The collective discussion during the NCI course highlighted the pervasiveness of health disparities across all areas represented by course participants and suggested these issues are the largest impediment to achieving cancer prevention goals.
The prognosis of endometrial cancer is strongly associated with stage at diagnosis, suggesting that early detection may reduce mortality. Women who are diagnosed with endometrial carcinoma often have a lengthy history of vaginal bleeding, which offers an opportunity for early diagnosis and curative treatment. We performed DNA methylation profiling on population-based endometrial cancers to identify early detection biomarkers and replicated top candidates in two independent studies. We compared DNA methylation values of 1,500 probes representing 807 genes in 148 population-based endometrial carcinoma samples and 23 benign endometrial tissues. Markers were replicated in another set of 69 carcinomas and 40 benign tissues profiled on the same platform. Further replication was conducted in The Cancer Genome Atlas and in prospectively collected endometrial brushings from women with and without endometrial carcinomas. We identified 114 CpG sites showing methylation differences with p values of ≤ 10(-7) between endometrial carcinoma and normal endometrium. Eight genes (ADCYAP1, ASCL2, HS3ST2, HTR1B, MME, NPY and SOX1) were selected for further replication. Age-adjusted odds ratios for endometrial cancer ranged from 3.44 (95%-CI: 1.33-8.91) for ASCL2 to 18.61 (95%-CI: 5.50-62.97) for HTR1B. An area under the curve (AUC) of 0.93 was achieved for discriminating carcinoma from benign endometrium. Replication in The Cancer Genome Atlas and in endometrial brushings from an independent study confirmed the candidate markers. This study demonstrates that methylation markers may be used to evaluate women with abnormal vaginal bleeding to distinguish women with endometrial carcinoma from the majority of women without malignancy.
In patients with advanced non-small-cell lung cancer (aNSCLC), tumor mutational burden (TMB) may vary by genomic ancestry; however, its impact on treatment outcomes is unclear. This retrospective, observational study describes treatment patterns of patients with aNSCLC by genomic ancestry and electronic health record (EHR)-reported race and/or ethnicity and evaluates differences in TMB, cancer immunotherapy (CIT) access, and treatment outcomes across racial and ancestral groups.Patients diagnosed with aNSCLC after January 1, 2011, were selected from a real-world deidentified clinicogenomics database and EHR-derived database; continuously enrolled patients were evaluated. Race and/or ethnicity was recorded using variables from the EHR database; genomic ancestry was classified by single-nucleotide polymorphisms on a next-generation sequencing panel. A threshold of 16 mutations per megabase was used to categorize TMB status.Of 59,559 patients in the EHR-derived database and 7,548 patients in the clinicogenomics database, 35,016 (58.8%) and 4,392 (58.2%) were continuously enrolled, respectively. CIT use was similar across EHR-reported race groups, ranging from 34.4% to 37.3% for non-Hispanic Asian and non-Hispanic Black patients, respectively. TMB levels varied significantly across ancestry groups (P < .001); patients of African ancestry had the highest median TMB (8.75 mutations per megabase; interquartile range, 4.35-14.79). In patients who had received CIT, high TMB was associated with improved overall survival compared with low TMB (20.89 v 11.83 months; hazard ratio, 0.60; 95% CI, 0.51 to 0.70) across genomic ancestral groups.These results suggest that equitable access to next-generation sequencing may improve aNSCLC outcome disparities in racially and ancestrally diverse populations.
742 Background: The anatomical side of the colon where a tumor arises has been shown to be prognostic in patients treated with first-line therapy; patients with tumors that arise from the left side of the colon have significantly longer survival compared with patients whose tumors arise from the right side of the colon. However, there is little evidence of whether this factor is prognostic in later lines of treatment. The objective of this study was to determine the impact of tumor side on the survival of metastatic colorectal cancer patients who received second line (2L) or third line (3L) therapy. Methods: Metastatic (stage IV) colorectal cancer patients in the Surveillance, Epidemiology, and End Results (SEER) database linked to Medicare claims diagnosed 2001-2005 who received 2L (n = 921) or 3L (n = 502) therapy were included in the study. Overall survival (OS) was determined from the start of the indicated line of therapy and was estimated using the Kaplan-Meier method; statistical differences were tested using the log-rank tests. Results: The distribution of tumor sites was similar for 2L and 3L treated patients (right: 36%; left: 58%; transverse: 6%; for 2L). The median follow up time from start of therapy was 11 months (mo) for 2L and 10 mo for 3L patients. Median OS for left-sided tumors receiving 2L+ therapy was 13.6 mo (95%CI: 11.9, 14.8) compared with 8.7 mo (95%CI: 7.5, 9.9) for right-sided tumors (log-rank p < 0.001). Similar results were seen in patients receiving 3L+ therapy, although the difference was of lesser magnitude. The median OS for patients with left-sided tumors was 10.8 mo (95%CI: 9.6, 12.9) compared with 7.6 mo (95%CI: 5.7, 9.4) for right-sided tumors (log-rank p = 0.002). Conclusions: These results suggest that side of tumor origin remains a prognostic factor for colorectal cancer patients treated in later lines of therapy (2L+).
Human papillomavirus (HPV) testing has been recently introduced as an alternative to cytology for cervical cancer screening. However, since most HPV infections clear without causing clinically relevant lesions, additional triage tests are required to identify women who are at high risk of developing cancer. We performed DNA methylation profiling on formalin-fixed, paraffin-embedded tissue specimens from women with benign HPV16 infection and histologically confirmed cervical intraepithelial neoplasia grade 3, and cancer using a bead-based microarray covering 1,500 CpG sites in over 800 genes. Methylation levels in individual CpG sites were compared using a t-test, and results were summarized by computing p-values. A total of 12 candidate genes (ADCYAP1, ASCL1, ATP10, CADM1, DCC, DBC1, HS3ST2, MOS, MYOD1, SOX1, SOX17 and TMEFF2) identified by DNA methylation profiling, plus an additional three genes identified from the literature (EPB41L3, MAL and miR-124) were chosen for validation in an independent set of 167 liquid-based cytology specimens using pyrosequencing and targeted, next-generation bisulfite sequencing. Of the 15 candidate gene markers, 10 had an area under the curve (AUC) of ≥ 0.75 for discrimination of high grade squamous intraepithelial lesions or worse (HSIL+) from
Abstract Background: Corticosteroids (CS) are often prescribed with cancer treatment to alleviate symptoms, treat comorbidities and manage treatment-related adverse events. The immunosuppressive properties of CS may decrease the effectiveness of cancer immunotherapy (CIT), and the effect may vary by tumor site. This study explored the association of baseline CS (bCS) use with time to next treatment (TTNT) in CIT-treated patients with advanced melanoma (aMel), advanced non-small cell lung cancer (aNSCLC) or advanced urothelial cancer (aUC). Methods: The Flatiron Health electronic health record-derived de-identified database was used to select patients diagnosed with aMel, aNSCLC or aUC between January 1, 2011, and June 30, 2017, who received CIT alone in any treatment line and were followed through March 30, 2018. bCS included intramuscular or intravenous administrations or oral orders ≤ 14 days before and ≤ 30 days after the CIT start date. TTNT is a measure of intermediate outcomes, such as cancer progression, in real-world data sources. A TTNT event was defined as initiation of a new line of non-maintenance treatment or death within 60 days of the last CIT treatment during the index line of therapy. Other patients were censored at the latter of either their last CIT administration or last recorded visit. The association of bCS with TTNT was estimated using multivariable Cox proportional hazards models adjusting for key baseline characteristics, including prior CS use. Results: Most patients were white men aged 66 to 72 years; median follow-up across tumor types was 3.9 to 5.5 months. One-fifth to one-third (19%-30%) of patients received bCS. More than half of patients (58%-61%) received a new treatment line during the study period, the milestone for measuring TTNT. Patients receiving bCS were more likely to have stage IV disease at diagnosis, brain or liver metastases (aNSCLC, aUC) and poorer ECOG performance status (aUC) at baseline. After adjusting for these and other important potential confounders, including prior CS use, bCS use was associated with shorter TTNT compared with no bCS use in multivariable models (aMel HR, 1.28 [95% CI: 1.03, 1.58]; aNSCLC HR, 1.40 [1.16, 1.70]; aUC HR, 1.36 [1.06, 1.82]). Conclusions: After adjustments for measured confounders, patients receiving bCS had a shorter TTNT than those who did not receive bCS, suggesting a shorter treatment duration that may limit the potential long-term benefits of CIT use. TTNT is commonly used as a proxy for disease progression in real-world data sources; however, treatment changes could be due to reasons other than progression. Further studies are needed to confirm these observations. Keywords/Indexing: Lung cancer: non-small cell; Melanoma/skin cancers [A.D. and P.K.D. contributed equally to this work.] Citation Format: Alexandra Drakaki, Preet K. Dhillon, Heather Wakelee, Stephen Y. Chui, Jinjoo Shim, Matthew Kent, Viraj Degaonkar, Tien Hoang, Virginia McNally, Patricia Luhn, Ralf Gutzmer. Association of baseline systemic corticosteroid use with time to next treatment in patients with advanced melanoma, non-small cell lung cancer or urothelial cancer receiving cancer immunotherapy in US clinical practice [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 5388.
Abstract Background: Increased risk for endometrial cancer is related to factors such as use of unopposed estrogen and obesity, and decreased risk is associated with oral contraceptive use and smoking. However, little is known about the molecular mechanisms by which these factors influence cancer risk. DNA methylation of promoter regions in tumor suppressor genes has been linked to endometrial cancer, suggesting DNA methylation may mediate the effects of risk factors on normal endometrium, leading to increased risk for cancer. Accordingly, we explored relationships between risk factors for endometrial cancer and DNA methylation patterns assessed in normal endometrial tissue. Materials and Methods: Formalin fixed paraffin embedded endometrial tissues from 63 women aged 28-53 (median= 43) who underwent a hysterectomy for benign indications were studied. DNA isolated from 1.0-mm cores was bisulfite treated and methylation profiles were generated using Illumina's GoldenGate array which includes 1505 CpG sites representing over 800 genes. Unsupervised hierarchical clustering analysis was used to identify groups of patients with similar methylation patterns and class comparison analysis was employed to identify differentially methylated genes based on predefined categories, representing endometrial cancer risk factors. Results: Global changes in DNA methylation, as measured by total or average methylation levels or clustering analysis were not associated with age. However, methylation levels of MT1A (p=0.0002) and CDH13 (p=0.0009) were increased and methylation levels of PKD2 (p=0.0009) were decreased among older women. Increased methylation of HS3ST2 (p=0.00006), MLF1 (p=0.0001), PLAUR (p=0.0004), MLH3 (p=0.0007), ISL1 (p=0.0007), and RASSF1 (p=0.0009) was related to women with a lifetime menstrual span of more than 30 years compared to those who reported having menstruated for less than 15 years. One gene (MMP3) was more methylated in women who had an older age at menarche (14+ years old) compared to those who had a younger age at menarche (<12 years old, p=0.0008). Furthermore, unsupervised hierarchical clustering suggested that age at menarche (p=0.05) distinguished three groups of women who had distinct methylation patterns. Conclusions: Our results suggest that DNA methylation patterns at specific loci from normal tissue are related to attained age, age at menarche and the lifetime menstrual span of women. In conjunction with methylation profiling of endometrial cancer, these data may demonstrate the importance of DNA methylation as a mechanism in the pathogenesis of endometrial cancer and lead to potential biomarkers for early detection. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4475. doi:1538-7445.AM2012-4475
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