Anna E. Coghill

BRAF Mutation Status and Survival after Colorectal Cancer Diagnosis According to Patient and Tumor Characteristics

Background: BRAF mutations in colorectal cancer (CRC) are disproportionately observed in tumors exhibiting microsatellite instability (MSI) and are associated with other prognostic factors. The independent association between BRAF mutation status and CRC survival, however, remains unclear. Methods: We evaluated the association between the BRAF c.1799T>A (p.V600E) mutation and survival in individuals with incident invasive CRC diagnosed between 1997 and 2007 in Western Washington State. Tumor specimens were tested for this BRAF mutation and MSI status. We used Cox regression to estimate HRs and 95% confidence intervals (CI) for the association between BRAF mutation status and disease-specific and overall survival. Stratified analyses were conducted by age, sex, tumor site, stage, and MSI status. Results: Among 1,980 cases tested, 12% were BRAF c.1799T>A (p.V600E) mutation–positive (n = 247). BRAF-mutated CRC was associated with poorer disease-specific survival adjusting for age, sex, time from diagnosis to enrollment, stage, and MSI status (HR, 1.43; 95% CI, 1.05–1.95). This association was limited to cases diagnosed at ages <50 (HR, 3.06; 95% CI, 1.70–5.52) and was not evident in cases with MSI-high tumors (HR, 0.94; 95% CI, 0.44–2.03). Associations with overall survival were similar. Conclusions: Our results show that the prevalence of BRAF mutations in CRC differs by patient and tumor characteristics and suggest that the association between BRAF status and CRC survival may differ by some of these factors. Impact: The presence of a BRAF c.1799T>A (p.V600E) mutation is associated with significantly poorer prognosis after CRC diagnosis among subgroups of patients. Cancer Epidemiol Biomarkers Prev; 21(10); 1792–8. ©2012 AACR.

Elevated Cancer-Specific Mortality Among HIV-Infected Patients in the United States

PURPOSE Despite advances in the treatment of HIV, HIV-infected people remain at increased risk for many cancers, and the number of non-AIDS-defining cancers is increasing with the aging of the HIV-infected population. No prior study has comprehensively evaluated the effect of HIV on cancer-specific mortality. PATIENTS AND METHODS We identified cases of 14 common cancers occurring from 1996 to 2010 in six US states participating in a linkage of cancer and HIV/AIDS registries. We used Cox regression to examine the association between patient HIV status and death resulting from the presenting cancer (ascertained from death certificates), adjusting for age, sex, race/ethnicity, year of cancer diagnosis, and cancer stage. We included 1,816,461 patients with cancer, 6,459 (0.36%) of whom were HIV infected. RESULTS Cancer-specific mortality was significantly elevated in HIV-infected compared with HIV-uninfected patients for many cancers: colorectum (adjusted hazard ratio [HR], 1.49; 95% CI, 1.21 to 1.84), pancreas (HR, 1.71; 95% CI, 1.35 to 2.18), larynx (HR, 1.62; 95% CI, 1.06 to 2.47), lung (HR, 1.28; 95% CI, 1.17 to 1.39), melanoma (HR, 1.72; 95% CI, 1.09 to 2.70), breast (HR, 2.61; 95% CI, 2.06 to 3.31), and prostate (HR, 1.57; 95% CI, 1.02 to 2.41). HIV was not associated with increased cancer-specific mortality for anal cancer, Hodgkin lymphoma, or diffuse large B-cell lymphoma. After further adjustment for cancer treatment, HIV remained associated with elevated cancer-specific mortality for common non-AIDS-defining cancers: colorectum (HR, 1.40; 95% CI, 1.09 to 1.80), lung (HR, 1.28; 95% CI, 1.14 to 1.44), melanoma (HR, 1.93; 95% CI, 1.14 to 3.27), and breast (HR, 2.64; 95% CI, 1.86 to 3.73). CONCLUSION HIV-infected patients with cancer experienced higher cancer-specific mortality than HIV-uninfected patients, independent of cancer stage or receipt of cancer treatment. The elevation in cancer-specific mortality among HIV-infected patients may be attributable to unmeasured stage or treatment differences as well as a direct relationship between immunosuppression and tumor progression.

Prediagnostic non-steroidal anti-inflammatory drug use and survival after diagnosis of colorectal cancer

Objective Non-steroidal anti-inflammatory drug (NSAID) use decreases both the incidence of colorectal cancer and recurrence of adenomas among patients with prior colorectal neoplasia. However, few studies have investigated the association between NSAID use and colorectal cancer-specific survival. The role of prediagnostic NSAID use was therefore examined in relation to colorectal cancer-specific survival among cases from the Seattle Colon Cancer Family Registry (Seattle Colon CFR). Methods This was a follow-up study that included incident cases of colorectal cancer from the Seattle Colon CFR. Cases were aged 20–74, diagnosed from 1997 to 2002, and were identified using the population-based Puget Sound SEER registry. Detailed information on history of NSAID use, including type, recency and duration, was collected through an interviewer-administered questionnaire. Follow-up for mortality was completed through linkages to the National Death Index. The main outcome measure was death due to colorectal cancer after diagnosis. Cox proportional hazards regression was used to investigate the relationship between prediagnostic NSAID use and colorectal cancer-specific mortality among cases. Results NSAID use prior to colorectal cancer diagnosis was associated with an ∼20% lower rate of colorectal cancer mortality after diagnosis compared with never use (HR 0.79; 95% CI 0.65 to 0.97). This relationship appeared to be duration dependent, with longer reported use prior to diagnosis associated with lower rates of colorectal cancer mortality among cases. The most pronounced reductions in mortality were observed among cases diagnosed with proximal disease (HR 0.55; 95% CI 0.37 to 0.82), whereas no association was observed between NSAID use prior to diagnosis and colorectal cancer-specific mortality among cases diagnosed with distal or rectal disease. Conclusions The findings suggest that regular use of NSAIDs prior to diagnosis is associated with improved colorectal cancer survival, particularly among cases diagnosed with proximal disease and in longer term NSAID users.

Anal Cancer Incidence in the United States, 1977–2011: Distinct Patterns by Histology and Behavior

Background: Although anal squamous cell carcinoma (SCC) and adenocarcinoma (ADC) are generally combined in cancer surveillance, their etiologies likely differ. Here, we describe demographic characteristics and trends in incidence rates (IR) of anal cancer by histology (SCC, ADC) and behavior (invasive, in situ) in the United States. Methods: With data from the Surveillance, Epidemiology, and End Results (SEER) Program, we estimated age-adjusted anal cancer IRs across behavior/histology by demographic and tumor characteristics for 2000–2011. Trends in IRs and annual percent changes during 1977–2011 were also estimated and compared with rectal cancer. Results: Women had higher rates of SCC [rate ratio (RR), 1.45; 95% confidence interval (CI), 1.40–1.50] and lower rates of ADC (RR, 0.68; 95% CI, 0.62–0.74) and squamous carcinoma in situ (CIS; RR, 0.36; 95% CI, 0.34–0.38) than men. Blacks had lower rates of SCC (RR, 0.82; 95% CI, 0.77–0.87) and CIS (RR, 0.90; 95% CI, 0.83–0.98) than non-Hispanic whites, but higher rates of ADC (RR, 1.48; 95% CI, 1.29–1.70). Anal cancer IRs were higher in men and blacks aged <40 years. During 1992–2011, SCC IRs increased 2.9%/year, ADC IRs declined nonsignificantly, and CIS IRs increased 14.2%/year. SCC and ADC IR patterns and trends were similar across anal and rectal cancers. Conclusions: Rates of anal SCC and CIS have increased strongly over time, in contrast to rates of anal ADC, similar to trends observed for rectal SCC and ADC. Impact: Anal SCC and ADC likely have different etiologies, but may have similar etiologies to rectal SCC and ADC, respectively. Strong increases in CIS IRs over time may reflect anal cancer screening patterns. Cancer Epidemiol Biomarkers Prev; 24(10); 1548–56. ©2015 AACR.

Epstein-Barr Virus Antibodies and the Risk of Associated Malignancies: Review of the Literature

Epstein-Barr virus (EBV), a ubiquitous herpes virus that infects 90% of humans by adulthood, is linked to the development of various cancers, including nasopharyngeal carcinoma, gastric cancer, Burkitt lymphoma, non-Hodgkin lymphoma (NHL), and Hodgkin lymphoma. We reviewed the literature published since 1980 regarding an association between antibodies against EBV proteins and the risk of EBV-associated malignancies. Immunoglobulin A antibody levels that are elevated before diagnosis have consistently been associated with the risk of nasopharyngeal carcinoma, and patients with Hodgkin lymphoma have significantly higher immunoglobulin G antibody levels than disease-free controls. However, the link between the immune response to EBV and other EBV-associated malignancies was less clear. Although evidence of an association between the risk of Burkitt lymphoma and immunoglobulin G antibodies was consistent for available studies, the sample sizes were limited. Evidence for a link between antibodies against EBV and risk of either gastric cancer or NHL was inconsistent. Future investigations should account for tumor EBV status because only 7%-10% of gastric tumors and select NHL subtypes are related to EBV infection. Comparing differences in the associations between the humoral immune response to EBV and disease risk across cancers may help elucidate how this ubiquitous virus contributes to distinct tumors globally.

Contribution of HIV infection to mortality among cancer patients in Uganda

Objective:HIV infection is associated with cancer risk. This relationship has resulted in a growing cancer burden, especially in resource-limited countries where HIV is highly prevalent. Little is known, however, about how HIV affects cancer survival in these settings. We therefore investigated the role of HIV in cancer survival in Uganda. Design:Retrospective cohort (N = 802). Methods:Eligible cancer patients were residents of Kyadondo County, at least 18 years of age at cancer diagnosis, and diagnosed between 2003 and 2010 with one of the following: breast cancer, cervical cancer, non-Hodgkins lymphoma, Hodgkins lymphoma, or esophageal cancer. Patients were classified as HIV-infected at cancer diagnosis based on a documented positive HIV antibody test, medical history indicating HIV infection, or an HIV clinic referral letter. The primary outcome, vital status at 1 year following cancer diagnosis, was abstracted from the medical record or determined through linkage to the national hospice database. The risk of death during the year after cancer diagnosis was compared between cancer patients with and without evidence of HIV infection using Cox proportional hazards regression. Results:HIV-infected cancer patients in Uganda experienced a more than two-fold increased risk of death during the year following cancer diagnosis compared to HIV-uninfected cancer patients [hazard ratio 2.28; 95% confidence interval (CI) 1.61–3.23]. This association between HIV and 1-year cancer survival was observed for both cancers with (hazard ratio 1.56; 95% CI 1.04–2.34) and without (hazard ratio 2.68; 95% CI 1.20–5.99) an infectious cause. Conclusion:This study demonstrates the role of HIV in cancer survival for both cancers with and without an infectious cause in a resource-limited, HIV-endemic setting.

Pre-diagnostic NSAID use but not hormone therapy is associated with improved colorectal cancer survival in women

Background:Non-steroidal anti-inflammatory drugs (NSAIDs) and hormone therapy (HT) independently decrease the risk of colorectal cancer. However, their role in altering survival after a colorectal cancer diagnosis is not well established.Methods:We examined the association between the use of these common medications before diagnosis and colorectal cancer survival among women in western Washington State diagnosed with incident colorectal cancer from 1997 to 2002. Cases were ascertained using the Surveillance, Epidemiology and End Results cancer registry; mortality follow-up was completed through linkages to the National Death Index. Cox proportional hazards regression was used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs).Results:We observed no overall association between colorectal cancer survival and pre-diagnostic NSAID use. However, when stratified by tumour sub-site, NSAID use was associated with a reduced risk of colorectal cancer mortality for women diagnosed with proximal (HR=0.55; 95% CI: 0.32–0.92), but not distal or rectal (HR=1.32; 95% CI: 0.83–2.10) tumours. The usage of HT was not associated with colorectal cancer survival overall or by tumour sub-site.Conclusion:Usage of NSAIDs before diagnosis may be associated with improved colorectal cancer survival among women diagnosed with proximal tumours. The usage of HT does not appear to have a function in altering colorectal cancer mortality.

Common single nucleotide polymorphisms in the estrogen receptor β promoter are associated with colorectal cancer survival in postmenopausal women

Loss of estrogen receptor β (ERβ) expression in the gut is associated with colorectal cancer (CRC) initiation and progression. Germline single-nucleotide polymorphisms (SNP) in genes for the sex-steroid hormone receptors are not strongly associated with CRC risk; however, these SNPs have not previously been evaluated in relation to survival after diagnosis. We enrolled 729 women, ages 50 to 74, diagnosed with invasive CRC between 1997 and 2002 in 13 counties covered by the Seattle-Puget Sound Surveillance Epidemiology and End Results cancer registry. Participants provided germline DNA. We selected 99 tag-SNPs for the androgen receptor (AR), ERα (ESR1), ERβ (ESR2), and progesterone receptor (PGR) genes. Mortality outcomes were ascertained from the National Death Index. During a median of 6.6 years of follow-up, 244 deaths occurred (161 from CRC). We identified 20 SNPs (12 of ESR2 and 8 of PGR) for replication in 1,729 women diagnosed with incident invasive CRC (555 deaths; 405 from CRC) from three prospective cohort studies that participate in the Genetics and Epidemiology of Colorectal Cancer Consortium. Three correlated SNPs in the promoter of ESR2 (rs2987983, rs3020443, and rs2978381) were statistically significant predictors of CRC-specific and overall survival. Minor alleles of each were associated with improved survival [for rs2987983, CRC-specific HR, 0.77; 95% confidence interval (CI), 0.60-0.99 in the initial study, and HR, 0.79; CI, 0.64-0.98 in replication]. No associations were noted for SNPs of AR, ESR1, or PGR. SNPs in the promoter of ESR2 may be important to pathways related to the association between ERβ and tumor progression and metastasis.

Risk factors for eclampsia: a population-based study in Washington State, 1987-2007

OBJECTIVE We sought to investigate whether previously identified risk factors are associated with eclampsia in a contemporary, heterogeneous cohort of women. STUDY DESIGN Data were collected from birth certificate and hospital discharge records and used to conduct a population-based case-control study among women giving birth to singletons in Washington State from 1987 through 2007. We used multivariable logistic regression to estimate odds ratios and 95% confidence intervals. Multiple imputation procedures were used to address missing data. RESULTS Risk of eclampsia was greater in nulliparous compared to parous women. Being a young mother (< 20 years) or an older mother (≥ 35 years) were each associated with elevated eclampsia risk. Longer birth interval, low socioeconomic status, gestational diabetes, prepregnancy obesity, and weight gain during pregnancy above or below recommended guidelines were positively associated with eclampsia. Multiparity and smoking were inversely associated with eclampsia risk. CONCLUSION Exposures identified more than a decade ago continue to be associated with eclampsia in contemporary birth cohorts.

Epstein–Barr Virus Serology as a Potential Screening Marker for Nasopharyngeal Carcinoma among High-Risk Individuals from Multiplex Families in Taiwan

Background: Nasopharyngeal carcinoma (NPC) is an Epstein–Barr virus (EBV)–associated cancer that is highly treatable when diagnosed early, with 5-year disease-free survival of approximately 90%. However, NPC is typically diagnosed at advanced stages, in which disease-free survival is <50%. There is, therefore, a need for clinical tools to assist in early NPC detection, particularly among high-risk individuals. Methods: We evaluated the ability of anti-EBV IgA antibodies to detect incident NPC among high-risk Taiwanese individuals. NPC cases (N = 21) and age- and sex-matched controls (N = 84) were selected. Serum collected before NPC diagnosis was tested for ELISA-based IgA antibodies against the following EBV peptides: EBNA1, VCAp18, EAp138, Ead_p47, and VCAp18 + EBNA1 peptide mixture. The sensitivity, specificity, and screening program parameters were calculated. Results: EBNA1 IgA had the best performance characteristics. At an optimized threshold value, EBNA1 IgA measured at baseline identified 80% of the high-risk individuals who developed NPC during follow-up (80% sensitivity). However, approximately 40% of high-risk individuals who did not develop NPC also tested positive (false positives). Application of EBNA1 IgA as a biomarker to detect incident NPC in a previously unscreened, high-risk population revealed that 164 individuals needed to be screened to detect 1 NPC and that 69 individuals tested positive per case detected. Conclusions: EBNA1 IgA proved to be a sensitive biomarker for identifying incident NPC, but future work is warranted to develop more specific screening tools to decrease the number of false positives. Impact: Results from this study could inform decisions about screening biomarkers and referral thresholds for future NPC early-detection program evaluations. Cancer Epidemiol Biomarkers Prev; 23(7); 1213–9. ©2014 AACR.