Significant Predictor Of Relapse-free Survival Research Articles

Deep Sequencing Is a Widely Applicable Tool for Relapse Prediction in Acute Myeloid Leukemia with Mutated NPM1

Analysis of measurable residual disease (MRD) is a powerful tool for assessment of treatment response in acute myeloid leukemia (AML). In patients with mutation in NPM1, reverse transcription quantitative polymerase chain reaction (RT-qPCR) is recommended by European Leukemia Net for refinement of risk stratification and monitoring after treatment. However, since RT-qPCR is mutation-specific and requires stringent quality control, many clinical laboratories restrict NPM1 monitoring to the type A mutation (c.860_863dupTCTG) although >50 mutations have been reported in exon 12. Deep sequencing is an alternative method, performed on DNA, that covers all NPM1 exon 12variants in the same assay. Guidelines for its clinical use are however lacking. We here performed a retrospective analysis in a population-based cohort of AML patients to evaluate if deep sequencing MRD analysis of NPM1 during chemotherapy provides prognostic information. Adult patients with AML with mutated NPM1 treated with curative intent in our region during 2006-2016 who achieved complete remission (CR) or CR with incomplete count recovery (CRi) were eligible for the study. This time period was chosen to avoid inclusion of patients treated based on molecular MRD status. Through review of the national AML registry, clinical charts, and screening of diagnostic samples, 99 patients with mutated NPM1 were identified. Of these, 97 patients (60 women and 37 men, median age 64 years, range 19-82) had bone marrow slides for isolation of DNA from at least one time point during treatment. DNA from 257 bone marrow aspirate slides were assessed for MRD using deep sequencing of NPM1. Based on previous comparison with RT-qPCR (Pettersson et al, Int J Lab Hematol 2021;43:664-674), variant allele frequency (VAF) of ≥0.05% was chosen as cut-off to define deep sequencing MRD positivity (MRD pos). For subgroup analyses, patients were divided into groups of treatment intensity; high-dose (cytarabine- and daunorubicin-based, n=67) or low-dose (cytarabine- and daunorubicin-, or azacytidine-based, n=30) treatment regimens. Thirty-one patients underwent allogeneic stem cell transplantation (alloSCT). We first evaluated if deep sequencing MRD status during consolidation (n=70, analyzed after 2 or 3 cycles) had an impact on prognosis. Both 3-year relapse-free survival (RFS) (26.7±11.4% vs 71.6±6.2%, p=<0.001, Figure) and overall survival (OS) (33.3±12.2% vs 72.7±6%, p=0.004) were lower for patients that were MRD pos at any time point during consolidation than for MRD neg patients. Among MRD pos patients, 12/15 (80%) relapsed and 13/15 (87%) died, compared to 19/55 (35%) and 23/55 (42%) MRD neg patients. In univariate analyses, also age and treatment intensity, but not alloSCT or DNMT3A mutation status, predicted RFS and OS. FLT3-ITD predicted OS but not RFS, and there was no effect of FLT3-ITD allelic ratio. In Cox regression multivariate analysis including MRD, age, FLT3-ITD and treatment intensity, MRD pos was the only significant predictor of RFS (Hazard ratio (HR): 2.54, p=0.019). In the multivariate analysis, FLT3-ITD (HR: 2.43, p=0.014) and treatment intensity (HR: 0.43, p=0.035) were significant for OS (MRD pos HR: 1.75, p=0.13). When dividing the cohort based on treatment intensity, the effect of MRD status was most obvious in patients treated with low-dose regimens. When deep sequencing MRD analysis was performed post first cycle (n=96), it had no statistically significant effect on either RFS or OS. At the end of treatment (n=51), deep sequencing MRD status had a strong prognostic value with 3-year RFS and OS for MRD pos patients 30±14.5% and 40±15.5%, compared to 73.2±6.9% and 78±6.5% for MRD neg patients ( p=0.003 and p=0.006, respectively). In summary, this population-based study shows that MRD status by deep sequencing of NPM1 is predictive of both RFS and OS when assessed during or after consolidation. The study confirms the threshold of deep sequencing MRD pos of VAF 0.05% previously obtained by comparison with RT-qPCR. Since deep sequencing can be used for all NPM1 mutations, it is widely applicable and extends the use of molecular MRD analysis and risk refinement to patients with rare mutations in NPM1.

Molecular landscape and clinical significance of exon 11 mutations in KIT gene among patients with gastrointestinal stromal tumor: a retrospective exploratory study.

This aim of this study was to investigate the prognostic significance of KIT exon 11 mutation subtypes in patients with GISTs. A total of 233 consecutive patients diagnosed with GISTs at the First Affiliated Hospital of Zhengzhou University from January 2013 to August 2018 were included in this study. The prevalence and mutation landscape of exon 11 in KIT was presented. The clinicopathological characteristics and prognosis among the different mutation subtypes were analyzed. All the statistical analyses were performed by SPSS22.0. Somatic mutational analysis indicated that point mutations were the most frequently detected mutations followed by deletions & compound mutations and insertion and tandem duplication mutations in the stomach. Point mutations showed a low mitotic count and a high risk of recurrence, and deletions and compound mutations have a high mitotic count while insertions and tandem duplication mutations showed a low mitotic count with an intermediate recurrence risk. Point mutations and deletions frequently occurred in sequence region codons 550-560 of exon 11, while compound mutations, insertion, and tandem duplication were mainly detected in codons 557-559, 572-580, and 577-581, respectively. The multi-variation analysis demonstrated that tumor diameter and high recurrence risk groups had worse prognostic values. However, mutation types were not significant predictors of relapse-free survival (RFS) in GISTs. Survival analysis suggested no significant difference in RFS between the 557/558 deletion and the other deletions. This study suggested that mutations in exon 11 of the KIT gene were common with intermediate/high recurrence risk in GISTs patients. Tumor diameter ≥5 cm, and deletions mutations might predict a worse prognosis.

Abstract P4-07-28: Early relapse and predictors of relapse-free survival in neoadjuvant chemotherapy-treated breast cancer patients

Abstract RationaleNeoadjuvant chemotherapy (NAC) for the treatment of early and locally advanced breast cancer is shown to cause effective tumour shrinkage, allowing breast conserving surgery. However, rates of recurrence remain high following surgical excision of NAC-treated breast tumours. We investigated relapse-free survival (RFS) in NAC-treated breast cancer patients; the primary aim of this study was to estimate probability of early relapse (<5 years) and identify possible predictor variables. MethodsWe retrospectively reviewed NAC-treated breast cancer patients diagnosed between January 2013 and August 2018 at the Royal Cornwall Hospital, UK. Patients met inclusion criteria with >3 cycles of NAC, surgery and follow-up >1 year. Demographic, histopathological and surgical data were collected including age, TNM classification, tumour histology, breast cancer immunohistochemical marker receptor status (ER, PR, HER2), NAC dose, adjuvant radiotherapy, type of breast and nodal surgery, pathologic response to NAC, number of positive lymph nodes (LN) at surgical removal and lymph node ratio (LNR). Tumour histology was categorised by inflammatory versus non-inflammatory. TNM classification was used for tumour staging. TNM nodal classification was categorised as N0 or N1 according to axillary LN cytology. LN classification data was missing for patients with inconclusive LN status at diagnosis. LNR was calculated as the ratio of positive LN to total number of LN removed at surgery. NAC response was categorised as pathologic complete (pCR) or incomplete (no-pCR). Kaplan-Meier method was used to compare survival functions for categorical variables. The Cox proportional hazards model was used at univariate and multivariate analysis for predictor variables that satisfied the proportional hazards assumption, to calculate hazard ratios for RFS. p-values <0.05 were taken as statistically significant. Results165 of 190 women were eligible for analysis. Median (IQR) age at diagnosis was 51.7 years (45.5-60.3). 68 patients (41.2%) achieved pCR following NAC and 147 (89.1%) received adjuvant RT. 30 relapses (18.2%) were recorded during follow-up, of which 24 (80%) were distant metastases. The Kaplan-Meier survival function estimated a 25% (95% CI, 17-36) probability of relapse by year five post-surgery. At univariate Cox analysis, RFS was associated with fewer positive LN (p = 0.001), lower LNR (p < 0.001) and TNM node classification N0 at diagnosis (p < 0.001). Table 1 below shows the results of multivariate Cox proportional hazards regression. Small sample size might conceal statistical significance of some covariates. ConclusionsOver 1 in 4 NAC-treated breast cancer patients relapsed within 5 years of surgery, usually with distant metastases. At univariate analysis, relapse-free survival (RFS) was individually associated with decreased LNR, fewer positive LN and TNM node classification N0. LNR remained a significant predictor of RFS at multivariate analysis with risk of relapse for a LNR of 1, 9-fold higher than a LNR of 0. Age, tumour histology, HER2 receptor status, TNM tumour classification, NAC dose and response to NAC had no significant association with RFS in this sample size. Risk FactorSubjectsHazard Ratio (95% CI)p-valueAge1651.042 (0.998 - 1.088)0.064Tumour histology (inflammatory = 1, other = 0)1651.268 (0.302 - 5.331)0.746HER2 receptor status (HER2+ = 1, HER2- = 0)1651.217 (0.357 - 4.150)0.754TNM tumour classification (T3-4 = 1, T1-2 = 0)1650.852 (0.298 - 2.442)0.766TNM node classification (N1 = 1, N0 = 0)1021.684 (0.428 - 6.622)0.455NAC dose (full dose = 1, reduced dose = 0)1651.091 (0.393 - 3.028)0.866NAC response in breast (pCR = 1, no-pCR = 0)1650.696 (0.199 - 2.442)0.572Lymph node ratio1649.426 (2.061 - 43.099)0.004 Citation Format: Natalie Martin, Julia Pasztorova, Isabella Hibell, Duncan Wheatley. Early relapse and predictors of relapse-free survival in neoadjuvant chemotherapy-treated breast cancer patients [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-07-28.

Should Adenocarcinoma of Cervix be Treated Differently to Squamous Cell Carcinoma?

The purpose of this study was to evaluate the overall survival (OS), relapse-free survival (RFS) and patterns of failure, in patients with SCC and ADC of cervix treated with definitive radiotherapy and to determine whether ADC should be treated differently. Total of 494 patients treated between January 1996 and December 2012 with definitive radiotherapy were included for analysis. Survival probabilities were estimated using Kaplan–Meier method, and differences between the groups were compared using long-rank test. Cox proportional hazards models were used to determine the role of histology after adjusting for potential confounders impacting on survival. The 5-year RFS of node-negative SCC and ADC was 79% and 75% and of node-positive SCC and ADC was 51% and 37%, respectively. The 5-year OS was 74% for both node-negative SCC and ADC and 54% and 42% for node-positive SCC and ADC, respectively. This difference in RFS and OS among these four subgroups was not significant. The tumour volume (p = 0.005), corpus invasion (p = 0.022) and lymph node involvement (p < 0.001) were significant predictors of RFS, whereas histology (p = 0.204) was not. Increasing age (p < 0.001), ECOG performance score 2 (p = 0.04), tumour volume (p = 0.009) and lymph node involvement (p < 0.001) were predictive for OS, but histology (p = 0.458) was not. There was no difference in pelvic and extra-pelvic failure of the two histological subtypes. Both these histological types exhibit similar clinical behaviour and survival when matched for prognostic factors. Hence, current standard of care was equally effective in both histological types.

Survival analyses and immunohistochemical study of primary signet ring cell carcinoma of the lung adenocarcinoma.

BackgroundThe clinicopathological features, immunohistochemical (IHC) characteristics and survival outcomes of primary lung adenocarcinoma with signet ring cells (LAdSRCs) component were analyzed.MethodsA retrospective analysis of primary LAdSRCs consecutively collected from 2010 to 2014 was performed and compared with lung adenocarcinoma (ADC). We investigated the survival outcomes and the expression of cytokeratin 7 (CK7), CK20, thyroid transcription factor-1 (TTF-1) and villin in these 35 cases of primary LAdSRCs.ResultsWe identified 1,715 patients in total, 35 (2.0%) of whom had signet ring cell (SRC) component. Excepting for 2 cases without IHC information, a CK profile (CK7+/CK20–) were identified in 69.7% (23/33) of LAdSRC; 22 (66.7%) of 33 LAdSRCs exhibited positive TTF-1 expression, but no other TTF-1 positive was found in signet ring cell carcinoma (SRCC) of other organs, and villin was not identified in these 33 cases. Age, sex, tumor size, surgery resection, smoking history, tumor stage, nodal stage, predominant histology subtype, pathology and adjuvant therapy were all significant predictors of relapse-free survival (RFS) and overall survival (OS) in univariable analysis. Compared to lung ADC, the lung ADCs with SRC component had an inferior prognosis. In multivariable analysis, sex, tumor size, tumor stage, nodal stage, predominant histology subtype and adjuvant therapy were still significant predictors for both RFS and OS while the pathology [RFS: hazard ratio (HR), 0.918; 95% confidence interval (CI), 0.581–1.492; P=0.712; OS: HR, 1.392; 95% CI, 0.820–2.364; P=0.221, respectively] was not.ConclusionsUnivariable analysis revealed primary LAdSRC is a rare ADC subtype with a worse prognosis compared with ADC. The high percentage expression of TTF-1 and immunostaining profiles CK7+/CK20- in primary LAdSRC is significant to identify the source of SRCCs.

Early achievement of full donor chimerism after allogeneic hematopoietic stem cell transplantation predicts lower relapse risk in patients with acute lymphoblastic leukemia

BackgroundAcute lymphoblastic leukemia (ALL) remains one of the most difficult-to-cure hematological malignancies. Allogeneic hematopoietic stem cell transplantation (HSCT) provides curative potential but a substantial proportion of patients eventually will relapse. It is unknown if there are any modifiable factors exists that could improve survival or predict relapse immediately after HSCT is unknown. The aim of this study was to explore whether achieving early (<30 days) full donor chimerism (FDC) could predict disease relapse after allogeneic HSCT in ALL patients. A second objective is to examine the impact of achieving early donor chimerism on survival. MethodsThis study retrospectively enrolled 55 ALL patients undergoing allogeneic HSCT during the 10-year period from 1999 to 2008. Analysis of short tandem repeats (STR) was used to determine donor chimerism, and was prospectively followed at the time of engraftment and on days 30. Patients with early treatment-related mortality (<30 days), without STR analysis, or who were lost to follow-up before FDC were excluded. Survival analyses were performed using Kaplan–Meier Methods. Cox proportional hazard analyses were performed for poor prognostic factors associated with overall survival (OS) and relapse-free survival (RFS). ResultsThe general characteristics were comparable between patients with early donor chimerism (n = 31) and those with late donor chimerism (n = 24). Survival analyses showed patients with early FDC had both lower probability of relapse (χ2 = 5.770, p = 0.022) and longer RFS than those with late chimerism. The OS was not different according to the chimerism status on days 30. In the Cox proportional hazard analyses, early FDC is a significant factor predictive for longer RFS (HR = 0.264, p = 0.010). ConclusionOur results indicate that the achievement of early FDC within 30 days after allogenic HSCT can be used as a significant predictor of RFS. The results underscored the need to improve outcome in ALL patients with late FDC.

Short-term and mid-term survival in bronchial sleeve resection by robotic system versus thoracotomy for centrally located lung cancer.

The aim of this study was to compare the short-term and mid-term results of patients with centrally located lung cancer who underwent bronchial sleeve resection by robotic system or thoracotomy. From September 2014 to September 2015, 103 patients, including 17 robotic and 86 open cases, were included in our study. All the clinicopathological data, operative details and follow-up information were investigated. There were no intraoperative deaths. The mean console time was 113.59 min. The operative time for robotic surgery (155.06 ± 44.75 min), even in our initial cases, was comparable to that for thoracotomy (150.30 ± 47.84 min, P = 0.71). The 30-day mortality rate in the robotic and thoracotomy groups was 1 (6%) patient and 2 (2%) patients, respectively, with no significant difference (P = 0.43). A total of 4 (24%) patients in the robotic group and 22 (26%) patients in the thoracotomy group experienced postoperative complications (P = 0.86). In multivariable analysis, tumour size and postoperative radiotherapy were significant predictors of relapse-free survival, whereas only the intensive care unit stay was a significant predictor of overall survival. There was no significant difference in relapse-free survival (log-rank P = 0.16) and overall survival (log-rank P = 0.59) between the 2 groups. Robotic surgery for bronchial sleeve resection is safe and feasible and has similar oncological outcomes compared with open procedures. But long-term survival still needs to be investigated.

Analysis of mutational and clinicopathologic characteristics of lung adenocarcinoma with clear cell component.

IntroductionLung adenocarcinoma with clear cell component is extremely rare and the cases reported in literature remain scarce. The biological behaviors, clinicopathologic characteristics, mutational status and prognosis of lung adenocarcinoma with clear cell component are still uncertain.MethodsThirty-eight lung adenocarcinomas with clear cell component and 1659 lung adenocarcinomas were subjected to the study. All the corresponding clinicopathologic data, the distributions of relapse-free survival (RFS) and overall survival (OS), and the status of gene mutations were investigated.ResultsOf 1697 adenocarcinomas, 38 (2.2%) had clear cell component. Fifty percent of adenocarcinomas with clear cell component (11/22) harbored EGFR mutation, 41 percent (9/22) harbored KRAS mutation and 5 percent (1/22) harbored AKT1 mutation. Univariable analysis revealed that sex, age, tumor stage, tumor size, nodal stage and pathology were all significant predictors of RFS and OS while the tumor size and nodal stage were still significant predictors in multivariable analysis. There were significantly differences in RFS and OS for lung adenocarcinomas with clear cell component compared with those lung adenocarcinomas.ConclusionsLung adenocarcinoma with clear cell component is a rare, malignant tumor with poor prognosis and displays more frequent EGFR and KRAS mutations.

Intravenous high‐dose interferon with or without maintenance treatment in melanoma at high risk of recurrence: meta‐analysis of three trials

Resected stage IIB-IIIC malignant melanoma has a poor prognosis with a high risk of relapse and death. Treatment with adjuvant interferon alfa-2b (IFN-α-2b) is associated with improved relapse-free and overall survivals (OS), but the most appropriate dose and duration of treatment are unknown. In this article, we present an individual patient data random effects meta-analysis of melanoma patients from the U.K., Greek, and Chinese randomized trials. All patients were randomized either to IFN-α-2b 15-20 MIU/m(2) IV daily 5 days per week for 4 weeks (IV) or to the same regimen followed by IFN-α-2b 9-10 MIU/m(2) administered three times per week for 48 weeks (IV and SC). Allowing for dose interruptions and reductions, an equivalent total dose of IFN-α-2b was delivered in all three studies. We assessed whether IV was noninferior to IV and SC in terms of relapse-free survival (RFS) and investigated tumor and patient characteristics that impacted on outcomes. Median follow-up of 716 stage IIB-IIIC patients was 5.4 years. Noninferiority of IV compared to IV and SC could not be conferred for RFS (hazard ratio [HR] 1.16, 95% confidence interval [CI] 0.89-1.52; noninferior P = 0.17). Stage (P < 0.0001), site (acral vs. other, P < 0.0001), and Breslow thickness (P = 0.02) were significant predictors of RFS. The HR for death was 1.13 for IV compared to IV and SC, (95% CI 0.91-1.39). Stage (P < 0.0001) and Breslow thickness (P = 0.001) were significant independent predictors of OS. The available data suggest that where adjuvant high-dose interferon is being considered there is no evidence to deviate from the year long regimen described in the Eastern Cooperative Oncology Group and Intergroup studies.

Long-Term Follow-up of Continuous Imatinib Plus Combination Chemotherapy in Patients with Newly Diagnosed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia

Introduction: The effect of imatinib plus combination chemotherapy were assessed in 87 patients, aged 16-71 years, with newly diagnosed Philadelphia Chromosome-Positive (Ph+) acute lymphoblastic leukemia (ALL).Methods: Imatinib (600 mg/day orally) was administered continuously with combination chemotherapy, starting from eighth day of remission induction treatment, then through 5 courses of consolidation or until allogeneic hematopoietic cell transplantation (HCT). Patients who were not transplanted were maintained on imatinib for 2 years. Molecular response monitoring was performed at the central lab (Asan Medical Center) with quantitative RT-PCR assays for peripheral blood or bone marrow BCR-ABL RNA in serial; at the time of diagnosis, at hematologic complete remission (HCR), and every 3 months thereafter. The molecular response was defined as complete (MCR) if the BCR-ABL/G6PDH ratio was less than 1x10-5.Results: Between October 2005 and February 2009, total 89 patients with newly diagnosed Ph+ALL were enrolled. With median follow-up of 5 years among survivors (range: 2.6-8.9 years) and data were frozen up in July, 2014. Two patients were not assessed, one due to a final diagnosis of CML blastic phase and one for refusal of the protocol treatment 4 months after enrollment. Eighty-two patients (94%) achieved HCR at a median 25 days (range, 14-69 days). Among these 82 HCR patients, 40 experienced recurrence of leukemia and 5-year relapse free survival (RFS) rate was 36.8%. Median time of RFS was 33 months (95% CI 20-46 months). In all, 24 patients died without leukemia progression or recurrence. Causes of treatment related morality were infection (n=5), bleeding (n=2), and HCT related complication (n=17). The 5-year overall survival (OS) rate was 33.4% and the median time of OS was 22.9 months (95% CI, 7.95-37.97 months). In total, 56 patients (68%) underwent allogeneic HCT in first HCR and had received a median 2 courses (range, 0-5 courses) of consolidation prior to HCT. At a median follow-up of 5-years (range, 2.1-8.4 years) after HCT, 23 patients experienced leukemia recurrence (cumulative incidence, 59.1%; 95% CI, 49.7%-68.5%). Of these 23 patients, 17 showed new molecular evidence of disease recurrence before hematologic relapse. Six patients, however, experienced hematologic recurrence without preceding molecular evidence of leukemia recurrence. The 5-year OS rate of patient underwent allogeneic HCT at first HCR was 52.6% and the median time of OS was 72.0 months (95% CI, 17.49-126.50 months). In the patients who completed the five cycles of consolidation, 7 patients were maintained on imatinib. Among these 7 patients, four patients finished 2-year imatinib maintenance. At median follow-up of 4 years (range, 1.9-7.4 years) after maintenance, 6 patients relapsed. The median time of RFS of patient who received maintain therapy was 40.7 months (95% CI, 24.38-57.19 months). One patient with relapse received HCT at second HCR after salvage therapy and two patients died with leukemia recurrence. Cumulative MCR rate was 88.5%, and median time to MCR was 54 days (range, 13-384 days). Median time of MCR duration was 13 months (range, 0.9-60.3 months). MCR achievement within 3months after remission induction was significant predictor of RFS (P=0.004) and OS (P=0.003). Thirty two patients who lost of MCR had significantly inferior RFS (P<0.0001) and OS (P=0.001) then 41 who maintained MCR. Total mean imatinib dose intensity over the entire treatment period was 80% (range, 22-110%) and mean imatinib dose intensity during remission induction was 85% (range, 22-131%). Imatinib dose intensity during remission induction; >90% vs. ¡Â90%; was significantly associated with median HCR duration (44 vs. 13 months, P=0.001, Fig. 1), median overall survival (39 vs. 10 months, P<0.0001, Fig. 2), and 3-year MCR rate (61% vs. 19%, P=0.001, Fig. 3). The probability for maintaining MCR at 3 years according to total imatinib dose intensity; >80% vs. ¡Â80%; was 57% (95% CI, 43.0-75.5%) and 33% (95% CI, 12.3-55.4%), respectively (P=0.05).Conclusions: The higher imatinib dose intensity is correlated with the better molecular response and the superior overall outcome. The quantitative monitoring of BCR-ABL transcript levels is useful in identifying subgroups of Ph+ALL patients at a high risk of relapse. [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Clinical impact of FDG PET-CT on the management of patients with locally advanced cervical carcinoma

To evaluate the impact of staging FDG PET-CT on the initial management of patients with locally advanced cervical carcinoma (LACC) and any prognostic variables predicting survival. Retrospective analysis of consecutive patients undergoing FDG PET-CT for staging of LACC in a single tertiary referral centre, between April 2008 and August 2011. Comparison was made between MRI and PET-CT findings and any subsequent impact on treatment intent or radiotherapy planning was evaluated. Sixty-three patients underwent FDG PET-CT for initial staging of LACC. Major impact on management was found in 20 patients (32%), a minor impact in five (8%), and no impact in 38 (60%). In those patients where PET-CT had a major impact, 12 had more extensive local nodal involvement, five had occult metastatic disease, two had synchronous tumours, and one patient had equivocal lymph nodes on MRI characterized as negative. PET-positive nodal status at diagnosis was found to be a statistically significant predictor of relapse-free survival (p<0.05). Staging FDG PET-CT has a major impact on the initial management of approximately one-third of patients with LACC by altering treatment intent and/or radiotherapy planning. PET-defined nodal status is a poor prognostic indicator.

583P - Impact of Adjuvant Chemotherapy (Ac) on Relapse-Free Survival (Rfs) is Different According to Post-Chemoradiation Pathologic Stage (Ypstage) in Rectal Cancer

ABSTRACT Aim: In contrast with colon cancer, survival benefit from adjuvant chemotherapy (AC) in rectal cancer is still unclear. For patients (pts) who are treated with preoperative chemoradiation (preop CRT), post-chemoradiation pathologic stage (ypStage) is known to be a major determinant of long term outcome. We aimed to describe clinical benefit from AC in terms of relapse-free survival (RFS) according to ypStage in rectal cancer. Methods: Retrospective analysis was done for data which were derived from prospective database of preop CRT - treated pts in National Cancer Center, Korea. Pts with initially nonmetastatic rectal cancer who received preop CRT followed by surgery (Jan 2001–Dec 2009) were included. Completeness of AC schedule was reviewed: undergoing chemotherapy cycles covering at least 16 weeks was considered completion. Results: Among a total of 743 pts, ypT0N0 or ypTisN0 (ypStage 0) / ypStage I/ ypStage II/ ypStage III/ ypStage IV were 119 (16.0%), 192 (25.9%), 203 (27.3%), 219 (29.5%), 10 (1.4%), respectively. 625 (84.1%) completed scheduled AC (fluoropyrimidine monotherapy in 95%), and 88 (11.8%) omitted or stopped AC, while 30 (4.0%) were excluded due to follow-up loss or disease progression. Completing AC was not associated with RFS in all pts (5-yr RFS 75.9% vs 73.6%, hazard ratio for relapse (HR) 0.95, p = 0.84), but significantly affected RFS in ypStage III (5-yr RFS 56.6% vs 21.4%, HR 0.45, p = 0.014). Among ypStage 0, I, and II, completing AC was not related to RFS (5-yr RFS 85.0% v 84.1%, HR 1.01, p = 0.969). Multivariate analysis revealed completion of AC was still a significant predictor of RFS after adjustment to initial carcinogembryonic antigen (CEA) level, nodal stage, and circumferential margin (CRM) status (table). HR (95% confidence interval) p value initial CEA 1.83 (1.22 - 2.76) 0.004 ypN2 2.08 (1.38 - 3.16) 0.001 completion of AC 0.37 (0.20 - 0.70) 0.002 positive CRM 2.21 (1.18 - 4.15) 0.014 Conclusions: Completion of AC affected RFS in ypstage III rectal cancer, while it did not in earlier stages. This study suggests survival benefit from AC could be limited to ypStage III in preop CRT treated rectal cancer. Disclosure: All authors have declared no conflicts of interest.

Molecular patterns in deficient mismatch repair colorectal tumours: results from a French prospective multicentric biological and genetic study.

Background:To test the prognostic value of tumour protein and genetic markers in colorectal cancer (CRC) and examine whether deficient mismatch repair (dMMR) tumours had a distinct profile relative to proficient mismatch repair (pMMR) tumours.Methods:This prospective multicentric study involved 251 stage I–III CRC patients. Analysed biomarkers were EGFR (binding assay), VEGFA, thymidylate synthase (TS), thymidine phosphorylase (TP) and dihydropyrimidine dehydrogenase (DPD) expressions, MMR status, mutations of KRAS (codons 12–13), BRAF (V600E), PIK3CA (exons 9 and 20), APC (exon 15) and P53 (exons 4–9), CpG island methylation phenotype status, ploidy, S-phase, LOH.Results:The only significant predictor of relapse-free survival (RFS) was tumour staging. Analyses restricted to stage III showed a trend towards a shorter RFS in KRAS-mutated (P=0.005), BRAF wt (P=0.009) and pMMR tumours (P=0.036). Deficient mismatch repair tumours significantly demonstrated higher TS (median 3.1 vs 1.4) and TP (median 5.8 vs 3.5) expression relative to pMMR (P<0.001) and show higher DPD expression (median 14.9 vs 7.9, P=0.027) and EGFR content (median 69 vs 38, P=0.037) relative to pMMR.Conclusions:Present data suggesting that both TS and DPD are overexpressed in dMMR tumours as compared with pMMR tumours provide a strong rationale that may explain the resistance of dMMR tumours to 5FU-based therapy.

Increased efficacy of a dose-dense regimen of neoadjuvant chemotherapy in breast carcinoma: a retrospective analysis

Neoadjuvant chemotherapy is being increasingly used in the treatment of breast carcinoma. We performed a single-center retrospective analysis of the results of neoadjuvant therapy in 376 breast carcinoma patients treated with three different regimens combining doxorubicin and paclitaxel (AT), dose-dense doxorubicin and cyclophosphamide with sequential weekly paclitaxel (DD AC-P), or the combination of trastuzumab with chemotherapy (DD AC-PT). The expression of estrogen receptors (ER), progesterone receptors (PR) and human epidermal growth factor receptor (HER)-2 was determined immunohistochemically. Pathological response was determined in 318 patients. Pathological complete response (pCR) was observed in 18% of patients. The pCR rate was significantly higher in patients treated with DD regimen (22 vs. 13%) and younger than 55 years (23 vs. 13%). The pCR rate was higher in patients with triple negative (TN) tumors (43%) and tumors over-expressing HER-2 (HER-2+; 28%) compared to patients with ER- or PR-positive tumors not expressing HER-2 (ER/PR+HER-2-; 6%). In patients with TN tumors pCR rate was significantly higher after treatment with DD AC-P compared to AT (61 vs. 22%, p=0.005). pCR was associated with significantly improved relapse-free survival (RFS) and overall survival (OS), but when analysis was performed based on tumor phenotype, the difference was significant only in patients with TN tumors. In multivariate analysis, pCR, stage, and ER expression were significant predictors of RFS, while pCR, stage, ER and DD regimen were significant predictors of OS. In conclusion, present data indicate superiority of a DD regimen in obtaining pCR in patients with breast carcinoma treated with neoadjuvant chemotherapy. The difference in efficacy is due mostly to markedly higher pCR rate in patients with TN tumors.

Clinicopathological significance of hypoxia-inducible factor-1 alpha (HIF-1α) expression in gastric cancer

Hypoxia is a common feature of rapidly growing solid tumors. Therefore, cellular adaptation to hypoxia and altered glucose metabolism are fundamental to the biology of cancer cells. Hypoxia-inducible factor-1α (HIF-1α) is a transcription factor for more than 60 genes recognized to control the delivery of oxygen and nutrients through the induction of angiogenesis and glycolysis under hypoxic conditions. Therefore, inhibition of the expression of HIF-1α can be expected to be potentially tumor-specific molecular target-based therapy. In this study, we evaluated the significance of HIF-1α expression in relationship to clinicopathological factors, prognosis, vascular endothelial growth factor (VEGF) expression, and microvessel density (MVD). Paraffin-embedded tumor specimens from 128 patients who underwent gastrectomy at Kurume University from 2004 to 2005 were used to assess the clinical significance of HIF-1α expression. We used the ABC method to perform an immunohistochemical analysis of the HIF-1α and VEGF expression. Eighty-four (65.6%) of gastric cancer specimens were positive for HIF-1α expression. Multivariate analysis showed that histology, depth of invasion, VEGF expression, and MVD were significantly associated with HIF-1α expression. On relapse-free and overall survival curves, the HIF-1α-negative group was significantly higher than the HIF-1α-positive group. Moreover, HIF-1α(+)/VEGF(+) patients had the worst prognosis. HIF-1α expression was identified as a significant predictor of relapse-free survival and overall survival by multivariate Cox's proportional hazard analyses. Overexpression of HIF-1α was found to be an indicator of poor prognosis for patients with gastric cancer and was significantly correlated with histology, depth of invasion, VEGF, and MVD.

Postoperative Better Than Preoperative C-reactive Protein at Predicting Outcome After Potentially Curative Nephrectomy for Renal Cell Carcinoma

Preoperative C-reactive protein (CRP) predicts metastasis and mortality in localized renal cell carcinoma (RCC). However, the predictive potential of after resection of localized RCC remains unclear. Therefore, we assessed the absolute ability of postoperative CRP to predict metastases and mortality as a continuous variable. Patients with clinically localized (T1-T3N0M0) clear-cell RCC were followed for 1 year postoperatively. Metastases were identified radiologically and mortality by death certificate. Univariate and multivariate binary logistic regression analyses examined 1 year relapse-free survival (RFS) and overall survival (OS) across patient and disease characteristics. Of the 110 patients in this study, 16.4% developed metastases and 6.4% died. Mean (SD) postoperative CRP for patients who did and did not develop metastases were 69.06 (73.55) mg/L and 5.27 (7.80), respectively. Mean (SD) postoperative CRP for patients who did and did not die were 89.31 (69.51) mg/L and 10.88 (30.32), respectively. In multivariate analysis, T-stage (OR: 12.452, 95% CI: 2.889-53.660) and postoperative CRP ((B: .080, SE: .025; P < .001) were significant predictors of RFS. T-Stage (OR: 11.715; 95% CI: 1.102-124.519) and postoperative CRP (B: .017; SE: .007; P < .001) were also significant predictors of OS. After adjusting for postoperative CRP, preoperative CRP was not predictive of these outcomes. Postoperative, not preoperative, CRP is the better predictor of metastasis and mortality following nephrectomy for localized RCC. Clinicians should consider absolute postoperative CRP to identify high-risk patients for closer surveillance or additional therapy. Predictive algorithms should consider incorporating postoperative CRP as a continuous variable to maximize predictive ability.

Absolute Preoperative C-Reactive Protein Predicts Metastasis and Mortality in the First Year Following Potentially Curative Nephrectomy for Clear Cell Renal Cell Carcinoma

C-reactive protein is an inflammatory biomarker associated with tumor burden and metastasis in renal cell carcinoma. Recent studies suggest that preoperative C-reactive protein predicts metastasis and mortality after nephrectomy for localized renal cell carcinoma. However, these studies dichotomized C-reactive protein (typically 10 mg/l or greater vs less than 10 mg/l). Considering the continuous range of C-reactive protein (less than 1 mg/l to greater than 100 mg/l) we assessed the ability of absolute preoperative C-reactive protein to predict metastases and mortality as a continuous variable. Patients with clinically localized (T1-T3N0M0) clear cell renal cell carcinoma were followed for 1 year postoperatively. Metastases were identified radiologically and mortality was determined by death certificate. Univariate and multivariate binary logistic regression analyses examined 1-year relapse-free survival and overall relative survival across patient and disease characteristics. Of the 130 patients in this study metastases developed in 24.6% and 10.8% of the patients died. Mean (SD) preoperative C-reactive protein for patients in whom metastases did and did not develop was 89.17 (74.17) and 9.16 (30.62) mg/l, respectively. Mean preoperative C-reactive protein for patients who did and did not die was 102.61 (77.32) and 19.52 (46.10) mg/l, respectively. On multivariate analysis SSIGN score (p <0.001) and preoperative C-reactive protein (B 0.027, SE 0.003, p <0.001) were significant predictors of relapse-free survival, and preoperative platelets (p = 0.009) and preoperative C-reactive protein (B 0.011, SE 0.008, p <0.001) were significant predictors of overall relative survival. Absolute preoperative C-reactive protein is a robust predictor of metastasis and mortality after nephrectomy for localized renal cell carcinoma. Clinicians should consider absolute preoperative C-reactive protein to identify high risk patients for closer surveillance or additional therapy. In addition, predictive algorithms and models of metastasis should consider incorporating C-reactive protein as a continuous variable to maximize predictive ability.

Gene Expression Profiling of Paraffin-Embedded Primary Melanoma Using the DASL Assay Identifies Increased Osteopontin Expression as Predictive of Reduced Relapse-Free Survival

Gene expression studies in melanoma have been few because tumors are small and cryopreservation is rarely possible. The purpose of this study was to evaluate the Illumina DASL Array Human Cancer Panel for gene expression studies in formalin-fixed melanoma primary tumors and to identify prognostic biomarkers. Primary tumors from two studies were sampled using a tissue microarray needle. Study 1: 254 tumors from a melanoma cohort recruited from 2000 to 2006. Study 2: 218 tumors from a case-control study of patients undergoing sentinel node biopsy. RNA was obtained from 76% of blocks; 1.4% of samples failed analysis (transcripts from <250 of the 502 genes on the DASL chip detected). Increasing age of the block and increased melanin in the tumor were associated with reduced number of genes detected. The gene whose expression was most differentially expressed in association with relapse-free survival in study 1 was osteopontin (SPP1; P = 2.11 x 10(-6)) and supportive evidence for this was obtained in study 2 used as a validation set (P = 0.006; unadjusted data). Osteopontin level in study 1 remained a significant predictor of relapse-free survival when data were adjusted for age, sex, tumor site, and histologic predictors of relapse. Genes whose expression correlated most strongly with osteopontin were PBX1, BIRC5 (survivin), and HLF. Expression data were obtained from 74% of primary melanomas and provided confirmatory evidence that osteopontin expression is a prognostic biomarker. These results suggest that predictive biomarker studies may be possible using stored blocks from mature clinical trials.

Predictors of response to reinduction chemotherapy for patients with acute myeloid leukemia who do not achieve complete remission with frontline induction chemotherapy

Eighty-one patients with acute myeloid leukemia who had persistent leukemia following standard induction therapy with cytarabine plus daunorubicin (7+3 regimen) underwent reinduction therapy with a combination of mitoxantrone, etoposide, and high-dose cytarabine (HiDAC). Patients achieving complete remission (CR) then received consolidation therapy with HiDAC plus mitoxantrone. Patients with matched sibling donors were referred for allogeneic bone marrow transplantation (BMT) in CR-1. The overall response rate to reinduction was 53%. The major adverse predictors of CR on multivariate analysis were poor risk cytogenetics, a higher % bone marrow blasts prior to reinduction therapy and increased age. The median relapse-free survival (RFS) was 9 months and the estimated 2-year RFS was 30%. No significant predictors of RFS or overall survival (OS) were found among the patients achieving CR. Patients undergoing allogeneic BMT in CR-1 after double induction had a 50% 2-year OS. Patients relapsing after achieving CR with double induction had a poor outcome with a 4% 1-year OS. The results indicate that patients with poor risk cytogenetics or marrow blast percentage >or= 60% following 7+3 induction have a low probability of achieving CR with reinduction and should be considered for novel approaches to improve CR rates. Patients achieving CR are at high risk of relapse and should be considered for allogeneic BMT or novel strategies to attempt to reduce relapse rates.

The Role of Microsatellites as a Prognostic Factor in Primary Malignant Melanoma

To determine the impact of microsatellites as a prognostic factor in primary cutaneous melanoma. Retrospective cohort study. Tertiary referral center. Patients A total of 504 patients with a history of primary melanoma observed for 2 years or having experienced a first relapse. Overall survival (OS) and relapse-free survival (RFS). Forty-five patients had evidence of microsatellites in their primary melanoma. Presence of microsatellites significantly correlated with the presence of several other histologic high-risk factors such as tumor thickness, ulceration, Clark level, vascular factors, and mitotic rate. Univariate analysis demonstrated decreased RFS and OS in patients with microsatellites. Presence of microsatellites was associated with increased locoregional metastasis but not distant metastasis. In multivariate analysis, with the inclusion of 6 other clinical and histologic factors, presence of microsatellites was a significant predictor of RFS but not OS. Patients with clinical macrosatellites had a trend toward worsening OS compared with those with microsatellites. The presence of microsatellites is intimately tied to other markers of melanoma aggressiveness. Microsatellites appear to predict locoregional relapse and RFS but neither distant metastasis nor OS. These results may have implications for patient care as well as the inclusion of microsatellites in stage III of the current classification.