was established. Primary EGFR T790M mutation is a rare event in NSCLC cases, but the therapeutic strategies for this subtype of patients should be precisely considered.

ALK, ROS1 and RET fusions in 1139 lung adenocarcinomas: A comprehensive study of common and fusion pattern-specific clinicopathologic, histologic and cytologic features

BackgroundTo have a comprehensive investigation of the clinicopathologic, histologic and cytologic features of fusion-positive lung adenocarcinomas. MethodsQuantitative real-time reverse transcriptase PCR (qRT-PCR) and reverse transcriptase PCR (RT-PCR) were simultaneously performed to screen ALK, ROS1 and RET fusions in resected tumor samples from 1139 Chinese lung adenocarcinoma patients, with validation of positive results using fluorescent in situ hybridization. Clinicopathologic characteristics, predominant histologic subtype and cytomorphology were assessed in fusion-positive lung adenocarcinomas and compared to those harboring EGFR, KRAS, HER2 or BRAF mutations. ResultsThere were 58 (5.1%) ALK fusions, 11 (1.0%) ROS1 fusions and 15 (1.3%) RET fusions. Tumors with ROS1 fusions had significantly larger diameter than ROS1 fusion-negative tumors (P=0.007), whereas all the 15 tumors harboring RET fusions were ≤3cm in diameter (P=0.001). The three fusion genes were all more prevalent in solid-predominant adenocarcinoma. Compared to fusion-negative lung adenocarcinomas, tumors harboring a fusion gene had significantly higher prevalence of extracellular mucin (P<0.001), cribriform pattern (P<0.001), signet ring cells (P<0.001) and hepatoid cytology (P<0.001). No significant difference in relapse-free survival (P=0.147) and overall survival (P=0.444) was observed between fusion-positive and fusion-negative patients. ConclusionsThis study showed fusion-positive lung adenocarcinomas had identifiable common and fusion-pattern specific clinicopathologic, histologic and cytologic features, offering implications for fusion genes screening.

Patterns and Biologic Features of p53 Mutation Types in Korean Breast Cancer Patients.

PurposeThe p53 gene is one of the most frequently mutated genes in breast cancer. We investigated the patterns and biologic features of p53 gene mutation and evaluated their clinical significance in Korean breast cancer patients.MethodsPatients who underwent p53 gene sequencing were included. Mutational analysis of exon 5 to exon 9 of the p53 gene was carried out using polymerase chain reaction-denaturing high performance liquid chromatography and direct sequencing.ResultsA total of 497 patients were eligible for the present study and p53 gene mutations were detected in 71 cases (14.3%). Mutation of p53 was significantly associated with histologic grading (p<0.001), estrogen receptor and progesterone receptor status (p<0.001), HER2 status (p<0.001), Ki-67 (p=0.028), and tumor size (p=0.004). The most frequent location of p53 mutations was exon 7 and missense mutation was the most common type of mutation. Compared with patients without mutation, there was a statistically significant difference in relapse-free survival of patients with p53 gene mutation and missense mutation (p=0.020, p=0.006, respectively). Only p53 missense mutation was an independent prognostic factor for relapse-free survival in multivariate analysis, with an adjusted hazard ratio of 2.29 (95% confidence interval, 1.08-4.89, p=0.031).ConclusionMutation of the p53 gene was associated with more aggressive clinicopathologic characteristics and p53 missense mutation was an independent negative prognostic factor in Korean breast cancer patients.

Double CEBPA Mutations Are Not Associated With Favorable Clinical Outcome In Pediatric AML: A Report From The Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG)

BackgroundCCAAT/enhancer binding protein alpha (CEBPA) is a transcription factor that coordinates cellular differentiation. Mutations in the CEBPA genes are found in about 10% of patients with AML and are associated with favorable prognosis. However, recent data suggests that the favorable prognosis is restricted only to the patients with double CEBPA mutations and normal karyotype. These data have large implications for risk-stratified therapy and require confirmation. In this study, we investigated CEBPA mutation status and clinical outcome of the pediatric AML patients treated in the Japanese Pediatric Leukemia/Lymphoma Study Group (JPLSG) AML-05 study. Patients & MethodsAML-05 study, registered at http://www.umin.ac.jp/ctr/as UMIN000000511, is a nation-wide multi-institutional study for children (age <18 years) with de novo AML enrolled from 11/1/2006 to 12/31/2010. Cases with acute promyelocytic leukemia or Down syndrome were excluded. Patients were stratified by the specific cytogenetic characters and morphological treatment response into 3 risk groups; CBF-AML patients to the low risk (LR) group, those with either unfavorable cytogenetics (-7, 5q-, t(16;21)(p11;q22), Ph1, FLT3-ITD) or poor induction responders to the high risk (HR) group, and the rest to the intermediate risk (IR) group. In this trial, morphology was prospectively diagnosed by a central review system. Cytogenetic tests were carried out in regional laboratories, but the reports were reviewed centrally. FLT3-internal tandem duplication (ITD) was examined for all patients. Using the surplus RNA from the AML-05 study, CEBPA gene mutation was analyzed by RT-PCR and direct sequencing. ResultsOf the 317 evaluable patients, 73 patients (23.0%) had normal karyotype, 42 patients (13.2%) were FLT3-ITD positive, and 19 patients (6.0%) had both normal karyotype and FLT3-ITD. Among the 54 cases with normal karyotype and negative FLT3-ITD, 16 patients (29.6%) had a single CEBPA mutation and 17 patients (31.5%) had double or more (hereafter described as Double) CEBPA mutations. Between the CEBPA wild type (WT) and Double mutated patients, there were no statistically significant differences in relapse-free survival (RFS) (53.9% vs. 71.1%, P=0.27) nor overall survival (OS) (68.9% vs. 64.7%, P=0.57).An in-frame insertion of 6bp (ACCCGC) in CEBPAtrans-activator (TAD2) domain, resulting in a His-Pro duplication (HP196-197 ins), was detected in 131 patients (41.3% of all patients) in the current study, a considerably high incidence. However, this insertion was previously reported as polymorphism in adult AML (Leukemia 2008). When categorizing this insertion cases as CEBPA WT, 24 patients were CEBPA mutated among the 54 cases with normal karyotype and negative FLT3-ITD; 11 patients (20.4%) with single CEBPA mutation and 13 patients (24.1%) with Double CEBPA mutations. Although not statistically significant, there was a tendency of higher RFS (83.3% vs. 55.5%, P=0.20) and OS (79.1% vs. 63.3%, P=0.39) in patients with Double CEBPA mutations versus WT patients. ConclusionsThe current study is the first Japanese nation-wide investigation of the clinical significance of CEBPA mutations in pediatric AML. Our results suggest that CEBPA mutations have no prognostic impact on children with AML. Disclosures:No relevant conflicts of interest to declare.

Comparison of Autologous Hematopoietic Cell Transplantation and Chemotherapy as Postremission Treatment in Non-M3 Acute Myeloid Leukemia in First Complete Remission

Randomized trials of acute myeloid leukemia (AML) in first complete remission (CR1) showed that autologous hematopoietic cell transplantation (auto-HCT) improves relapse-free survival (RFS) but not overall survival (OS), compared with chemotherapy. Using a database of 2518 adult patients with AML in CR1, we conducted a 5-month landmark analysis and found that auto-HCT improves 3-year RFS but not OS compared with chemotherapy. A number of randomized trials in patients with AML in CR1 have been conducted and they showed that auto-HCT improves RFS but not OS, compared with chemotherapy. However, because these trials have had compliance problems, the value of auto-HCT still has not been clearly established. Using a database of 2518 adult patients with AML in CR1, we retrospectively analyzed the outcome of auto-HCT and compared it with intensive nonmyeloablative chemotherapy using landmark analyses. In 103 auto-HCT recipients, OS and RFS at 3 years from treatment were 65% and 57%, respectively. Multivariate analysis showed that unfavorable risk cytogenetics and entry into CR1 after 2 courses of induction treatment predicted a poor outcome. Because the median time interval between CR1 and auto-HCT was 153 days, landmark analyses at 5 months after CR1 were performed to compare 1290 patients who received chemotherapy alone (median age, 52 years; range, 16-70) with 103 who received auto-HCT (median age, 48 years; range, 16-67). Auto-HCT improves 3-year RFS (58% vs. 37%; P < .001) but not OS compared with chemotherapy alone. Among patients with unfavorable risk cytogenetics or those who required 2 courses to reach CR1, there was no significant difference in RFS between the 2 groups. Auto-HCT can be considered as a postremission therapy for AML patients with favorable or intermediate risk cytogenetics who achieve CR1 after a single course of induction treatment.

Prognostic relevance of partial hormone receptor expression in stage I breast cancer.

e11021 Background: Patients whose tumors express only one hormone receptor (1HR) are usually considered hormone-sensitive regarding treatment decisions. However, certain retrospective analyses suggest that patients bearing ER+/PR- or ER-/PR+ tumors may have worse outcomes than those with ER+/PR+ (HR) phenotype. The aim of this study was to correlate partial expression of hormone receptors (ER+/PR- or ER-/PR+) with several well known prognostic factors and their possible influence on the incidence of local and distant failure, relapse free survival (RFS) and overall survival (OS) in women with early breast cancer treated at GOCS institutions. Methods: We evaluated 327 patients with stage I breast cancer (T1a,b,cN0M0; AJCC 2010) diagnosed between January 1991 and December 2009. Further analyses were conducted upon a cohort of 282 patients who were divided between those whose tumors expressed both HR and those with only 1HR. Results: The median age was 54.2 years (29-89). Median follow-up was 9.4±4.4 years (0.2-22.9). Both HR and 1HR were expressed in 242 and 40 patients respectively. Similar adjuvant treatment was administered in both groups although the number of mastectomies was higher in the subgroup with only 1HR (22.5% vs. 5.8%, P =. 0003). Univariate analyses showed no difference between both groups when correlated with age, body mass index, histologic type, T stage, histologic and nuclear grade, mitotic index, vascular invasion, necrosis and margin status. However, 1HR tumors had a higher rate of lymphovascular invasion (21.9% vs. 9.5%, P =.038) and HER2 expression (57.1% vs. 21.9%, P = .035). Treatment failure was more frequent in patients with only 1HR (12.5% vs. 5%, P =.064). Distant progression was also more common in this subgroup (80% vs. 58.3%, P =.334). There were no statistically significant differences in RFS and OS among groups. Conclusions: The expression of only 1HR constitutes a phenotype that could have a more aggressive biology and be associated with higher risk of recurrence than tumors with both receptors. Analysis of more patients, larger tumor size and N1 disease is warranted to confirm this hypothesis and have a better prognostic assessment.

Body Mass Index Is Not Associated with Treatment Outcomes of Breast Cancer Patients Receiving Neoadjuvant Chemotherapy: Korean Data

PurposeThe effects of body mass index on pathologic complete response and survival have not been reported in Korean patients with breast cancer. The purpose of this study was to evaluate the predictive or prognostic value of obesity in breast cancer receiving neoadjuvant chemotherapy.MethodsA total of 438 stage II or III breast cancer patients treated with neoadjuvant chemotherapy were enrolled and analyzed retrospectively.ResultsIn the study, 319 patients (72.8%) were normal weight, 100 patients (22.8%) were overweight, and 19 patients (4.3%) were obese. Baseline clinicopathologic characteristics were not different among the groups, except for age. There were no differences in pathologic complete response rate between the groups (9.7% in normal weight, 10.0% in overweight, 5.3% in obese; p=0.804). Neither overweight nor obese patients showed a significant difference in relapse-free survival compared to normal weight patients (p=0.523 and p=0.931, respectively). Also, no significant difference in overall survival (p=0.520 and p=0.864, respectively) was observed.ConclusionObesity or higher body mass index was not significantly associated with pathologic complete response and survival in Korean patients with breast cancer who received neoadjuvant chemotherapy. Our results suggest that the prognostic impact of body mass index is different from that of Western patients.

Methylation of Cancer-Stem-Cell-Associated Wnt Target Genes Predicts Poor Prognosis in Colorectal Cancer Patients

Gene signatures derived from cancer stem cells (CSCs) predict tumor recurrence for many forms of cancer. Here, we derived a gene signature for colorectal CSCs defined by high Wnt signaling activity, which in agreement with previous observations predicts poor prognosis. Surprisingly, however, we found that elevated expression of Wnt targets was actually associated with good prognosis, while patient tumors with low expression of Wnt target genes segregated with immature stem cell signatures. We discovered that several Wnt target genes, including ASCL2 and LGR5, become silenced by CpG island methylation during progression of tumorigenesis, and that their re-expression was associated with reduced tumor growth. Taken together, our data show that promoter methylation of Wnt target genes is a strong predictor for recurrence of colorectal cancer, and suggest that CSC gene signatures, rather than reflecting CSC numbers, may reflect differentiation status of the malignant tissue.

Clinical features and outcomes of Hodgkin’s lymphoma in Korea: Consortium for Improving Survival of Lymphoma (CISL)

Ethnic and regional differences in the epidemiology and pathological aspects of Hodgkin's lymphoma (HL) between Western and Asian patients may be associated with differences in clinical features and prognosis. We retrospectively analyzed the clinical and histopathological characteristics, therapeutic outcomes, and prognostic factors of 539 HL patients treated at 16 centers in Korea. We found that the incidence of histological subtypes of HL in Korea was similar to that in Western and other Asian countries. However, the incidence peaked between 16 and 30years of age, unlike the bimodal age distribution seen in Western countries. In patients with stage I-IIA non-bulky disease, the complete response (CR) rate was similar between combined modality therapy and chemotherapy alone (93% vs. 84%, P = 0.44), and there was no difference in relapse-free survival (RFS) and overall survival (OS). Patients with stage I-II disease plus unfavorable factors and those with advanced-stage disease treated with combination chemotherapy regimens had an overall CR rate of 77%, with no difference between doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and non-ABVD regimens (77.2% vs. 76.8%, P = 0.95). Among those patients who achieved final CR, there was no significant difference in RFS or OS between those who achieved interim CR and PR. Only the presence of B symptoms was independently predictive of a shorter RFS. Age > 45years, Eastern Cooperative Oncology Group 2-4, and B symptoms were independent risk factors for death. Although the incidence of HL was lower in Korea than in Western countries, the distribution of morphological subtypes, treatment outcomes, and patient prognosis were similar.

Impact of Allogeneic Transplantation From Matched Related and Unrelated Donors on Clinical Outcome In Younger Adult AML Patients with FLT3 Internal Tandem Duplications

AbstractAbstract 909 Background:Internal tandem duplications of FLT3 (FLT3-ITD) occur in approximately one third of acute myeloid leukemia (AML) patients and are associated with poor outcome. It has been suggested that allogeneic hematopoietic stem cell transplantation (allo-HSCT) from a matched related donor (MRD) can overcome the negative impact of FLT3-ITD. However, for those patients without MRD it is unclear, whether the adverse impact can be abrogated by allo-HSCT from a matched unrelated donor (MUD). Aims:To assess clinical outcome in AML with FLT3-ITD after allo-HSCT from MRD and MUD. Methods:The study included 437 adult patients (median age, 47 years; range, 16–60 years) with newly diagnosed, FLT3-ITD positive AML enrolled on five prospective treatment trials of the German-Austrian AML Study Group (AMLSG) between 1993 and 2008. Patients with acute promyelocytic and core binding factor leukemia were excluded. FLT3-ITD was diagnosed by genomic DNA PCR and Genescan analysis. Mutant to wild-type FLT3-ITD ratio (allelic ratio) was available in 78%, and FLT3-ITD insertion site was determined by direct sequencing in 59% of the patients.The strategy of allo-HSCT changed in November 2006. Before the amendment, only patients with MRD were intended to receive allo-HSCT in first complete remission (CR), whereas thereafter, the spectrum of donors was extended to MUD. To account for the time dependency of allo-HSCT, landmark analyses for univariable analyses and Andersen Gill models for multivariable analyses were used. Results:CR rates before and after the amendment were 72% and 68%, respectively (p=0.63). Before amendment, 71 of 234 (30%) patients received allo-HSCT (48 MRD, 23 MUD), after amendment, 58 of 77 (74%) patients (16 MRD, 42 MUD). After amendment, the cohort was characterized by a significantly higher white blood count (WBC) (p=0.002), higher allelic ratio (p=0.04) and a higher frequency of FLT3-ITD insertion site in the beta-1-sheet (p=0.05). Comparing the two cohorts before and after amendment, there was no significant difference in relapse-free survival (RFS) (p=0.51) and overall survival (OS) (p=0.45). To account for the differences in the frequencies of unfavorable prognostic markers, we performed multivariable analyses in the whole population including the following variables: age, log(WBC), allo-HSCT from MRD or MUD, NPM1 mutation and median dichotomized allelic ratio. This model revealed allo-HSCT from MRD (HR 0.64, p=0.03) and age (difference of ten years) (HR 1.19, p=0.02) as significant prognostic parameters, whereas allo-HSCT from MUD was not significant (HR 0.82, p=0.31). In subset analysis, based on the availability of FLT3-ITD insertion site, the beneficial impact of allo-HSCT from MRD (HR 0.48, p=0.02) was even more pronounced, and FLT3-ITD insertion site in the beta-1-sheet appeared as a significant variable (HR 1.67, p=0.01). Landmark analyses for RFS at five months revealed a beneficial impact of allo-HSCT from both MRD and MUD, whereas at later time points the beneficial impact of allo-HSCT from MUD disappeared. There was no significant difference in cumulative incidence of relapse (p=0.25) and death (p=0.50) between allo-HSCT from MRD and MUD. Of 167 patients who relapsed, four received allo-HSCT from a haplo-identical family donor (HID), 54 from MUD and 12 from MRD. Overall survival for relapsed patients without transplantation and those with allo-HSCT from MRD was below 10% after one year and was significantly inferior compared to patients receiving allo-HSCT from MUD or HID with 49% after one year (p<0.0001). Conclusions:Allo-HSCT from MRD and also from MUD, if performed early during first CR, improves survival of younger adult patients with FLT3-ITD positive AML. Outcome after relapse was generally very poor, with allo-HSCT from MUD or HID having a beneficial effect. Disclosures:No relevant conflicts of interest to declare.