Isaac J. Ergas

Association of Serum Level of Vitamin D at Diagnosis With Breast Cancer Survival: A Case-Cohort Analysis in the Pathways Study.

Importance There are long-standing interests in the potential benefits of vitamin D for preventing breast cancer recurrence and mortality, yet data from prospective cohort studies are limited. Objective To investigate a serum biomarker of vitamin D status, 25-hydroxyvitamin D (25OHD) measured at the time of breast cancer diagnosis, to determine the association with prognosis. Design, Setting, and Participants The Pathways Study is a prospective cohort study of breast cancer survivors established in 2006. Enrollment was completed in 2013; follow-up is ongoing. The cohort was established in Kaiser Permanente Northern California, a large integrated health care delivery system in northern California. Women with a diagnosis of incident invasive breast cancer were typically consented and enrolled within 2 months of diagnosis. The overall enrollment rate was 46% (4505 of 9820). Participants are followed for health outcomes and comorbidities at 12, 24, 48, 72, and 96 months after baseline interview. A case-cohort design was used for efficiency assay of 25OHD, selecting 1666 cohort members with serum samples and ensuring representation in the subcohort of races and clinical subtypes. The data analysis was performed from January 5, 2014, to March 15, 2015. Main Outcomes and Measures Primary outcomes are breast cancer recurrence, second primary cancer, and death. Results Mean (SD) age was 58.7 (12.4) years. Serum 25OHD concentrations were lower in women with advanced-stage tumors, and the lowest in premenopausal women with triple-negative cancer. Levels were also inversely associated with hazards of disease progression and death. Compared with the lowest tertile, women with the highest tertile of 25OHD levels had superior overall survival (OS). This association remained after adjustment for clinical prognostic factors (hazard ratio [HR], 0.72; 95% CI, 0.54-0.98). Among premenopausal women, the association with OS was stronger, and there were also associations with breast cancer–specific survival and invasive disease–free survival (OS: HR, 0.45; 95% CI, 0.21-0.96; breast cancer–specific survival: HR, 0.37; 95% CI, 0.15-0.93; invasive disease–free survival: HR, 0.58; 95% CI, 0.34-1.01; all after full adjustment). Conclusions and Relevance Serum 25OHD levels were independently associated with breast cancer prognostic characteristics and patient prognosis, most prominently among premenopausal women. Our findings from a large, well-characterized prospective cohort provide compelling observational evidence on associations of vitamin D with lower risk of breast cancer morbidity and mortality.

Employment status and quality of life in recently diagnosed breast cancer survivors.

Breast cancer survivors are less likely to be employed than similar healthy women, yet effects of employment on the well being of survivors are largely unknown. In a prospective cohort study of 2013 women diagnosed from 2006 to 2011 with invasive breast cancer in Kaiser Permanente Northern California, we describe associations between hours worked per week and change in employment with quality of life (QOL) from diagnosis through active treatment.

BMI, Lifestyle Factors and Taxane-Induced Neuropathy in Breast Cancer Patients: The Pathways Study

Background: Lifestyle factors may be associated with chemotherapy‐induced peripheral neuropathy (CIPN). We examined associations between body mass index (BMI) and lifestyle factors with CIPN in the Pathways Study, a prospective cohort of women with invasive breast cancer. Methods: Analyses included 1237 women who received taxane treatment and provided data on neurotoxicity symptoms. Baseline interviews assessed BMI (normal: <25 kg/m2; overweight: 25‐29.9 kg/m2; obese: ≥30 kg/m2), moderate‐to‐vigorous physical activity (MVPA) (low: <2.5; medium: 2.5‐5; high: >5 hours/week) and fruit/vegetable intake (low: <35 servings/week; high: ≥35 servings/week). Baseline and six‐month interviews assessed antioxidant supplement use (nonuser, discontinued, continued user, initiator). CIPN was assessed at baseline, six months, and 24 months using the Functional Assessment of Cancer Therapy‐Taxane Neurotoxicity (FACT‐NTX); a 10% decrease was considered clinically meaningful. Results: At baseline, 65.6% of patients in the sample were overweight or obese, 29.9% had low MVPA, 57.5% had low fruit/vegetable intake, and 9.5% reported antioxidant supplement use during treatment. In multivariable analyses, increased CIPN was more likely to occur in overweight (odds ratio [OR] = 2.37, 95% confidence interval [CI] = 1.19 to 4.88) and obese patients (OR = 3.21, 95% CI = 1.52 to 7.02) compared with normal weight patients at 24 months and less likely to occur in patients with high MVPA compared with those with low MVPA at six (OR = 0.56, 95% CI = 0.34 to 0.94) and 24 months (OR = 0.43, 95% CI = 0.21 to 0.87). Compared with nonusers, patients who initiated antioxidant use during treatment were more likely to report increased CIPN at six months (OR = 3.81, 95% CI = 1.82 to 8.04). Conclusions: Obesity and low MVPA were associated with CIPN in breast cancer patients who received taxane treatment.

Association Between Complementary and Alternative Medicine Use and Breast Cancer Chemotherapy Initiation: The Breast Cancer Quality of Care (BQUAL) Study

IMPORTANCE Not all women initiate clinically indicated breast cancer adjuvant treatment. It is important for clinicians to identify women at risk for noninitiation. OBJECTIVE To determine whether complementary and alternative medicine (CAM) use is associated with decreased breast cancer chemotherapy initiation. DESIGN, SETTING, AND PARTICIPANTS In this multisite prospective cohort study (the Breast Cancer Quality of Care [BQUAL] study) designed to examine predictors of breast cancer treatment initiation and adherence, 685 women younger than 70 years with nonmetastatic invasive breast cancer were recruited from Columbia University Medical Center, Kaiser Permanente Northern California, and Henry Ford Health System and enrolled between May 2006 and July 31, 2010. Overall, 306 patients (45%) were clinically indicated to receive chemotherapy per National Comprehensive Cancer Network guidelines. Participants were followed for up to 12 months. EXPOSURES Baseline interviews assessed current use of 5 CAM modalities (vitamins and/or minerals, herbs and/or botanicals, other natural products, mind-body self-practice, mind-body practitioner-based practice). CAM use definitions included any use, dietary supplement use, mind-body use, and a CAM index summing the 5 modalities. MAIN OUTCOMES AND MEASURES Chemotherapy initiation was assessed via self-report up to 12 months after baseline. Multivariable logistic regression models examined a priori hypotheses testing whether CAM use was associated with chemotherapy initiation, adjusting for demographic and clinical covariates, and delineating groups by age and chemotherapy indication. RESULTS A cohort of 685 women younger than 70 years (mean age, 59 years; median age, 59 years) with nonmetastatic invasive breast cancer were recruited and followed for up to 12 months to examine predictors of breast cancer treatment initiation. Baseline CAM use was reported by 598 women (87%). Chemotherapy was initiated by 272 women (89%) for whom chemotherapy was indicated, compared with 135 women (36%) for whom chemotherapy was discretionary. Among women for whom chemotherapy was indicated, dietary supplement users and women with high CAM index scores were less likely than nonusers to initiate chemotherapy (odds ratio [OR], 0.16; 95% CI, 0.03-0.51; and OR per unit, 0.64; 95% CI, 0.46-0.87, respectively). Use of mind-body practices was not related to chemotherapy initiation (OR, 1.45; 95% CI, 0.57-3.59). There was no association between CAM use and chemotherapy initiation among women for whom chemotherapy was discretionary. CONCLUSIONS AND RELEVANCE CAM use was high among patients with early-stage breast cancer enrolled in a multisite prospective cohort study. Current dietary supplement use and higher number of CAM modalities used but not mind-body practices were associated with decreased initiation of clinically indicated chemotherapy. Oncologists should consider discussing CAM with their patients during the chemotherapy decision-making process.

The Impact of DNA Input Amount and DNA Source on the Performance of Whole-Exome Sequencing in Cancer Epidemiology

Background: Whole-exome sequencing (WES) has recently emerged as an appealing approach to systematically study coding variants. However, the requirement for a large amount of high-quality DNA poses a barrier that may limit its application in large cancer epidemiologic studies. We evaluated the performance of WES with low input amount and saliva DNA as an alternative source material. Methods: Five breast cancer patients were randomly selected from the Pathways Study. From each patient, four samples, including 3 μg, 1 μg, and 0.2 μg blood DNA and 1 μg saliva DNA, were aliquoted for library preparation using the Agilent SureSelect Kit and sequencing using Illumina HiSeq2500. Quality metrics of sequencing and variant calling, as well as concordance of variant calls from the whole exome and 21 known breast cancer genes, were assessed by input amount and DNA source. Results: There was little difference by input amount or DNA source on the quality of sequencing and variant calling. The concordance rate was about 98% for single-nucleotide variant calls and 83% to 86% for short insertion/deletion calls. For the 21 known breast cancer genes, WES based on low input amount and saliva DNA identified the same set variants in samples from a same patient. Conclusions: Low DNA input amount, as well as saliva DNA, can be used to generate WES data of satisfactory quality. Impact: Our findings support the expansion of WES applications in cancer epidemiologic studies where only low DNA amount or saliva samples are available. Cancer Epidemiol Biomarkers Prev; 24(8); 1207–13. ©2015 AACR.

Genetic ancestry is not associated with breast cancer recurrence or survival in U.S. latina women enrolled in the kaiser permanente pathways study

Background: The U.S. Hispanic/Latino population is heterogeneous both socioculturally and by the proportion of European, Indigenous American, and African ancestry of the regions from which individuals originate. A previous study reported that genetic ancestry was associated with breast cancer survival among Latinas, independent of sociodemographic and tumor characteristics, suggesting that a genetic factor associated with ancestry may affect breast cancer survival. Methods: We evaluated the association of genetic ancestry with breast cancer outcomes among 506 Latina women with invasive breast cancer in the Pathways Study, a cohort study within Kaiser Permanente, an integrated health care delivery system. Proportional hazards models were used to assess the effect of ancestry on breast cancer recurrence (53 events), breast cancer–specific mortality (31 events) and all-cause mortality (54 events), with a mean follow-up time of 6 years. Results: Indigenous American ancestry was not associated with breast cancer recurrence [HR = 1.00 per 10% increase; 95% confidence interval (CI), 0.86–1.16], breast cancer mortality (HR = 0.95; 95% CI, 0.77–1.17), or all-cause mortality (HR = 0.93; 95% CI, 0.80–1.08). Adjustment for sociodemographic variables, tumor characteristics, and treatment did not alter the associations. Conclusions: Our results suggest that previously reported differences in breast cancer survival by genetic ancestry may be overcome by improving health care access and/or quality. Impact: Improving health care access and quality may reduce breast cancer disparities among U.S. Latinas. Cancer Epidemiol Biomarkers Prev; 26(9); 1466–9. ©2017 AACR.

Abstract 4126: The association of serum 25-hydroxyvitamin D with breast cancer characteristics and prognosis in the Pathways Study

Background: Vitamin D may be protective against breast cancer (BC), yet current evidence from epidemiologic studies is inconsistent. We previously reported lowest serum 25-hydyroxyvitamin D (25OHD) levels in premenopausal women with the triple-negative (TN) subtype. We aimed to validate our findings in an independent cohort and to further investigate 25OHD levels in association with breast cancer prognosis. Methods: Using a case-cohort design, 1664 invasive breast cancer patients were selected from the Pathways Study, a prospective cohort at Kaiser Permanente Northern California (KPNC). 25OHD levels were measured by immunochemiluminometric assay in blood samples collected close to diagnosis. Demographic and lifestyle information at baseline came from in-person interviews, and information on cancer characteristics, treatment, recurrence and death were obtained from KPNC cancer registries and clinical databases. We examined quartiles of 25OHD in association with BC characteristics (stage, grade, estrogen receptor status, TN subtype) using logistic regression, and with disease-free survival (DFS) and overall survival (OS) using Cox proportional hazards regression with covariate adjustment. Pending analyses will account for sampling in which biospecimens from all minorities, all non-Lum A subtypes (Lum B/TN/HER2-overexpressing), and a subset (30%) of white Lum A subtypes were selected. Results: Blood collection in winter-spring, younger age, obesity, black or Hispanic race/ethnicity, current smoking, low moderate-vigorous physical activity, no vitamin D supplement use, and low dietary vitamin D intake were associated with low serum 25OHD levels. In premenopausal women, 25OHD levels were associated inversely with cancer stage and grade, and those with the TN subtype had the lowest levels (Q4: adjusted OR vs. Lum A=0.41, 95% CI=0.19-0.86). Among white women after a median follow-up time of 5.9 y (range 2.5-7.8 y), high 25OHD levels were associated with longer DFS (Q4: adjusted HR=0.67, 95% CI=0.45-0.98), as well as OS (Q4: adjusted HR=0.58, 95% CI=0.36-0.92). Additional adjustment for stage, grade, subtype and treatment received had minimal effects on the above associations. The associations with DFS and OS appeared stronger in premenopausal women than in postmenopausal women. Conclusion: In a large prospective cohort of breast cancer patients, we validated our previous findings of 25OHD levels being associated with lower odds of TN tumor subtype in premenopausal patients. Moreover, preliminary results indicate that high 25OHD levels at the time of diagnosis were associated with longer DFS and OS, the relationships were independent of cancer characteristics and treatment, and may be stronger in premenopausal women. These findings support potential benefits of maintaining sufficient vitamin D levels for improved breast cancer prognosis. Citation Format: Song Yao, Chi-Chen Hong, Marilyn L. Kwan, Ting-Yuan Cheng, Li Tang, Susan E. McCann, Isaac J. Ergas, Janise M. Roh, Warren Davis, Christine B. Ambrosone, Lawrence H. Kushi. The association of serum 25-hydroxyvitamin D with breast cancer characteristics and prognosis in the Pathways Study. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4126. doi:10.1158/1538-7445.AM2014-4126

Perioperative Intravesical Chemotherapy for Patients with Non-Muscle Invasive Bladder Cancer: Understanding the Extent of and Sources of Variation in Guideline-Recommended Use

OBJECTIVE To examine intravesical chemotherapy (IVC) use according to non-muscle-invasive bladder cancer patient disease risk, and the contributions of multilevel factors to variation in proficient use among patients with low-intermediate disease. METHODS This study included 988 patients diagnosed with non-muscle-invasive bladder cancer in an integrated health system in Northern California from 2015-2017. We calculated IVC receipt by disease risk, and among patients with low-intermediate risk disease, assessed the relationship between multilevel factors and IVC receipt using a logistic regression model with random intercepts for provider and service area, and patient-, provider-, and service area-level fixed effects. We further assessed the association of provider- and service area-level factors with IVC use by examining intraclass correlation coefficients. RESULTS Similar proportions of low-intermediate (36%) and high-risk (34%) patients received IVC. In the multivariate analysis, including low-intermediate risk patients, service area volume was strongly and statistically significantly associated with IVC use (adjusted odds ratio, high- vs low-volume: 0.08, 95% Confidence Interval: 0.01-0.58). Provider- and service area-level intraclass correlation coefficients were large, (38%, P = .0009 and 39% P = .03, respectively) indicating that much of the variance in IVC use was explained by factors at these levels. CONCLUSION Our findings highlight opportunities to improve proficient use of IVC. Future research should assess provider- and practice-level barriers to IVC use among low-intermediate risk patients.

Abstract IA27: Disparities in breast cancer survivorship and outcomes

In the U.S., women of European ancestry have historically had the highest incidence of breast cancer compared to other major race/ethnicity groups. In recent years, the incidence rate for black women has approached that of white women, while rates for Asian and Hispanic women are about 25% lower than for white or black women. However, once diagnosed with breast cancer, black women have poorer survival rates than white women. The most recent “Annual Report to the Nation on the Status of Cancer” using nationwide cancer-registry data from 2006-2013 (Jemal et al., JNCI, 2017) reported a higher age- and stage-adjusted relative mortality risk after breast cancer of 1.71 (95% confidence interval (CI), 1.66-1.76) for non-Hispanic blacks compared to non-Hispanic whites. Hispanic women also experienced a slightly increased relative mortality risk of 1.14 (95% CI, 1.10-1.18) compared to white women, while Asians experienced a lower relative mortality risk of 0.84 (95% CI, 0.80-0.88). The reasons for such disparities in outcomes after breast cancer are complex. One suggested contributing factor is differences in access to care, as blacks and Hispanics tend to be of lower socioeconomic status than whites or Asians. It is possible to minimize the effects of access to health care by examining outcomes after breast cancer diagnosis in an integrated health care setting such as Kaiser Permanente Northern California (KPNC), in which all patients have health insurance coverage with access to the same health care providers. We are currently conducting the Pathways Study, a prospective cohort study of 4,505 women diagnosed with breast cancer with enrollment from 2006-2013. This diverse cohort includes 557 Hispanics, 578 Asians, and 358 blacks. Preliminary analyses in the larger population of 11,176 women who were diagnosed with invasive breast cancer in KPNC and eligible for the Pathways Study found that, despite the uniform health care access, racial disparities in mortality after breast cancer were qualitatively similar to those observed nationally. With 1,738 total deaths as of September 20, 2016, and adjusted for age and stage at diagnosis, compared to white women, black women had an increased relative mortality risk of 1.59 (95% CI, 1.24-2.03). For Hispanic women, the relative risk was 0.92 (95% CI, 0.72-1.19), and for Asians it was 0.70 (95% CI, 0.51-0.97). Among the subset of women enrolled in the Pathways Study (n=538 total deaths), comparable relative risks were 1.74 (95% CI, 1.35-2.24) for black women, 0.99 (95% CI, 0.75-1.29) for Hispanic women, and 0.73 (95% CI, 0.52-1.02) for Asians. Similar black-white differences were also seen for breast cancer-specific mortality and recurrence in the Pathways Study cohort in which recurrences are being documented. These observations indicate that health care access is unlikely to explain racial/ethnic disparities in breast cancer outcomes. As the Pathways Study, we will be able to explore aspects of health care utilization, such as treatment-related factors such as treatment delay, adherence, and early discontinuation. We will also be able to explore presence of comorbid conditions or use of non-cancer medications that may influence mortality and breast cancer outcomes. In the Pathways Study, we are collecting data on lifestyle and psychosocial factors (e.g., food intake, physical activity, social support, doctor-patient communications, and quality of life); linking to geospatial databases to characterize the social and built environment of cohort members; and conducting genome-wide assays. For example, in preliminary analyses that adjusted additionally for estrogen receptor status, body mass index, educational attainment, and physical activity, black-white differences in mortality persisted even though they were somewhat attenuated (relative risk of 1.43; 95% CI, 1.09-1.86). Along with other studies that are examining breast cancer outcomes in different populations, the Pathways Study is poised to contribute to better understanding of the persistent black-white differences in mortality after breast cancer, and thus identify avenues to improve outcomes for all women with breast cancer. Citation Format: Lawrence H. Kushi, Isaac J. Ergas, Janise M. Roh, Scarlett Lin Gomez, Marilyn L. Kwan, Catherine Thomsen, Song Yao, Christine B. Ambrosone. Disparities in breast cancer survivorship and outcomes [abstract]. In: Proceedings of the Tenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2017 Sep 25-28; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2018;27(7 Suppl):Abstract nr IA27.

Understanding racial/ethnic differences in breast cancer-related physical well-being: the role of patient–provider interactions

PurposeRacial/ethnic differences in cancer symptom burden are well documented, but limited research has evaluated modifiable factors underlying these differences. Our objective was to examine the role of patient–provider interactions to help explain the relationship between race/ethnicity and cancer-specific physical well-being (PWB) among women with breast cancer.MethodsThe Pathways Study is a prospective cohort study of 4505 women diagnosed with breast cancer at Kaiser Permanente Northern California between 2006 and 2013. Our analysis included white, black, Hispanic, and Asian participants who completed baseline assessments of PWB, measured using the Functional Assessment of Cancer Therapy for Breast Cancer, and patient–provider interactions, measured by the Interpersonal Processes of Care Survey (IPC) (N = 4002). Using step-wise linear regression, we examined associations of race/ethnicity with PWB, and changes in associations when IPC domains were added.ResultsWe observed racial/ethnic differences in PWB, with minorities reporting lower scores than whites (beta, black: − 1.79; beta, Hispanic: − 1.92; beta, Asian: − 1.68; p < 0.0001 for all comparisons). With the addition of health and demographic covariates to the model, associations between race/ethnicity and PWB score became attenuated for blacks and Asians (beta: − 0.63, p = 0.06; beta: − 0.68, p = 0.02, respectively) and, to a lesser extent, for Hispanic women (beta: − 1.06, p = 0.0003). Adjusting for IPC domains did not affect Hispanic–white differences (beta: − 1.08, p = 0.0002), and slightly attenuated black–white differences (beta: − 0.51, p = 0.14). Asian–white differences narrowed substantially (beta: − 0.31, p = 0.28).ConclusionsIPC domains, including those capturing perceived discrimination, respect, and clarity of communication, appeared to partly explain PWB differences for black and Asian women. Results highlight opportunities to improve providers’ interactions with minority patients, and communication with minority patients about their supportive care needs.