Surveillance, Epidemiology, And End Results Cohort Research Articles

Abstract P2-07-12: A prognostic prediction nomogram (PDIDC) for breast Paget's disease with infiltrating ductal carcinoma patients: A SEER cohort analysis

Abstract Purpose The aim of the study was to develop a specific nomogram for prediction of prognosis for breast Paget's disease with infiltrating ductal carcinoma (PD-IDC) patients. Patients and Methods Patients data were obtained by the Surveillance, Epidemiology, and End Results (SEER) program (N=2502). Study outcome was Breast Cancer Specific Survival (BCSS). Cox proportional hazards model was applied to identify risk factors and develop predictive model. For internal validation, discrimination was calculated with the concordance index (C-index) using the bootstrap method and calibration assessed. Results NPI classification, skin symptom, tumor site and age showed significant association with BCSS(table.1)and were used to build the PDIDC nomogram and to calculate risk score. PDIDC nomogram's C-index (0.791, 95%CI 0.783-0.818) showed better discrimination power than NPI classification (0.691, 95%CI, 0.650-0.735, P= 0.000) and AJCC staging (0.718, 95%CI, 0.695-0.741, P=0.000). Patients were divided into high-risk (1882/2502, 75.21%) and low-risk (620/2502, 24.78%) subgroups with the optimal cut-off of risk scores (4.28). The total BCSS of low-risk subgroup was 77.8% (95%CI 74.4%-81.4%) vs. 31.1% (95%CI 19.4-49.8) of high-risk group (P=0.000). Bootstrap internal validation demonstrated an average C-index of 0.739 (95% CI, 0.692-0.746). The nomogram calibration was validated to be accurate in predicting 5-year and 10-year survival. Variable finally selected for risk predicted model.PredictorHazard RatioP Value95% CINPI classification Good1 Moderate2.170.0001.51-3.14Poor7.260.0004.96-10.63Skin symptom Without1 With1.760.0001.34-2.32Tumor site Centrally located1 Non-centrally located1.250.0421.07-1.56Age*1.010.0001.01-1.03* Continuous variable. Conclusion Utilizing NPI classification, skin symptom, tumor site and age, we developed the PDIDC nomogram to predict the 5-year and 10-year BCSS of breast PD-IDC patients. Citation Format: Tan L, Chen K, Jiang WG, You N, Wang Y, Sanders A, Liang G, Liu Z, Ling Y, Zhong W, Tian Z, Gong C. A prognostic prediction nomogram (PDIDC) for breast Paget's disease with infiltrating ductal carcinoma patients: A SEER cohort analysis [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 P2-07-12.

Changing patterns and survival improvements of young breast cancer in China and SEER database, 1999-2017.

ObjectiveBreast cancer in young females was usually considered more aggressive and requires aggressive therapy. We investigated whether early detection and improved treatments changed the patterns of characteristics, management and outcomes of young breast cancer patients over time.MethodsFemales under 40 years of age diagnosed with breast cancer during the periods 1999−2017 and 1999−2015 were identified in the Fudan University Shanghai Cancer Center (FUSCC) and the population-based Surveillance, Epidemiology, and End Results (SEER) registry, respectively. Clinicopathologic characteristics and treatment information were collected. Patients diagnosed before 2013 were followed up.ResultsThe proportions of young breast cancer patients were 15.0% and 5.3% in the FUSCC and SEER cohorts, respectively. In the FUSCC cohort, there was a significant increase in the proportion of ductal carcinoma in situ (DCIS) (from 8.8% to 16.9%; P<0.0001) and it remained stable in SEER cohort. The proportion of T1-stage tumors increased dramatically in the FUSCC cohort (from 35.3% to 41.9%; P=0.008), whereas it decreased in SEER cohort (from 42.4% to 33.0%; P<0.0001). The percentage of estrogen receptor (ER)-positive cancers was consistently increased in both the invasive ductal carcinoma (IDC) and DCIS patients in the two cohorts. Breast-conserving surgery and immediate implant reconstruction after mastectomy both exhibited increased use over time in the FUSCC cohort. Both the FUSCC and SEER cohorts showed a significantly better prognosis in the recent time period. ConclusionsWith the increased early-stage and ER-positive diseases in young patients as well as better systemic treatment strategies, improved survival has been observed in recent years. There has been a substantial de-escalation in surgical therapies in young breast cancer patients.

Important Therapeutic Considerations in T1b Penile Cancer: Prognostic Significance and Adherence to Treatment Guidelines.

The clinical implications and contemporary management of T1b penile cancer are unknown. National treatment guidelines advocate surgical lymph node examination (SLNE) for T1b disease. The aim of this study was to evaluate the prognosis of T1b disease and adherence to corresponding treatment guidelines. We analyzed 296 patients from two academic centers, and 1263 patients from the Surveillance, Epidemiology, and End Results (SEER) registry (median follow-up 48.3 and 21months, respectively). Multivariate Cox and Fine-Gray regressions were applied for penile cancer-specific survival (PCSS) analyses. In the academic center cohort, 28.3% of T1 patients had T1b disease, all of whom underwent SLNE. Nodal metastases were detected in 86.7% of T1b patients and 13.2% of T1a patients (p < 0.001). Using T1a as a reference, PCSS was significantly poorer in the T1b patients, with an adjusted hazard ratio (aHR) of 4.10 (p = 0.03). In the SEER cohort, 16.8% of T1 patients were classified as T1b. SLNE was performed in 21.7% of the T1b patients versus 38.2% of the T2 patients (p = 0.002). The probability of nodal metastases was 2.23-fold higher in T1b patients than in T1a patients (p < 0.001). In clinical N0M0 patients without SLNE, compared with T1a disease, T1b was associated with an aHR of 4.40 and a subdistribution HR of 4.53 for PCSS (both p = 0.003). T1b penile cancer is strongly associated with nodal metastases and adverse PCSS, and is poorly managed according to guidelines recommended in the nationwide registry.

Evaluating the Effect of Lymph Node Status on Survival in Large Colon Cancer.

Objective: This study aimed to investigate the effect of lymph node status on survival in large colon cancer.Methods: In the first cohort, patients diagnosed with non-metastatic colon cancer (N = 176,834) were identified from the Surveillance, Epidemiology, and End Results (SEER) database between January 1988 and December 2005. Further analyses were conducted in the other cohort (N = 855) from the Fudan University Shanghai Cancer Center (FUSCC) database.Results: In the SEER cohort, CSS differences increased as the tumor enlarged until a threshold tumor size group (tumor measuring 7–8 cm, P < 0.001) was reached, in which node positivity showed the maximum negative effect on CSS; multivariate Cox analyses showed that tumors measuring 7–8 cm presented a significant lower risk of cancer-specific mortality compared with those measuring 2–4 cm [hazard ratio (HR) = 1.087; 95% confidence interval (CI) = 1.014–1.165, P = 0.018]. In the FUSCC cohort, N0 tumors measuring 21–40 mm presented a higher risk of recurrence compared with those measuring 41–80 mm.Conclusions: Mortality risk of node positivity increased as tumor enlarged until a threshold tumor size (tumor size of 7–8 cm) was reached, mainly resulting from larger tumors without lymph node involvement being a surrogate for biologically indolent colon cancer of tumor recurrence. Our study could provide both researchers and clinicians a better understanding of colon cancer biology.

Proposal and validation of a modified staging system to improve the prognosis predictive performance of the 8th AJCC/UICC pTNM staging system for gastric adenocarcinoma: a multicenter study with external validation

BackgroundThe 8th edition of the American Joint Committee on Cancer/Union for International Cancer Control (AJCC/UICC) pathological tumor-node-metastasis (pTNM) staging system may have increased accuracy in predicting prognosis of gastric cancer due to its important modifications from previous editions. However, the homogeneity in prognosis within each subgroup classified according to the 8th edition may still exist. This study aimed to compare and analyze the prognosis prediction abilities of the 8th and 7th editions of AJCC/UICC pTNM staging system for gastric cancer and propose a modified pTNM staging system with external validation.MethodsIn total, clinical data of 7911 patients from three high-capacity institutions in China and 10,208 cases from the Surveillance, Epidemiology, and End Results (SEER) Program Registry were analyzed. The homogeneity, discriminatory ability, and monotonicity of the gradient assessments of the 8th and 7th editions of AJCC/UICC pTNM staging system were compared using log-rank χ2, linear-trend χ2, likelihood-ratio χ2 statistics and Akaike information criterion (AIC) calculations, on which a modified pTNM classification with external validation using the SEER database was proposed.ResultsConsiderable stage migration, mainly for stage III, between the 8th and 7th editions was observed in both cohorts. The survival rates of subgroups of patients within stage IIIA, IIIB, or IIIC classified according to both editions were significantly different, demonstrating poor homogeneity for patient stratification. A modified pTNM staging system using data from the Chinese cohort was then formulated and demonstrated an improved homogeneity in these abovementioned subgroups. This staging system was further validated using data from the SEER cohort, and similar promising results were obtained. Compared with the 8th and 7th editions, the modified pTNM staging system displayed the highest log-rank χ2, linear-trend χ2, likelihood-ratio χ2, and lowest AIC values, indicating its superior discriminatory ability, monotonicity, homogeneity and prognosis prediction ability in both populations.ConclusionsThe 8th edition of AJCC/UICC pTNM staging system is superior to the 7th edition, but still results in homogeneity in prognosis prediction. Our modified pTNM staging system demonstrated the optimal stratification and prognosis prediction ability in two large cohorts of different gastric cancer populations.

Microsatellitosis in Patients with Melanoma.

Microsatellitosis (mS) in melanoma has been considered a marker of unfavorable tumor biology, leading to the current American Joint Committee on Cancer staging of IIIB/C/D disease, despite few investigative studies of this entity limited by the small sample sizes and incomplete nodal microstaging. We sought to better characterize outcomes and prognostic factors in a multi-institutional cohort of patients with mS and nodal microstaging. The Sentinel Lymph Node Working Group cohort included 414 mS patients who underwent sentinel lymph node (SLN) biopsy. Cox regression analysis was used to evaluate the prognostic significance of established clinicopathologic characteristics. Melanoma-specific survival (MSS) of patients with mS was compared with 3002 similarly staged patients from the Surveillance, Epidemiology, and End Results (SEER) Program registry. The median age of the mS cohort was 64.9years; 39.6% were female. Median thickness was 3mm, 40.6% of cases were ulcerated, and the SLN positivity rate was 46.7%. Increasing thickness, male sex, and SLN positivity were significantly associated with poorer MSS. Stage IIIB/C/D 5-year MSS rates were 86.3% (95% confidence interval [CI] 79.4-93.3%), 54.1% (95% CI 45.4-59.7%), and 44.2% (95% CI 25.4-63.0%), respectively. MSS survival for the stage IIIB mS cohort was significantly better than a similarly staged SEER cohort (5-year MSS of 70.1%, 95% CI 66.0-74.2%), while no significant difference was observed for the stage IIIC or D cohorts. SLN metastases are common and are a significant prognostic factor in patients with mS. Survival in stage IIIB patients with mS was considerably more favorable than their stage would otherwise suggest, which has important implications for decisions regarding adjuvant therapy for patients with mS.

Sex-Dependent Staging in Non–Small-Cell Lung Cancer; Analysis of the Effect of Sex Differences in the Eighth Edition of the Tumor, Node, Metastases Staging System

IntroductionNon–small-cell lung cancer (NSCLC) has disproportionately negative outcomes in men compared with women. The importance of the relationship between sex and tumor, node, metastases (TNM) staging system remains unknown. The objective of this study was to investigate the effect of sex on NSCLC survival for each stage in the eighth edition of the TNM staging system in NSCLC. Patients and MethodsTwo cohorts treated surgically with curative intent between 2000 and 2010 were analyzed. The primary cohort was from Australia with a second population set from the Surveillance, Epidemiology, and End Results (SEER) database. Univariate and multivariate analyses of putative and validated prognostic factors were undertaken to investigate sex-dependent prognostication with detailed analyses of sex differences in each TNM stage. The primary outcome was disease-specific survival (DSS) at 5 years. ResultsInclusion criteria were met by 555 patients in the Australian cohort, 335 men (60.4%) and 220 (39.6%) women; and 47,706 patients from the SEER cohort, 24,671 men (51.7%) and 23,035 women (48.3%). Five-year DSS was significantly worse for men in multivariate analyses for the Australian (hazard ratio [HR], 1.44; 95% confidence interval [CI], 1.04-1.98; P = .026) and SEER (HR, 1.24; 95% CI, 1.20-1.28; P < .001) cohorts. Detailed analysis of TNM stage sex differences revealed a consistent pattern of men having worse survival than women across stages in both cohorts. ConclusionThe poorer survival in men with NSCLC presents research and clinical communities with an important challenge. This study’s findings suggest that for men and women diagnosed with NSCLC, and managed surgically, stage-specific outcomes should be quoted separately and consideration to a rapid prognostic score with sex combined with staging as a key element.

21-Gene Recurrence Score Assay Predicts Benefit of Post-Mastectomy Radiotherapy in T1-2 N1 Breast Cancer.

Purpose: Post-mastectomy radiotherapy (PMRT) yields improvements in both locoregional control and overall survival (OS) for women with T1-2 N1 breast cancer. The value of PMRT in this population has been questioned given advances in systemic therapy. The 21-gene recurrence score (RS) assay was evaluated as a predictor of OS among women with T1-2 N1 breast cancer who received or did not receive PMRT.Experimental Design: An observational cohort study was performed on women with T1-2 N1 estrogen receptor-positive breast cancer from the National Cancer Database (NCDB) and, as a validation cohort, from the surveillance, epidemiology, and end results (SEER) registry who underwent mastectomy and were evaluated for RS. Multivariable parametric accelerated failure time models were used to estimate associations of RS and PMRT with OS using propensity score-adjusted matched cohorts.Results: In both the NCDB (N = 7,332) and SEER (N = 3,087) cohorts, there was a significant interaction of RS and PMRT with OS (P = 0.009 and P = 0.03, respectively). PMRT was associated with longer OS in women with a low RS [NCDB: time ratio (TR) = 1.70; 95% CI (confidence interval), 1.30-2.22; P < 0.001; SEER: TR = 1.85; 95% CI, 1.33-2.57; P < 0.001], but not in women with an intermediate RS (NCDB: TR = 0.89; 95% CI, 0.69-1.14; P = 0.35; SEER: TR = 0.84; 95% CI, 0.62-1.14; P = 0.26), or a high RS (NCDB: TR = 1.10; 95% CI, 0.91-1.34; P = 0.33; SEER: TR = 0.79; 95% CI, 0.50-1.23; P = 0.28).Conclusions: Longer survival associated with PMRT was limited to women with a low RS. PMRT may confer the greatest OS benefit for patients at the lowest risk of distant recurrence. These results caution against omission of PMRT among women with low RS. Clin Cancer Res; 24(16); 3878-87. ©2018 AACR.

Incidence proportions and prognosis of breast cancer patients with bone metastases at initial diagnosis.

IntroductionPopulation‐based data on the incidence and prognosis of bone metastases at diagnosis of breast cancer are currently limited. Hence, we conducted this study to analyze the incidence proportions and prognostic factors of patients with breast cancer and bone metastases at the time of cancer diagnosis.Materials and methodsPatients with primary invasive breast cancer and bone metastases at initial diagnosis between 2010 and 2014 were identified using the Surveillance, Epidemiology, and End Results (SEER) dataset and Fudan University Shanghai Cancer Center (FUSCC) cohort. Multivariable logistic regression was performed to identify predictors of the presence of bone metastases at diagnosis. Univariate and multivariate analyses were performed to determine the effects of each variable on survival.ResultsOf 229, 195 patients from SEER database included in the analysis, 8295 patients had bone metastases at initial diagnosis, reflecting 3.6% of the entire study population, and 65.1% of the subset with metastatic disease to any distant site. Patients with hormone receptor (HR)‐positive human epidermal growth factor receptor 2 (HER2)‐negative represented the highest incidence proportions among patients with metastatic disease (73.9%). Among entire cohort, multivariable logistic regression identified eight factors as predictors of the presence of bone metastases at diagnosis. Median OS for the patients with bone metastases in SEER and FUSCC cohorts was 30.0 and 68.2 months, respectively. Patients with HR‐positive HER2‐positive subtype had the longest median OS, and patients with triple‐negative subtype showed the shortest median OS. Multivariable Cox model in SEER cohort confirmed age, histology, grade, tumor subtype, extraosseous metastatic sites, history of primary surgery, insurance status, marital status, and income as independent prognostic factors for both OS and BCSS.ConclusionsThe findings of this study provide population‐based estimates of the incidence and prognosis for patients with bone metastases at initial diagnosis of breast cancer.

Primary Melanoma Histologic Subtype: Impact on Survival and Response to Therapy.

Two primary histologic subtypes, superficial spreading melanoma (SSM) and nodular melanoma (NM), comprise the majority of all cutaneous melanomas. NM is associated with worse outcomes, which have been attributed to increased thickness at presentation, and it is widely expected that NM and SSM would exhibit similar behavior once metastasized. Herein, we tested the hypothesis that primary histologic subtype is an independent predictor of survival and may impact response to treatment in the metastatic setting. We examined the most recent Surveillance, Epidemiology, and End Results (SEER) cohort (n = 118 508) and the New York University (NYU) cohort (n = 1621) with available protocol-driven follow-up. Outcomes specified by primary histology were studied in both the primary and metastatic settings with respect to BRAF-targeted therapy and immunotherapy. We characterized known driver mutations and examined a 140-gene panel in a subset of NM and SSM cases using next-generation sequencing. All statistical tests were two-sided. NM was an independent risk factor for death in both the SEER (hazard ratio [HR] = 1.55, 95% confidence interval [CI] = 1.41 to 1.70, P < .001) and NYU (HR = 1.47, 95% CI = 1.05, 2.07, P = .03) cohorts, controlling for thickness, ulceration, stage, and other variables. In the metastatic setting, NM remained an independent risk factor for death upon treatment with BRAF-targeted therapy (HR = 3.33, 95% CI = 1.06 to 10.47, P = .04) but showed no statistically significant difference with immune checkpoint inhibition. NM was associated with a higher rate of NRAS mutation (P < .001), and high-throughput sequencing revealed NM-specific genomic alterations in NOTCH4, ANK3, and ZNF560, which were independently validated. Our data reveal distinct clinical and biological differences between NM and SSM that support revisiting the prognostic and predictive impact of primary histology subtype in the management of cutaneous melanoma.

Prognosis and nomogram for predicting postoperative survival of duodenal adenocarcinoma: A retrospective study in China and the SEER database

As primary duodenal adenocarcinoma is rare, the prognostic factors of this disease remain insufficiently explored, especially in China. We identified postoperative duodenal adenocarcinoma patients at a Chinese double-center (from 2006 to 2016) or who were registered with the Surveillance, Epidemiology, and End Results (SEER) database (from 2004 to 2014). Clinicopathological features and significant prognostic factors for cancer-specific survival (CSS) were reviewed and analyzed by using univariate and multivariate Cox proportional hazards regression. Then, a nomogram predicting CSS was constructed based on the SEER database and validated externally by using the separate Chinese cohort. Totally, 137 patients from the Chinese double-center and 698 patients from the SEER database were included for analysis. The multivariate analyses showed that age, tumor grade and TNM stage were independent prognostic factors. The nomogram constructed using these factors showed a clear prognostic superiority to the AJCC-TNM classification, 7th ed. (C-index: SEER cohort, 0.693 vs 0.625, P < 0.001; Chinese cohort, 0.677 vs 0.659, P < 0.001, respectively). In summary, the valuable prognostic factors in patients with duodenal adenocarcinoma were age, tumor grade and TNM stage. This study developed a nomogram that can precisely predict the CSS for postoperative duodenal adenocarcinoma patients.

Trends in incidence and 5‐year mortality in men with newly diagnosed, metastatic prostate cancer—A population‐based analysis of 2 national cohorts

Early detection has increased prostate cancer (PCa) incidence. Randomized trials have demonstrated that early detection reduces the incidence of de novo metastatic PCa. Concurrently, life-prolonging treatments have been introduced for patients with advanced PCa. On a populations-based level, the authors analyzed whether early detection and improved treatments changed the incidence and 5-year mortality of men with de novo metastatic PCa. Men diagnosed with PCa during the periods 1980 to 2011 and 1995 to 2011 were identified in the US Surveillance, Epidemiology, and End Results (SEER) program and the Danish Prostate Cancer Registry (DaPCaR), respectively, and stratified according to period of diagnosis. Age-standardized incidence rates were calculated. Five-year mortality rates for de novo metastatic PCa were analyzed using competing risk analysis. Totals of 426,266 and 47,024 men were identified in SEER and DaPCaR, respectively. Of these, 29,555 and 6874 had de novo metastatic PCa. The incidence of de novo metastatic PCa decreased (from 12.0 to 4.4 per 100,000 men) in the SEER cohort (1980-2011), whereas it increased (from 6.7 to 9.9 per 100,000 men) in the DaPCaR cohort (1995-2011). Five-year PCa mortality in the SEER cohort was stable for men diagnosed with de novo metastatic PCa from 1980 to 1994 and increased slightly in the latest periods studied (P < .0001), whereas it decreased by 16.6% (P < .0001) in the DaPCaR cohort. Despite earlier detection, de novo metastatic PCa remains associated with a high risk of 5-year disease-specific mortality. The reduced 5-year PCa mortality in the Danish cohort is largely explained by lead-time. Early detection strategies do indeed decrease the incidence of de novo metastatic PCa, as observed in the SEER cohort. This achievement, however, must be weighed against the unsolved issue of overdetection and overtreatment of indolent PCa. Cancer 2018;124:2931-8. © 2018 American Cancer Society.

Defining the Young Oral Cavity Cancer Patient

Emerging data have suggested an increased incidence of oral cavity squamous cell (OCSCC) in young patients without traditional risk factors. However, the cause remains unclear. Here we seek to further characterize the young OCSCC patient population and better define the transition from young to traditional oral cancer patients. The Surveillance, Epidemiology, and End Results (SEER) database (2004-2011) and the University of Michigan Head and Neck Cancer Epidemiology Database (UMHNC) (1998-2016) were queried for cases of OCSCC (excluding stage IVb and Lip) resulting in 9,766 and 232 patients respectively. Additional clinical and histopathologic variables were collected. Data were extracted from the electronic medical record and research databases, with institutional IRB approval. Descriptive statistics and Kaplan-Meier survival analyses were performed using SPSS Statistics Version 24 (IBM Corp, NY). Using the SEER database, we identified two significant demographic shifts in OCSCC that described 40 years of age as a transition point defining the young cohort. There is a transition in the male to female ratio from near equivalence (1.2:1) in young patients to a greater male predominance (1.6:1) in patients over 40 (P =.002). The second shift is seen in anatomic subsite, where the vast majority of tumors arise in the oral tongue among young patients compared to a more even distribution of subsites in traditional patients (90.3% vs 58.5% oral tongue primary; P < .001). These demographic trends were validated in the UMHNC cohort, where patients in the young (<40) group showed a male: female ratio of 0.8:1.0 (compared to 1.3:1.0) and 84.1% (compared to 35.6%) of tumors arising from the oral tongue (P =.183 and <.001, respectively). Traditional patients were significantly more likely to have exposure to known risk factors for OCSCC (tobacco use 81.0% vs 43.2%, P<.001; alcohol use 52.1% vs 9/1%, P<.001). In the SEER cohort, the 5-year disease-specific (DSS) of young and traditional patients did not differ significantly among stage III and IV patients, although both remained poor for stage IV disease at 49% and 37%, respectively. We have objectively identified 40 years of age as a transition point for two distinct features for young, low-risk OCSCC patients, including a higher proportion of female patients and tumors airing from the oral tongue, using national cohort data validated with our institutional data. DSS does not differ between young and traditional patients for advanced disease and remains very poor. These patients comprise an interesting and important cohort given their lack of traditional risk factors yet similarly poor outcomes. By defining an objective measure of age, further investigation into the biologic mechanisms for tumorigenesis in this group is essential for characterizing disease in these patients.

Abstract P2-06-03: Clinicopathologic characteristics and genomic essence analyses revealed estrogen receptor positive, progesterone receptor negative and human epidermal growth factor receptor 2 negative breast cancer to be more basal-like and endocrine resistant

Abstract Background: Estrogen receptor positive/ progesterone receptor negative/ human epidermal growth factor receptor 2 negative (ER+/PR-/HER2-) tumors define a distinct subtype of ER+ breast cancer, characterized by poor response to endocrine therapy and poor prognosis. The genomic landscape of ER+/PR-/HER2- tumor has yet to be systematically studied,and driver events for tumor progression and endocrine resistance with loss of PR expression are yet to be identified. Methods: We assessed 13,410 ER+/PR-/HER2- patients from Surveillance, Epidemiology, and End Results (SEER), the Cancer Genome Atlas (TCGA) and Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) for clinicopathologic characteristics, survival and genomic analyses. Patients were divided into endocrine-resistant and endocrine-sensitive groups using an endocrine therapy sensitivity score [(0.8*ER+1.2*PGR+BCL2+SCUBE2)/4], and we further explored genomic events enriched in the endocrine-resistant group. Results: Clinicopathologic features and survival outcomes of ER+/PR-/HER2- patients were worse than ER+/PR+/HER2- in SEER and METABRIC cohort. The genomic landscape of ER+/PR-/HER2- tumors revealed them to have more aggressive properties, like a higher percentage of luminal B (29-35%) and basal-like (4-16%) subtypes; more intClust subtypes with high genomic instability (intClust1, 6); more TP53 mutation and less PIK3CA mutation; and more copy number variation events. ER+/PR-/HER2- tumors have more focal amplification events, including 8p11.23 (ZNF703) and 17q23.1 (RPS6KB1) and more focal deletion events, such as 17q21.31 (BRCA1) and 14q24.3 (MLH3). Pathifier pathway analyses showed that up-regulated pathways in ER+/PR-/HER2-tumors included those associated with biosynthesis, metabolism, drug resistance and DNA replications (FDR&amp;lt;0.1). Endocrine sensitivity score for ER+/PR-/HER2- group was significantly lower than ER+/PR+/HER2- group. When split by 1st quartile of endocrine sensitivity score, up to 72.7% of ER+/PR-/HER2- tumors were grouped into the endocrine-resistant group. Mutant-allele tumor heterogeneity (MATH) score is significantly lower in the endocrine-resistant group. Several focal SCNA events were more common in the endocrine-resistant group (P&amp;lt;0.05), including 8q24.21 amplification with only the MYC gene in the “peak” region. Pathways unregulated in the endocrine-resistant group of ER+/PR-/HER2- tumor included MYC pathway and mTORC1 signaling (FDR&amp;lt;0.25). Conclusion: ER+/PR-/HER2- breast cancer was a heterogeneous tumor group and featured more basal-like and luminal B characteristics. The ER+/PR-/HER2- tumors are relatively resistant to endocrine therapy, and MYC pathway enrichment and corresponding 8q24.21 amplification might be one of the drug-resistance mechanisms. Our study provides an overall understanding of the distinct genomic landscape of ER+/PR-/HER2- breast cancer. Further investigations into the pathways activated with the loss of PR expression may provide clues for novel changes in the therapeutic regimens of ER+/PR-/HER2- breast cancer. Citation Format: Liu X, Ma D, Jiang Y-Z, Liu Y-R, Yu K-D, Shao Z-M. Clinicopathologic characteristics and genomic essence analyses revealed estrogen receptor positive, progesterone receptor negative and human epidermal growth factor receptor 2 negative breast cancer to be more basal-like and endocrine resistant [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-06-03.

Rethinking childhood ependymoma: a retrospective, multi-center analysis reveals poor long-term overall survival

Ependymoma is the third most common brain tumor in children, but there is a paucity of large studies with more than 10 years of follow-up examining the long-term survival and recurrence patterns of this disease. We conducted a retrospective chart review of 103 pediatric patients with WHO Grades II/III intracranial ependymoma, who were treated at Dana-Farber/Boston Children’s Cancer and Blood Disorders Center and Chicago’s Ann & Robert H. Lurie Children’s Hospital between 1985 and 2008, and an additional 360 ependymoma patients identified from the Surveillance Epidemiology and End Results (SEER) database. For the institutional cohort, we evaluated clinical and histopathological prognostic factors of overall survival (OS) and progression-free survival (PFS) using the log-rank test, and univariate and multivariate Cox proportional-hazards models. Overall survival rates were compared to those of the SEER cohort. Median follow-up time was 11 years. Ten-year OS and PFS were 50 ± 5% and 29 ± 5%, respectively. Findings were validated in the independent SEER cohort, with 10-year OS rates of 52 ± 3%. GTR and grade II pathology were associated with significantly improved OS. However, GTR was not curative for all children. Ten-year OS for patients treated with a GTR was 61 ± 7% and PFS was 36 ± 6%. Pathological examination confirmed most recurrent tumors to be ependymoma, and 74% occurred at the primary tumor site. Current treatment paradigms are not sufficient to provide long-term cure for children with ependymoma. Our findings highlight the urgent need to develop novel treatment approaches for this devastating disease.

Rethinking the Current American Joint Committee on Cancer TNM Staging System for Medullary Thyroid Cancer

Controversy exists around the American Joint Committee on Cancer (AJCC) TNM staging system for medullary thyroid cancer (MTC). Because of the rarity of the disease and limited available data, the staging system for MTC has been largely extrapolated from staging for differentiated thyroid cancer. To evaluate how well the current (seventh and eighth editions) AJCC TNM staging system correlates with survival for patients with MTC and to suggest a possible revision. This population-based retrospective cohort analysis used the National Cancer Database to select patients aged 18 years or older diagnosed with MTC in the United States between 1998 and 2012. Patient demographic and tumor characteristics were assessed, and pathologic tumor stages were provided as T, N, and M categories. Recursive partitioning with bootstrapping was used to divide patients by TNM stages into groups with similar survival. The newly identified groupings were validated in a Surveillance, Epidemiology, and End Results (SEER) cohort. Data analysis was conducted between July 17, 2016, and November 11, 2016. Overall survival and disease-specific survival. Of the 3315 patients with MTC included in the analysis, 1941 (58.6%) were women. The median (interquartile range) age was 54 (42-65) years, and 2839 (85.6%) self-reported their race/ethnicity as white. The current AJCC TNM staging system classified 941 of these patients (28.4%) as stage I, 907 (27.4%) as stage II, 424 (12.9%) as stage III, and 1043 (31.5%) as stage IV. Recursive partitioning analysis yielded 4 TNM groups: stage I (T1N0-1aM0, T2N0M0), stage II (T1N1bM0, T2N1a-bM0, and T3N0M0), stage III (T3N1a-bM0, T4N0-1bM0), and stage IV (T1-4N0-1bM1). Based on these proposed TNM groupings, 1797 of the 3315 patients (54.2%) were classified as stage I, 684 (20.6%) as stage II, 669 (20.2%) as stage III, and 165 (5.0%) as stage IV. Under the proposed TNM groupings, survival differences across TNM groups were more distinct than under the current AJCC TNM staging system. With stage I as the reference, the hazard ratios of the proposed TNM groupings and the current AJCC TNM staging system were 2.19 (95% CI, 1.37-3.12) vs 1.45 (95% CI, 1.09-1.92) for stage II, 4.20 (95% CI, 2.75-5.75) vs 2.17 (95% CI, 1.59-2.89) for stage III, and 10.97 (95% CI, 5.52-18.57) vs 5.33 (95% CI, 4.13-6.86) for stage IV. In a SEER cohort, the proposed TNM groupings were better at discriminating survival than was the current AJCC TNM staging system. The current AJCC TNM staging system for MTC appears to be less than optimal in distinguishing risk of mortality among stage groups, upstaging a significant number of patients to stage IV. The current AJCC TNM staging system could be improved with the new TNM groupings proposed here for more accurate risk stratification and potential treatment selection.

Outcomes of elderly patients with muscle invasive bladder cancer (MIBC) treated with cystectomy or radiation therapy (RT): A surveillance epidemiology and end results (SEER) database analysis.

e16001 Background: Cystectomy and RT are both utilized in the management of MIBC. Elderly pts are more likely to be treated with non-surgical approaches that include RT. Using the SEER database, we evaluated outcomes in elderly pts with MIBC. Methods: Inclusion required pts ≥75 years with MIBC (T2-4, N0-3, M0). Cohorts were based on treatment received: cystectomy; RT; TURBT or no treatment. A propensity score was developed to address differences in treatment allocation according to age, race, sex, T and N stage, tumor location, and year of diagnosis. Propensity-adjusted competing risks analysis compared cancer specific mortality (CSM) between cohorts. Results: We identified 8506 pts with MIBC treated from 2007-2012. Of the 8423 pts with adequate treatment data, 26% had cystectomy (2196), 21% underwent RT (1752), 49% received TURBT alone (4128), 3% (262) received no treatment, and 1% (85) received both RT and cystectomy. Compared to RT, cystectomy cohort had a significantly higher proportion of pts &lt; 80 yrs (49% vs. 25%) and was surgically staged with a higher degree of node + (22% vs. 4%) and ≥T3 disease (58% vs. 17%; all P &lt; 0.001). At median follow-up of 10 mo (0-71), 48% (1061) of cystectomy pts and 61% (1064) of RT pts had died. MIBC was the leading cause of death (31% cystectomy, 39% RT). On propensity adjusted analysis, RT was associated with significantly worse CSM (HR: 1.62; 95% CI: 1.45-1.82) compared to cystectomy. Patients treated with TURBT or no treatment had the worst outcomes (5 year CSM: 71% each). Conclusions: Even in elderly pts with competing morbidities, MIBC accounted for more deaths than other causes. In this SEER cohort, non-surgical approaches involving RT were associated with significantly worse outcomes compared to cystectomy. However, worse performance status, less concurrent chemotherapy use, discrepancies between pathologic and clinical staging, use of lower dose RT, or lack of completion TURBT could not be examined and could have contributed to worse outcomes in the RT cohort. These results highlight the need for aggressive management of fit elderly patients with cystectomy or multimodality BPT.

Thermal Ablation versus Surgical Resection for the Treatment of Stage T1 Hepatocellular Carcinoma in the Surveillance, Epidemiology, and End Results Database Population

PurposeTo compare survival outcomes of small solitary hepatocellular carcinomas (HCCs) treated with thermal ablation vs resection in the Surveillance, Epidemiology, and End Results (SEER) cohort. Materials and MethodsSEER data (November 2014 submission) were searched for histologic diagnoses of HCC and stage T1 disease (≤ 5-cm solitary tumor without vascular invasion). Comparison was made between thermal ablation and resection as the primary treatment. Overall and disease-specific survival were compared by log-rank tests (stratified for presence of fibrosis) and Cox regression (with tumor size and presence of fibrosis covariates). ResultsOf 264 patients with ≤ 2-cm HCCs, 185 underwent thermal ablation and 79 underwent resection. Patients undergoing ablation had higher Ishak scores (P = .0002). There was no difference in survival (observed P = .698, disease-specific P = .446). Of 544 patients with 2.1–4-cm HCCs, 335 underwent thermal ablation and 209 underwent resection. Patients undergoing ablation were more likely to have higher Ishak scores (P < .001), but had slightly smaller tumors (2.9 vs 3.1 cm; P < .001). There was no difference in survival (observed P = .174, disease-specific P = .609). Of 112 patients with 4.1–5-cm HCCs, 46 underwent thermal ablation and 66 underwent resection. Patients undergoing ablation had higher Ishak scores (P = .0002). Surgical resection was associated with improved survival (observed P = .009, disease-specific P = .046). ConclusionsThere was no difference in overall or disease-specific survival between surgical resection and thermal ablation for T1 HCCs ≤ 4 cm after adjusting for the presence of histologic fibrosis and tumor size in the SEER cohort. Significant benefit was observed with surgery for tumors measuring 4.1–5 cm.

Forty-Year Analysis of Randomized Clinical Trials in Patients with Acute Myeloid Leukemia Treated with Remission Induction Chemotherapy

Several population-based cancer registries have consistently reported improvements in overall survival (OS) for patients (pts) with AML treated with intensive chemotherapy (IC) across all age groups extending up to the age of 80 years. While major advances in supportive care and greater numbers of allogeneic transplantations have contributed to improvements in OS in AML, the role of experimental IC regimens has not been comprehensively analyzed. We conducted a systematic review of all phase three randomized clinical trials (RCTs) in AML conducted over the past forty years to evaluate the contribution of experimental IC regimens in clinical outcomes, along with OS in these pts based on the Surveillance, Epidemiology, and End Results (SEER) database.The following electronic databases were searched for eligible non-acute promyelocytic leukemia trials covering the period from 1973 to 2016: Cochrane Controlled Trials Register, PubMed, Embase databases and American Society of Hematology (ASH), American Society of Clinical Oncology (ASCO) and European Hematology Association (EHA) websites for conference abstracts. Analyses were restricted to phase three RCTs using IC regimens. The principal outcomes examined in the experimental arms (EAs) and control arms (CAs) included complete remission (CR) rates, leukemia-free survival (LFS), and OS. Outcomes were stratified by age and cytogenetic risk, in studies where information was available. RCTs were classified as including younger or older AML pts based on whether >65% of the patients in a study were < 60 or ≥ 60 years (yrs) old, respectively. We also evaluated the outcomes of pts diagnosed with AML outside of clinical trials by analyzing survival trends of 61,000 AML pts in SEER registry.A total of 71 studies comprising 36,796 AML pts were included. The majority of pts in RCTs were < 60 years (68.6%); 54.3% were male. Eligibility criteria for study entry across all RCTs included a mean ECOG performance status of 2-3, mean upper limit (UL) of serum creatinine of 2.3 mg/dl and mean UL of serum bilirubin of 2.6 mg/dl. Mean CR (stratified by age and cytogenetics), mean LFS, OS and treatment-related mortality were similar between EA and CA cohorts (Table 1). Over the study period, there was no trend towards improved CR in EAs and CAs in both younger and older AML trials or even when stratified by cytogenetic risk groups. Similarly, no significant change in LFS trend was observed over time in the EAs and CAs in both younger and older pts. However, over time EAs in younger and older AML trials had a significant increase in median OS, at a rate of 29.52 days/yr (d/yr) (6.84-51.84; P=.01), and 13.68 d/yr (1.8-25.92; P=.05), respectively (Figure 1). For those in CAs, the corresponding rates for younger and older pts was 32.76 d/yr (8.64-56.88; P=.009) and 12.24 d/yr (2.88-27.93; P=.10), respectively. By comparison, there was a significant trend towards improvement in median OS over time in the SEER cohort for younger pts, defined as < 60 yrs (18.36 d/yr; 30-212.4, P<.0001). For the older SEER cohort (≥ 60 yrs) although the survival trend was statistically significant (0.36 d/yr; 0.36-0.72, P=.003) due to large patient numbers, this improved survival was not clinically meaningful (Figure 2).This systematic review of evidence from phase three RCTs in AML suggests a minimal improvement in OS with use of experimental IC regimens, with gains mostly seen in younger pts. No significant improvements in LFS trends were observed in any age group, demonstrating a lack of aggregate clinical efficacy of experimental drugs over this time period. Greater survival gains in OS in pts enrolled in CAs of RCTs as compared to the SEER population suggests a strong selection bias in RCTs, thereby limiting extrapolation of study findings to the real world population. [Display omitted] [Display omitted] [Display omitted] DisclosuresCarraway:Celgene Corporation: Research Funding, Speakers Bureau; Baxalta: Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

Clinical Nomogram for Predicting Survival of Esophageal Cancer Patients after Esophagectomy.

The aim of this study was to construct an effective clinical nomogram for predicting the survival of esophageal cancer patients after esophagectomy. We identified esophageal cancer patients (n = 4,281) who underwent esophagectomy between 1988 and 2007 from the Surveillance, Epidemiology, and End Results (SEER) 18 registries database. Clinically significant parameters for survival were used to construct a nomogram based on Cox regression analyses. The model was validated using bootstrap resampling and a Chinese cohort (n = 145). A total of 4,109 patients from the SEER database were included for analysis. The multivariate analyses showed that the factors of age, race, histology, tumor site, tumor size, grade and depth of invasion, and the numbers of metastases and retrieved nodes were independent prognostic factors. All of these factors were selected into the nomogram. The nomogram showed a clear prognostic superiority over the seventh AJCC-TNM classification (C-index: SEER cohort, 0.716 vs 0.693, respectively; P < 0.01; Chinese cohort, 0.699 vs 0.680, respectively; P < 0.01). Calibration of the nomogram predicted the probabilities of 3- and 5-year survival, which corresponded closely with the actual survival rates. This novel prognostic model may improve clinicians’ abilities to predict individualized survival and to make treatment recommendations.