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Purpose: The International Ki67 Working Group (IKWG) has developed training for immunohistochemistry (IHC) scoring reproducibility and recommends cut points of ≤ 5% and ≥ 30% for prognosis in ER+, HER2−, stage I/II breast cancer. We examined scoring reproducibility following IKWG training and evaluated these cut points for selecting patients for further testing with the 21-gene Recurrence Score (RS) assay. Methods: We included 307 women aged 50+ years with node-negative, ER+PR+HER2− breast cancer and with available RS results. Slides from the diagnostic biopsy were stained for Ki67 and scored using digital image analysis (IA). Two IHC pathologists underwent IKWG training and visually scored slides, blinded to each other and IA readings. Interobserver reproducibility was examined using intraclass correlation (ICC) and Kappa statistics. Results: Depending on reader, 8.8–16.0% of our cohort had Ki67 ≤ 5% and 11.4–22.5% had scores ≥ 30%. The ICC for Ki67 scores by the two pathologists was 0.82 (95% CI 0.78–0.85); it was 0.79 (95% CI 0.74–0.83) for pathologist 1 and IA and 0.76 (95% CI 0.71–0.80) for pathologist 2 and IA. For Ki67 scores ≤ 5%, the percentages with RS < 26 were 92.6%, 91.8%, and 90.9% for pathologist 1, pathologist 2, and IA, respectively. For Ki67 scores ≥ 30%, the percentages with RS ≥ 26 were 41.5%, 51.4%, and 27.5%, respectively. Conclusion: The IKWG's Ki67 training resulted in moderate to strong reproducibility across readers but cut points had only moderate overlap with RS cut points, especially for Ki67 ≥ 30% and RS ≥ 26; thus, their clinical utility for a 21-gene assay testing pathway remains unclear. [ABSTRACT FROM AUTHOR]

Background: Breast density is strongly associated with breast cancer risk. Fully automated quantitative density assessment methods have recently been developed that could facilitate large-scale studies, although data on associations with long-term breast cancer risk are limited. We examined LIBRA assessments and breast cancer risk and compared results to prior assessments using Cumulus, an established computer-assisted method requiring manual thresholding. Methods: We conducted a cohort study among 21,150 non-Hispanic white female participants of the Research Program in Genes, Environment and Health of Kaiser Permanente Northern California who were 40–74 years at enrollment, followed for up to 10 years, and had archived processed screening mammograms acquired on Hologic or General Electric full-field digital mammography (FFDM) machines and prior Cumulus density assessments available for analysis. Dense area (DA), non-dense area (NDA), and percent density (PD) were assessed using LIBRA software. Cox regression was used to estimate hazard ratios (HRs) for breast cancer associated with DA, NDA and PD modeled continuously in standard deviation (SD) increments, adjusting for age, mammogram year, body mass index, parity, first-degree family history of breast cancer, and menopausal hormone use. We also examined differences by machine type and breast view. Results: The adjusted HRs for breast cancer associated with each SD increment of DA, NDA and PD were 1.36 (95% confidence interval, 1.18–1.57), 0.85 (0.77–0.93) and 1.44 (1.26–1.66) for LIBRA and 1.44 (1.33–1.55), 0.81 (0.74–0.89) and 1.54 (1.34–1.77) for Cumulus, respectively. LIBRA results were generally similar by machine type and breast view, although associations were strongest for Hologic machines and mediolateral oblique views. Results were also similar during the first 2 years, 2–5 years and 5–10 years after the baseline mammogram. Conclusion: Associations with breast cancer risk were generally similar for LIBRA and Cumulus density measures and were sustained for up to 10 years. These findings support the suitability of fully automated LIBRA assessments on processed FFDM images for large-scale research on breast density and cancer risk. [ABSTRACT FROM AUTHOR]

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]

PURPOSE: To examine the impact of TP53 gain-of-function (GOF) and non-GOF mutations on prognosis of advanced pancreatic ductal adenocarcinoma (PDAC) among patients with KRAS , CDKN2A , and SMAD4 comutations. METHODS: This cohort included patients with locally advanced, recurrent, and de novo metastatic PDAC with next-generation sequencing performed from November 2017 to May 2022. We defined R175H, R248W, R248Q, R249S, R273H, R273L, and R282W as GOF and all other p53 mutations (mutp53) as non-GOF. We used Cox regression modeling to examine the association between GOF and non-GOF mutp53 and overall survival (OS), adjusting for demographics, performance status, Charlson comorbidity index, receipt of chemotherapy, and KRAS , CDKN2A , and SMAD4 comutations. RESULTS: Of 893 total eligible patients, 68.5% had tumors with mutp53, 90.1% had KRAS mutations (mutKRAS), 44.7% had CDKN2A mutations (mutCDKN2A), and 17.0% had SMAD4 mutations. Among patients with mutp53, 121 had GOF and 491 had non-GOF. GOF mutp53 was associated with worse OS than non-GOF mutp53 (hazard ratio [HR], 1.27; 95% CI, 1.02 to 1.59) and wild-type p53 (wtp53; HR, 1.24; 95% CI, 0.98 to 1.57), whereas non-GOF was not associated with worse OS than wtp53 (HR, 0.95; 95% CI, 0.80 to 1.13). In addition, mutKRAS was associated with worse OS than wild-type KRAS in patients with mutCDKN2A (HR, 1.57; 95% CI, 0.88 to 2.80) but not in patients with wild-type CDKN2A (HR, 1.03; 95% CI, 0.76 to 1.39). CONCLUSION: GOF and non-GOF mutp53 were associated with differential prognosis in advanced PDAC. The adverse effect of mutKRAS on OS appeared to be primarily driven by patients with mutCDKN2A. Our results provide new insight that could be helpful for prognostic stratification in clinical practice and for aiding future clinical trial designs. Examining p53 mutations may provide insights into the prognosis of patients with pancreatic cancer. [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]

Mammographic density (MD) phenotypes are strongly associated with breast cancer risk and highly heritable. In this GWAS meta-analysis of 24,192 women, we identify 31 MD loci at P < 5 × 10−8, tripling the number known to 46. Seventeen identified MD loci also are associated with breast cancer risk in an independent meta-analysis (P < 0.05). Mendelian randomization analyses show that genetic estimates of dense area (DA), nondense area (NDA), and percent density (PD) are all significantly associated with breast cancer risk (P < 0.05). Pathway analyses reveal distinct biological processes involving DA, NDA and PD loci. These findings provide additional insights into the genetic basis of MD phenotypes and their associations with breast cancer risk. Mammographic density represents one the strongest predictors of breast cancer risk. Here the authors perform genome-wide association study meta-analysis of women screened with full-field digital mammography and identify 31 previously unreported loci associated with mammographic density phenotypes. [ABSTRACT FROM AUTHOR]

Purpose: Reports suggest that up to 50% of women with hormone receptor-positive (HR+) breast cancer (BC) do not complete the recommended 5 years of adjuvant endocrine therapy (AET). We examined the impact of an outreach program at Kaiser Permanente Northern California (KPNC) on adherence and discontinuation of AET among patients who initiated AET. Methods: We assembled a retrospective cohort of all KPNC patients diagnosed with HR+, stage I–III BC initiating AET before (n = 4287) and after (n = 3580) implementation of the outreach program. We compared adherence proportions and discontinuation rates before and after program implementation, both crude and adjusted for age, race/ethnicity, education, income, and stage. We conducted a pooled analysis of data from six Cancer Research Network (CRN) sites that had not implemented programs for improving AET adherence, using identical methods and time periods, to assess possible secular trends. Results: In the pre-outreach period, estimated adherence in years 1, 2, and 3 following AET initiation was 75.2%, 71.0%, and 67.3%; following the outreach program, the estimates were 79.4%, 75.6%, and 72.2% (p-values <.0001 for pairwise comparisons). Results were comparable after adjusting for clinical and demographic factors. The estimated cumulative incidence of discontinuation was 0.22 (0.21–0.24) and 0.18 (0.17–0.19) at 3 years for pre- and post-outreach groups (p-value <.0001). We found no evidence of an increase in adherence between the study periods at the CRN sites with no AET adherence program. Conclusion: Adherence and discontinuation after AET initiation improved modestly following implementation of the outreach program. [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]

Purpose: To investigate the implications of a cancer diagnosis on medication adherence for pre-existing comorbid conditions, we explored statin adherence patterns prior to and following a new diagnosis of breast, colorectal, or prostate cancer among a multi-ethnic cohort.Methods: We identified adults enrolled at Kaiser Permanente Northern California who were prevalent statin medication users, newly diagnosed with breast, colorectal, or prostate cancer between 2000 and 2012. Statin adherence was measured using the proportion of days covered (PDC) during the 2-year pre-cancer diagnosis and the 2-year post-cancer diagnosis. Adherence patterns were assessed using generalized estimating equations, for all cancers combined and stratified by cancer type and race/ethnicity, adjusted for demographic, clinical, and tumor characteristics.Results: Among 10,177 cancer patients, statin adherence decreased from pre- to post-cancer diagnosis (adjusted odds ratio (ORadj):0.91, 95% confidence interval (95% CI):0.88-0.94). Statin adherence decreased from pre- to post-cancer diagnosis among breast (ORadj:0.94, 95% CI:0.90-0.99) and colorectal (ORadj:0.79, 95% CI:0.74-0.85) cancer patients. No difference in adherence was observed among prostate cancer patients (ORadj:1.01, 95% CI:0.97-1.05). Prior to cancer diagnosis, adherence to statins was generally higher among non-Hispanic whites and multi-race patients than other groups. However, statin adherence after diagnosis decreased only among these two populations (ORadj:0.85, 95% CI:0.85-0.92 and ORadj:0.86, 95% CI:0.76-0.97), respectively.Conclusions: We found substantial variation in statin medication adherence following diagnosis by cancer type and race/ethnicity among a large cohort of prevalent statin users in an integrated health care setting.Implications For Cancer Survivors: Improving our understanding of comorbidity management and polypharmacy across diverse cancer patient populations is warranted to develop tailored interventions that improve medication adherence and reduce disparities in health outcomes. [ABSTRACT FROM AUTHOR]

Purpose: The purpose of the study was to assess the feasibility of quantifying long-term trends in breast tumor DNA copy number variation (CNV) profiles.Methods: We evaluated CNV profiles in formalin-fixed paraffin-embedded (FFPE) tumor specimens from 30 randomly selected Kaiser Permanente Northern California health plan women members diagnosed with breast cancer from 1950 to 2010. Assays were conducted for five cases per decade who had available tumor blocks and pathology reports.Results: As compared to the tumors from the 1970s to 2000s, the older tumors dating back to the 1950s and 1960s were much more likely to (1) fail quality control, and (2) have fewer CNV events (average 23 and 31 vs. 58 to 69), fewer CNV genes (average 5.1 and 3.7k vs. 8.1 to 10.3k), shorter CNV length (average 2,440 and 3,300k vs. 5,740 to 9,280k), fewer high frequency Del genes (37 and 25% vs. 54 to 76%), and fewer high frequency high_Amp genes (20% vs. 56 to 73%). On average, assay interpretation took an extra 60 min/specimen for cases from the 1960s versus 20 min/specimen for the most recent tumors.Conclusions: Assays conducted in the mid-2010s for CNVs may be feasible for FFPE tumor specimens dating back to the 1980s, but less feasible for older specimens. [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: 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]

We examined the clinical/pathologic features of ipsilateral second breast cancers (IP-SBCs) following breast-conserving surgery (BCS) for DCIS among community-treated patients and ascertained the degree of correlation between the features of index DCIS and IP-SBC events. From a Cancer Research Network cohort of DCIS patients diagnosed 1990-2001 and treated with BCS, we identified women who subsequently developed an ipsilateral DCIS or invasive breast cancer. All index DCIS tumors underwent expert pathology review. Pathologic characteristics of IP-SBCs were abstracted from available medical records. Logistic regression was used to examine associations between pathologic characteristics and identify factors associated with invasive versus non-invasive IP-SBC. Of 1969 DCIS patients, 182 developed an IP-SBC within a median of 38 months (range 6-160). IP-SBCs were slightly more commonly non-invasive (53 %) versus invasive (47 %). Of invasive IP-SBCs, 31 % were high grade, 67 % were <20 mm, 74 % were estrogen receptor positive, 7 % were HER2 positive, and 16 % were node positive. Of non-invasive IP-SBCs, 33 % were high grade. Comparing index DCIS and IP-SBC specimens, there was moderate-high correlation for HR status and grade. Among patients with IP-SBCs, those who were younger and whose index DCIS tumors were HR negative had shorter intervals (within 3 years) between index and IP-SBC diagnoses. No index DCIS feature was statistically significantly associated with an IP-SBC that was invasive versus non-invasive. Understanding the characteristics of SBCs and identifying correlations between these and index DCIS events could influence treatment choices for DCIS, and may help patients and providers develop treatment paradigms for SBCs. [ABSTRACT FROM AUTHOR]

Background: Various patient, treatment, and pathologic factors have been associated with an increased risk of local recurrence (LR) following breast-conserving therapy (BCT) for ductal carcinoma in situ (DCIS). However, the strength and importance of individual factors has varied; whether combining factors improves prediction, particularly in community practice, is uncertain. In a large, population-based cohort of women with DCIS treated with BCT in three community-based practices, we assessed the validity of the Memorial Sloan-Kettering Cancer Center (MSKCC) DCIS nomogram, which combines clinical, pathologic, and treatment features to predict LR. Methods: We reviewed slides of patients with unilateral DCIS treated with BCT. Regression methods were used to estimate risks of LR. The MSKCC DCIS nomogram was applied to the study population to compare the nomogram-predicted and observed LR at 5 and 10 years. Results: The 495 patients in our study were grouped into quartiles and octiles to compare observed and nomogram-predicted LR. The 5-year absolute risk of recurrence for lowest and highest quartiles was 4.8 and 33.1 % (95 % CI 3.1-6.4 and 24.2-40.9, respectively; p < 0.0001). The overall correlation between 10-year nomogram-predicted recurrences and observed recurrences was 0.95. Compared with observed 10-year LR rates, the risk estimates provided by the nomogram showed good correlation, and reasonable discrimination with a c-statistic of 0.68. Conclusions: The MSKCC DCIS nomogram provided good prediction of the 5- and 10-year LR when applied to a population of patients with DCIS treated with BCT in a community-based practice. This nomogram, therefore, is a useful treatment decision aid for patients with DCIS. [ABSTRACT FROM AUTHOR]

Purpose: The optimal treatment strategy for ductal carcinoma in situ (DCIS) continues to evolve and should consider the consequences of initial treatment on the likelihood, type, and treatment of recurrences. Methods: We conducted a retrospective cohort study using two data sources of patients who experienced a recurrence (DCIS or invasive cancer) following breast-conserving surgery (BCS) for index DCIS: patients with an index DCIS diagnosed from 1997 to 2008 at the academic institutions of the National Comprehensive Cancer Network (NCCN; N = 88) and patients with an index DCIS diagnosed from 1990 to 2001 at community-based integrated healthcare delivery sites of the Health Maintenance Organization Cancer Research Network (CRN) ( N = 182). Results: Just under half of local recurrences in both cohorts were invasive cancer. While 40 % of patients in both cohorts underwent mastectomy alone at recurrence, treatment of the remaining patients varied. In the earlier CRN cohort, most other patients underwent repeat BCS (39 %) with only 18 % receiving mastectomy with reconstruction, whereas only 16 % had repeat BCS and 44 % had mastectomy with reconstruction in the NCCN cohort. Compared with patients not treated with radiation, those who received radiation for index DCIS were less likely to undergo repeat BCS (NCCN: 6.6 vs. 37 %, p = 0.001; CRN: 20 vs. 48 %, p = 0.0004) and more likely to experience surgical complications after treatment of recurrence (NCCN: 15 vs. 4 %, p = 0.17; CRN: 40 vs. 25 %, p = 0.09). Conclusion: We found that treatment of recurrences after BCS and subsequent complications may be affected by the use of radiotherapy for the index DCIS. Initial treatment of DCIS may have long-term implications that should be considered. [ABSTRACT FROM AUTHOR]

Purpose: Re-examine association of fluoxetine and paroxetine with risk of testicular cancer noted in drug screening, with 4 years more follow-up and expanded study of these and other antidepressant drugs. Methods: In the Kaiser Permanente Medical Care Program in Northern California, 906 men with testicular cancer diagnosed August 1996-December 2010 were compared with 38,253 matched controls with race/ethnicity recorded regarding receipt of antidepressant drugs at least 2 years before diagnosis or control index date. Analyses emphasized duration of use and histological subgroups. Results: With control for race/ethnicity and use of other antidepressant drugs, odds ratios (OR) and 95 % confidence intervals (CI) for associations with testicular cancer were as follows: fluoxetine 1.22 (0.88-1.71), paroxetine 1.19 (0.78-1.83), and 1.21 (0.92-1.58) for all serotonin reuptake inhibitors. There was no statistically significant association with risk of all testicular cancers or their histological subtypes for any individual drug or for tricyclics or all antidepressants combined except for citalopram with all testicular cancers 2.55 (1.43-4.52) and those of mixed histology 4.36 (1.50-12.68) and nefazodone with embryonal cancers 9.79 (1.85-51.81). These could readily be chance findings in the context of the many analyses that were performed. Duration of use was not associated with risk of the drugs and drug groups with sufficient numbers of exposed cases for analysis. Conclusions: We found little evidence to support a testicular carcinogenic effect of fluoxetine, paroxetine, or other antidepressant drugs, but a weakly positive association is not ruled out. The signals in prior screening may have been due to chance and/or uncontrolled confounding. [ABSTRACT FROM AUTHOR]

We aimed to identify clinicopathologic factors associated with local recurrence (LR) in a large population of DCIS patients treated with breast-conserving therapy between 1990-2001 in three health plans. Regression methods were used to estimate relative risks (RR) of LR. Among 2,995 patients, 325 had a LR [10.9 %; median follow-up 4.8 years (range 0.5-15.7)]. After adjusting for health plan and treatment, risk of LR was increased among women <45 years (RR = 2.1, 95 % CI 1.5-2.8), African-Americans (RR = 1.6; 95 % CI 1.1-2.1) and those with DCIS detected because of signs/symptoms (RR = 1.6; 95 % CI 1.2-2.0). After also adjusting for age and diagnosis year, pathologic features associated with increased LR were larger lesion size (RR = 2.9 for ≥20 low power fields of DCIS; 95 % CI 1.6-5.6) and involved (RR = 2.9; 95 % CI 1.6-5.2), or close margins (RR = 2.4; 95 % CI 1.6-3.8). Presentation with symptoms/signs was associated with increased risk of invasive recurrence; while African-American race, larger tumor size, and involved/close tumor margins were more strongly associated with increased risk of DCIS recurrence. Our findings suggest some risk factors differ for non-invasive and invasive LRs and that most factors are only moderately associated with increased LR risk. Future research efforts should focus on non-clinicopathologic factors to identify more powerful risk factors for LR. [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]

Background Breast-conserving surgery (BCS) is the most common treatment for ductal carcinoma in situ (DCIS); however, how often women experience subsequent diagnostic evaluations over time is not known. Methods We identified 2948 women with DCIS who were treated with BCS from 1990 to 2001 and followed for up to 10 years at three integrated health-care delivery systems. We calculated the percentages of diagnostic mammograms and ipsilateral invasive procedures following the initial breast excision to treat DCIS, estimated the 10-year cumulative incidence of these procedures, and determined hazard ratios for both types of procedures with Cox regression modeling. All statistical tests were two-sided. Results Over 10 years, 907 women (30.8%) had 1422 diagnostic mammograms and 1813 (61.5%) had 2305 ipsilateral invasive procedures. Diagnostic mammograms occurred in 7.3% of women in the first 6 months and continued at a median annual rate of 4.3%. Ipsilateral invasive procedures occurred in 51.5% of women in the first 6 months and continued at a median annual rate of 3.1%. The estimated 10-year cumulative risk of having at least one diagnostic mammogram after initial DCIS excision was 41.0% (95% confidence interval [CI] = 38.5% to 43.5%); at least one invasive procedure, 65.7% (95% CI = 63.7% to 67.8%); and either event, 76.1% (95% CI = 74.1% to 78.1%). Excluding events in the first 6 months following initial DCIS excision, corresponding risks were 36.4% (95% CI = 33.8% to 39.0%) for diagnostic mammograms, 30.4% (95% CI = 26.9% to 33.8%) for invasive procedures, and 49.5% (95% CI = 45.6% to 53.5%) for either event. Conclusions Women with DCIS treated with BCS continue to have diagnostic and invasive breast procedures in the conserved breast over an extended period. The frequency of ongoing diagnostic breast evaluations should be included in discussions about treatment. [ABSTRACT FROM PUBLISHER]

The article discusses a study concerning the relationship between attention-deficit/hyperactivity disorder (ADHD) medications and increased risk of serious cardiovascular events in young and middle-aged adults. It cites increased prescribing as factor behind the increase in ADHD diagnoses. A total of 443,198 individuals have been considered in the study, 150,359 of whom use ADHD medications at baseline in which results show that methylphenidate accounted for 45% of current medication use while amphetamine accounted for 44%. Findings suggest that an increased risk of serious cardiovascular events is not associated with current or new use medications for ADHD.

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 Diabetes mellitus is associated with an increased risk of colorectal neoplasia and diabetes medications may further influence the risk. Observational studies of the effect of diabetes medications on colonic neoplasia may be biased if use of diabetes medications is associated with undergoing lower endoscopy. This study examined the association between diabetes therapies and use of lower endoscopy. Methods This retrospective cohort study included patients with diabetes in an integrated, prepaid health plan. The primary exposure variables were use of sulfonylureas, metformin, thiazolidinediones (TZDs), and insulin. The outcome measure was completion of a flexible sigmoidoscopy or colonoscopy. Cox proportional hazards modeling, accounting for the time-varying nature of the medication exposures, was used to generate estimates of the relative hazard (HR) of lower endoscopy with different medications. Results The study included 44 169 patients followed for a mean duration of 4.2 years (SD = 2.5 years); 34% underwent at least one lower endoscopy. Patients who filled a diabetes medication prescription were more likely to undergo lower endoscopy (HR = 1.13, 95%CI 1.06-1.21). Compared to those taking only sulfonylureas, patients receiving sulfonylureas and metformin (HR = 1.12, 95%CI 1.06-1.18) or metformin alone (HR = 1.17, 95%CI 1.07-1.26) were more likely to undergo lower endoscopy. For all medications, new use was associated with undergoing lower endoscopy ( p < 0.05 for all comparisons). Conclusions Diabetic patients receiving medications are more likely to undergo lower endoscopy than those on diet control alone, particularly in the first year after initiating a new medication class and if taking metformin. Copyright © 2007 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

A letter to the editor commenting on the article "Use of Benzodiazepines or Benzodiazepine Related Drugs and the Risk of Cancer: a Population-Based Case-Control Study," is presented.

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]

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 node-negative 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]