Superior Disease-free Survival Research Articles

Capecitabine-based chemotherapy in early-stage triple-negative breast cancer: a meta-analysis

IntroductionThe efficacy and safety of adjuvant capecitabine in early-stage triple-negative breast cancer remains undefined. A meta-analysis was conducted to elucidate whether capecitabine-based regimens could improve survival in early-stage triple-negative breast cancer (TNBC).MethodsThe current study searched Medline, Embase, Cochrane Library, Web of Science, and ClinicalTrials.gov proceedings up to 2023.9. Disease-free survival (DFS), overall survival (OS), and grade 3–4 adverse events (AEs) were assessed. Extracted or calculated hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were pooled.ResultsThe capecitabine-based regimens showed significant advantages in DFS (HR = 0.81, 95% CI: 0.73–0.90; P <.001) and OS (HR = 0.75, 95% CI: 0.65–0.87; P <.001) from 12 randomized controlled trials (RCTs) with 5,390 unselected participants. Subgroup analysis of DFS showed analogous results derived from patients with lymph node negative (HR = 0.68, 95% CI: 0.50–0.92; P = .006) and capecitabine duration no less than six cycles (HR = 0.73; 95% CI: 0.62-0.86; P <.001). Improvement of DFS in the addition group (HR = 0.77, 95% CI: 0.68–0.87; P <.001) and adjuvant setting (HR = 0.79, 95% CI: 0.70–0.89; P <.001) was observed. As to safety profile, capecitabine was associated with more frequent stomatitis (OR = 5.05, 95% CI: 1.45–17.65, P = .011), diarrhea (OR = 6.11, 95% CI: 2.12–17.56; P =.001), and hand–foot syndrome (OR = 31.82, 95% CI: 3.23–313.65, P = .003).ConclusionsAdjuvant capecitabine-based chemotherapy provided superior DFS and OS to early-stage TNBC. The benefits to DFS in selected patients with lymph node negative and the addition and extended duration of capecitabine were demonstrated.

Prognostic impact of reduced HER2 protein expression in post-neoadjuvant therapy resection specimens: A single institution experience and review of the literature

BackgroundRetesting for Human epidermal growth factor receptor-2 (HER2) in post-neoadjuvant therapy resection is variable, and data is conflicting regarding the prognostic significance of changes in HER2 expression pre and post therapy. MethodsWe identified 104 patients with localized HER2 IHC 3+ breast cancer who received neoadjuvant trastuzumab(T)/pertuzumab(P) containing chemotherapy at Yale Cancer Center between 2012 and 2022. Patients were divided into 3 cohorts by response and HER2 IHC in the residual disease: Cohort 1 pathologic complete response (pCR), Cohort 2 pre-treatment IHC 3+/post treatment IHC 1+/2+, and Cohort 3 pre-treatment IHC 3+/post-treatment IHC 3+. Kaplan-Meier survival analysis was performed to assess recurrence free survival at 36 months. ResultsThe overall pCR rate was 62.5% (65/104), while 37.5% (39/104) of patients had residual disease (RD). Among patients with RD, 58.9% (23/39) remained IHC 3+ and 41.1% (16/39) had reduced HER2 expression IHC1+ or 2+. In patients with HER2 IHC 3+ RD, 26% (6/23) developed local recurrence or distant metastasis while none of patients with post NAT HER2 IHC 1+ or 2+ RD had relapse (p = 0.0309). In patients with pCR, 6.15% (4/65) had recurrence. Kaplan-Meier survival analysis revealed superior disease-free survival in patients with reduced HER2 IHC expression compared to those with remained IHC 3+ (log rank p = 0.004). ConclusionWe conclude that reduced HER2 expression by IHC following neoadjuvant treatment was associated with lower recurrence rates in HER2 IHC 3+ breast cancer. If confirmed, RD HER2 IHC expression could be used as a prognostic biomarker to stratify patients in adjuvant trials and identify patients who may benefit from more intensive adjuvant therapy and post therapy surveillance.

Prediction of disease-free survival of N1/2 non-small cell lung cancer after adjuvant chemotherapy by the biomarker RPMB

No molecular biomarkers have been proven applicable in clinical practice to identify patients who can benefit from adjuvant chemotherapy in non-small cell lung cancer (NSCLC). In this study, we established a biomarker, RPMB, short for promotor methylation burden of DNA repair genes (DRGs), to identify the subgroup of patients who might benefit from adjuvant chemotherapy in NSCLC. Methylation profiles of 828 NSCLC primary tumors and their clinical information were downloaded from The Cancer Genome Atlas (TCGA) database. The RPMB for each patient after radical resection was calculated and its correlation with the prognosis of NSCLC was extensively investigated. DRGs of NSCLC were much more hypomethylated than the other genes (all p＜0.001). RPMB was defined as the ratio of methylated DRGs to the total number of all the DRGs. Patients with higher RPMB values tended to be nonsmokers, had adenocarcinoma, were female and had peripheral tumors. Subgroup analysis of forest plot among different clinical factors showed that high RPMB was significantly correlated to better disease-free survival (DFS) in pathologic N-positive patients after adjuvant chemotherapy (HR = 0.404, n = 62, p = 0.034). Notably, more superior DFS was exhibited in high RPMB NSCLCs with N1 nodal stage compared with those with low RPMB values (HR = 0.348, n = 47, p = 0.043). High RPMB might be used as a potential predictor to identify suitable N-positive NSCLC patients who can benefit from adjuvant chemotherapy after radical surgery.

Comparative Study of Long-Term Outcomes of Laparoscopic Liver Resection versus Radiofrequency Ablation for Single Small Hepatocellular Carcinoma Located in Left Lateral Segments of the Liver.

Background and Objectives: Laparoscopic liver resection (LLR) is now widely recognized as the primary surgical option for hepatocellular carcinomas (HCC) smaller than 3 cm located in the left lateral segment of the liver. Nevertheless, there is a scarcity of studies comparing laparoscopic liver resection with radiofrequency ablation (RFA) in these cases. Materials and Methods: We retrospectively compared the short- and long-term outcomes of Child-Pugh class A patients who underwent LLR (n = 36) or RFA (n = 40) for a newly diagnosed single small (≤3 cm) HCC located in the left lateral segment of the liver. Results: Overall survival (OS) was not significantly different between the LLR and RFA groups (94.4% vs. 80.0%, p = 0.075). However, disease-free survival (DFS) was better in the LLR group than in the RFA group (p < 0.001), with 1-, 3-, and 5-year DFS rates of 100%, 84.5%, and 74.4%, respectively, in the LLR group vs. 86.9%, 40.2%, and 33.4%, respectively, in the RFA group. The hospital stay was significantly shorter in the RFA group than in the LLR (2.4 vs. 4.9 days, p < 0.001). The overall complication rate was higher in the RFA group than in the LLR group (15% vs. 5.6%). In patients with an α-fetoprotein level of ≥20 ng/mL, the 5-year OS (93.8% vs. 50.0%, p = 0.031) and DFS (68.8% vs. 20.0%, p = 0.002) rates were greater in the LLR group. Conclusions: LLR showed superior OS and DFS compared to RFA in patients with a single small HCC situated in the left lateral segment of the liver. LLR can be considered for patients with an α-fetoprotein level of ≥20 ng/mL.

Real-world tolerance and outcomes of oxaliplatin-based adjuvant chemotherapy for stage III colon cancer-Does dose intensity matter?

Fluoropyrimidine and oxaliplatin-based adjuvant chemotherapy delivered as 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX), or capecitabine and oxaliplatin (CAPOX) is the standard of care for resected stage III colon cancer. Without randomized trial data, we compared real-world dose intensity, survival outcomes, and tolerability of these regimens. Records of patients treated with FOLFOX or CAPOX in the adjuvant setting for stage III colon cancer across four institutions in Sydney during 2006-2016 were reviewed. The relative dose intensity (RDI) of fluoropyrimidine and oxaliplatin of each regimen, disease-free survival (DFS), overall survival (OS), and incidence of grade ≥2 toxicities were compared. Characteristics of patients receiving FOLFOX (n=195) and CAPOX (n=62) were evenly matched. FOLFOX patients had a higher mean RDI for both fluoropyrimidine (85% vs. 78%, p<0.01) and oxaliplatin (72% vs. 66%, p=0.06). In spite of a lower RDI, CAPOX patients trended toward a better 5-year DFS (84% vs. 78%, HR=0.53, p=0.068) and similar OS (89% vs. 89%, HR=0.53, p=0.21) compared to the FOLFOX group. This difference was most pronounced in the high-risk (T4 or N2) group where 5-year DFS was 78% versus 67% (HR=0.41, p=0.042). Patients receiving CAPOX experienced more grade ≥2 diarrhea (p=0.017) and hand-foot syndrome (p<0.001) but not peripheral neuropathy or myelosuppression. In a real-world setting, patients who received CAPOX had similar OS rates when compared to those receiving FOLFOX in the adjuvant setting in spite of lower RDI. In the high-risk population, CAPOX appears to demonstrate a superior 5-year DFS over FOLFOX.

Early assessment of circulating exosomal lncRNA-GC1 for monitoring neoadjuvant chemotherapy response in gastric cancer.

The timing of surgery for patients with gastric cancer (GC) who undergo neoadjuvant chemotherapy (neoCT) was mainly guided by serial radiologic imaging. However, an earlier assessment was indispensable to avoid delayed treatment for nonresponders and excessive toxicity for responders. Our previous study has identified circulating extracellular vesicles-derived lncRNA-GC1 as a biomarker for early detection and monitoring progression of GC. However, the potential role of neoCT remains poorly understood. In this explorative biomarker analysis, we conducted a multi-cohort study to examine longitudinal levels of circulating extracellular vesicles-derived lncRNA-GC1 in 798 patients enrolled in the RESONANCE study (NCT01583361). Both circulating extracellular vesicles-derived lncRNA-GC1 and traditional gastrointestinal biomarkers were assessed at defined time nodes. Computed tomography (CT) scans were performed before treatment and 8-10 weeks and assessed based on the RECIST criteria. Circulating extracellular vesicles-derived lncRNA-GC1 could be detected in 96.3% of patients at baseline, and significant reductions were observed before cycle 2 (P<0.0001). Levels of circulating extracellular vesicles-derived lncRNA-GC1 showed a stronger correlation with tumor burden and exhibited earlier dynamic changes than the traditional gastrointestinal biomarkers during the first cycle of neoCT. Strong agreement was observed between circulating extracellular vesicles-derived lncRNA-GC1 response (reduction >50%) and radiographic response (Cohen's κ, 0.704). Importantly, circulating extracellular vesicles-derived lncRNA-GC1 maintained predictive value in two external cohorts. Patients with circulating extracellular vesicles-derived lncRNA-GC1 response showed superior disease-free survival [hazard ratio (HR), 0.6238; 95% CI, 0.4095-0.9501; P=0.0118] and overall survival (HR, 0.6131; 95% CI, 0.4016-0.9358; P=0.0090). Circulating extracellular vesicles-derived lncRNA-GC1 is an early marker of neoCT efficacy and predicts superior survival in GC patients treated with neoCT.

Should we change the treatment plan in early hepatocellular carcinoma with chronic kidney disease?

BackgroundChronic kidney disease (CKD) has been considered to be a poor prognostic factor for hepatocellular carcinoma (HCC). However, few studies have focused on early HCC and the impact of CKD on survival, which should be considered in curative treatment for early HCC.Materials and methodsPatients with BCLC stage 0/A were enrolled from 2009 to 2019. A total of 383 patients were divided into Control group and CKD group, based on estimated glomerular filtration rate. Overall survival (OS) and disease-free survival (DFS) of different treatments were determined using the Kaplan–Meier method.ResultsThe Control group had a significantly better OS than the CKD group (72.6 months vs. 56.7 months; p = 0.003). DFS was similar between the groups (62.2 months vs. 63.8 months, p = 0.717). In the Control group, the surgically treated (OP) group had significantly superior OS (65.0 months vs. 80.0 months, p = 0.014) and DFS (50.9 months vs. 70.2 months, p = 0.020) than the radiofrequency ablation-treated group. In the CKD group, the OP group showed a survival advantage in OS (70.6 months vs. 49.2 months, p = 0.004), while DFS was similar between treatment groups (56.0 months vs. 62.2 months, p = 0.097).ConclusionCKD should not be considered to be a poor prognostic factor in early HCC patients. Moreover, hepatectomy should be carried out in CKD patient with early HCC for better prognosis if feasible.

Neoadjuvant chemotherapy (NAC) versus adjuvant chemotherapy (AC) in patients with clinically node-positive upper tract urothelial cancer (UTUC) who underwent radical nephroureterectomy (RNU).

486 Background: UTUC is less common and associated with poorer stage-for-stage prognosis compared to urothelial bladder cancer. AC is regarded as a standard-of-care in high-risk UTUC based on superior disease-free survival compared to observation in the POUT trial, though fewer than 10% of patients in this trial had lymph node involvement.1 CheckMate 274 revealed lesser magnitude of benefit with adjuvant nivolumab in UTUC compared to bladder cancer on post hoc analysis.2 The preferred sequence of perioperative systemic therapy in node positive UTUC remains unclear. Methods: We queried the National Cancer Database for adult patients with clinically node positive (cTanyN1-3M0) UTUC diagnosed between 2004 and 2018. Patients were divided into two groups based on the perioperative treatment strategy - NAC or AC. Patients who did not undergo RNU were excluded from analyses. Fisher’s exact and Mann Whiney U tests were used to compare frequency distributions. Cox Proportional Hazards regression was employed for multivariate analysis of factors associated with overall survival. Models were adjusted for age, sex, race, income, educational level, clinical T stage, insurance status, and the Charlson Comorbidity Index. Results: A total of 862 patients were identified - 362 (42%) underwent NAC while 500 (58%) received AC. No significant differences were noted between the groups regarding age, sex, or insurance status. Patients with cT1-2 UTUC more often received NAC (27.9% vs 11.8%, P &lt;0.001) while those with cT3-4 disease more frequently received AC (38.9% vs 57.4%, p&lt;0.001). Rates of NAC vs AC were not significantly different based on clinical N stage (P = 0.35). Overall survival in the NAC group was significantly longer than the AC group (median of 47.1 vs. 20.2 months, log-rank P &lt; 0.001). On multivariable analysis, only the sequence of perioperative chemotherapy was independently predictive of overall survival (Hazard Ratio of 1.38 for AC, with 95% CI 1.14-1.68, P = 0.001). Conclusions: In this large retrospective analysis of outcomes among patients with clinically node positive UTUC who underwent RNU, NAC was associated with significantly longer overall survival compared to AC.

Ki67 increase after core needle biopsy associated with worse disease outcome in HER2-negative breast cancer patients

Ki67 would change after core needle biopsy (CNB) in invasive breast cancer. However, whether Ki67 alteration (ΔKi67) influences disease outcomes remains unclear. Here we aim to evaluate the prognostic value of ΔKi67. Patients with paired CNB and open excision biopsy (OEB) samples between January 2009 and June 2016 were retrospectively analyzed. ΔKi67 was calculated as the absolute difference between Ki67 level in CNB and OEB samples, and the median value of 5% was adopted to category patients into high- and low ΔKi67 groups. Disease-free survival (DFS) and overall survival (OS) were compared between different ΔKi67 groups. Overall, 2173 invasive breast cancer patients were included. Median Ki67 was higher in OEB than CNB samples: 25.00% versus 20.00% (P < 0.001). Axillary nodal status, STI, histological grading, and molecular subtype were independently associated with ΔKi67 (P < 0.05). In the whole population, patients with low ΔKi67 showed superior 5-year DFS (89.6% vs 87.0%, P = 0.026), but similar OS (95.8% vs 94.3%, P = 0.118) compared to those with high ΔKi67. HER2 status at surgery was the only significant factor interacting with ΔKi67 on both DFS (P = 0.026) and OS (P = 0.007). For patients with HER2-negative disease, high ΔKi67 was associated with worse 5-year DFS (87.2% vs 91.2%, P = 0.004) as well as impaired 5-year OS (93.9% vs 96.8%, P = 0.010). ΔKi67 had no significant impact on survival of HER2-positive patients. Ki67 increase after CNB was significantly associated with worse disease outcomes in HER2-negative, but not in HER2-positive patients, which warrants further study.

Adjuvant gemcitabine+S1 as adjuvant therapy for resectable pancreatic cancer: A real-world experience in a single-center retrospective study.

673 Background: Current clinical guidelines recommended adjuvant chemotherapy for all resectable pancreatic cancer after operation. The treatment choices included Gemcitabine monotherapy, S1 monotherapy, Gemcitabine+Capecitabine or mFOLFIRINOX. However, the role of Gemcitabine+S1 combination as adjuvant chemotherapy was not clear. We aimed to investigate the benefit of adjuvant chemotherapy with Gemcitabine+S1 in resectable pancreatic cancer. Methods: We retrospectively reviewed the medical records of patients with resectable pancreatic cancer who underwent curative surgery and adjuvant treatments at Taichung Veterans General Hospital (Taichung, Taiwan) between January 2014 and July 2021. The clinical characteristics and outcomes were analyzed. Results: A total of 102 patients received operation were analyzed. 73 patients received adjuvant chemotherapy, including 35 patients received Gemcitabine+S1 combination. Median follow-up period was 22.7 months. The disease-free survival (DFS) and overall survival (OS) among patients received Gemcitabine+S1 combination were 15.5 months and 32.8 months, respectively. Compared with Gemcitabine monotherapy, there was a trend of superior DFS (10.5 months in Gemcitabine monotherapy, p = 0.071), but no OS benefits (23.1 months, p = 0.441) with Gemcitabine+S1 combination. When focusing on more advanced disease status (stage II and III), the Gemcitabine+S1 combination had statistically significant longer DFS (14.7 months vs. 8.6 months; p = 0.015) and OS (30.3 months vs. 21.7 months; p = 0.036), compared with Gemcitabine monotherapy. Conclusions: In our retrospective study, Gemcitabine+S1 combination could be another choice for resectable pancreatic cancer, especially in more advanced disease (stage II and III). Further result from prospective study (JSAP-04) is pending.

Effect of Different Durations of Adjuvant Capecitabine Monotherapy on the Outcome of High-Risk Stage II and Stage III Colorectal Cancer: A Retrospective Study Based on a CRC Database.

(1) Background: The duration of adjuvant chemotherapy recommended by the NCCN guidelines is 6 months. However, patients are not compliant with intravenous chemotherapy for many reasons; therefore, one approach is to obtain a survival benefit by prolonging the duration of capecitabine monotherapy. (2) Methods: A total of 355 qualified colorectal cancer (CRC) patients from January 2010 to December 2020 at West China Hospital of Sichuan University were selected to receive capecitabine monotherapy for 6−9 months and >12 months. The main endpoints were overall survival (OS) and disease-free survival (DFS). (3) Results: Among stage III patients, in the >12 months (12M) and 6−9 months (6M) groups, the 5-year DFS rates were 80.7%% and 66.8%, respectively, and the 5-year OS rates were 94.7%% and 88.8%, respectively. Among high-risk stage II patients, in the >12 months (12M) and 6−9 months (6M) groups, the 5-year DFS rates were 81.5% and 78.6%, respectively, and the 5-year OS rates were 93.1% and 84.2%, respectively. (4) Conclusions: Twelve months of chemotherapy demonstrated superior OS and DFS to that of six months in the stage III group but showed no difference in the high-risk stage II group. The better OS and DFS observed in the 12-month treatment period could be of value in selected cases.

Comparison of survival outcomes following radiotherapy versus radical hysterectomy in patients with stage IIA cervical squamous cell carcinoma

This study explored the differences in survival outcomes of cervical squamous cell carcinoma (SCC) patients diagnosed with stage IIA who underwent radical hysterectomy (RH) versus radiotherapy (RT). Eligible stage IIA cervical SCC cases were screened from the C4 database. They were divided into RH and RT groups based on their treatments and in a 1:2 ratio utilizing propensity score matching (PSM). Their 5-year overall survival (OS) and disease-free survival (DFS) before and after PSM were compared. Before PSM analysis, the results showed that patients from the RT group (n = 421) had significantly poorer 5-year OS and DFS rates compared with the RH group (n = 761) (OS: 77.2%vs. 85.6%, p &lt; 0.001, HR = 1.789; DFS: 74.9% vs. 80.0%, p = 0.006, HR = 1.447). After stratification in a 1:2 ratio, PSM analysis results showed that the 5-year OS and DFS rates of stage IIA1 patients from the RT group (n = 226) were significantly poorer than the RH group (n = 429) (OS: 78.1% vs. 87.2%, p &lt; 0.001, HR = 2.203; DFS: 78.2% vs. 83.7%, p = 0.011, HR = 1.681), while no significant difference in 5-year OS and DFS rates were observed between the RT (n = 173) and RH (n = 266) groups (OS: 75.2% vs. 83.8%, p = 0.054; DFS: 71.4% vs. 79.5%, p = 0.070) of stage IIA2 patients. RH was associated with better OS and DFS outcomes than RT in cervical SCC patients diagnosed with stage IIA disease. Subgroup analyses showed that RH had superior OS and DFS benefits than RT in stage IIA1 cases, while no significant difference in survival was observed for stage IIA2 patients.

Immune-based classification of HPV-associated oropharyngeal cancer with implications for biomarker-driven treatment de-intensification.

There is significant interest in treatment de-escalation for human papillomavirus-associated (HPV+) oropharyngeal squamous cell carcinoma (OPSCC) patients given the generally favourable prognosis. However, 15-30% of patients recur after primary treatment, reflecting a need for improved risk-stratification tools. We sought to develop a molecular test to risk stratify HPV+ OPSCC patients. We created an immune score (UWO3) associated with survival outcomes in six independent cohorts comprising 906 patients, including blinded retrospective and prospective external validations. Two aggressive radiation de-escalation cohorts were used to assess the ability of UWO3 to identify patients who recur. Multivariate Cox models were used to assess the associations between the UWO3 immune class and outcomes. A three-gene immune score classified patients into three immune classes (immune rich, mixed, or immune desert) and was strongly associated with disease-free survival in six datasets, including large retrospective and prospective datasets. Pooled analysis demonstrated that the immune rich group had superior disease-free survival compared to the immune desert (HR=9.0, 95% CI: 3.2-25.5, P=3.6×10-5) and mixed (HR=6.4, 95% CI: 2.2-18.7, P=0.006) groups after adjusting for age, sex, smoking status, and AJCC8 clinical stage. Finally, UWO3 was able to identify patients from two small treatment de-escalation cohorts who remain disease-free after aggressive de-escalation to 30Gy radiation. With additional prospective validation, the UWO3 score could enable biomarker-driven clinical decision-making for patients with HPV+ OPSCC based on robust outcome prediction across six independent cohorts. Prospective de-escalation and intensification clinical trials are currently being planned. CIHR, European Union, and the NIH.

Characterization of Survival Outcomes and Clinical and Molecular Modulators in Adult Patients with Core-Binding Factor Acute Myeloid Leukemia (CBF-AML) Treated with Hidac Consolidation: An Alliance Legacy Study

Introduction CBF-AML is a specific disease entity defined by the presence of either t(8;21)(q22q22)RUNX1-RUNX1T1, or inv(16)(p13.1q22) or t(16;16)(p13.1;q22) creating the CBFB-MYH11 fusion gene, and is associated with a relatively favorable prognosis. Yet, outcomes are variable and relapse occurs in ~50% of patients (pts). Whereas several clinical and molecular features have been suggested to modulate survival, consensus data are sparse. Moreover, there is persistent controversy about the optimal dose intensity of cytarabine consolidation, which complicates interpretation of correlative studies with respect to outcome associations. Thus, we analyzed outcomes of a large cohort of CBF-AML pts treated with high-dose cytarabine (HiDAC) consolidation with respect to cytogenetic subtypes and co-existing molecular features. We analyzed clinical and molecular characteristics and outcomes of 304 pts with CBF-AML aged 18-59 years [y; inv(16)/t(16;16), n=186; t(8;21), n=118] who were similarly treated and achieved a complete remission upon standard cytarabine/anthracycline induction followed by HiDAC on frontline Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology protocols between 1986-2016. All pts had centrally reviewed cytogenetics and samples from 136 pts underwent comprehensive molecular profiling of 80 AML-associated genes for association studies. Kaplan-Meier method was used to estimate probabilities of disease-free survival (DFS) and overall survival (OS), and the log-rank test evaluated differences between survival distributions. Cox proportional hazard regression analyses was used for DFS and OS univariable and multivariable modeling. Results Thirty-eight percent of pts relapsed and 69% were alive 5y after diagnosis (median OS): 12.5y with median follow-up of 8.6y. Outcomes of t(8;21) and inv(16)/t(16;16) AML were similar; relapse rates: 35% vs 40%, 5y OS rates, 64% vs 72%, respectively. Although outcome of pts with inv(16) was not significantly different from outcome of t(16;16) pts, the latter had, by trend, a superior DFS (5y rates, 75% vs 47%, P=0.07); their OS was not significantly different (5y rates, 81% vs 64%, P=0.24). As secondary cytogenetic abnormalities are common and impact on survival has yielded controversial results, we next analyzed the impact on outcomes of our pt cohort. None of the frequently observed secondary abnormalities [i.e., loss of X or Y chromosomes, +8, or del(9q) in t(8;21) pts and +22 or +8 in inv(16)/t(16;16) pts] affected the outcomes of CBF-AML pts we analyzed, which contrasts with some previous reports. The presence of a complex karyotype also did not negatively affect the favorable survival of CBF-AML pts. Next, we assessed the impact of recurrent gene mutations on pt outcomes. While KIT mutations have previously been shown to confer inferior survival, our data suggest that presence of a KIT mutation negatively affects DFS of both t(8;21) and inv(16)/t(16;16) AML pts [5y rates, t(8;21) 36% vs 67%, P= 0.03; inv(16)/t(16;16), 21% vs 61%, P<0.001], and also OS in inv(16)/t(16;16) pts (5y rates, 52% vs 74%, P=0.04). Co-existing FLT3-TKD mutations were almost exclusively found in inv(16)/t(16;16) in 16/18 cases. Though a negative prognostic impact of FLT3-TKD has been suggested, this was not found in our cohort (5y rates, DFS, 56% vs 55%, P=0.93; OS, 78% vs 68%, P=0.69). Furthermore, neither the presence of NRAS or KRAS mutations affected survival outcomes. In multivariable analyses for OS, a higher percentage of peripheral blood blasts was the only feature associated with inferior survival [HR, 1.14 (95% CI, 1.04-1.25), P=0.004]. Conclusions Our analysis of a large cohort of younger CBF-AML pts treated on frontline protocols with 7+3-based induction therapy and HiDAC consolidation, showed though these pts are considered favorable risk, they demonstrate varying long-term survival. Clinically, the presence of high blast count at time of diagnosis, was a strong adverse prognosticator for inferior survival. With respect to recurrent co-occurring cytogenetic aberrations or gene mutations, only KIT mutations associated with inferior survival in pts with t(8;21) and in those with inv(16)/t(16;16). Support: U10CA180821, U10CA180882, U24CA196171; https://acknowledgments.alliancefound.org. Clinicaltrials.gov: NCT00048958(CALGB 8461), NCT00899223(CALGB 9665), NCT00900224(CALGB 20202) *co-senior authors

Association of hematologic response and assay sensitivity on the prognostic impact of measurable residual disease in acute myeloid leukemia: a systematic review and meta-analysis.

Measurable residual disease (MRD) is associated with relapse and survival in acute myeloid leukemia (AML). We aimed to quantify the impact of MRD on outcomes across clinical contexts, including its association with hematologic response and MRD assay sensitivity. We performed systematic literature review and meta-analysis of 48 studies that reported the association between MRD and overall survival (OS) or disease-free survival (DFS) in AML and provided information on the MRD threshold used and the hematologic response of the study population. Among studies limited to patients in complete remission (CR), the estimated 5-year OS for the MRD-negative and MRD-positive groups was 67% (95% Bayesian credible interval [CrI], 53-77%) and 31% (95% CrI, 18-44%), respectively. Achievement of an MRD-negative response was associated with superior DFS and OS, regardless of MRD threshold or analytic sensitivity. Among patients in CR, the benefit of MRD negativity was highest in studies using an MRD cutoff less than 0.1%. The beneficial impact of MRD negativity was observed across MRD assays and timing of MRD assessment. In patients with AML in morphological remission, achievement of MRD negativity is associated with superior DFS and OS, irrespective of hematologic response or the MRD threshold used.

Upregulated Ubiquitin D is a Favorable Prognostic Indicator for Rectal Cancer Patients Undergoing Preoperative Concurrent Chemoradiotherapy.

PurposeFor locally advanced rectal cancer, neoadjuvant concurrent chemoradiotherapy (CCRT) allows tumor downstaging and makes curative radical proctectomy possible. However, we lack a genetic biomarker to predict cancer prognosis or treatment response. We investigated the association between ubiquitin D (UBD) expression and clinical outcomes in rectal cancer patients receiving CCRT.Patients and MethodsWe analyzed the genes associated with the protein modification process (GO:0036211) and identified the UBD gene as the most relevant among the top 7 differentially expressed genes associated with CCRT resistance. We collected tissue specimens from 172 rectal cancer patients who had received CCRT followed by a curative proctectomy. We examine the relationship between UBD expression and patient characteristics, pathological findings, and patient survival, such as metastasis-free survival (MeFS) and disease-specific survival.ResultsUpregulated UBD expression was associated with lower pre-CCRT tumor T stage (P = 0.009), lower post-CCRT tumor T stage (P < 0.001), lower post-CCRT nodal stage (P < 0.001), less vascular invasion (P = 0.015), and better tumor regression (P < 0.001). Using univariate analysis, we found that high UBD expression was correlated with better disease-free survival (DFS) (P < 0.0001), local recurrence-free survival (LRFS) (P < 0.0001) and MeFS (P < 0.0001). Moreover, multivariate analysis demonstrated that high UBD expression was associated with superior DFS (P < 0.001), LRFS (P = 0.01), and MeFS (P = 0.004).ConclusionUBD upregulation was linked to better clinical prognosis, favorable pathological features, and good treatment response in rectal cancer patients undergoing CCRT. These results suggest UBD is a biomarker for rectal cancer.

Long-term Outcomes of Local and Metastatic Small Cell Carcinoma of the Urinary Bladder and Genomic Analysis of Patients Treated With Neoadjuvant Chemotherapy.

Small cell carcinoma of the bladder (SCCB) is a rare variant of bladder cancer with poor outcomes. We evaluated long-term outcomes of nonmetastatic (M0) and metastatic (M1) SCCB and correlated pathologic response with genomic alterations of patients treated with neoadjuvant chemotherapy (NAC). Clinical history and pathology samples from SCCB patients diagnosed at our institution were reviewed. One hundred and ninety-nine SCCB patients were identified. (M0: 147 [74%]; M1: 52 [26%]). Among M0 patients, 108 underwent radical cystectomy (RC) (NAC: 71; RC only: 23; adjuvant chemotherapy: 14); 14 received chemoradiotherapy; the rest received chemotherapy alone or no cancer-directed therapy. RC-only patients had a median follow-up of 9.1 years, and median disease-free survival (DFS) and overall survival (OS) were 1.1 and 1.2 years, respectively. NAC patients had pathologic response (<pT2pN0) and pathologic complete response (pT0pN0) rates of 48% and 38%, respectively, with median follow-up of 7.2 years, and median DFS and OS of 5.6 and 14.5 years, respectively. NAC responders (<ypT2N0) had superior median DFS (14.5 vs. 0.6 years, hazard ratio [HR] 0.24, P< .001) and OS (14.5 vs. 2.5 years, HR 0.31, P = .002). DFS rates for responders and nonresponders were 76% and 27% at 5 years, and 71% and 23% at 10 years, respectively. Local and central nervous system recurrences were infrequent. Median progression-free survival (PFS) and OS for M1 disease were 6.9 and 10.3 months, respectively. Genomic profiling was performed on 47 NAC patients. Loss of ERCC2 function was significantly enriched among those with pathologic complete response to NAC (mutations present in 50% of pathologic complete responders vs. 15% nonresponders, P = .045). M0 SCCB is chemo-sensitive and patients have excellent long-term survival following response to NAC. Patients with M1 disease have poor survival despite systemic therapy. Loss-of-function mutations of ERCC2 were associated with pathologic complete response to NAC.

Impact of substage and histologic type in stage I ovarian carcinoma survival: a multicenter retrospective observational study

ObjectiveThis international study aimed to investigate the impact of substage, histological type and other prognostic factors on long-term survival for stage I ovarian carcinoma.MethodsOur study was a retrospective multicenter cohort...

669P Neoadjuvant chemotarget therapy with cetuximab, docetaxel, and cisplatin in locally advanced resectable oral/oropharygeal squamous cell carcinoma: A multicenter phase III trial (Eagle trial)

The role of neoadjuvant therapy in head and neck cancer is controversial, this trial aimed to evaluate the efficacy of neoadjuvant chemotarget therapy with docetaxel, cisplatin, and cetuximab (TPE) followed by surgery and postoperative radiotherapy (S+PORT) versus S+PORT in patients with locally advanced resectable oral/oropharyngeal squamous cell carcinoma (OOPSCC). In this open-label, multicenter, randomized (1:1 ratio), phase 3 trial (NCT01434394), the patients with stage III or IVA OOPSCC received neoadjuvant TPE followed by S+PORT or S+PORT. Two cycles of neoadjuvant TPE (cetuximab 250mg/m2 on d1, d8, d15; cisplatin 75mg/m2 on d1; and docetaxel 75mg/m2 on d1) was performed with initial cetuximab 400mg/m2. The end points included pCR (pathologic complete response), overall survival (OS), disease free survival (DFS), loco-regional recurrence free survival (LRFS), distant metastasis free survival (DMFS), and disease-special survival (DSS). Of the 284 patients enrolled in this trial, 228 completed all treatment including 81.2% (112/138) in the TPE arm and 85.3% (126/136) in control arm. The incidence of grade 3 or 4 treatment related AEs was 42.0% in the TPE arm and 44.9% in the control arm. The ORR and pCR rate of neoadjuvant therapy was 43.4% (59/136) and 10.5% (14/133). After a median follow-up of 100 months, there was no significant difference in OS (HR=1.14, P=0.43), DFS (HR=1.16, P=0.35), LRFS (HR=1.18, P=0.3), DMFS (HR=1.19, P=0.28), DSS (HR=1.02, P=0.93) between the TPE and control arms. Among the patients completed all treatment, the difference was neither significant between the TPE and control arms, with OS (HR=0.91, P=0.61), DFS (HR=0.96, P=0.82), LRFS (HR=0.99, P=0.97), DMFS (HR=0.98, P=0.89), DSS (HR=0.92, P=0.69). In the TPE arm, patients with pCR had superior OS (HR=0.38, P=0.03) and DFS (HR=0.31, P=0.01) compared with non-pCR patients. Our study failed to demonstrate that adding neoadjuvant TPE therapy improves survival in patients with locally advanced resectable OOPSCC, while those patients with pCR have survival benefit from neoadjuvant TPE therapy.

Haplo-Peripheral Blood Stem Cell Plus Cord Blood Grafts for Hematologic Malignancies Might Lead to Lower Relapse Compared with Haplo-Peripheral Blood Stem Cell Plus Bone Marrow Grafts

To compare the outcomes between peripheral blood stem cell (PBSC)+cord blood and PBSC+bone marrow (BM) grafts in the setting of haploidentical donor (HID) transplantation, 110 patients were enrolled in this retrospective study, including 54 recipients of haplo-PBSC+cord transplants and 56 recipients of haplo-PBSC+BM transplants. Chimerism analyses revealed that by day 30 post-transplantation, 94.3% of surviving patients in the haplo-PBSC+cord group had achieved full haploidentical chimerism and 5.7% had <10% cord chimerism, whereas 100% of surviving patients in the haplo-PBSC+BM group had achieved full donor chimerism. The cumulative incidence of platelet engraftment at 30 days was 92.6% in the haplo-PBSC+cord group versus 89.3% in the haplo-PBSC+BM group (P =.024), that of grade II-IV acute graft-versus-host disease (GVHD) at 100 days was 31.5% versus 48.2% (P =.060), and 1-year relapse was 13.0% versus 25.0% (P =.027), nonrelapse mortality was 9.3% versus 12.5% (P =.76), disease-free survival (DFS) was 77.7% versus 62.5% (P =.028), and overall survival (OS) was 81.4% versus 69.6% (P =.046). Multivariate analysis identified haplo-PBSC+cord transplantation as a protective factor for relapse (hazard ratio [HR], .31; P =.007), DFS (HR, .40; P =.007), and OS (HR, .44; P =.016). Overall, haplo-PBSC+cord transplantation led to faster platelet engraftment, lower relapse, and superior DFS and OS compared with haplo-PBSC+BM transplantation and thus might be a better transplant mode in the setting of HID transplantation.