Cancer-specific Death Research Articles

Distinct Molecular Profiles of Sporadic Early-Onset Colorectal Cancer: A Population-Based Cohort and Systematic Review.

The observed increase in the incidence of early-onset colorectal cancer (EOCRC) is being driven by sporadic cases, but the molecular characteristics of these tumors are not fully understood. Our objective was to investigate the prevalence of microsatellite instability (MSI) and selected mutations in sporadic EOCRC, and their association with survival. Firstly, we compared the prevalence of molecular characteristics and survival within a population-based cohort study of 652 stage II and III colon cancer patients in Northern Ireland, comparing sporadic early-onset (<50 years, n= 35) with older (60-69 years, n= 179) patients. Secondly, a systematic review for studies reporting the prevalence of MSI, mismatch repair deficiency (dMMR), or BRAF, KRAS, NRAS, PIK3CA, and TP53 mutations in sporadic EOCRC was conducted. A meta-analysis was performed to calculate pooled estimates of the prevalence of molecular features in sporadic EOCRC. Firstly, within the cohort study, EOCRC patients did not have a significantly increased risk of colorectal cancer-specific death (adjusted hazard ratio 1.20; 95% confidence interval [CI] 0.61-2.39) compared with 60- to 69-year-olds. Second, 32 studies were included in the systematic review. The pooled analysis estimated a prevalence of 10% (95% CI 7%-14%) for MSI high/dMMR in sporadic EOCRC. BRAF and KRAS mutations had a prevalence of 1% (95% CI 0%-3%) and 32% (95% CI 23%-40%), respectively. The molecular characteristics of sporadic EOCRC differ from those of cancers in older adults, particularly regarding reduced prevalence of BRAF mutations. Ten percent of sporadic EOCRC display MSI high/dMMR. Further studies are needed to address survival in sporadic EOCRC cases and whether molecular profiles influence EOCRC outcomes in this patient group.

Abstract P011: Clonal hematopoiesis and risk of lethal prostate cancer: a prospective cohort study with long-term follow-up

Abstract Background: Clonal hematopoiesis (CH), the presence of acquired mutations in leukemia driver genes, promotes systemic inflammation and is common among aging men. Prostate cancer, a subset of which is lethal, also develops in aging men. We hypothesized that CH contributes to development of lethal prostate cancer. Methods: We conducted nested case-cohort studies for metastatic prostate cancer and prostate cancer-specific death (lethal prostate cancer) within the prospective Health Professionals Follow-up Study. First, we followed 1155 men free of prostate cancer and cardiovascular disease at blood draw (1993-1995) for development of lethal prostate cancer over up to 26 years. Second, we followed 532 men with incident non-metastatic prostate cancer for development of lethal prostate cancer. We sequenced blood DNA from 1488 participants for putative CH driver mutations in the 9 most common CH-defining genes with a custom targeted panel (VariantPlex, Invitae, Inc.) at ultra-high depth (mean, 18,000x), employing unique molecular identifiers for error correction. CH variant calling used a novel ensemble calling approach, ArCCH, validated with in-silico tumor dilutions and blinded technical replicates, which had high accuracy for variant allele frequencies (VAFs) as low as 0.1%. We estimated hazard ratios (HRs) with 95% confidence intervals (CIs) in proportional hazards regression with Prentice case-cohort weights. Results: In a random sample of 968 men initially free of prostate cancer and cardiovascular disease (median age at blood draw 60 years, interquartile range 52 to 67), 80% of men had CH at a variant allele frequency (VAF) of &amp;gt;0.1%, 15% had VAFs &amp;gt;2%, and 3% had VAFs &amp;gt;10%; 75% of men had variants in epigenetic modifier genes (DNMT3A, TET2, ASXL1), and 21% had variants in DNA repair genes (PPM1D, TP53, CHEK2). CH burden was strongly age-associated, with approximately one additional CH variant per decade of age at blood draw (mean difference 1.07 variants, 95% CI 0.93 to 1.21). Among men initially free from prostate cancer, after adjusting for age at blood draw, CH clones between 0.1% and 10% VAF were not related to lethal prostate cancer (206 events total; HR 0.93, 95% CI 0.49-1.76 for VAFs 2-10% vs. no variants detected at &amp;gt;0.1% VAF). Results for epigenetic modifiers and DNA repair genes were similar. While inconclusive, data were compatible with positive associations among younger men (&amp;lt; 65 years) or for VAFs &amp;gt;10%. Among men initially diagnosed with non-metastatic prostate cancer, results were similarly null for progression to lethal prostate cancer (164 events). Conclusions: This large prospective study with long-term follow-up suggests that low-level CH is unlikely a major contributor to and not well suited for early detection of lethal prostate cancer. Citation Format: Konrad H. Stopsack, Irenaeus C. Chan, Evelyn Schmidt, Alex Panchot, Samantha McNulty, Nicole A. Schreiber, Yiwen Zhang, Kathryn L. Penney, Michael F. Berger, Luis A. Diaz, Ross L. Levine, Kelly L. Bolton, Lorelei A. Mucci, Philip W. Kantoff. Clonal hematopoiesis and risk of lethal prostate cancer: a prospective cohort study with long-term follow-up. [abstract]. In: Proceedings of the AACR Special Conference: Precision Prevention, Early Detection, and Interception of Cancer; 2022 Nov 17-19; Austin, TX. Philadelphia (PA): AACR; Can Prev Res 2023;16(1 Suppl): Abstract nr P011.

An Updated Analysis of the Survival Endpoints of ASCENDE-RT

Using the primary endpoint of time to biochemical progression (TTP), Androgen Suppression Combined with Elective Nodal and Dose Escalated Radiation Therapy (ASCENDE-RT) randomized National Comprehensive Cancer Network patients with intermediate and high-risk prostate cancer to low-dose-rate brachytherapy boost (LDR-PB) or dose-escalated external beam boost (DE-EBRT). Randomization to the LDR-PB arm resulted in a 2-fold reduction in biochemical progression compared with the DE-EBRT group at a median follow-up of 6.5 years (P < .001). Herein, the primary endpoint and secondary survival endpoints of the ASCENDE-RT trial are updated at a 10-year median follow-up. Patients were randomly assigned to either the LDR-PB or the DE-EBRT arm (1:1). All patients received 1 year of androgen deprivation therapy and 46 Gy in 23 fractions of pelvic RT. Patients in the DE-EBRT arm received an additional 32 Gy in 16 fractions, and those in the LDR-PB arm received an 125I implant prescribed to a minimum peripheral dose of 115 Gy. Two hundred patients were randomized to the DE-EBRT arm and 198 to the LDR-PB arm. The 10-year Kaplan-Meier TTP estimate was 85% ± 5% for LDR-PB compared with 67% ± 7% for DE-EBRT (log rank P < .001). Ten-year time to distant metastasis (DM) was 88% ± 5% for the LDR-PB arm and 86% ± 6% for the DE-EBRT arm (P=.56). There were 117 (29%) deaths. Ten-year overall survival (OS) estimates were 80% ± 6% for the LDR-PB arm and 75% ± 7% for the DE-EBRT arm (P=.51). There were 30 (8%) patients who died of prostate cancer: 12 (6%) in the LDR-PB arm, including 2 treatment-related deaths, and 18 (9%) in the DE-EBRT arm. Men randomized to the LDR-PB boost arm of the ASCENDE-RT trial continue to experience a large advantage in TTP compared with those randomized to the DE-EBRT arm. ASCENDE-RT was not powered to detect differences in its secondary survival endpoints (OS, DM, and time to prostate cancer-specific death) and none are apparent.

Current picture of anaplastic thyroid cancer patients' care and meetable needs: A survey of 94 Institutions from the EORTC Endocrine and Head and Neck Cancer Groups

Anaplastic thyroid carcinoma (ATC) is a rare cancer accounting for 40% of thyroid cancer-specific deaths. In the last 5 years, improved insights into molecular pathways led the Food and Drug Administration to license BRAF/MEK inhibitors (B/Mi) in BRAFV600E-mutant ATC, and pembrolizumab in solid cancer with high tumour mutational burden (TMB-H) (≥10 mutations/megabase) (mut/Mb). In Europe, clinicians face challenges in prescribing novel treatments, as the European Medical Association (EMA) has not licensed B/Mi nor immunotherapy (IO) for ATC so far. Some patients manage to receive these drugs through alternative ways. We investigated the extent of this phenomenon launching an online survey from March 12th to 19th 2021 open to 239 Institutions in the EORTC Endocrine and Head & Neck Cancer Groups. Questions enquired about the number of ATC patients evaluated/year, feasibility of BRAF assessment, accessibility to B/Mi-IO, availability of clinical trials and interest in new studies. Colleagues from 94 Institutions (20 Countries) joined: 30 centres evaluated ≥5 ATC patients/year, with an overall incidence >200 patients/year. 80.8% tested BRAF status, 43.6% by next-generation sequencing. 62.7% and 70% of responders reported limitations in prescribing B/Mi and IO, respectively: either the impossibility of offering them, or drugs accessibility exclusively under certain conditions (e.g. health insurance, clinical trials, compassionate use, off-label). Only 13.8% had clinical trials ongoing while 91.5% of sites claimed ATC-dedicated trials. Disparities in access to novel treatments are diffuse. Access to cutting-edge therapies is an urgent issue in this setting, and clinical trials seem feasible within an appropriate network.

Phosphodiesterase 5 Inhibitor Potentiates Epigallocatechin 3-O-Gallate-Induced Apoptotic Cell Death via Activation of the cGMP Signaling Pathway in Caco-2 Cells.

Epigallocatechin 3-O-gallate (EGCG) is a predominant component in green tea with various health benefits. The 67 kDa laminin receptor (67LR) is a nonintegrin cell surface receptor that is overexpressed in various types of cancer; 67LR was identified a cell surface EGCG target that plays a pivotal role in tumor growth, metastasis, and resistance to chemotherapy. However, the plasma concentration of EGCG is limited, and its molecular mechanisms remain unelucidated in colon cancer. In this study, we found that the phosphodiesterase 5 (PDE5) inhibitor, vardenafil (VDN), potentiates EGCG-induced apoptotic cell death in colon cancer cells. The combination of EGCG and VDN induced apoptosis via activation of the endothelial nitric oxide synthase/cyclic guanosine monophosphate/protein kinase Cδ signaling pathway. In conclusion, the PDE5 inhibitor, VDN, may reduce the intracellular PDE5 enzyme activity that potentiates EGCG-induced apoptotic cell death in Caco-2 cells. These results suggest that PDE5 inhibitors can be used to elevate cGMP levels to induce 67LR-mediated, cancer-specific cell death. Therefore, EGCG may be employed as a therapeutic candidate for colon cancer.

Development and validation of a new stage-specific nomogram model for predicting cancer-specific survival in patients in different stages of colon cancer: A SEER population-based study and external validation.

The effects of laterality of the primary tumor on survival in patients in different stages of colon cancer are contradictory. We still lack a strictly evaluated and validated survival prediction tool, considering the different roles of tumor laterality in different stages. A total of 101,277 and 809 colon cancer cases were reviewed using the Surveillance, Epidemiology, and End Results database and the First Affiliated Hospital of Xi 'an Jiaotong University database, respectively. We established training sets, internal validation sets and external validation sets. We developed and evaluated stage-specific prediction models and unified prediction models to predict cancer-specific survival and compared the prediction abilities of these models. Compared with right-sided colon cancers, the risk of cancer-specific death of left-sided colon cancer patients was significantly higher in stage I/II but was markedly lower in stage III patients. We established stage-specific prediction models for stage I/II and stage III separately and established a unified prediction model for all stages. By evaluating and validating the validation sets, we reported high prediction ability and generalizability of the models. Furthermore, the stage-specific prediction models had better predictive power and efficiency than the unified model. Right-sided colon cancer patients have better cancer-specific survival than left-sided colon cancer patients in stage I/II and worse cancer-specific survival in stage III. Using stage-specific prediction models can further improve the prediction of cancer-specific survival in colon cancer patients and guide clinical decisions.

Race and Ethnicity, Stage-Specific Mortality, and Cancer Treatment in Esophageal and Gastric Cancers: Surveillance, Epidemiology, and End Results (2000–2018)

Race and Ethnicity, Stage-Specific Mortality, and Cancer Treatment in Esophageal and Gastric Cancers: Surveillance, Epidemiology, and End Results (2000–2018)

Establishment and validation of a nomogram for predicting immune-related prognostic features in trunk melanoma-specific death.

Trunk melanoma is one of the most common and deadly types of melanomas. Multiple factors are associated with the prognosis of patients with trunk melanoma. Currently, direct, and reliable clinical tools for early assessment of individual specific risk of death are limited, and most of them are prediction models for all-cause death. Their accuracy in predicting competitiveness events, which make up a relatively large portion, may be substantially compromised. Hence, we conducted this study to investigate the risk factors of trunk melanoma-specific death to establish a comprehensive prediction model suitable for clinical application. Patients with trunk melanoma analyzed in this study were from the SEER program [2010-2015]. The random sampling method was used to split the included cases into the training and validation cohorts at a ratio of 7:3. Univariate and multivariate competing risk models were used to screen the independent influencing factors of specific death, and then a nomogram covering these independent predictors was constructed. The concordance index (C-index) and a calibration curve were used to evaluate the calibration degree and accuracy of the nomogram. We identified 21,198 patients with trunk melanoma from the SEER database, and 3,814 of them died (17.99%). Among the death cases, deaths from other causes accounted for 66.50%The prognostic nomogram included 8 variables and 16 independent influencing factors. The overall C-index in the training set was 0.89, and the receiver operating characteristic (ROC) curve for predicting 1-, 3-, and 5-year survival was 0.928 [95% confidence interval (CI): 0.911-0.945], 0.907 (95% CI: 0.895-0.918), and 0.891 (95% CI: 0.879-0.902), respectively. The C-index of the model in the validation set was 0.89, and the area under the ROC curve (AUC) for predicting 1-, 3-, and 5-year cancer-specific death (CSD) was 0.927 (95% CI: 0.899-0.955), 0.916 (95% CI: 0.901-0.930), and 0.905 (95% CI: 0.899-0.921). Both the training set and the validation set showed the ideal calibration degree. This model can be used as a potential tool for prognostic risk management of trunk melanoma in the presence of many competing events.

Post-diagnostic Zinc Supplement Use and Prostate Cancer Survival Among Men With Nonmetastatic Prostate Cancer.

Biological and experimental evidence support restoration of normal zinc levels in malignant prostate cells as a promising prostate cancer treatment, yet the influence of zinc supplementation after diagnosis on prostate cancer survival in a human population is unknown. We prospectively assessed post-diagnostic zinc supplementation in relation to prostate cancer survival among 5,788 men with nonmetastatic prostate cancer in the Health Professionals Follow-up Study (1986-2019). We used Cox regression models to estimate the multivariable hazard ratios and 95% confidence intervals of lethal prostate cancer (distant metastases or prostate cancer-specific death) and all-cause mortality according to post-diagnostic zinc supplement use and dosage. During a median follow-up of 11 years, we documented 527 lethal prostate cancer events and 3,198 all-cause deaths. Fifteen percent of men reported zinc supplement use post-diagnosis. Compared to nonusers, post-diagnostic zinc supplement use was associated suggestively with a lower risk of lethal prostate cancer (HR [95% CI], 0.82 [0.60-1.13]) and significantly with all-cause mortality (0.84 [0.74-0.96]). The inverse association was mostly observed among men who used post-diagnostic zinc supplements of 1-24 mg/d (lethal prostate cancer: 0.55 [0.32-0.96]; all-cause mortality: 0.77 [0.64-0.93]), while higher dosage did not show a lower risk. Post-diagnostic low-dose zinc supplement use among nonmetastatic prostate cancer patients was associated with lower risk of lethal prostate cancer and all-cause mortality. A potential benefit of low-dose post-diagnostic zinc supplement for prostate cancer survival merits further study.

Impact of adequate lymph nodes dissection on survival in patients with stage I rectal cancer.

The NCCN guidelines recommended an assessment of ≥ 12 lymph nodes (LN) as an adequate LN dissection (LND) for rectal cancer (RC). However, the impact of adequate LND on survival in stage I RC patients remained unclear. Thus, we aimed to compare the survival between stage I RC patients with adequate and inadequate LND. A total of 1,778 stage I RC patients in the SEER database from 2010 to 2017 treated with radical proctectomy were identified. The association between ≥ 12 LND and survival was examined using the multivariate Cox regression and the multivariate competing risk model referenced to < 12 LND. Stage I RC patients with ≥ 12 LND experienced a significantly lower hazard of cancer-specific death compared with those with < 12 LND in both multivariate Cox regression model (adjusted HR [hazard ratio], 0.44, 95% CI, 0.29-0.66; P < 0.001) and the multivariate competing risk model (adjusted subdistribution HR [SHR], 0.45, 95% CI, 0.30-0.69; P < 0.001). Further, subgroup analyses performed by pT stage. No positive association between ≥ 12 LND and survival was found in pT1N0 RC patients (adjusted HR: 0.62, 95%CI, 0.32-1.19; P = 0.149; adjusted SHR: 0.63, 95%CI, 0.33-1.20; P = 0.158), whereas a positive association between ≥ 12 LND and survival was found in pT2N0 RC patients (adjusted HR: 0.35, 95%CI, 0.21-0.58; P < 0.001; adjusted SHR: 0.36, 95%CI, 0.21-0.62; P < 0.001). The long-term survival benefit of adequate LND was not found in pT1N0 but in pT2N0 RC patients, which suggested that pT2N0 RC patients should be treated with adequate LND and those with inadequate LND might need additional therapy.

Risk and survival in colorectal cancer with increasing body mass index: A nationwide population-based cohort study.

The aim was to explore potential associations between the body mass index (BMI) and the risk of colorectal cancer (CRC), including subsites of the colon, and cancer-specific death. A registry-based cohort study was conducted with baseline data gathered from the Norwegian Tuberculosis Screening Programme, collected between 1963 and 1975, and linked to follow-up data from the Cancer Registry of Norway and the Norwegian Cause of Death Registry. Cox regression models were used to explore associations between BMI and CRC risk and cancer-specific death. Of 1723 692 included individuals, 76 616 developed CRC during 55 370 707 person-years of follow-up. In men, a 5kg/m2 increase in BMI was associated with an increased risk of colon cancer, including both right and left subsites, and rectal cancer. Allowing for nonlinearities, we found a U-shaped association for the right colon and an inverse U-shape for the left colon and rectum cancer. In women, a 5kg/m2 increase in BMI in early adulthood was associated with increased risk of colon cancer, including both subsites. In women, an increased risk of CRC death with increasing BMI was found for colon cancer. Men of all ages have an increased risk of CRC with increasing BMI, with the highest risk for right-sided colon cancer. An increased risk for colon cancer was also found in women with high BMI in early adulthood. Furthermore, women of all age groups appeared to have an increased risk of CRC death with higher BMI.

The prognostic significance of further axillary dissection for sentinel lymph node micrometastases in female breast cancer: A competing risk analysis using the SEER database.

Sentinel lymph node (SLN) biopsy has been widely recognized as an excellent surgical and staging procedure for early-stage breast cancer, and its development has greatly improved the detection of micrometastases. However, the axillary treatment of micrometastasis has been the subject of much debate. We identified 427,131 women diagnosed with breast cancer from 2010 to 2018 in the Surveillance, Epidemiology, and End Results (SEER) database. Patients whose nodal status was micrometastases (pTxN1miM0) were classified into two groups: the SLNB only group and SLNB with complete ALND group, and we used these classifications to carry out propensity-score matching (PSM) analysis. The primary and secondary endpoints were OS and BCSS, respectively. We then implemented the Kaplan-Meier method and Cox proportional hazard model and used Fine and Gray competitive risk regression to identify factors associated with the risk of all-cause mortality. After the PSM, 1,833 pairs were included in total. The SLNB with complete ALND showed no significant difference in OS (HR=1.04, 95% CI: 0.84-1.28, P=0.73) or BCSS (HR= 1.03, 95% CI: 0.79-1.35, P=0.82) compared to the SLNB only group, and axillary treatment was not associated with breast cancer-specific death (BCSD) (HR=1.13, 95% CI: 0.86-1.48, P=0.400) or other cause-specific death (OCSD) (HR=0.98, 95% CI:0.70-1.38, P=0.920). There was no statistically significant difference in the cumulative incidence of BCSD (Grey's test, P=0.819) or OCSD (Grey's test, P=0.788) for between the two groups either. For different molecular subtypes, patients in the SLNB only group showed no statistically significant differences from those in the SLNB with complete ALND group with Luminal A (HR=1.00, 95% CI:0.76-1.32, P=0.98) or Luminal B (HR=0.82, 95% CI:0.42-1.62, P=0.55) but similar OS to HER2-enriched (HR=1.58, 95% CI:0.81-3.07, P=0.19) or triple negative breast cancers (HR=1.18, 95% CI:0.76-1.81, P=0.46). Our results suggest that in early breast cancer patients with micrometastasis, complete ALND does not seem to be required and that SLNB suffices to control locoregional and distant disease, with no significant adverse effects on survival compared to complete ALND.

Survival Contradiction in Stage II, IIIA, And IIIB Colon Cancer: A Surveillance, Epidemiology, and End Result-Based Analysis.

There exists an inconsistency between stage and survival in the current American Joint Committee on Cancer (AJCC) staging system for colon cancer. In this study, we compared the clinicopathological characteristics and prognosis of colon cancer patients with stage II, IIIA, and IIIB disease based on the surveillance, epidemiology, and end results (SEER) database. Kaplan-Meier analysis was used to generate overall survival (OS) and cancer-specific survival (CSS) curves. The Cox regression was employed to identify risk factors. The competing risk model was completed by the cumulative incidence function and Gray's test. In the final population of 31,361 colon cancer patients, Kaplan-Meier curve analysis showed that stage IIIA had the highest OS and CSS, followed by stage IIA and IIIB, and IIB and IIC showed the worst OS and CSS. In the Cox model, the stage was proven to be an independent prognostic factor. In the competing risk model, stage IIIA colon cancer patients had the lowest 5-year cancer-specific death rate in stages II, IIIA, and IIIB. In conclusion, the prognosis of colon cancer patients in stage IIA was worse than that of patients in stage IIIA, while the survival rate of stage IIB and IIC was lower than that of stage IIIB.

The Incidence, Risk Factors and Predictive Nomograms for Early Death of Elderly Patients with Diffuse Large B-Cell Lymphoma

Background: Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy that is diagnosed in approximately 60% of patients in older age. However, the early mortality and risk factors associated with elderly DLBCL are little known. Methods: Elderly patients diagnosed with DLBCL in the Surveillance, Epidemiology, and End Results (SEER) database from 2000 to 2019 were selected as a trial cohort. In addition, elderly DLBCL patients from Peking University Third Hospital were used as an external validation cohort. Univariate and multivariate logistic regression analysis were used to identify risk factors. Nomogram models were constructed according to significant risk factors to predict overalland cancer-specific early death. In addition, the predictive value of the model was verified by receiver operating characteristic (ROC) analysis. Calibration plotwas used to evaluate the calibration ability. The clinical value of nomogram was evaluated by decision curve analysis (DCA). Results: A total of 15242 elderly DLBCL patients from SEER database and 152 patients from Peking University third hospital were included in this study. In the SEER database, 36.6%(5584/15242) patients had early death, and 30.7%(4680/15242) patients had cancer-specific early death. Marital status, Ann Arbor stage, surgical treatment, radiotherapy and chemotherapy are significant risk factors for overall and cancer-specific early mortality in elderly patients with DLBCL. Nomograms were constructed according to these risk factors. ROC analysis showed that the AUC of OS was 0.764 (0.756-0.772) and that of CSS was 0.742(0.733-0.751). The AUC of the verification group was 0.767 (0.689-0.846) for OS and 0.742(0.743-0.83) for CSS. The calibration plots and DCA analysis showed that the model had good early death prediction and clinical application value. Conclusion: This study establishes and validates a predictive nomogram model for elderly diffuse large B-cell lymphoma, which plays an important role in making better treatment strategies for physicians. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Trends in survival for cancer patients aged 65 years or over from 1995 to 2014 in the United States: A population-based study.

Adults aged 65 years and above account for over half of all cancer diagnoses in the United States, but little is known about trend of elderly cancer survival in the United States. We aimed to assess the survival trend for elderly cancer in the United States from 1995 to 2014. We used data from Surveillance, Epidemiology, and End Results 12 registries and included 1,112,441 eligible patients aged 65 years or older who were diagnosed between 1995 and 2014 with cancer and followed up until December 2019. Overall and stage-specific 5-year relative survival, ratio of observed survival to expected survival, with 95% confidence intervals (CIs) of elderly cancer patients stratified by age were estimated during four periods (1995-1999, 2000-2004, 2005-2009, and 2010-2014). Cox proportional hazards models were used to estimate hazard ratios for cancer-specific death among patients diagnosed during 2000-2004, 2005-2009, 2010-2014, compared diagnoses in 1995-1999. We also calculated stage distribution and treatment rate during four periods. In the United States, 5-year relative survival for elderly cancer patients improved from 57.3% (95% CIs 57.0-57.5) in 1995-1999 to 60.7% (60.5-60.9) in 2010-2014. After controlling for sociodemographic and tumor characteristics, about a 19% reduction in cancer-specific deaths among diagnoses in 2010-2014 compared with 1995-1999. Cancer survival improved for elderly patients in all age groups, with exception of stable survival for patients aged 85 and above. Comparing 1995-1999 with 2010-2014, relative survival improved from 84.7% (84.3-85.1) to 86.7% (86.3-87.0) for localized stage and from 12.4% (12.1-12.7) to 18.7% (18.4-19.0) for distant stage for all cancers combined. The trends in stage distribution and treatment rate for all cancers combined were relatively stable. In the United States, survival for elderly cancer patients has improved slightly from 1995 to 2014, possibly mainly due to advances in treatment. Further studies are warranted to explore interventions to improve elderly cancer survival.

LBODP092 Proposal Of Indication For Completion Thyroidectomy In Follicular Thyroid Carcinoma Using TERT Promoter Mutational Status

Abstract Background Stepwise surgical approach with hemithyroidectomy and completion thyroidectomy was used to solve the dilemma of definite characterization of follicular thyroid carcinoma (FTC). However, which patients will be candidates for completion thyroidectomy has been controversial. The aim of this study is to clarify the selection criteria for completion thyroidectomy using TERT promoter mutation. Methods A total of 87 FTC patients who had information about TERT promoter mutation from August 1995 to November 2020 were investigated. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each of the WHO 2017 classifications were calculated. Results Of the 87 patients, 8 patients (9.2%) had initial distant metastasis, and 15 patients (17.2%) had persistent disease or developed structural recurrence. Threshold diameter for initial distant metastasis, disease recurrence, and cancer-specific death was 2cm in minimally invasive FTC (MI-FTC) with mutant TERT (M-TERT) and in encapsulated angioinvasive FTC (EA-FTC) with M-TERT, while in MI-FTC with wild-type TERT (WT-TERT) and EA-FTC with WT-TERT it was 4cm. Cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each WHO 2017 classification were significantly different only in patients with WT-TERT (P = 0. 001, P = 0. 019, and P = 0. 005, respectively). Conclusions The data suggested that 2 cm may be a critical threshold diameter for deciding completion thyroidectomy in MI-FTC with M-TERT and EA-FTC with M-TERT. TERT promoter mutational status can be a game changer for selecting candidates for completion thyroidectomy. Presentation: No date and time listed

OR26-1 Alternative Polyadenylation as a Therapeutic Vulnerability in Prostate Cancer

Abstract Prostate cancer is the second leading cause of male cancer death in the United States. While localized disease can be cured by radiation or surgery, metastatic prostate cancer presents a clinical challenge. Metastatic prostate cancer can initially be controlled by endocrine therapies that target the androgen receptor (AR), however, these tumors will inevitably develop resistance. This stage of the disease, termed castration-resistant prostate cancer (CRPC), is responsible for the majority of prostate cancer-specific deaths. Truncated AR variant (AR-V) proteins are broadly enriched in CRPC cell lines and clinical samples, and can function as ligand-independent, constitutively active transcription factors. We found that blocking an alternative poly(A) site located in AR intron 3 reduced expression of multiple AR-V mRNA and protein species and increased expression of full-length (FL) AR mRNA and protein in 22Rv1 and LNCaP95 CRPC cells. We found the cleavage and polyadenylation specificity factor (CPSF) component, CPSF1, regulates selection of this alternative poly(A) site based on the finding that knockdown of CPSF1 also reduced expression of AR-Vs and increased expression of FL-AR in 22Rv1 and LNCaP95 cells. Further, knockdown of CPSF1 inhibited growth of these CRPC cell lines, as well as androgen-dependent LNCaP cells. To define how CPSF1 regulates alternative polyadenylation of AR and to determine novel pathways that are manipulated by CPSF1 in prostate cancer, we identified CPSF1-dependent gene expression using RNA-seq and CPSF1-dependent poly(A) site usage using poly(A)-ClickSeq (PAC-Seq). Gene set enrichment analysis of RNA-seq data revealed the Glycolysis Hallmark gene was positively regulated by CPSF1, and nominated multiple differentially-expressed genes encoding regulators of glycolysis as CPSF1 targets. These results highlight AR independent pathways that are also regulated by CPSF1 in prostate cancer. We are currently integrating RNA-Seq and PAC-seq datasets to define novel CPSF1 regulated pathways that can be targeted therapeutically in prostate cancer. This research will determine trans-acting factors and cis-regulatory elements that drive alternative polyadenylation of AR mRNA transcripts to promote CRPC progression. This research will also identify AR independent targets of CPSF1 that could be exploited for development of new therapies for CRPC. Presentation: Monday, June 13, 2022 11:00 a.m. - 11:15 a.m.

Prognostic effects of surgery or radiotherapy on adenoid cystic carcinoma of the head and neck: a retrospective cohort study

There is little evidence exploring prognostic effects of surgery and radiotherapy on adenoid cystic carcinoma (ACC) of the head and neck. This study sought to evaluate the prognostic effects of surgery or radiotherapy on ACC of the salivary gland, oropharynx, and nose, nasal cavity, and middle ear. In this cohort study, the data of 2,392 participants with ACC of the head and neck were extracted from the Surveillance, Epidemiology and End Results (SEER) database. Participants were divided into the salivary gland group (n=1,351), the mouth and oropharynx group (n=563), and the nose, nasal cavity, and middle ear group (n=478). Baseline characteristics were assessed via questionnaires or laboratory analysis and outcome variables were all-cause death and cancer-specific death of patients. Baseline data were collected in 2004, and patients were followed-up to 2016. The survival time of patients were recorded. Univariate and multivariate Cox regression analyses explored the effects of surgery and radiotherapy on overall prognosis of ACC patients. Fine-Gray test assessed the effects of surgery and radiotherapy on cancer-specific mortality of ACC patients. In total, 766 died and 1,626 survived with a median survival time of 9.92 years. After adjusting for confounders, patients with ACC of the salivary gland who underwent surgery had a decreased risk of all-cause mortality [hazard ratio (HR) =0.51; 95% confidence interval (CI): 0.36-0.71] and cancer-specific mortality (HR =0.57; 95% CI: 0.34-0.97). Surgery was found to be a protective factor for the risk of all-cause mortality (HR =0.47; 95% CI: 0.28-0.78) and cancer-specific mortality (HR =0.70; 95% CI: 0.33-1.50) of patients with ACC of the mouth and oropharynx after adjusting for confounders. After adjusting for confounders, patients with ACC of the nose, nasal cavity, and middle ear who underwent surgery had a decreased risk of all-cause mortality (HR =0.46; 95% CI: 0.30-0.70) and cancer-specific mortality (HR =0.35; 95% CI: 0.20-0.61). Surgery was associated with a decreased risk of mortality in patients with ACC of the salivary gland, oropharynx, and nose, nasal cavity, and middle ear, which suggested the value of surgery for improving their prognosis.

Metabolomic profile of prostate cancer-specific survival among 1812 Finnish men

BackgroundAbnormal metabolism and perturbations in metabolic pathways play significant roles in the development and progression of prostate cancer; however, comprehensive metabolomic analyses of human data are lacking and needed to elucidate the interrelationships.MethodsWe examined the serum metabolome in relation to prostate cancer survival in a cohort of 1812 cases in the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study. Using an ultrahigh-performance LC-MS/MS platform, we identified 961 known metabolites in prospectively collected serum. Median survival time from diagnosis to prostate cancer-specific death (N=472) was 6.6 years (interquartile range=2.9–11.1 years). Cox proportional hazards regression models estimated hazard ratios and 95% confidence intervals of the associations between the serum metabolites (in quartiles) and prostate cancer death, adjusted for age at baseline and diagnosis, disease stage, and Gleason sum. In order to calculate risk scores, we first randomly divided the metabolomic data into a discovery set (70%) and validated in a replication set (30%).ResultsOverall, 49 metabolites were associated with prostate cancer survival after Bonferroni correction. Notably, higher levels of the phospholipid choline, amino acid glutamate, long-chain polyunsaturated fatty acid (n6) arachidonate (20:4n6), and glutamyl amino acids gamma-glutamylglutamate, gamma-glutamylglycine, and gamma-glutamylleucine were associated with increased risk of prostate cancer-specific mortality (fourth versus first quartile HRs=2.07–2.14; P-values <5.2×10−5). By contrast, the ascorbate/aldarate metabolite oxalate, xenobiotics S-carboxymethyl-L-cysteine, fibrinogen cleavage peptides ADpSGEGDFXAEGGGVR and fibrinopeptide B (1-12) were related to reduced disease-specific mortality (fourth versus first quartile HRs=0.82–0.84; P-value <5.2×10−5). Further adjustment for years from blood collection to cancer diagnosis, body mass index, smoking intensity and duration, and serum total and high-density lipoprotein cholesterol did not alter the results. Participants with a higher metabolic score based on the discovery set had an elevated risk of prostate cancer-specific mortality in the replication set (fourth versus first quartile, HR=3.9, P-value for trend<0.0001).ConclusionsThe metabolic traits identified in this study, including for choline, glutamate, arachidonate, gamma-glutamyl amino acids, fibrinopeptides, and endocannabinoid and redox pathways and their composite risk score, corroborate our previous analysis of fatal prostate cancer and provide novel insights and potential leads regarding the molecular basis of prostate cancer progression and mortality.

Racial Disparity in Accessibility and Outcomes of Adjuvant Radiotherapy in Stage I High Intermediate Risk Endometrial Adenocarcinoma: A National Database Study

<h3>Purpose/Objective(s)</h3> Based on PORTEC-2 study in 2010, vaginal brachytherapy (VB) was found to be non-inferior to whole pelvic radiation (WPRT) in terms of survival and loco-regional control with a more favorable toxicity Profile. VB is now the preferred choice of adjuvant treatment in patients with high-intermediate risk (HIR) endometrial cancer, especially those with negative Lymphovascular space invasion. In this study we assessed the accessibility and outcomes of this recommended regimen in the different groups of race/ethnicity. <h3>Materials/Methods</h3> The Surveillance, Epidemiologic, and End Results (SEER) database was used to identify patients who met PORTEC-2 inclusion criteria. All patients underwent surgery followed by either vaginal brachytherapy (VB) or whole pelvic radiation (WPRT). Patients with stage I disease, grade 1 with ≥ 50% myometrial invasion (MI), grade 2 with any invasion, and grade 3 with < 50% MI were included in the analysis. Patients were excluded if any lymph nodes were examined or involved, if they received any chemotherapy. Lymphovascular space invasion was not available in the database. HIR endometrial adenocarcinoma was defined as the presence of 2 of the following: age>60, grade 3, and ≥50% myometrial invasion. Radiation status was extracted from the SEER Radiation/Chemotherapy database. Race/ethnicity was defined as non-Hispanic White (NHW), non-Hispanic Black (NHB), Hispanic and others/unknown. Cox regression analysis was performed to calculate hazard of cancer specific death and overall death both before and after counting for race/ethnicity with following variables in the model: grade, radiation status, myometrial invasion. <h3>Results</h3> Between 2005- 2015, 571 patients met PORTEC-2 inclusion criteria of whom 349 (61.1%) and 222 (38.9%) received WPRT and VB, respectively. Rate of VB was 38.9% overall, 41.1% in NHW however 29.0% in H and only 27.0% in NHB (p<0.05). There was no difference in grade and myometrial invasion between the study groups nor within categories of race/ethnicity (p=0.21 and 0.89, respectively). Cox regression analysis revealed an overall 66% decrease in the hazard of cancer specific death in the VB group as compared to WPRT group (HR=0.34, 95% CI: 0.16-0.73, p<0.01); this decrease was 67% in non-Hispanic White subjects (HR=0.33, 95% CI: 0.12-0.86, p<0.05) however no significant change was noted in NHB (HR=0.55, 95% CI: 0.11-2.67, p=0.45). Moreover, after adjusting for confounding variables, hazard of cancer specific death in NHB was 2.62 times higher than NHW (HR=2.62, 95% CI: 1.22-5.62, p=0.01). <h3>Conclusion</h3> Administration of VB following surgery has become significantly more popular after publication of the PORTEC-2 results however racial disparity exists against both accessibility to and outcomes of this treatment modality. Being a NHB is a risk factor for lack of accessibility as well as failure to respond to PORTEC-2 regimen; future studies on genetic predispositions are recommended.