Terms Of Relapse-free Survival Research Articles

Dual time point 18F-fluorodeoxyglucose positron emission tomography/computed tomography fusion imaging (18F-FDG PET/CT) in primary breast cancer

BackgroundTo evaluate the clinicopathological and prognostic significance of the percentage change between maximum standardized uptake value (SUVmax) at 60 min (SUVmax1) and SUVmax at 120 min (SUVmax2) (ΔSUVmax%) using dual time point 18F-fluorodeoxyglucose emission tomography/computed tomography (18F-FDG PET/CT) in breast cancer.MethodsFour hundred and sixty-four patients with primary breast cancer underwent 18F-FDG PET/CT for preoperative staging. ΔSUVmax% was defined as (SUVmax2 − SUVmax1) / SUVmax1 × 100. We explored the optimal cutoff value of SUVmax parameters (SUVmax1 and ΔSUVmax%) referring to the event of relapse by using receiver operator characteristic curves. The clinicopathological and prognostic significances of the SUVmax1 and ΔSUVmax% were analyzed by Cox’s univariate and multivariate analyses.ResultsThe optimal cutoff values of SUVmax1 and ΔSUVmax% were 3.4 and 12.5, respectively. Relapse-free survival (RFS) curves were significantly different between high and low SUVmax1 groups (P = 0.0003) and also between high and low ΔSUVmax% groups (P = 0.0151). In Cox multivariate analysis for RFS, SUVmax1 was an independent prognostic factor (P = 0.0267) but ΔSUVmax% was not (P = 0.152). There was a weak correlation between SUVmax1 and ΔSUVmax% (P < 0.0001, R2 = 0.166). On combining SUVmax1 and ΔSUVmax%, the subgroups of high SUVmax1 and high ΔSUVmax% showed significantly worse prognosis than the other groups in terms of RFS (P = 0.0002).ConclusionDual time point 18F-FDG PET/CT evaluation can be a useful method for predicting relapse in patients with breast cancer. The combination of SUVmax1 and ΔSUVmax% was able to identify subgroups with worse prognosis more accurately than SUVmax1 alone.

Efficacy and Safety of Daily All-Trans Retinoic Acid Monotherapy As Maintenance Therapy for Acute Promyelocytic Leukemia

Introduction Acute promyelocytic leukemia (APL) is a distinct subtype of acute myeloid leukemia with a unique chromosomal translocation t(15;17), causing promyelocytic leukemia gene fusion with the retinoic acid receptor α gene (PML-RARα). Therapeutic All-trans retinoic acid (ATRA) converts PML-RARα into transcriptional activator, induces APL differentiation. ATRA added during all treatment period have been reported to improve the outcomes of newly diagnosed APL. However, the benefits of maintenance therapy for patients with acute promyelocytic leukemia (APL) who achieved molecular complete remission (CRmol) are uncertain. In this study, we evaluated the efficacy and toxicity of daily ATRA monotherapy comparing with ATRA for 15 days with or without additional chemotherapy. Materials and Methods A retrospective data on 129 patients with newly diagnosed APL was conducted between February 2007 and August 2014. Induction and consolidation therapy were based on PETHEMA protocol. Among 113 patients (87.6%) who achieved CRmol following induction and 3 cycles of consolidation chemotherapy, 35 patients were treated daily with ATRA monotherapy (ATRAdaily), 39 with intermittent ATRA monotherapy for 15 days every 3 months (ATRA15), and 39 with ATRA plus continuous low-dose 6 mercaptopurine and methotrexate chemotherapy (ATRA/CT) for 2 years as a maintenance therapy. Event-free survival was defined as the time of CRmol to the development of events, which were defined by relapse, death, and toxicity that required hospitalization or dose reduction. Results The median age of patients was 46 years (range, 18-80 years). There was no significant difference among the three groups (ATRAdaily, ATRA15, and ATRA/CT) in terms of age, sex, ECOG PS, WBC count, platelet count, fibrinogen, prothrombin time, and Sanz risk score. Among the 12 relapsed patients during maintenance therapy, 3 presented molecular relapse and 9 hematologic relapse. Six (15.4%) relapses were observed in the ATRA15 group, whereas 2 (5.7%) and 4 (10.3%) relapses were observed in the ATRAdaily and ATRA/CT groups, respectively. At a median follow-up of 75.3 months (range: 9.0-140.4 months) from CRmol, the 5-year relapse free survival (RFS) for patients receiving maintenance therapy with ATRAdaily was higher than that of the patients in the ATRA15 or ATRA/CT groups without a statistically significant difference, 93.0 ± 4.8%, 84.6 ± 5.8%, and 88.0 ± 5.7%, respectively (P = 0.447). The 5-year overall survival (OS) rate was 92.7 ± 5.1%, 94.6 ± 3.7%, and 91.2 ± 5.0% for the ATRAdaily, ATRA15, and ATRA/CT groups, respectively (P = 0.601). However, ATRA/CT group frequently had myelosuppression (n = 11, 28.2%). The 5-year EFS rate was 81.5 ± 7.6%, 86.4 ± 5.7%, and 51.7 ± 8.2% for the ATRAdaily, ATRA15, and ATRA/CT groups, respectively (P &lt; 0.001). In the multivariate analysis, maintenance therapy in the ATRA/CT group compared to ATRAdaily showed a significantly lower EFS (HR = 2.14, 95% CI = 1.06-4.31, P = 0.023). ECOG PS ≥ 2 was also associated with lower EFS (P = 0.033). Sanz risk score was the only adverse prognostic factor for RFS, and OS (HR = 6.20, 95% CI = 1.29-29.90, P = 0.023; HR=5.30, 95% CI = 1.10-25.63, P = 0.038). Conclusions In conclusion, in the present study, ATRAdaily as a maintenance therapy for patients with newly diagnosed APL who achieved CRmol showed non-inferiority compared with ATRA/CT in terms of RFS and OS. In addition, ATRAdaily maintenance therapy can be a feasible and effective choice in terms of myelosuppression or hepatotoxicity. In the future, well-conducted systematic studies of long term survivorship, quality of life, and treatment-related complications are needed to confirm these observations. Figure Disclosures No relevant conflicts of interest to declare.

Hyprofractionated Versus Conventionally Fractionated Radiation Therapy for Patients with Intermediate- or High-Risk, Localized, Prostate Cancer: 7-Year Outcomes From the Randomized, Multicenter, Open-Label, Phase 3 HYPRO Trial

In the multicenter, phase 3, HYpofractionated irradiation for PROstate cancer trial, hypofractionated (HF) radiation therapy was compared with conventionally fractionated (CF) radiation therapy. In previous reports, we could not demonstrate the postulated superiority of hypofractionation in terms of relapse-free survival at 5 years. The frequent use of long-term androgen deprivation therapy might have had substantial effects on relapse-free survival. In the current analysis, we provide updated 7-year relapse-free survival outcomes. We enrolled patients with intermediate- to high-risk T1b-T4NX-N0MX-M0 localized prostate cancer. Patients were randomly assigned (1:1) to either HF (64.6 Gy in 19 fractions) or CF (78.0 Gy in 39 fractions) radiation therapy. Based on an estimated α/β ratio for prostate cancer of 1.5 Gy, the EQD2 was 90.4 Gy for HF versus 78.0 Gy for CF radiation therapy. The primary endpoint of the present analysis is relapse-free survival at 7 years. A total of 820 patients were enrolled, of whom 804 were assessable for the current evaluation (407 HF versus 397 CF). Median follow-up was 89 months (interquartile range, 83-99). Concomitant androgen deprivation therapy was prescribed for 537 (67%) of 804 patients for a median duration of 32 months (interquartile range, 10-44). Treatment failure at 7 years was reported in 220 (27.4%) of 804 patients, 107 (26.3%) in HF versus 113 (28.5%) in CF radiation therapy. Seven-year relapse-free survival was 71.7% (95% confidence interval [CI], 66.4-76.4) for HF versus 67.6% (95% CI, 62.0-72.5) for CF (P = .52). Overall survival was 80.8% (95% CI, 76.5-84.4) in HF versus 77.6% (95% CI, 73.0-81.5) in CF radiation therapy (P = .17). The current results of 7-year relapse-free survival confirmed our previous findings that the hypothesized dose escalation in the HF arm did not translate to superior tumor control compared with the CF arm.

551P - Clinical impact of mucinous and poorly differentiated tumours on the outcome of patients with stage II colon cancer: A TOSCA subgroup analysis

BackgroundASCO and ESMO guidelines have identified inadequate sampling of lymph nodes, pT4 primary tumors, obstruction or perforation, lymphovascular and perineural invasion, and poorly differentiated tumors as negative prognostic factors supporting the clinicians in treating their patients with stage II colon cancer (CC). However, the influence of histological subtypes on the risk of death or disease recurrence remains controversial. MethodsThe phase III, multicenter, randomized TOSCA trial compared 3 vs. 6 months of fluoropyrimidine-oxaliplatin adjuvant chemotherapy in 3,759 patients with high-risk stage II or stage III CC. Objective of this sub-study was to investigate the role of the histological subtype [(mucinous adenocarcinoma (MUC) or non-mucinous adenocarcinoma (NMUC)] on the impact of the treatment duration in terms of relapse-free survival (RFS) and overall survival (OS) in the subgroup of patients with high-risk stage II, grade 3CC. ResultsOut of 3,614 patients from 130 centres enrolled in the per-protocol population defined in the TOSCA trial, 85 MUC and 389 NMUC patients were included in this analysis. No statistical differences were found between 3 vs. 6 months groups in both histological subgroups in terms of baseline characteristics, except for tumor side. The proportion of patients with right-sided cancer was higher for patients with MUC than NMUC. A significant interaction between treatment duration and histology was observed on both RFS (p=0.027) and OS (p=0.017). In the subgroup of patients with MUC, worse RFS (adjusted hazard ratio [HR], 3.95; 95% confidence interval [CI], 1.03–15.17; p=0.045) and OS (HR, 9.56; 95% CI, 1.14–79.98; p=0.037) were detected for patients treated in the 3 months arm. No statistically significant differences were detected in the subgroup of patients with NMUC. ConclusionsBoth MUC and poorly differentiated subtypes have unfavorable clinical characteristics. Patients with MUC, grade 3, stage II CC require special attention and may need 6 months of oxaliplatin-based chemotherapy. Larger studies are required to clarify the possible negative effect of the histological subtype to improve the prognosis of these patients. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Sorafenib Versus Observation Following Radical Metastasectomy for Clear-cell Renal Cell Carcinoma: Results from the Phase 2 Randomized Open-label RESORT Study

BackgroundIn selected metastatic renal cell carcinoma (mRCC) patients, radical metastasectomy followed by observation is a potential strategy. It is still to be defined whether systemic therapy should be administered following metastasectomy. ObjectiveTo assess the potential benefit of postoperative treatment with sorafenib compared with observation alone after radical metastasectomy in mRCC patients. Design, setting, and participantsThe RESORT trial was a multicenter, randomized, open-label, phase 2 study conducted between November 2012 and November 2017 in Italy. Patients with clear-cell mRCC pretreated with nephrectomy and undergoing radical metastasectomy (three or fewer lesions) were eligible for the study. Patients were randomized (1:1) within 12 wk from metastasectomy to sorafenib (standard dose 400 mg twice daily) or observation for a maximum of 52 wk. Stratification factors were interval from nephrectomy, site, and number of lesions. Overall, 76 patients were screened and 69 were randomized: 33 were assigned to sorafenib and 36 to observation. The primary endpoint was recurrence-free survival (RFS). Secondary endpoints were overall survival and the safety profile. Outcome measurements and statistical analysisRFS curves were estimated with the Kaplan-Meier method, and the log-rank test was used to statistically compare the curves. Results and limitationsAt a median follow-up of 38 mo, median RFS was 37 mo (95% confidence interval [CI] 20–not available [NA]) in the observation arm versus 21 mo (95% CI 11–NA) in the sorafenib arm (log-rank test p = 0.404), with 12-, 24-, and 36-mo RFS probability of 74% versus 63%, 59% versus 49%, and 50% versus 41%, respectively, in the observation versus the sorafenib arm. Any-grade adverse event (AE) rates were 84% in the sorafenib arm and 31% in the observation arm; grade ≥3 AE rates were 22% and 3% in the sorafenib and the observation arm, respectively, with a rate of treatment discontinuation for AEs of 19% in the sorafenib arm. ConclusionsThis prospective study showed that systemic treatment with sorafenib did not increase RFS as compared with observation in mRCC patients following radical metastasectomy. Patient summaryThis article reports the clinical outcome of patients with metastatic renal cell carcinoma treated with sorafenib or managed with an observation-alone strategy after the radical surgery of metastases. We found that sorafenib did not improve the patient outcome in terms of relapse-free survival in this selected population.

S1613 ALLOGENEIC HEMATOPOIETIC CELL TRANSPLANTATION CAN ABROGATE INCREASING RISK OF RELAPSE FROM PERSISTENT MUTATIONS MEASURED BY TARGETED SEQUENCING AT REMISSION IN NORMAL KARYOTYPE ACUTE MYELOID LEUKEMIA

Background:Normal karyotype acute myeloid leukemia (NK AML) currently does not have a universal measurable residual disease (MRD) target, thus making next generation sequencing (NGS) more attractive as an MRD monitoring tool. Also, there is limited knowledge on selecting consolidation therapy based on the MRD status at time of first achievement of complete remission (CR1) in NK AML between allogeneic hematopoietic cell transplantation (allo‐HCT) and chemotherapy.Aims:Current study aims to investigate the impact of type of consolidation therapy on the long‐term outcomes according to the NGS‐based MRD status at CR1 in NK AMLMethods:A total of 139 patients diagnosed with NK‐AML, treated, and achieved CR1 were included in this study. Paired bone marrow or peripheral blood samples were obtained at diagnosis and at CR1. Using a panel of 45 genes commonly mutated in AML, 278 samples were sequenced using Illumina Hiseq 2500 followed by variant calling procedures (Avg. on‐target coverage 895x).Treatment outcomes were evaluated in terms of overall survival (OS), relapse free survival (RFS), and cumulative incidence of relapse (CIR). The prognostic impact of risk factors for OS, RFS, and CIR was determined using Mantel‐Byar test, which is a Cox proportional hazard model considering time‐dependent covariates, and Fine‐Gray proportional hazard regression model considering competing events. Variant allele frequency (VAF) of 0.2% was defined as minimum sensitivity to detect MRD and as MRDpos given the mutation was present at diagnosis.Results:Of 139 patients, 124 patients (89.2%) carried 363 mutations at diagnosis and 15 patients without detected mutations were excluded from further analyses. At CR1, 72/124 patients carried 121 persistent mutations over 0.2% (Fig A). Mutations in genes associated with DNA methylation such as DNMT3A (n = 33/40), followed by IDH2 (n = 13/21), and TET2 (n = 10/15) were highly persistent. In contrary, mutations in NPM1 and signaling related genes show lower frequency of persistence (n = 4/49 and n = 12/70). As mutations in DNMT3A, TET2, and ASXL1 are often associated with age‐related clonal hematopoiesis, they were excluded in MRD assessment. Based on MRD status (50 positive and 74 negative cases) and the type of consolidation therapy they are treated with (65 with allo‐HCT and 59 with chemotherapy only), we performed subgroup analyses (Fig B).In univariate analyses on the entire cohort, MRD status at CR1 did not affect long‐term outcome, while allo‐HCT was associated with a better RFS (p = 0.009), a lower CIR (p = 0.008) and, a trend of better in OS. We further stratified the cohort into 4 subgroups based on the two factors (i.e. MRD status at CR1 and the type of consolidation therapy). Most notably, for MRDpos patients, the benefit of allo‐HCT became more apparent in terms of RFS (p = 0.002), CIR (p = 0.002), and OS (p = 0.011) (Fig C). In contrast, this benefit from allo‐HCT over chemotherapy was not observed in MRDneg group (Fig D). Multivariate analyses confirmed that allo‐HCT was an independent favorable prognostic factor for OS (Hazard Ratio (HR); 0.33, p = 0.011), RFS (HR; 0.28, p = 0.002) and CIR (HR; 0.20, p = 0.002) in the MRDpos group.Summary/Conclusion:NGS‐based MRDpos patients at CR1 show better long‐term outcome when received allo‐HCT as consolidation therapy while no survival difference was observed regardless of type of consolidation therapy in MRDneg patients. The present study highlights urgent demand for the development of a decision‐making algorithm for selection of consolidation therapy according to NGS‐based MRD status at CR1 in NK AML.image

Impact of serum vitamin D on the response and the prognosis in breast cancer patients treated with neoadjuvant chemotherapy.

e12088 Background: Neoadjuvant chemotherapy (NAC) is one of the standard therapeutic strategies for operable early breast cancer (BC). A relationship between chemotherapy response and the prognosis has been suggested, especially in HER2+ or triple negative breast cancer (TNBC). Recently, the impact of vitamin D (VD) on pathological complete response (pCR) after NAC has been reported, however, there are no data regarding the relationship between VD level and the efficacy of NAC in Japanese BC patients. Methods: This study included 236 patients with BC at clinical stage I-III, who were treated with anthracycline and taxane-based NAC. HER2-directed therapies were used for HER2+ tumors. Serum 25, hydroxyl VD levels were evaluated using by ELISAusing blood samples obtained before NAC. VD deficiency was defined as &lt;20 ng/ml. Results: Pathological complete response (pCR) was obtained in 52 patients (22.0%). The pCR rate was significantly higher in the patients with HER2+ or TNBC compared with hormone receptor (HR)+/HER2-tumors (p&lt;0.0001). Median VD level was 10.7 ng/ml, and only 7 patients (3.0%) had a VD level ≥20 ng/ml. These results show that most Japanese women are deficient for VD. VD levels increase with age, and the VD levels are significantly higher in postmenopausal patients than in the premenopausal patients (p=0.0029). Patients were dichotomized into VD-low and -high groups at the median value (10.7 ng/ml). Serum VD was not associated with pCR in the all cohort, however, pCR rate was higher in VD-high group in premenopausal patients, especially in the patients withHER2+ or TNBC (p=0.0328). High VD was significantly associated with better prognosis in terms of relapse-free survival (p=0.0327) and distant metastasis-free survival (p=0.0051). This association was observed both in pre- and post-menopausal patients, especially in the patients with HER2+ or TNBC. Conclusions: High VD levels were associated with high pCR rate in premenopausal patients with HER2+ or TNBC. High VD levels were also associated with better prognosis operable BC patients treated with NAC, although VD levels of most Japanese BC patients were lower than the cut-off value.

First survival outcomes and additional secondary analyses from PURE-01: Pembrolizumab (pembro) before radical cystectomy (RC) in muscle-invasive urothelial bladder carcinoma (MIBC).

391 Background: PURE-01 is a phase 2 study of Pembro before RC in MIBC: the primary endpoint (pathologic complete response [pT0]) was met in advance ( Necchi et al. JCO 2018). While the study is still recruiting patients (pts), we analyzed the interim long-term outcomes in terms of relapse-free survival (RFS) and the role of multiparametric bladder magnetic resonance imaging (mpMRI) in predicting major pathologic response (pT&lt;2) in RC. Methods: Pts with clinical stage T2-3bN0M0 received 3 courses of 200mg Pembro, before RC. Pts were staged and re-assessed with mpMRI before RC. 1-y RFS (overall and by pathologic stage) after Pembro and RC was compared with that from clinical stage-matched cohort of San Raffaele Urological Institute (URI, n=1021) and of the RISC multicenter database (n=719, Bandini et al, Eur Urol Oncol 2018). mpMRI were performed in all pts through bladder catheterization. The apparent diffusion coefficient (ADC) changes post-Pembro were matched with pathologic response, qPCR and genomic data from RC samples (FoundationONE). Results: 70 pts have completed treatment thus far: with 27 pT0 (38.6%) and 44 pT&lt;2 (62.9%), activity was confirmed. 21 pts had ≥1y follow-up and were analyzed. Overall, 1-y RFS (95% CI) in PURE-01, URI and RISC were: 95.2 (86.6-100), 79.0 (76-82), and 69.7 (66.2-73.4). 1-y RFS after neoadjuvant chemotherapy and RC in URI and RISC were: 76.7 (61-97), and 76.5 (71-83). 1-y RFS for pT3-4 and/or pN+ pts were: 88.9 (71-100), 71.2 (67-76), and 57.1 (52-62). 39/70 pts had measurable disease for pre-post mpMRI changes. Pts with pT&lt;2 (n=16) on RC showed a median “mean ADC” of 0.98 mm2/s vs 0.84 mm2/s of non-responders (NR, n=23, p=0.098), despite an increased T-cell infiltrate. Pts with cell-cycle gene alterations in RC (n=8) were all NR and showed lower median “mean ADC” values (p=0.074). Conclusions: The early efficacy data further support the role of single-agent IO as neoadjuvant therapy in MIBC. Pembro may be beneficial at long-term also in pathologically high-risk pts, thus questioning the value of PD-L1 for pt selection. mpMRI and genomic data might help identifying those pts who may need re-TURB only instead of RC. Clinical trial information: NCT02736266.

Abstract P1-13-09: Long-term follow-up of two randomized controlled trials (N-SAS-BC01 trial and CUBC trial) comparing oral tegafur-uracil (UFT) versus classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant therapy in early breast cancer

Abstract Background: Two randomized controlled trials comparing the efficacy of oral tegafur-uracil (UFT) (2 years) with that of classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) (6 courses) were conducted in patients with resected early breast cancer. UFT is an oral fluoropyrimidine that combines tegafur, a prodrug of 5-fluorouracil, with uracil in a 1:4 molar ratio. One study was the N-SAS-BC01 trial (Watanabe et al, J Clin Oncol 2009), which was conducted in patients with high-risk node-negative breast cancer (n=733). The other was the CUBC trial (Park et al, Br J Cancer 2009), which was performed in patients with node-positive breast cancer (n=377). We reported the pooled analysis of these two randomized control trials using individual patient data (Ohashi et al, Breast Cancer Res Treat 2010). This pooled analysis showed that UFT was non-inferior to CMF in terms of inhibiting recurrence of estrogen receptor (ER)-positive early breast cancer. In addition, an exploratory subgroup analysis showed that UFT may be more effective in ER-positive patients who were 50 years or older. The present study was conducted to investigate the long-term efficacy of UFT or CMF in patients with early breast cancer. Methods: Long-term follow-up data for disease recurrence and survival were collected. Hazard ratios (HR) were determined using the Cox model stratified by study and adjusted for clinical characteristics, namely age, tumor size, nodal status, histological type, ER, and progesterone receptor (PgR). Survival curves were estimated by the Kaplan-Meier method. Hochberg multiplicity adjustment was applied in the previous pooled analysis, and non-inferiority of UFT versus CMF was shown in terms of relapse-free survival (RFS) in the ER-positive patient group. We investigated the non-inferiority of UFT in the same patient group with updated data. Restricted mean survival time (RMST) was calculated to consider the relative efficacy of UFT. This study is registered with JapicCTI-163321. Results: In total, 1,057 patients were analyzed (CMF, n=528; UFT n=529). The median follow-up time was 11.1 years (12.1 years in the N-SAS-BC 01 trial and 8.3 years in the CUBC trial). Table 1 shows the 10-year RFS and overall survival (OS) in all patients and ER-positive patients. The difference in RMST between arms at 20 years in terms of RFS was -2.7 months in all patients and 3.4 months in ER-positive patients. Table 2 shows the HR for RFS according to ER status and age. UFT (%)CMF (%)UFT to CMF; HR (95% CI)10-year RFSall patients74.477.11.02 (0.81–1.30)ER-positive patients75.075.10.91 (0.66–1.27)10-year OSall patients86.886.90.98 (0.72–1.34)ER-positive patients89.987.90.86 (0.54–1.37) Age &amp;lt;50 yearsAge ≥50 yearsER negative1.76 (0.95–3.26)0.93 (0.58–1.51)ER positive1.29 (0.74–2.23)0.76 (0.50–1.16) Conclusion: This study shows that UFT was shown to be non-inferior to CMF in terms of RFS in ER-positive early breast cancer. This result is similar to that of the previous pooled analysis. Sponsor: Taiho Pharmaceutical Co., LTD Citation Format: Yonemori K, Ohsumi S, Takao S, Tokuda Y, Ito Y, Nakagami K, Takahashi M, Yoshidome K, Nakayama T, Yamaguchi Y, Ohashi Y, Inaji H, Watanabe T. Long-term follow-up of two randomized controlled trials (N-SAS-BC01 trial and CUBC trial) comparing oral tegafur-uracil (UFT) versus classical cyclophosphamide, methotrexate, and 5-fluorouracil (CMF) as adjuvant therapy in early breast cancer [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P1-13-09.

Long-term outcomes of progestin plus metformin as a fertility-sparing treatment for atypical endometrial hyperplasia and endometrial cancer patients.

ObjectiveThe present study investigated long-term outcomes of medroxyprogesterone acetate (MPA) plus metformin therapy in terms of control of atypical endometrial hyperplasia (AEH) and endometrial cancer (EC), and post-treatment conception.MethodsWe retrospectively analyzed 63 patients (42 with EC; 21 with AEH) who underwent fertility-sparing management using MPA plus metformin. MPA (400 mg/day) and metformin (750–2,250 mg/day) were administered to achieve complete response (CR). Metformin was administered until conception, even after MPA discontinuation.ResultsOf the total patients, 48 (76%) had a body mass index (BMI) ≥25 kg/m2 and 43 (68%) showed insulin resistance. Sixty-one patients (97%) achieved CR within 18 months. CR rates at 6, 8–9, and 12 months were 60%, 84%, and 90%, respectively. During a median follow-up period of 57 months (range, 13–115 months), relapse occurred in 8 of 61 patients (13.1%) who had achieved CR. Relapse-free survival (RFS) in all patients at 5 years was 84.8%. Upon univariate analysis, patients with BMI ≥25 kg/m2 had significantly better prognoses than did those with BMI <25 kg/m2 (odds ratio=0.19; 95% confidence interval=0.05–0.66; p=0.009). Overall pregnancy and live birth rates per patient were 61% (19/31) and 45% (14/31), respectively.ConclusionsMPA plus metformin is efficacious in terms of RFS and post treatment conception. Moreover, metformin may be more efficacious for patients with BMI ≥25 kg/m2.

Predictive factors of pathological lateral pelvic lymph node metastasis in patients without clinical lateral pelvic lymph node metastasis (clinical stage II/III): The analysis of data from the clinical trial (JCOG0212)

BackgroundMesorectal excision (ME) is the standard surgical procedure for lower rectal cancer. However, in Japan, total or tumor-specific ME with lateral pelvic lymph node dissection (LLND) is the standard surgical procedure for patients with clinical stages II or III lower rectal cancer, because lateral pelvic lymph node metastasis occasionally occurs in these patients. The aim of study was to elucidate the predictive factors of pathological lateral pelvic lymph node metastasis in patients without clinical lateral pelvic lymph node metastasis. MethodsData form the clinical trial (JCOG0212) was analyzed. The JCOG0212 was a randomized controlled trial to confirm the non-inferiority of mesorectal excision alone to mesorectal excision with lateral lymph node dissection for clinical stage II/III patients who don't have clinical lateral pelvic lymph node metastasis in terms of relapse free survival. This study was conducted at a multitude of institution33 major hospitals in Japan. Among the 351 patients who underwent lateral lymph node dissection in the JCOG0212 study, 328 patients were included in this study. Associations between pathological lateral pelvic lymph node metastasis and preoperative and postoperative factors were investigated. The preoperative factors were age, sex, clinical stage, tumor location, distance from anal verge, tumor size, and short-axis diameter of lateral pelvic lymph node on computed tomography and the postoperative factors were pathological T, pathological N, and histological grade. ResultsAmong the 328 patients, 24 (7.3%) had pathological lateral pelvic lymph node metastasis. In multivariable analysis of the preoperative factors, patient age (p = 0.067), tumor location (p = 0.025), and short-axis diameter of lateral pelvic lymph node (p = 0.002) were significantly associated with pathological lateral pelvic lymph node metastasis. ConclusionsPatient age, tumor location, and short-axis diameter of lateral pelvic lymph node were predictive factors of pathological lateral pelvic lymph node metastasis.

P-239 - Impact of adding oxaliplatin to fluoropyrimidines in the adjuvant therapy in stage II in colon cancer: Experience in Ramon y Cajal Universitary Hospital

Introduction: The addition of oxaliplatin to fluorouracil and leucovorin as adjuvant chemotherapy (AC) for patients with stage II and III colon cancer (CC) has been analyzed in two large, randomized trials, MOSAIC and C-07 trials. The updated results of these studies showed that the addition of oxaliplatin enhances overall survival by approximately 5% in patients with stage III disease but has no effect in patients with stage II disease. Methods: We retrospectively included patients with stage II CC that were operated between 2009 and 2014 in the Ramon y Cajal University Hospital. We perform a multivariable Cox model analysis to estimate the benefit of the chemotherapy stratifying by oxaliplatin. We have analyzed whether receiving AC improves the relapse free survival (RFS) and overall survival (OS) and has been stratified according to the presence of at least one classic high risk factor (HRF). Additionally, it has been evaluated whether the addition of oxaliplatin improves the results. Results: 246 were identified. 151 were men (61%). 117 patients had at least one HRF (47%), 52 received AC (44%) of which 33 with oxaliplatin (63%). Patients without any HRF, 27 received AC (21%) of which 19 with oxaliplatin (70%). The median follow-up was 58.2 months. Globally, adjuvant chemotherapy (either with some HRF or without any) showed no benefit in RFS (Hazard ratio (HR) of 1.48 and 1.36, respectively). The benefit in OS was significant for patients with at least one HRF (HR 0.33, p: 0.007) but not in those patients without any HRF (HR 0.52, p: 0.54). Patients with stage II treated with oxaliplatin and fluoropyrimidines showed no benefit in terms of RFS neither with any HRF (HR 0.58, p: 0.33) nor without any (HR 1.11, p 0.936). In terms of OS, there is only benefit in those patients with some HRF (HR 0.16, p: 0.03). Conclusion: The AC in patients with stage II show benefit in OS in those patients with at least one HRF, especially with the addition of oxaliplatin. In those patients without any HRF, there is no benefit with AC, even with addition of oxaliplatin.

322 - Comparison of Mitoxantrone-Based Salvage Therapies (MEC vs CLAG-M) in Relapsed or Refractory Acute Myeloid Leukemia

Introduction: Primary refractory and early relapsed acute myeloid leukemia (RR-AML) continue to pose a therapeutic challenge. There are currently a number of treatment strategies for RR-AML, with performance status, cytogenetics, and availability of appropriately matched allogenic hematopoietic cell transplant (HCT) donors all influencing that clinical decision. Salvage therapy treatment regimens for refractory and relapsed disease are not standardized but include mitoxantrone, etoposide, and cytarabine (MEC) and cladribine, cytarabine, filgrastim, and mitoxantrone (CLAG-M), among many others. While previous studies have established the roles of MEC, and CLAG-M independently and have retrospectively compared MEC vs CLAG; no retrospective analysis of MEC vs CLAG-M has been published to date, though both remain commonly used regimens in practice. In this retrospective single-center analysis we compare the outcomes of patients receiving MEC or CLAG-M as salvage therapy for RR-AML. Methods: The study included 55 patients with RR-AML who received MEC or CLAG-M between 09/01/2009 and 12/31/2016. Information about sociodemographics, disease and transplant characteristics and clinical outcomes were obtained by medical record review. The probabilities of overall survival (OS) and relapse-free survival (RFS) were estimated according to the Kaplan Meier method and log-rank test was used to compare outcomes between patients who received either of the two regimens. Results: Fifty five consecutively treated patients with RR-AML were included in this analysis, 44 patients received MEC and 11 patients received CLAG-M. The median age of patient was 58.5 years (18-75) among MEC recipients and 54 years (23-64) in the CLAG-M group, with 53% being males. The majority of patients had relapsed disease (n=38, 69%). High risk subtypes of AML, as determined by cytogenetics and molecular studies, predominated with 87% (48/55) being high risk. Cytoreduction was achieved in 30 (68%) of patients who received MEC, and 8 (73%) patients who received CLAG-M achieved cytoreduction. HCT was pursued in 33 (75%) of patients who received MEC and 9 (82%) who received CLAG-M. Median follow-up after transplant was 30 months from treatment with either MEC or CLAG-M (5 - 60 months), 17 (52%) and 3 (27%) were alive from the MEC and CLAG-M groups respectively. In the follow-up interval for transplanted patients, 9 (27%) from the MEC group and 6 (55%) from the CLAG-M group relapsed, with a median time to relapse from the date of transplant of 9.1 months (0.4 -30 months) and 2.9 months (1.8 - 11 months), respectively. Median time to relapse for patients who received HCT was 12 months (0-76 months) for the MEC group and 5.5 months (2-35 months) for the CLAG-M group. Relapse free survival at 24 months between the MEC and CLAG-M treatment groups that went to HCT were 67% (51-87%) and 11% (1.8-71%), respectively with an associated hazard ratio (HR) of 3.86 (1.55-9.59, CI 95%, p 0.0016). Similarly, overall survival analysis at 24 months was 66% and 11% for MEC and CLAG-M respectively, with a HR of 3.85 (1.51 - 9.81, 95% CI, p=0.002). Discussion: While induction therapies for AML are fairly standard, there are numerous potential salvage therapies that serve to bridge a person to transplant in RR-AML. With allowances that a degree of agent availability and provider familiarity with treatment likely biases the selection of one regimen over another, our results would suggest a treatment benefit both in terms of RFS and OS in patients with RR-AML who receive MEC over CLAG-M and ultimately go to HCT. Disclosures No relevant conflicts of interest to declare.

Urinary dysfunction after rectal cancer surgery: Results from a randomized trial comparing mesorectal excision with and without lateral lymph node dissection for clinical stage II or III lower rectal cancer (Japan Clinical Oncology Group Study, JCOG0212)

BackgroundPostoperative urinary dysfunction is a major complication of rectal cancer surgery. A randomized controlled trial (JCOG0212) concluded that the noninferiority of mesorectal excision alone to mesorectal excision with lateral lymph node dissection was not confirmed in terms of relapse-free survival. MethodsEligibility criteria included histologically proven clinical stage II/III rectal cancer, a main lesion located in the rectum with the lower margin below the peritoneal reflection, and the absence of lateral lymph node enlargement. After confirming R0 resection by mesorectal excision, patients were randomized intraoperatively. The residual urine volume was measured three times. Urinary dysfunction was defined as ≥50 mL residual urine occurring at least once or no measurement of residual urinary volume. This trial was registered with the UMIN Clinical Trials Registry, number C000000034. ResultsIn the mesorectal excision alone and the mesorectal excision with lateral lymph node dissection groups, the incidence of early urinary dysfunction were 58% and 59%, respectively. A tumor location in the lower rectum (vs. upper rectum) and a blood loss of ≥500 mL (vs. <500 mL) were associated with an increased risk of early urinary dysfunction. However, only blood loss was independently predictive of early urinary dysfunction (relative risk, 1.25 [95% CI: 1.10–1.55], p = .04). ConclusionsMesorectal excision with lateral lymph node dissection is not associated with a significant increase in the incidence of urinary dysfunction. Urinary dysfunction is associated with tumor location and blood loss.

Subsite-dependent prognostic impact of age in patients with nasopharyngeal and oropharyngeal cancer

Backgroud: Outcome results in elderly head and neck cancer (HNC) patients (pts) treated with concurrent chemoradiation are controversial. Comparative effectiveness analyses showed a lack of benefit in multimodal treatment; however, retrospective highly selected series reported older patients to have similar outcome compared to younger ones albeit with high burden of toxicities. Material and methods: Locally advanced oropharyngeal (OPC) and nasopharyngeal cancer (NPC) pts treated at our institution with concurrent platinum based chemotherapy (CHT) and intensity modulated radiation therapy (IMRT) techniques from 2004 to 2015 were retrospectively evaluated. Overall survival (OS) and Relapse Free Survival (RFS) Kaplan-Meier curves were estimated and compared with the log-rank test; acute toxicity rate >G3 according to Common Toxicity Criteria Adverse Event v4.0 was also analyzed, distinguishing between patients >65 years old (elderly) and ≤65 old. HPV status was recorded in all OPC patients. Results: 375 pts received IMRT-CHT, 215 in OPC and 160 in NPC cohort. Elderly pts represented 26% and 11% of OPC and NPC pts, respectively. OPC HPV positive cases were similarly represented in older (73% of the cases) and younger pts (66%); HPV positivity maintained a significant prognostic role independently of age and also across different age group. On the contrary, age did not significantly impact on survival in OPC. Five-years RFS was 68% in older versus 76% in younger patients p = 0.391; the corresponding figures for OS were 93% versus 87% p = 0.541. There was no significant difference in cumulative acute toxicity rate = G3 (39% in elderly vs 36% in younger p = 0.778). When analyzed separately, no difference was shown for what concerns dysphagia and mucositis. NPC pts showed a different outcome according to age both in terms of RFS (5-years probabilities 41% in elderly vs 80% in younger pts, p < 0.001) and OS (48% vs 90%, p < 0.001), which turned out to be a negative prognostic factor in this disease. Also for NPC pts, the two age subgroups did not significantly differ in acute toxicity rate = G3 (56% vs 61%, p = 0.800). No different platinum total dose was adopted in OPC and NPC elderly pts. Conclusion: We observed a subsite-specific impact of age on treatment outcome: older NPC pts showed markedly worse survival than the younger counterparts, while in OPC pts such an effect was inconsistent. HPV status was confirmed to be a positive prognostic factor independently of age.

Long-term outcomes of laparoscopy-assisted distal gastrectomy with suprapancreatic nodal dissection for clinical stage I gastric cancer: a multicenter phase II trial (JCOG0703)

Laparoscopic gastrectomy has become a common surgical treatment for gastric cancer in eastern Asian countries. However, a large-scale prospective study to investigate the benefit of laparoscopy-assisted distal gastrectomy (LADG) regarding long-term outcomes has never been reported. We have already reported the short-term outcomes of this study. Here we report long-term outcomes as the secondary endpoints of this study after a 5-year follow-up period. This study comprised patients with clinical stage I gastric cancer who were able to undergo a distal gastrectomy. LADG with D1 plus suprapancreatic lymph node dissection was performed by credentialed gastric surgeons who had each conducted at least 30 LADG and 30 open gastrectomy procedures. The primary endpoint was the proportion of patients who developed either anastomotic leakage or pancreatic fistula. The secondary endpoints included overall survival and relapse-free survival. From November 2007 to September 2008, 176 eligible patients were enrolled, comprising 140 patients with pathological stage IA disease, 23 patients with pathological stage IB disease, 9 patients with pathological stage II disease, and 4 patients with pathological stage IIIA disease. No patients had recurrent disease, and three of the patients died within the follow-up period. The 5-year overall survival was 98.2% (95% confidence interval 94.4-99.4%) and the 5-year relapse-free survival was 98.2% (95% confidence interval 94.4-99.4%). The long-term outcomes of stage I gastric cancer patients undergoing LADG seem comparable to those of patients undergoing an open procedure, although this result should be confirmed by a randomized control trial. We have already completed accrual of 921 patients for a multicenter randomized phase III trial (JCOG0912) to confirm the noninferiority of LADG compared with open gastrectomy in terms of relapse-free survival.

Promoter hypermethylation of Wnt inhibitory factor-1 in patients with lung cancer: A systematic meta-analysis.

Background:Promoter hypermethylation of Wnt inhibitory factor-1 (WIF-1)—a tumor suppressor gene—has been detected in several types of human tumors. However, the association between WIF-1 promoter hypermethylation and lung cancer remains to be elucidated. Therefore, we conducted this study to evaluate the clinical significance of WIF-1 promoter hypermethylation in lung cancer.Methods:A comprehensive literature search was conducted to obtain eligible studies. The combined odds ratios (ORs) or hazard ratios and 95% confidence intervals were used to estimate the strength of associations.Results:A total of 8 eligible publications with 626 cases and 512 controls were included in our study. The combined ORs revealed that WIF-1 promoter hypermethylation was significantly higher in lung cancer than in controls (OR 10.53, P < 0.001). Moreover, WIF-1 promoter hypermethylation was significantly associated with smoking behavior (OR 1.88, P = 0.002). No significant correlation was found between WIF-1 promoter hypermethylation and sex status, age status, tumor stage, and pathological types in cancer. Multivariate analysis results indicated the absence of correlation between WIF-1 promoter hypermethylation and with relapse-free survival and overall survival. Subgroup analysis by sample type demonstrated that promoter hypermethylation of WIF-1 was significantly associated with an increased risk of lung cancer in the tissue (OR 7.89, P < 0.001), blood (OR 21.83, P = 0.034), and pleural effusion subgroups (OR 157.43, P = 0.001).Conclusions:Promoter hypermethylation of WIF-1 may play a crucial role in lung cancer carcinogenesis. It may be a noninvasive biomarker using blood or pleural effusion detection. WIF-1 promoter hypermethylation is correlated with smoking behavior, but not with sex status, age status, tumor stage, pathological types, and the prognosis of lung cancer patients in terms of relapse-free survival and overall survival. More investigations, including a larger number of subjects, are required to further confirm the findings of our analysis.

Reduced Expression of SMAD4 Is Associated with Poor Survival in Colon Cancer.

SMAD4 loss is associated with the development of metastases and poor prognosis. We evaluated expression of SMAD4 protein and its association with tumor characteristics, including biomarkers and outcome in terms of relapse-free survival and overall survival. We used 1,564 stage II/III colon cancer samples from PETACC-3 to evaluate SMAD4 expression by immunohistochemistry. SMAD4 protein expression was validated by assessing mRNA expression using available expression array data. SMAD4 expression was also studied on 34 adenomas and 10 colon cancer liver metastases with their primaries. Loss of SMAD4 immunoreactivity was defined as focal or diffuse. Cases without SMAD4 loss were subdivided into those with strong and weak expression. SMAD4 protein expression was informative in 1,381/1,564 cases. SMAD4 loss was found in 293/1,381 (21%) cases. Of 1,088 cases without SMAD4 loss (79%), 530 showed weak and 558 strong expression. SMAD4 loss occurred also in adenomas, but less extensively than in carcinomas. Liver metastases followed mostly the expression pattern of the primary tumor. SMAD4 loss, including weak expression, identified patients with poor survival in stage II as well as III and in both treatment arms. SMAD4 loss was less frequent in tumors with microsatellite instability and more frequent in those with loss of heterozygosity of 18q. We conclude that clonal loss of SMAD4 expression in adenomas, carcinomas, and liver metastases increases with disease progression. SMAD4 loss, and to a lesser extent weak expression, is strongly associated with poor survival regardless of stage. Clin Cancer Res; 22(12); 3037-47. ©2016 AACR.

Abstract P4-09-01: FGFR1 protein expression is associated with prognosis in primary breast cancer: A comprehensive analysis of gene copy number, mRNA and protein expression

Abstract Background: The Cancer Genome Atlas (TCGA) showed that copy number gain/amplification of FGFR1 was around 10% in primary breast cancer. FGFR1 gene amplification in breast cancer has been reported in some studies, more likely seen in ER-positive subtype. Several preclinical and clinical studies demonstrated that FGFR1 was one of novel targets of therapy for metastatic breast cancer. Previous studies suggested that aberrant FGFR1 expression was associated with poor prognosis, while there was no report that compared copy number aberration, mRNA and protein expression. The aim of this study is to analyze FGFR1 gene copy number, expression levels of FGFR1 mRNA and FGFR1 protein in ER-positive/HER2-negative primary breast cancer, and to examine the relationship between FGFR1 status and clinicopathological parameters including prognosis. Methods: The cohort of this study included 307 ER-positive/HER2-negative primary invasive breast cancer patients treated with standard care at Kumamoto University Hospital between June 2000 and January 2011. We performed a comprehensive analysis of FGFR1 at the levels of gene copy number, mRNA and FGFR1 protein expression analyzed by qPCR, qRT-PCR and immunohistochemistry, respectively. Results: FGFR1 gain/amplification was identified in 43 (14.0%) out of 307 patients. FGFR1 gain/amplification had significantly associated with higher nuclear grade (p=0.010). No correlations between FGFR1 mRNA expression levels and any clinicopathological factors were found. Expression levels of FGFR1 protein was positively associated with invasive tumor size (p=0.039). Modest positive correlations between these three (FGFR1 gene gain/amplification, expression levels of FGFR1 mRNA and FGFR1 protein) were found. The univariate analysis revealed that high FGFR1 protein expression was significantly related to poor prognosis (p=0.0019, HR: 2.63, 95%CI: 1.17-5.98) in terms of relapse-free survival (RFS) but not breast cancer-specific survival. The univariate analysis did not show that any factors except FGFR1 protein expression were significantly associated with RFS in this cohort. Conclusion: Expression levels of FGFR1 protein may be an independent prognostic factor in terms of RFS for ER-positive/HER2-negative breast cancer patients receiving standard care. Citation Format: Tomiguchi M, Yamamoto Y, Yamamoto-Ibusuki M, Yamaguchi R, Fujiki Y, Fujiwara S, Sueta A, Takeshita T, Inao T, Iwase H. FGFR1 protein expression is associated with prognosis in primary breast cancer: A comprehensive analysis of gene copy number, mRNA and protein expression. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-09-01.

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.