Population-based Cohort Of Older Women Research Articles

Characterizing the Impact of Race and Redlining on Receipt of Guideline-Compliant Locoregional Therapy among Older Women with Breast Cancer

Breast cancer (BC) is one of few malignancies in which improved locoregional control has been shown to improve overall survival. Contemporary redlining, or mortgage lending bias on the basis of home location, is a form of structural racism which has been demonstrated to impact BC survival in older patients. Self-reported race has been thought to serve as a surrogate for interpersonal racism and has similarly been shown to have associations with survival, redlining, and access to care. We aim to examine the relationship between race, redlining, and the receipt of guideline compliant locoregional therapy (LRT) in older women with BC. Women aged 66-90 years with an initial Stage I-III BC diagnosis in 2010-2017 and known metropolitan statistical area (MSA) were identified in SEER-Medicare. Redlining was estimated using Home Mortgage Disclosure Act data (2010-2017). Guideline compliant LRT was assessed based on whether patients underwent surgery (lumpectomy or mastectomy), and if surgery was performed, whether they received adjuvant radiation treatment per the National Quality Forum and National Comprehensive Cancer Network guidelines in effect during the study period. A multiple logistic regression model was fitted to estimate ORs for the relationship between redlining and receipt of guideline compliant LRT, accounting for covariates (age, race/ethnicity, comorbidities, dual enrollment, tumor stage, hormone receptor status, census region, and year of diagnosis). Cluster bootstrap at the MSA-level was used to obtain P-values and confidence intervals. The cohort included 64,987 women: 31% aged 66-70, 82% Non-Hispanic (NH) White, 7.4% NH Black, 24% with 2+ comorbidities, 12% with dual Medicaid/Medicare enrollment, 60% stage I, 31% stage II, and 77% HR+/HER2-. Overall, 6.4% did not undergo surgery; 84% received guideline compliant LRT. Women in the highest redlining areas had 81% guideline compliant LRT compared to 84-85% in the least, low and moderate redlined areas (p<0.001). However, model results revealed that contemporary redlining was not a predictor of guideline compliant LRT. NH Black women were less likely than NH White women to receive guideline-compliant LRT (OR 0.77, 95% CI 0.71-0.84, p<0.001). No significant differences were noted between NH White and NH Asian or Hispanic women. In this population-based cohort of older women with breast cancer, NH Black race, even after adjusting for several important clinical and demographic factors, was associated with a lower likelihood of receiving guideline-compliant LRT. This finding demonstrates the profound impact of interpersonal racism on receipt of cancer-directed therapies. Though contemporary redlining did not significantly impact guideline-compliant LRT, further work is needed to identify systematic factors explaining known associations between contemporary redlining and BC survival.

Age and Racial Disparities in the Utilization of Anticancer, Antihypertension, and Anti-diabetes Therapies, and in Mortality in a Large Population-Based Cohort of Older Women with Breast Cancer.

This study examined the receipt of therapies for cancer, hypertension, and diabetes in association with age and racial disparities in mortality among women with breast cancer. This study identified 92,829 women diagnosed with breast cancer at age ≥ 65years in 2007-2015 with follow-up to 2016 from the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database. There were substantial age and racial disparities in the prevalence of hypertension and diabetes, which was higher in women ≥ 75 (86.3% and 32.0%) than younger women 65-74 (72.8% and 29.3%), and the highest in Black women (91.1% and 49.1%), followed by Asian women (80.2% and 40.5%), and White women (77.6 and 27.8%). Black women were significantly less likely to receive chemotherapy (odds ratio: 0.70, 95% CI: 0.64-0.75), radiation therapy (0.87, 0.83-0.92), and hormone therapy (0.80, 0.76-0.85), but significantly more likely to receive antihypertensive (1.26, 1.19-1.33) and antidiabetic (1.19, 1.10-1.28) drugs than White women, after adjusting for sociodemographic and tumor factors. As compared to White women, Black women had a significantly higher risk of all-cause mortality (1.46, 1.41-1.52), but it became insignificant after adjusting for treatment factors (1.01, 0.97-1.06), whereas the adjusted risk of breast cancer-specific mortality remained significantly higher (1.08, 1.01-1.15) in Black women; Asian and other ethnic women had a significantly lower risk of all-cause and breast cancer-specific mortality. There were substantial age and racial disparities in the prevalence of hypertension and diabetes and in the receipt of medications. Black women did not have a significantly higher risk of all-cause mortality but had a significantly higher risk of breast cancer-specific mortality as compared to White women.

Real-world patterns of treatment and recurrence by frailty status among older women with HR-positive, HER2-negative early breast cancer.

535 Background: Frail health status impacts clinical decision making for older cancer patients and their families, and frailty is independently associated with increased risks of mortality. Our objective was to describe differences in treatment and rates of recurrence by frailty status among older women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative early breast cancer. Methods: We performed a large, population-based retrospective cohort study of women aged 65 years and older diagnosed with first primary stage I-III HR+/HER2-breast cancer using the Surveillance, Epidemiology, and End Results Medicare-linked database between 2007 and 2015. Using administrative health claims, we ascertained information on breast cancer treatment and utilized validated claims-based algorithms to determine frailty status (robust, pre-frail, and frail) and identify subsequent invasive breast cancer recurrences. Relative hazards of recurrence were determined using Fine and Gray competing risks regression models with estimated subdistribution hazard ratios (SHR) and robust 95% confidence intervals (CI). Results: From an overall cohort of 46,027 women, most women (56%) were classified as robust at breast cancer diagnosis, whereas 37% and 7% were identified as pre-frail and frail, respectively. Compared to robust patients, frail patients were more likely to have stage III disease (10% vs. 7%) and receive mastectomy (27% vs. 18%), and less likely to receive radiation (35% vs. 57%) or chemotherapy (5% vs. 9%). Five-year cumulative incidences of recurrence were 15%, 18% and 22% among robust, pre-frail, and frail women, respectively. In multivariable competing risks models adjusted for age, race, stage, and treatment, frail (SHR 1.28, 95%CI 1.17-1.41) and pre-frail (SHR 1.15, 95%CI 1.09-1.21) women had a significantly increased risk of breast cancer recurrence. Conclusions: Independent of differences in treatment, frailty was associated with increased breast cancer recurrence risk in this population-based cohort of older women. However, the vast majority of older women living with HR+/HER2- early breast cancer were not identified as frail. These study results suggest that age alone is not an adequate indicator of physical resilience and underscores the need to consider additional factors when assessing the benefits and risks of treatments for the prevention of recurrence among HR+/HER2- early breast cancer patients.

Fractures in a nationwide population-based cohort of users of breast cancer hormonal therapy.

Although users of aromatase inhibitors have higher total fracture risk in some randomized trials, little is known about their risk outside of clinical trials or in older higher-risk cohorts. In a population-based retrospective cohort study, we identified all older US Medicare D prescription drug insurance plan-enrolled women who had initial breast cancer surgery in 2006-2008 and began hormonal therapy (an aromatase inhibitor (AI) or tamoxifen) within the subsequent year. Total nonvertebral and hip fractures through 2012 were identified using a validated algorithm. The association of fracture outcomes with hormonal therapy type was assessed using competing risk regression models that accounted for differences in measured baseline covariates. Treatment assignment bias was reduced using inverse probability of treatment weighting computed from propensity scores. Among 23,378 women taking hormonal therapy (23.2% aged 80 or over), there were 3000 total and 436 hip fractures. Although AI users were younger and had lower comorbidity, after propensity score weighting, these and other covariates were balanced. Total nonvertebral risk was higher for users of AIs compared with tamoxifen, HR 1.11 (1.02-1.21), but the small increase in risk for hip fracture was not statistically significant, HR 1.04 (0.84-1.30). Although total nonvertebral fracture risk was higher among AI users, differences in hip fractures were not significant in a large population-based cohort of older women. Use of aromatase inhibitors by older women is associated with high risk for nonvertebral fracture that is increased compared with use of tamoxifen. Fracture risk should be assessed among patients taking these medications.

Effect of bisphosphonates on knee replacement surgery

PurposeBone remodelling as a therapeutic target in knee osteoarthritis (OA) has gained much interest, but the effects of antiresorptive agents on knee OA have been conflicting, with no studies to...

A six-year trend of the healthcare cost of arthritis in a population-based cohort of older women

ABSTRACT&#x0D; ObjectivesTo examine the trend of the healthcare cost of arthritis in a population-based cohort of older women and to estimate the mean adjusted incremental healthcare costs, and selected percentiles.&#x0D; ApproachThis is a healthcare cost study based on individual-level data. Data included health survey and linked administrative data, from 2003 to 2009, from the Australian Longitudinal Study on Women’s Health. The Medicare Australia datasets include the Pharmaceutical Benefits Scheme (unit record data on claims for government-subsidized prescription medicines) and the Medicare Benefits Schedule (listing of health services subsidized by the Australian Government) datasets; they were the source for all healthcare utilization and cost data in this study. The main outcome measure was the incremental healthcare cost of arthritis (estimated from the Australian Government’s cost perspective) expressed as dollars per person per year. All costs were expressed in 2012 Australian dollars. Regression models were used to estimate the adjusted incremental costs of arthritis. The mean adjusted incremental healthcare cost of arthritis was computed using GLMs with a logarithmic-link function and a gamma distribution for costs. The adjusted incremental costs at the 25th, 50th, 75th, 90th and 95th percentiles were computed using Quantile Regression. These percentiles were chosen because cost data are skewed to the right and it was expected that there would be smaller differences between the lower percentiles but bigger differences between upper adjacent percentiles.&#x0D; ResultsData from 4287 women were included in the analysis. Adjusted incremental healthcare cost of arthritis did not increase significantly from 2003 to 2009. However, there were indications that costs at the lower percentiles decreased slightly over the study period while costs at higher (above 50th) percentiles increased. The estimated median cost was $480 (95% CI: $498 - $759) per person per year in 2009. However, ten percent of women had more than 300% higher cost than the “average person” with arthritis.&#x0D; ConclusionHealthcare cost of arthritis represents a substantial burden. However, considering only overall cost does not provide a detailed picture of expenditure. Our results suggest that higher cost patients had different experiences in arthritis cost over time, compared to patients with lower costs, although overall cost has not increased over time. As healthcare spending is concentrated in the high-cost patients, characterising these patients and formulating initiatives that target them could have a considerable impact on improving care and lowering health expenditure due to arthritis.

Pre-diagnosis health-related quality of life, surgery, and survival in women with advanced epithelial ovarian cancer: A SEER-MHOS study

ObjectiveHealth-related quality of life (HRQOL) has been found to be associated with overall survival in women with ovarian cancer. However, previous studies assessed HRQOL after surgery within clinical trial populations only. The study goal was to determine the association of pre-cancer diagnosis HRQOL with the likelihood of receiving surgery and with overall survival in a national, population-based cohort of older women with advanced ovarian cancer. MethodsThe Surveillance, Epidemiology, and End Results (SEER)-Medicare Health Outcomes Survey (MHOS) database was queried to identify 374 women aged 65years and older with advanced stage epithelial ovarian cancer from 1998 to 2011. Responses to the Short Form 36 (SF-36) and Veterans-RAND-12 (VR-12), two single-item global health questions, and Activities of Daily Living (ADLs) were abstracted. Multivariable models were used to quantify associations of HRQOL and ADL assessments with surgery and overall survival, adjusted for demographic and clinical characteristics. ResultsOf 374 women with a HRQOL assessment prior to diagnosis, 199 (53%) underwent surgery. Increases in physical and mental HRQOL domains were significantly associated with receipt of surgery. The relationship between HRQOL domains and overall survival were not statistically significant. For ADLs, only difficulty in toilet use was significantly associated with survival. ConclusionIn this population-based sample of older women with advanced epithelial ovarian cancer, pre-diagnosis HRQOL was predictive of receiving surgery, but not of overall survival.

A 6-year trend of the healthcare costs of arthritis in a population-based cohort of older women

Objective: To provide an accurate representation of the economic burden of arthritis by estimating the adjusted incremental healthcare cost of arthritis at multiple percentiles and reporting the cost trends across time. Methods: A healthcare cost study based on health survey and linked administrative data, where costs were estimated from the government's perspective in dollars per person per year. Quantile regression was used to estimate the adjusted incremental cost at the 25th, 50th, 75th, 90th, and 95th percentiles. Results: Data from 4287 older Australian women were included. The median incremental healthcare cost of arthritis was, in 2012 Australian dollars, $480 (95% CI: $498–759) in 2009; however, 5% of individuals had 5-times higher costs than the ‘average individual’ with arthritis. Healthcare cost of arthritis did not increase significantly from 2003 to 2009. Conclusion: Healthcare cost of arthritis represents a substantial burden for the governments. Future research should continue to monitor the economic burden of arthritis.

Associations between Environmental Exposures and Incident Colorectal Cancer by ESR2 Protein Expression Level in a Population-Based Cohort of Older Women

Cigarette smoking (smoking), hormone therapy (MHT), and folate intake (folate) are each thought to influence colorectal cancer risk, but the underlying molecular mechanisms remain incompletely defined. Expression of estrogen receptor β (ESR2) has been associated with colorectal cancer stage and survival. In this prospective cohort study, we examined smoking, MHT, and folate-associated colorectal cancer risks by ESR2 protein expression level among participants in the Iowa Women's Health Study (IWHS). Self-reported exposure variables were assessed at baseline. Archived, paraffin-embedded colorectal cancer tissue specimens were collected and evaluated for ESR2 protein expression by IHC. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI) for associations between smoking, MHT, or folate and ESR2-defined colorectal cancer subtypes. Informative environmental exposure and protein expression data were available for 491 incident colorectal cancer cases. Positive associations between ESR2-low and -high tumors and several smoking-related variables were noted, most prominently with average number of cigarettes per day (RR, 4.24; 95% CI, 1.81-9.91 for ESR2-low and RR, 2.15; 95% CI, 1.05-4.41 for ESR2-high for ≥40 cigarettes compared with nonsmokers). For MHT, a statistically significant association with ESR2-low tumors was observed with longer duration of exposure (RR, 0.54; 95% CI, 0.26-1.13 for >5 years compared with never use). No associations were found for folate. In this study, smoking and MHT were associated with ESR2 expression patterns. These data support possible heterogeneous effects from smoking and MHT on ERβ-related pathways of colorectal carcinogenesis in older women.

Associations between Cigarette Smoking, Hormone Therapy, and Folate Intake with Incident Colorectal Cancer by TP53 Protein Expression Level in a Population-Based Cohort of Older Women

Cigarette smoking (CS), hormone therapy (HT), and folate intake (FI) are each thought to influence colorectal cancer risk, but the underlying molecular mechanisms remain incompletely defined. The TP53 (p53) protein, encoded by the TP53 tumor-suppressor gene that is commonly mutated in colorectal cancer, can be readily assessed to differentiate biologically distinct colorectal cancer subtypes. In this prospective cohort study, we examined CS-, HT-, and FI-associated colorectal cancer risks by TP53 protein expression level among Iowa Women's Health Study (IWHS) participants. The IWHS recruited 41,836 randomly selected Iowa women, ages 55 to 69 years, with a valid driver's license at study entry in 1986. Self-reported exposure variables were assessed at baseline. Incident colorectal cancer cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected and evaluated for TP53 protein expression by immunohistochemistry. Multivariate Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI) for associations between CS, HT, or FI and TP53-defined colorectal cancer subtypes. Informative environmental exposure and protein expression data were available for 492 incident colorectal cancer cases: 222 (45.1%) TP53 negative, 72 (14.6%) TP53 low, and 198 (40.2%) TP53 high. Longer duration (>5 years) of HT was inversely associated with TP53 high colorectal cancers (RR, 0.50; 95% CI, 0.27-0.94). No other statistically significant associations were observed. These data support possible heterogeneous effects from HT on TP53-related pathways of colorectal carcinogenesis in older women.

169 Associations Between Cigarette Smoking and Incident Colorectal Cancer by ER Beta Protein Expression in a Population-Based Cohort of Older Women

169 Associations Between Cigarette Smoking and Incident Colorectal Cancer by ER Beta Protein Expression in a Population-Based Cohort of Older Women

Abstract 3652: Hormone therapy and incident colorectal cancer risk by ER beta protein expression level in a population-based cohort of older women.

Abstract Background: Hormone therapy (HT) may prevent colorectal cancer (CRC), but the molecular mechanisms have not been fully defined. Expression of estrogen receptor beta (ERβ) has been associated with CRC stage and survival and may influence HT-related prevention pathways. In this prospective cohort study, we examined HT-associated CRC risk by ERβ protein expression levels in the population-based Iowa Women's Health Study (IWHS). Methods: The IWHS recruited 41,836 randomly selected Iowa women, ages 55-69 years, with a valid driver's license at study entry (1986). Exposure variables were assessed at baseline, by self-report. Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected from 732 CRC cases, diagnosed through 12/31/2002, for molecular epidemiology studies. HT was categorized as never, former, and current and with durations of &amp;lt;=5 years or &amp;gt;5 years. ERβ protein expression was determined by immunohistochemistry on tissue microarrays. For each tumor core, both staining intensity (0-3) and proportion of cells stained (0-5) were scored. These two scores were added to determine negative (0), low (1-5) or high (6-8) ERβ protein expression levels. Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: Complete HT and ERβ data were available from 484 CRC cases. Associations between HT and CRC subtypes defined by ERβ expression level are shown in the Table. Conclusions: Data from the IWHS cohort suggest that current and longer-duration HT exposure favorably influence the risk for ERβ-neg or ERβ-low CRC cases to a greater degree than ERβ-high CRC cases. Further investigation is required to confirm these observations, and to clarify the underlying mechanisms. ERβ Neg or Low ERβ High Hormone Therapy Person years Events, N RR* (95% CI) Events, N RR* (95% CI) Never 341377 128 1.00 (Ref.) 196 1.00 (Ref.) Ever 212696 62 0.74 (0.54,1.03) 98 0.82 (0.63,1.07) Former 151535 48 0.79 (0.56,1.12) 67 0.73 (0.54,0.99) Current 61161 14 0.60 (0.33,1.09) 31 1.11 (0.74,1.64) P-trend 0.05 0.52 Duration &amp;lt; = 5yrs 148704 47 0.84 (0.59,1.19) 68 0.80 (0.60,1.08) &amp;gt;5yrs 60064 14 0.5 (0.26,0.93) 28 0.89 (0.59,1.34) P-trend 0.03 0.25 Citation Format: Lori S. Tillmans, Robert A. Vierkant, Alice H. Wang, Charles F. Lynch, Kristin E. Anderson, Amy J. French, Robert W. Haile, John D. Potter, Susan L. Slager, Thomas C. Smyrk, Stephen N. Thibodeau, James R. Cerhan, Paul J. Limburg. Hormone therapy and incident colorectal cancer risk by ER beta protein expression level in a population-based cohort of older women. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3652. doi:10.1158/1538-7445.AM2013-3652

Are Women with Thicker Cortices in the Femoral Shaft at Higher Risk of Subtrochanteric/Diaphyseal Fractures? The Study of Osteoporotic Fractures

Femoral shaft cortical thickening has been mentioned in reports of atypical subtrochanteric and diaphyseal (S/D) femur fractures, but it is unclear whether thickening precedes fracture or results from a preceding stress fracture and what role bisphosphonates might play in cortical thickening. Our objective was to examine the relationship of cortical thickness to S/D fracture risk as well as establish normal reference values for femoral cortical thickness in a large population-based cohort of older women. Using pelvic radiographs obtained in 1986-1988, we measured femoral shaft cortical thickness 3 cm below the lesser trochanter in women in the Study of Osteoporotic Fractures. We measured this in a random sample and in those with S/D fractures and femoral neck and intertrochanteric fractures. Low-energy S/D fractures were identified from review of radiographic reports obtained between 1986 and 2010. Radiographs to evaluate atypia were not available. Analysis used case-cohort, proportional hazards models. Cortical thickness as a risk factor for low-energy S/D femur fractures as well as femoral neck and intertrochanteric fractures in the Study of Osteoporotic Fractures, adjusting for age and bone mineral density in proportional hazards models. After age adjustment, women with thinner medial cortices were at a higher risk of S/D femur fracture, with a relative hazard of 3.94 (95% confidence interval = 1.23-12.6) in the lowest vs. highest quartile. Similar hazard ratios were seen for femoral neck and intertrochanteric fractures. Medial or total cortical thickness was more strongly related to fracture risk than lateral cortical thickness. In primarily bisphosphonate-naive women, we found no evidence that thick femoral cortices placed women at higher risk for low-energy S/D femur fractures; in fact, the opposite was true. Women with thin cortices were also at a higher risk for femoral neck and intertrochanteric fractures. Whether cortical thickness among bisphosphonate users plays a role in atypical S/D fractures remains to be determined.

Abstract 1676: Associations between hormone therapy with incident colorectal cancer by p53 protein expression in a population-based cohort of older women

Abstract Background: Cigarette smoking (CS) is an established colorectal cancer (CRC) risk factor. The p53 protein, encoded by the TP53 tumor suppressor gene that is commonly mutated in CRC, is important in cell cycle arrest needed to repair DNA damage or induce apoptosis to prevent tumor propagation. In this prospective cohort study, we examined CS-associated CRC risks by p53 protein expression level in the population-based Iowa Women's Health Study (IWHS). Methods: The IWHS recruited 41,836 randomly selected Iowa women, ages 55-69 years, with a valid driver's license at study entry (1986). CS and other exposure variables were assessed at baseline, by self-report. Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected from 732 CRC cases diagnosed through 12/31/2002. CS was categorized by smoking status (never, current, former), average number of cigarettes per day (1-19, 20-39, &amp;gt; 40) and cumulative pack-years (1-19, 20-39, &amp;gt; 40). P53 protein expression was determined by immunohistochemistry on tissue microarrays. Tumor cores were scored by combining both staining intensity and percent of cells stained to determine negative, low or high p53 protein expression levels. Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: Of the 732 available CRC cases, 486 (66%) had complete CS and p53 data. Associations between CS and CRC subtypes defined by p53 expression level are shown in the Table. Conclusions: These data demonstrate no clear heterogeneity of CS with CRC subtypes defined by p53 expression levels among older women. 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 1676. doi:1538-7445.AM2012-1676

Abstract 4492: Colorectal cancer survival by molecular subtypes in a population-based cohort of older women

Abstract Background: Despite recent advances in prevention and therapy, colorectal cancer (CRC) continues to account for nearly 50,000 deaths per year in the US. TNM stage is the current CRC prognostic standard, yet within-stage prognostic heterogeneity is well documented. Microsatellite instability (MSI), CpG island methylation phenotype (CIMP), and BRAF- and KRAS-mutation status represent candidate prognostic markers. However, associations between these markers and CRC survival have not been described in a population-based setting. Methods: Data and tissue resources were obtained from the Iowa Women's Health Study (IWHS), which recruited 41,836 women, ages 55-69 years, at study entry (1986). Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected from 732 representative CRC cases diagnosed through 12/31/2002. Established laboratory methods were used to characterize CRC cases: MSI-H or MSS/MSI-L (by instability in β3 vs. &amp;lt;3 out of 10 markers, respectively); CIMP+ or CIMP− (by promoter hypermethylation in β3 vs. 0-2 out of 5 genes, respectively); BRAFwt or BRAFmut (by fluorescent allele specific PCR to detect the V600E point mutation in exon 15); and KRASwt or KRASmut (by direct sequence analysis of codons 12 and 13 in exon 2). Cox regression models were fit to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for time to death of any cause adjusted for age, stage, grade, and treatment status. Results: CRC cases with informative molecular marker data ranged from 515/732 (70%) for KRAS to 548/732 (75%) for MSI status. Mean follow-up was 4.4 years for deceased individuals and 11.2 years for women alive at last contact. After multivariable adjustment, both MSS/MSI-L (p=0.004) and KRASmut (p=0.048) tumors were associated with poorer survival. Survival did not significantly differ across levels of CIMP and BRAF status. Conclusions: MSI and KRAS status may influence CRC survival among older women. 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 4492. doi:1538-7445.AM2012-4492

Abstract 1677: Associations between cigarette smoking with incident colorectal cancer by p53 protein expression in a population-based cohort of older women

Abstract Background: Cigarette smoking (CS) is an established colorectal cancer (CRC) risk factor. The p53 protein, encoded by the TP53 tumor suppressor gene that is commonly mutated in CRC, is important in cell cycle arrest needed to repair DNA damage or induce apoptosis to prevent tumor propagation. In this prospective cohort study, we examined CS-associated CRC risks by p53 protein expression level in the population-based Iowa Women's Health Study (IWHS). Methods: The IWHS recruited 41,836 randomly selected Iowa women, ages 55-69 years, with a valid driver's license at study entry (1986). CS and other exposure variables were assessed at baseline, by self-report. Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected from 732 CRC cases diagnosed through 12/31/2002. CS was categorized by smoking status (never, current, former), average number of cigarettes per day (1-19, 20-39, &amp;gt; 40) and cumulative pack-years (1-19, 20-39, &amp;gt; 40). P53 protein expression was determined by immunohistochemistry on tissue microarrays. Tumor cores were scored by combining both staining intensity and percent of cells stained to determine negative, low or high p53 protein expression levels. Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: Of the 732 available CRC cases, 486 (66%) had complete CS and p53 data. Associations between CS and CRC subtypes defined by p53 expression level are shown in the Table. Conclusions: These data demonstrate no clear heterogeneity of CS with CRC subtypes defined by p53 expression levels among older women. 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 1677. doi:1538-7445.AM2012-1677

Postmenopausal Hormone Therapy and Colorectal Cancer Risk in Relation to Somatic KRAS Mutation Status among Older Women

Postmenopausal hormone (PMH) therapy represents a controversial colorectal cancer (CRC) preventive intervention. Because colorectal carcinogenesis is a heterogeneous process, we evaluated associations between PMH therapy and incident CRC in relation to KRAS mutation status in a population-based cohort of older women [Iowa Women's Health Study (IWHS)]. The IWHS enrolled 41,836 randomly selected women, ages 55 to 69 years, in 1986. PMH therapy and other exposure data were recorded at baseline. Tissue samples from prospectively identified CRC cases (n = 507) were analyzed for somatic KRAS mutations (exon 2, codons 12 and 13). Multivariable Cox regression models were fit to estimate relative risks (RR) and 95% confidence intervals (CI). PMH therapy (ever vs. never) was inversely associated with KRAS mutation-negative (RR = 0.83; 95% CI, 0.66-1.06; P = 0.14) and KRAS mutation-positive (RR = 0.82; 95% CI, 0.58-1.16; P = 0.27) tumors, although the observed risk estimates were not statistically significant. When anatomic subsite was additionally considered, the strongest association was found for KRAS mutation-negative, distal colorectal tumors (RR = 0.64; 95% CI, 0.43-0.96; P = 0.03). To our knowledge, we provide the first report of KRAS-defined CRC risks associated with PMH therapy. These data suggest that PMH therapy may reduce CRC risk through mechanisms beyond KRAS mutation status but might provide greater benefits for KRAS mutation-negative than mutation-positive tumors (at least in the distal colorectum). Findings from this prospective cohort study provide novel insights about the molecular biology of PMH therapy-related CRC risk reduction.

Abstract 1892: Folate intake and incident colorectal cancer by KRAS mutation status in a population-based cohort of older women

Abstract Background: Folate intake (FI) appears to affect colorectal cancer (CRC) risk, but the molecular mechanism(s) involved are incompletely defined. In this study, we analyzed associations between FI and incident CRC, overall and by KRAS mutation status, in the population-based Iowa Women's Health Study (IWHS). Methods: The IWHS recruited 41,836 randomly selected Iowa women, ages 55-69 years, with a valid driver's license at study entry (1986). FI and other exposure variables were assessed at baseline, by self-report. Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were recently collected from 732 representative CRC cases diagnosed through 12/31/2002. FI (including supplements) was categorized by quartiles. KRAS mutation status (wildtype [wt] vs. mutated [mut]) was determined by direct sequence analysis of codons 12 and 13 (exon 2). Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: Of the 732 available CRC cases, 470 (64%) had complete FI and KRAS data. FI was not associated with incident CRC overall (for quartile 4 vs. quartile 1, RR = 1.03; 95% CI = 0.82-1.28; p trend = 0.90), or with the KRAS-wt or KRAS-mut subtypes (see Table). Conclusions: These data do not support an association between FI and incident CRC, overall or by KRAS-defined subtypes, among older, predominately white, non-Hispanic women. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1892. doi:10.1158/1538-7445.AM2011-1892

Abstract 1891: Cigarette smoking and incident colorectal cancer by KRAS mutation status in a population-based cohort of older women

Abstract Background: Cigarette smoking (CS) is an established, although relatively modest, colorectal cancer (CRC) risk factor. Emerging data suggest that CS might affect distinct pathways of colorectal carcinogenesis. In this study, we examined CS-associated CRC risks by KRAS mutation status in the population-based Iowa Women's Health Study (IWHS). Methods: The IIWHS recruited 41,836 randomly selected Iowa women, ages 55-69 years, with a valid driver's license at study entry (1986). CS and other exposure variables were assessed at baseline, by self-report. Incident CRC cases were ascertained by annual linkage with the Iowa Cancer Registry. Archived, paraffin-embedded tissue specimens were collected from 732 representative CRC cases diagnosed through 12/31/2002. CS was categorized by smoking status (current, former), average number of cigarettes per day (1-19, 20-39, &amp;gt; 40) and pack-years (1-19, 20-39, &amp;gt; 40); never smokers were defined as the reference group. KRAS mutation status (wildtype [wt] vs. mutated [mut]) was determined by direct sequence analysis of codons 12 and 13 (exon 2). Multivariate Cox regression models were fit to estimate relative risks (RRs) and 95% confidence intervals (CIs). Results: Of the 732 available CRC cases, 507 (69%) had complete CS and KRAS data. Each of the CS-related variables was more strongly associated with KRAS-wt vs. KRAS-mut tumors (see Table). However, event rates were relatively small in some cells, and tests for heterogeneity between KRAS-defined subtypes were not statistically significant (p &amp;gt; 0.05 for each comparison). Conclusions: These findings suggest that CS may affect colorectal carcinogenesis through KRAS-independent pathways, but additional data are needed from larger, more diverse study populations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1891. doi:10.1158/1538-7445.AM2011-1891

Chemotherapy use and risk of bone marrow suppression in a large population-based cohort of older women with breast and ovarian cancer

We studied 65,521 women with breast cancer and 7,420 women with ovarian cancer aged ≥ 65 identified from the 16 areas of the Surveillance, Epidemiology and End Results program linked with Medicare data during 1991-2002. Bone marrow toxicity associated with chemotherapy was defined using diagnosis codes from Medicare inpatient, outpatient and physician claims. The time to event Cox regression was utilized to estimate the risk of bone marrow toxicity. Use of anthracyclines, taxanes or platinums was associated with increased risks of short- (≤3 months) and long-term (>3 months) anemia and neutropenia in patients with breast cancer. Alkylating agents or antimetabolites were additional significant predictors of anemia in women with ovarian cancer. Patients who received chemotherapy (irrespective of regimens) were twice (breast cancer) or three times (ovarian cancer) as likely to develop thrombocytopenia compared to those not receiving chemotherapy. Among women with breast cancer, patients receiving cyclophosphamide, methotrexate and fluorouracil regimens (hazard ratio=19.0, 95% CI=11.2-32.5), platinum/taxane therapy (21.9, 11.9-40.4) or the cyclophosphamide, adriamycin and fluorouracil regimen (32.5, 19.6-53.9) were strongly associated with risk of aplastic anemia. There was a dose-response relationship between the use of taxane or platinum and the risk of bone marrow suppression, whereas the increased risk of bone marrow toxicity was consistently higher in those with use of alkylating agents or anthracycline-based regimens irrespective of the increasing number of cycles received. In conclusion, there was an association between chemotherapy use and clinical manifestations of bone marrow toxicities in a population-based setting.