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Simple Summary: SMARCA4-mutated tumors are associated with poor prognosis. However, it is not clear if male and female patients have the same or different prognosis and if additional common mutations within the tumor play a role in prognosis. We have found that male patients had substantially worse prognosis than female patients whose tumor carried a SMARCA4 mutation. In addition, different co-existing mutations including the mutation of TP53, KRAS, CDKN2A, STK11, and Keap1 were associated with differential prognosis. Our study provides helpful insight for prognostic stratification in clinical practice and for understanding the pathogenic mechanism of this unique subtype of malignancy. Background: Whether sex and co-mutations impact prognosis of patients with SMARCA4-mutated (mutSMARCA4) malignancies is not clear. Methods: This cohort included patients from Northern California Kaiser Permanente with next-generation sequencing (NGS) performed from August 2020 to October 2022. We used Cox regression modeling to examine the association between sex and overall survival (OS), adjusting for demographics, performance status, Charlson comorbidity index, receipt of treatment, tumor mutation burden (TMB), and TP53, KRAS, CDKN2A, STK11, and Keap1 co-mutations. Results: Out of 9221 cases with NGS performed, 125 cases (1.4%) had a mutSMARCA4. The most common malignancies with a mutSMARCA4 were non-small cell lung cancer (NSCLC, 35.2%), esophageal and stomach adenocarcinoma (12.8%), and cancer of unknown primary (11.2%). The most common co-mutations were p53 (mutp53, 59.2%), KRAS (mutKRAS, 28.8%), CDKN2A (mutCDKN2A, 31.2%), STK11 (mutSTK11, 12.8%), and Keap1 (mutKeap1, 8.8%) mutations. Male patients had substantially worse OS than female patients both among the entire mutSMARCA4 cohort (HR = 1.71, [95% CI 0.92–3.18]) with a median OS of 3.0 versus 43.3 months (p < 0.001), and among the NSCLC subgroup (HR = 14.2, [95% CI 2.76–73.4]) with a median OS of 2.75 months versus un-estimable (p = 0.02). Among all patients with mutSMARCA4, mutp53 versus wtp53 (HR = 2.12, [95% CI 1.04–4.29]) and mutSTK11 versus wtSTK11 (HR = 2.59, [95% CI 0.87–7.73]) were associated with worse OS. Among the NSCLC subgroup, mutp53 versus wtp53 (HR = 0.35, [0.06–1.97]) and mutKRAS versus wtKRAS (HR = 0.04, [0.003-.45]) were associated with better OS, while mutCDKN2A versus wtCDKN2A (HR = 5.04, [1.12–22.32]), mutSTK11 versus wtSTK11 (HR = 13.10, [95% CI 1.16–148.26]), and mutKeap1 versus wtKeap1 (HR = 5.06, [95% CI 0.89–26.61}) were associated with worse OS. Conclusion: In our cohort of patients with mutSMARCA4, males had substantially worse prognosis than females, while mutTP53, mutKRAS, mutCDKN2A, mutSTK11 and mutKeap1were differentially associated with prognosis among all patients and among the NSCLC subgroup. Our results, if confirmed, could suggest potentially unidentified mechanisms that underly this sex and co-mutation-dependent prognostic disparity among patients whose tumor bears a mutSMARCA4. [ABSTRACT FROM AUTHOR]

Background: Hydrochlorothiazide (HCTZ), a common diuretic known to be photosensitizing and previously associated with non‐melanoma skin cancer, was recently reported to be associated with two melanoma subtypes, nodular and lentigo, among residents of Denmark. Our goal was to examine whether Danish findings could be replicated in a US cohort, using a similar study design and analysis. Methods: Among non‐Hispanic White enrollees of Kaiser Permanente Northern California, we conducted an analysis of 9176 melanoma cases and 264 781 controls, matched on age, sex and time in health plan. We examined use of HCTZ prior to cancer diagnosis (cases) or comparable date for controls, categorized as never use, ever use and high use (≥50 000 mg). Electronic health records provided data on prescriptions, cancer diagnoses, and covariates. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for education, income and number of dermatology, internal medicine and urgent care visits. Results: We observed a small increase in risk of melanoma, all types combined, associated with high use (≥50 000 mg) of HCTZ (OR = 1.11, 95% CI 1.00–1.23) and no evidence of a dose–response. Risk was more elevated for lentigo subtype (OR = 1.57, 95% CI 1.01–2.42). The somewhat elevated risk for nodular subtype was not statistically significant (OR = 1.22, 95% CI 0.78–1.90). There was very little association of high use with the superficial spreading subtype (OR = 1.05, 95% CI 0.80–1.37). Conclusions: Our findings support a recent report of an association between high use of HCTZ and increased risk of the lentigo subtype of melanoma. [ABSTRACT FROM AUTHOR]

Background: It has been shown that racial/ethnic disparities exist with regard to initiation of and adherence to adjuvant endocrine therapy (AET). However, the relationship among American Indian/Alaska Native (AIAN) individuals is poorly understood, particularly among those who reside in urban areas. We evaluated whether AET initiation and adherence were lower among AIAN individuals than those of other races/ethnicities who were enrolled in the Kaiser Permanente of Northern California (KPNC) health system. Methods: We identified 23,680 patients from the period 1997 to 2014 who were eligible for AET (first primary, stage I‐III, hormone receptor–positive breast cancer) and used KPNC pharmacy records to identify AET prescriptions and refill dates. We assessed AET initiation (≥1 filled prescription within 1 year of diagnosis) and AET adherence (proportion of days covered ≥80%) every year up to 5 years after AET initiation. Results: At the end of the 5‐year follow‐up period, 83% of patients were AET initiators, and 58% were AET adherent. Compared with other races/ethnicities, AIAN women had the second‐lowest rate of AET initiation (non‐Hispanic Black [NHB], 78.0%; AIAN, 78.6%; Hispanic, 83.0%; non‐Hispanic White [NHW], 82.5%; Asian/Pacific Islander [API], 84.7%), the lowest rate of AET adherence after 1 year and 5 years of follow‐up (70.3% and 50.8%, respectively), and the greatest annual decline in AET adherence during the 4‐ to 5‐year period of follow‐up (a 13.8% decrease in AET adherence [from 64.6% to 50.8%]) after initiation of AET. In adjusted multivariable models, AIAN, Hispanic, and NHB women were less likely than NHW women to be AET adherent. At the end of the 5‐year period, total underutilization (combining initiation and adherence) in AET‐eligible patients was greatest among AIAN (70.6%) patients, followed by NHB (69.6%), Hispanic (63.2%), NHW (58.7%), and API (52.3%) patients, underscoring the AET treatment gap. Conclusion: Our results suggest that AET initiation and adherence are particularly low for insured AIAN women. In this study of 23,680 patients who were eligible for adjuvant endocrine therapy (AET), American Indian/Alaska Native (AIAN) women had the lowest AET adherence by the end of the 5‐year study period, and total underutilization (combining initiation and adherence) was greatest among AIAN (70.6%) patients, followed by non‐Hispanic Black (69.6%), Hispanic (63.2%), non‐Hispanic White (58.7%), and Asian/Pacific Islander (52.3%) patients, underscoring the AET treatment gap. [ABSTRACT FROM AUTHOR]

Background: Percent density (PD) is a strong risk factor for breast cancer that is potentially modifiable by lifestyle factors. PD is a composite of the dense (DA) and nondense (NDA) areas of a mammogram, representing predominantly fibroglandular or fatty tissues, respectively. Alcohol and tobacco use have been associated with increased breast cancer risk. However, their effects on mammographic density (MD) phenotypes are poorly understood. Methods: We examined associations of alcohol and tobacco use with PD, DA, and NDA in a population-based cohort of 23,456 women screened using full-field digital mammography machines manufactured by Hologic or General Electric. MD was measured using Cumulus. Machine-specific effects were estimated using linear regression, and combined using random effects meta-analysis. Results: Alcohol use was positively associated with PD (Ptrend = 0.01), unassociated with DA (Ptrend = 0.23), and inversely associated with NDA (Ptrend = 0.02) adjusting for age, body mass index, reproductive factors, physical activity, and family history of breast cancer. In contrast, tobacco use was inversely associated with PD (Ptrend = 0.0008), unassociated with DA (Ptrend = 0.93), and positively associated with NDA (Ptrend<0.0001). These trends were stronger in normal and overweight women than in obese women. Conclusions: These findings suggest that associations of alcohol and tobacco use with PD result more from their associations with NDA than DA. Impact: PD and NDA may mediate the association of alcohol drinking, but not tobacco smoking, with increased breast cancer risk. Further studies are needed to elucidate the modifiable lifestyle factors that influence breast tissue composition, and the important role of the fatty tissues on breast health. [ABSTRACT FROM AUTHOR]

Breast density is a modifiable factor that is strongly associated with breast cancer risk. We sought to understand the influence of newer technologies of full-field digital mammography (FFDM) on breast density research and to determine whether results are comparable across studies using FFDM and previous studies using traditional film-screen mammography. We studied 24,840 screening-age (40–74 years) non-Hispanic white women who were participants in the Research Program on Genes, Environment and Health of Kaiser Permanente Northern California and underwent screening mammography with either Hologic (Hologic, Inc. Marlborough, Massachusetts) or General Electric (General Electric Company, Boston, Massachusetts) FFDM machines between 2003 and 2013. We estimated the associations of parity, age at first birth, age at menarche, and menopausal status with percent density and dense area as measured by a single radiological technologist using Cumulus software (Canto Software, Inc. San Francisco, California). We found that associations between reproductive factors and mammographic density measured using processed FFDM images were generally similar in magnitude and direction to those from prior studies using film mammography. Estimated associations for both types of FFDM machines were in the same direction. There was some evidence of heterogeneity in the magnitude of the effect sizes by machine type, which we accounted for using random-effects meta-analysis when combining results. Our findings demonstrate the robustness of quantitative mammographic density measurements across FFDM and film mammography platforms. [ABSTRACT FROM AUTHOR]

Context: Epidemiologic analyses of gabapentin use and cancer risk in Kaiser Permanente Northern California were previously carried out in a collaborative study and independently evaluated in a UK database. Objective: To update these epidemiologic analyses with 7.5 more years of follow-up. Design: Case-control analyses using conditional logistic regression to estimate relative risk by odds ratios using the prior collaboration's criteria for identifying positive drug-cancer associations and our more stringent criteria requiring stronger association, lower p values, and evidence of dose response. New associations were reanalyzed with additional control for limited measures of smoking and alcohol use. Main Outcome Measures: Gabapentin-cancer associations. Results: No previously found associations met our stringent criteria, but cancers of the mouth/pharynx, esophagus, liver, and vagina did. All odds ratios for 3 or more and 8 or more prescriptions were moderately reduced by control for smoking and alcohol. Substantial elevations of risk of mouth/pharynx, liver, and vaginal cancers were associated with only 1 prescription dispensed. Sensitivity analyses aimed at possible confounding and other biases did not change our conclusions but did reveal a markedly increased risk of vaginal cancer in gabapentin users with epilepsy compared with users without. Conclusion: The reduced magnitude of relative risk with control for smoking and alcohol use suggests confounding by known risk factors. Biologically implausible elevated risk from just 1 prescription suggests confounding by indication. Either or both of these concerns applies to each of the 4 cancer sites associated with gabapentin use. Updated analyses show little if any evidence for carcinogenic effects of gabapentin. [ABSTRACT FROM AUTHOR]

Background: Several epidemiologic studies have reported strong inverse associations between metformin use and risk of colorectal cancer, although time-related biases, such as immortal time bias, may in part explain these findings. We reexamined this association using methods to minimize these biases. Methods: A cohort study was conducted among 47,351 members of Kaiser Permanente Northern California with diabetes and no history of cancer or metformin use. Follow-up for incident colorectal cancer occurred from January 1, 1997, until June 30, 2012. Cox regression was used to calculate HRs and 95% confidence intervals (CIs) for colorectal cancer risk associated with metformin use (ever use, total duration, recency of use, and cumulative dose). Results: No association was observed between ever use of metformin and colorectal cancer risk (HR, 0.90; 95% CI, 0.76-1.07) and there was no consistent pattern of decreasing risk with increasing total duration, dose, or recency of use. However, long-term use (≥5.0 years) appeared to be associated with reduced risk of colorectal cancer in the full population (HR, 0.78; 95% CI, 0.60-1.02), among current users (HR, 0.78; 95% CI, 0.59-1.04), and in men (HR, 0.65; 95% CI, 0.45-0.94) but not in women. Higher cumulative doses of metformin were associated with reduced risk. In initial users of sulfonylureas, switching to or adding metformin was also associated with decreased colorectal cancer risk. Conclusions: Our findings showed an inverse association between long-term use of metformin and colorectal cancer risk. Findings, especially the risk reduction among men, need to be confirmed in large, well-conducted studies. [ABSTRACT FROM AUTHOR]

Purpose: A majority of women with ductal carcinoma in situ (DCIS) receive breast-conserving surgery (BCS) but then face a risk of ipsilateral breast tumor recurrence (IBTR) which can be either recurrence of DCIS or invasive breast cancer. We developed a score to provide individualized information about IBTR risk to guide treatment decisions.Methods: Data from 2762 patients treated with BCS for DCIS at centers within the National Comprehensive Cancer Network (NCCN) were used to identify statistically significant non-treatment-related predictors for 5-year IBTR. Factors most associated with IBTR were estrogen-receptor status of the DCIS, presence of comedo necrosis, and patient age at diagnosis. These three parameters were used to create a point-based risk score. Discrimination of this score was assessed in a separate DCIS population of 301 women (100 with IBTR and 200 without) from Kaiser Permanente Northern California (KPNC).Results: Using NCCN data, the 5-year likelihood of IBTR without adjuvant therapy was 9% (95% CI 5–12%), 23% (95% CI 13–32%), and 51% (95% CI 26–75%) in the low, intermediate, and high-risk groups, respectively. Addition of the risk score to a model including only treatment improved the C-statistic from 0.69 to 0.74 (improvement of 0.05). Cross-validation of the score resulted in a C-statistic of 0.76. The score had a c-statistic of 0.67 using the KPNC data, revealing that it discriminated well.Conclusions: This simple, no-cost risk score may be used by patients and physicians to facilitate preference-based decision-making about DCIS management informed by a more accurate understanding of risks. [ABSTRACT FROM AUTHOR]

Background: High mammographic density is strongly associated with increased breast cancer risk. Some, but not all, risk factors for breast cancer are also associated with higher mammographic density. Methods: The study cohort (N = 24,840) was drawn from the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California and included non-Hispanic white females ages 40 to 74 years with a full-field digital mammogram (FFDM). Percent density (PD) and dense area (DA) were measured by a radiological technologist using Cumulus. The association of age at menarche and late adolescent body mass index (BMI) with PD and DA were modeled using linear regression adjusted for confounders. Results: Age at menarche and late adolescent BMI were negatively correlated. Age at menarche was positively associated with PD (P value for trend <0.0001) and DA (P value for trend <0.0001) in fully adjusted models. Compared with the reference category of ages 12 to 13 years at menarche, menarche at age >16 years was associated with an increase in PD of 1.47% (95% CI, 0.69-2.25) and an increase in DA of 1.59 cm2 (95% CI, 0.48-2.70). Late adolescent BMI was inversely associated with PD (P < 0.0001) and DA (P < 0.0001) in fully adjusted models. Conclusions: Age at menarche and late adolescent BMI are both associated with Cumulus measures of mammographic density on processed FFDM images. Impact: Age at menarche and late adolescent BMI may act through different pathways. The long-term effects of age at menarche on cancer risk may be mediated through factors besides mammographic density. [ABSTRACT FROM AUTHOR]

Background: Phosphodiesterase 5A inhibitors (PDEIs), a common treatment for erectile dysfunction, were recently linked to an increased risk of melanoma.Methods: We conducted two parallel case-control studies, using the Danish Nationwide Health Registries (DNHR) and the Kaiser Permanente Northern California (KPNC) electronic health records. Identifying men with histologically verified melanoma (cases) matched on birth year to 10 cancer-free controls, we estimated odds ratios (OR) for melanoma associated with high use of PDEIs (⩾100 tablets filled), adjusting for available confounders.Results: We identified 7045 DNHR and 2972 KPNC cases with invasive melanoma. The adjusted OR for invasive melanoma associated with high PDEI use was 1.22 (95% confidence interval (CI), 0.99-1.49) in DNHR and 0.95 (95% CI, 0.78-1.14) in KPNC. Odds ratios were highest for localised invasive melanoma in DNHR (OR, 1.21) and melanoma in situ in KPNC (OR, 1.15), and lowest for non-localised disease in both populations (ORs 0.75 and 0.61, respectively). The increased ORs were slightly attenuated upon adjustment for markers of health-care utilisation.Conclusions: We found little evidence for a causal association between PDEI use and risk of melanoma. The marginally increased risk of early stage disease likely resulted from more frequent health-care contacts among PDEI users. [ABSTRACT FROM AUTHOR]

Introduction: Studies have shown that a two-gene ratio (HOXB13:IL17BR) and a five-gene (BUB1B, CENPA, NEK2, RACGAP1, RRM2) molecular grade index (MGI) are predictive of clinical outcomes among early-stage breast cancer patients. In an independent population of lymph node-negative breast cancer patients from a community hospital setting, we evaluated the performance of two risk classifiers that have been derived from these gene signatures combined, MGI+HOXB13:IL17BR and the Breast Cancer Index (BCI). Methods: A case-control study was conducted among 4,964 Kaiser Permanente patients diagnosed with nodenegative invasive breast cancer from 1985 to 1994 who did not receive adjuvant chemotherapy. For 191 cases (breast cancer deaths) and 417 matched controls, archived tumor tissues were available and analyzed for expression levels of the seven genes of interest and four normalization genes by RT-PCR. Logistic regression methods were used to estimate the relative risk (RR) and 10-year absolute risk of breast cancer death associated with prespecified risk categories for MGI+HOXB13:IL17BR and BCI Results: Both MGI+HOXB13:IL17BR and BCI classified over half of all ER-positive patients as low risk. The 10-year absolute risks of breast cancer death for ER-positive, tamoxifen-treated patients classified in the low-, intermediate-, and high-risk groups were 3.7% (95% confidence interval (CI) 1.9% to 5.4%), 5.9% (95% CI 3.0% to 8.6%), and 12.9% (95% CI 7.9% to 17.6%) by MGI+HOXB13:IL17BR and 3.5% (95% CI 1.9% to 5.1%), 7.0% (95% CI 3.8% to 10.1%), and 12.9% (95% CI 7.1% to 18.3%) by BCI. Those for ER-positive, tamoxifen-untreated patients were 5.7% (95% CI 4.0% to 7.4%), 13.8% (95% CI 8.4% to 18.9%), and 15.2% (95% CI 9.4% to 20.5%) by MGI+HOXB13:IL17BR and 5.1% (95% CI 3.6% to 6.6%), 18.6% (95% CI 10.8% to 25.7%), and 17.5% (95% CI 11.1% to 23.5%) by BCI. After adjusting for tumor size and grade, the RRs of breast cancer death comparing high- versus low-risk categories of both classifiers remained elevated but were attenuated for tamoxifen-treated and tamoxifen-untreated patients. Conclusion: Among ER-positive, lymph node-negative patients not treated with adjuvant chemotherapy, MGI +HOXB13:IL17BR and BCI were associated with risk of breast cancer death. Both risk classifiers appeared to provide risk information beyond standard prognostic factors. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined whether glycemic control measured by serial homoglobin A1c was linked with colorectal adenoma risk. Patients with type 2 diabetes mellitus who were included in the study had at least one colorectal adenoma identified at either colonoscopy or sigmoidoscopy. Results showed that the adjusted mean HbA1c levels among those without adenomas was 8.20% versus 8.26% among those with at least one adenoma. It was concluded that glycemic control was not linked with the risk of colorectal adenoma.

The article discusses research on whether mammographic density predicts risk of second breast cancers among patients with ductal carcinoma in situ (DCIS). Medical records from Kaiser Permanente Northern California were reviewed for clinical factors and subsequent breast cancers. The association between mammographic density and risk of breast cancer events was examined using cox regression modeling. Results showed an increased risk of subsequent breast cancer among DCIS patients with dense breasts.

A negative association of statin use with liver cancer risk has been reported frequently. We added laboratory measurements, to our knowledge not included in previous investigations, to a case-control analysis of 2877 case patients and 142 850 matched control subjects enrolled in Kaiser Permanente Northern California. Addressing confounding by indication by restricting subjects to those with elevated cholesterol greatly attenuated the negative association; eg, the multivariable-adjusted odds ratio (OR) rose from 0.41 (95% confidence interval [CI] = 0.35 to 0.49) to 0.87 (95% CI = 0.55 to 1.39) for receipt of 18 or more prescriptions. Confounding by contraindication was addressed by controlling for degree of abnormality of liver function tests, alanine or aspartate transaminase, measured within one year of the elevated cholesterol and strongly related to risk. The negative association of statins disappeared for all numbers of prescriptions received, with an odds ratio of 1.21 (95% CI = 0.53 to 2.75) for 18 or more prescriptions. Findings cast doubt on the causality of the frequently observed preventive association. [ABSTRACT FROM AUTHOR]

BACKGROUND/OBJECTIVES Determining long-term trends in tumor biomarker expression is essential for understanding aspects of tumor biology amenable to change. Limiting the availability of such data, currently used assays for biomarkers are relatively new. For example, assays for the estrogen receptor (ER), which are the oldest, extend back only to the 1970s. METHODS To extend scant knowledge about the feasibility of obtaining long-term data on tumor biomarkers, we randomly selected 60 breast cancer cases (10 per decade) diagnosed between 1947–2009 among women members of the Kaiser Permanente Northern California health plan to obtain and analyze their formalin-fixed paraffin-embedded (FFPE) tumor specimens. For each tumor specimen, we created duplicate tissue microarrays for analysis. RESULTS We located tumor blocks and pathology reports for 50 of the 60 cases (83%), from which we randomly sampled 5 cases per decade for biomarker analysis (n = 30). All 30 cases displayed excellent morphology and exhibited biomarkers compatible with histologic type and grade. Test–retest reliability was also excellent: 100% for ER; 97% for human epidermal growth factor receptor 2 and epidermal growth factor receptor; 93% for progesterone receptor and cytokeratin 5/6; and 90% for Ki67 and molecular phenotype; the kappa statistic was excellent (>0.9) for 4 of the 7 biomarkers, strong (0.6–0.8) for 2, and fair for only 1 (owing to low prevalence). CONCLUSIONS These results indicate immunostaining for biomarkers commonly used to evaluate breast cancer biology and assign surrogate molecular phenotypes can reliably be employed on archival FFPE specimens up to 60 years old.

Introduction: Randomized trials indicate that adjuvant radiotherapy plus tamoxifen decrease the five-year risk of recurrence among ductal carcinoma in situ patients treated with breast-conserving surgery from about 20% to 8%. The aims of this study were to examine the use and impact of these therapies on risk of recurrence among ductal carcinoma in situ patients diagnosed and treated in the community setting. Methods: We identified 2,995 patients diagnosed with ductal carcinoma in situ between 1990 and 2001 and treated with breast-conserving surgery at three large health plans. Medical charts were reviewed to confirm diagnosis and treatment and to obtain information on subsequent breast cancers. On a subset of patients, slides from the index ductal carcinoma in situ were reviewed for histopathologic features. Cumulative incidence curves were generated and Cox regression was used to examine changes in five-year risk of recurrence across diagnosis years, with and without adjusting for trends in use of adjuvant therapies. Results: Use of radiotherapy increased from 25.8% in 1990-1991 to 61.3% in 2000-2001; tamoxifen increased from 2.3% to 34.4%. A total of 245 patients had a local recurrence within five years of their index ductal carcinoma in situ. The five-year risk of any local recurrence decreased from 14.3% (95% confidence interval 9.8 to 18.7) for patients diagnosed in 1990-1991 to 7.7% (95% confidence interval 5.5 to 9.9) for patients diagnosed in 1998-1999; invasive recurrence decreased from 7.0% (95% confidence interval 3.8 to 10.3) to 3.1% (95% confidence interval 1.7 to 4.6). In Cox models, the association between diagnosis year and risk of recurrence was modestly attenuated after accounting for use of adjuvant therapy. Between 1990-1991 and 2000-2001, the proportion of patients with tumors with high nuclear grade decreased from 46% to 32% (P = 0.03) and those with involved surgical margins dropped from 15% to 0% (P = 0.03). Conclusions: The marked increase in the 1990s in the use of adjuvant therapy for ductal carcinoma in situ patients treated with breast-conserving surgery in the community setting only partially explains the 50% decline in risk of recurrence. Changes in pathology factors have likely also contributed to this decline.

Background: Full-field digital mammography (FFDM) has largely replaced film-screen mammography in the US. Breast density assessed from film mammograms is strongly associated with breast cancer risk, but data are limited for processed FFDM images used for clinical care.Methods: We conducted a case-control study nested among non-Hispanic white female participants of the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California who were aged 40 to 74 years and had screening mammograms acquired on Hologic FFDM machines. Cases (n = 297) were women with a first invasive breast cancer diagnosed after a screening FFDM. For each case, up to five controls (n = 1149) were selected, matched on age and year of FFDM and image batch number, and who were still under follow-up and without a history of breast cancer at the age of diagnosis of the matched case. Percent density (PD) and dense area (DA) were assessed by a radiological technologist using Cumulus. Conditional logistic regression was used to estimate odds ratios (ORs) for breast cancer associated with PD and DA, modeled continuously in standard deviation (SD) increments and categorically in quintiles, after adjusting for body mass index, parity, first-degree family history of breast cancer, breast area, and menopausal hormone use.Results: Median intra-reader reproducibility was high with a Pearson's r of 0.956 (range 0.902 to 0.983) for replicate PD measurements across 23 image batches. The overall mean was 20.02 (SD, 14.61) for PD and 27.63 cm(2) (18.22 cm(2)) for DA. The adjusted ORs for breast cancer associated with each SD increment were 1.70 (95 % confidence interval, 1.41-2.04) for PD, and 1.54 (1.34-1.77) for DA. The adjusted ORs for each quintile were: 1.00 (ref.), 1.49 (0.91-2.45), 2.57 (1.54-4.30), 3.22 (1.91-5.43), 4.88 (2.78-8.55) for PD, and 1.00 (ref.), 1.43 (0.85-2.40), 2.53 (1.53-4.19), 2.85 (1.73-4.69), 3.48 (2.14-5.65) for DA.Conclusions: PD and DA measured using Cumulus on processed FFDM images are positively associated with breast cancer risk, with similar magnitudes of association as previously reported for film-screen mammograms. Processed digital mammograms acquired for routine clinical care in a general practice setting are suitable for breast density and cancer research. [ABSTRACT FROM AUTHOR]