Joanie Chung

Tamoxifen and Antidepressant Drug Interaction in a Cohort of 16,887 Breast Cancer Survivors.

BACKGROUND Controversy persists about whether certain antidepressants reduce tamoxifens effectiveness on lowering breast cancer recurrence. We investigated whether taking tamoxifen and antidepressants (in particular, paroxetine) concomitantly is associated with an increased risk of recurrence or contralateral breast cancer. METHODS We examined 16 887 breast cancer survivors (TNM stages 0-II) diagnosed between 1996 and 2007 and treated with tamoxifen in two California health plans. Women were followed-up through December 31, 2009, for subsequent breast cancer. The main exposure was the percent of days of overlap when both tamoxifen and an antidepressant (paroxetine, fluoxetine, other selective serotonin reuptake inhibitors, tricyclics, and other classes) were used. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using multivariable Cox regression models with time-varying medication variables. RESULTS Of the 16 887 women, half (n = 8099) used antidepressants and 2946 women developed subsequent breast cancer during the 14-year study period. We did not find a statistically significant increased risk of subsequent breast cancer in women who concurrently used paroxetine and tamoxifen. For 25%, 50%, and 75% increases in percent overlap days between paroxetine and tamoxifen, hazard ratios were 1.06 (95% CI = 0.98 to 1.14, P = .09), 1.13 (95% CI = 0.98 to 1.30, P = .09), and 1.20 (95% CI = 0.97 to 1.49, P = .09), respectively, in the first year of tamoxifen treatment but were not statistically significant. Hazard ratios decreased to 0.94 (95% CI = 0.81 to 1.10, P = .46), 0.89 (95% CI = 0.66 to 1.20, P = .46), and 0.85 (95% CI = 0.54 to 1.32, P = .46) by the fifth year (all non-statistically significantly). Absolute subsequent breast cancer rates were similar among women who used paroxetine concomitantly with tamoxifen vs tamoxifen-only users. For the other antidepressants, we again found no such associations. CONCLUSIONS Using the comprehensive electronic health records of insured patients, we did not observe an increased risk of subsequent breast cancer in women who concurrently used tamoxifen and antidepressants, including paroxetine.

Metformin and breast and gynecological cancer risk among women with diabetes

Objective We investigated if metformin lowers breast, endometrial, and ovarian cancer risk in women with type 2 diabetes mellitus compared with women who used other antidiabetic medications. Research design and methods We followed a cohort of 66 778 female patients with diabetes for a maximum of 12 years (median 6 years). We examined breast, endometrial, and ovarian cancer risk, and the composite cancer risk. We examined drug categories using pharmacy records: metformin only; metformin combination regimens; non-metformin regimens; and non-users. We used χ2 analyses to examine categorical variables. We conducted multivariable Cox regression models with time-dependent drug use status. Results Women who used metformin combination regimens versus metformin only had a 15% lower breast cancer risk (adjusted HR=0.85, 95% CI 0.69 to 1.04). After stratifying by glycated hemoglobin (HbA1c), the association attenuated in those who had poorly controlled HbA1c (adjusted HR=1.06, 95% CI 0.73 to 1.55). Given the small numbers of ovarian and endometrial cancer outcomes, we examined these as a composite. The risk of all cancers combined was similar in those who used metformin combination regimens versus metformin only (adjusted HR=0.92, 95% CI 0.78 to 1.10). We found no significant differences for breast cancer or all cancers combined when we compared risks in non-metformin users versus metformin only users. Conclusions Women who used metformin and other antidiabetic drugs had a lower breast cancer risk compared with women who used metformin only, but the results were not significant. We also found no difference in overall cancer risks when we compared women who used other antidiabetic drugs (no metformin) versus metformin users.

Cardiovascular Disease After Aromatase Inhibitor Use.

Importance Cardiovascular disease (CVD) is an important cause of death in older patients with breast cancer. However, limited information exists on the long-term effect of aromatase inhibitor (AI) use on CVD risk in breast cancer survivors. To this point, no other population-based studies have been able to adjust for CVD risk factors or cardiovascular medications. Objective To determine the long-term influence of adjuvant endocrine therapies on CVD in a cohort of postmenopausal breast cancer survivors in analyses that accounted for major CVD risk factors, medication use, chemotherapy, and radiotherapy. Design, Setting, and Participants A retrospective cohort of postmenopausal women with breast cancer diagnosed from January 1, 1991, to December 31, 2010, and followed up through December 31, 2011 (maximum, 21 years [72 886 person-years]), was evaluated using records from a managed care organization with nearly 20 community hospitals in California. A total of 13 273 postmenopausal women with hormone receptor-positive breast cancer without prior CVD were included. Cardiovascular disease incidence was compared across endocrine therapy categories. Information on demographics, comorbidity, medication, use, and CVD risk was captured from electronic health records. Multivariate Cox proportional hazards models using time-dependent endocrine drug use variables and propensity scores were conducted. Data analysis was conducted from September 15, 2014, to February 1, 2016. Exposures Women were grouped by endocrine therapy status (tamoxifen citrate only, AI only, both, or neither). Main Outcomes and Measures Person-year rates of CVD for each therapy group. Results During 72 886 person-years in 13 273 women (mean [SD] age, 66.8 [8.1] years) with follow-up through 2011, we observed 3711 CVD events. In multivariable analyses (reported as hazard ratio [95% CI]), AI-only users had a similar risk of cardiac ischemia (myocardial infarction and angina) (adjusted, 0.97 [0.78-1.22]) and stroke (adjusted, 0.97 [0.70-1.33]) as tamoxifen-only users (reference). However, we found an increased risk of other CVD (dysrhythmia, valvular dysfunction, and pericarditis) (adjusted, 1.29 [1.11-1.50]) in women who used AIs only or sequentially after tamoxifen (1.26 [1.09-1.45]) vs tamoxifen (reference) as well nonhormone users (1.18 [1.02-1.35]). Conclusions and Relevance The risk of the most serious cardiovascular events (cardiac ischemia or stroke) was not elevated in AI-only users compared with tamoxifen users. The finding that other CVD events combined were greater in AI users requires further study.

Aromatase inhibitors, tamoxifen, and endometrial cancer in breast cancer survivors.

The risks of both endometrial cancer and postmenopausal breast cancer are increased by obesity and higher endogenous estrogen levels. Although aromatase inhibitors reduce breast cancer incidence, their influence on endometrial cancer is uncertain.

A hybrid approach to identify subsequent breast cancer using pathology and automated health information data.

Purpose:Many cancer registries do not capture recurrence; thus, outcome studies have often relied on time-intensive and costly manual chart reviews. Our goal was to build an effective and efficient method to reduce the numbers of chart reviews when identifying subsequent breast cancer (BC) using pathology and electronic health records. We evaluated our methods in an independent sample. Methods:We developed methods for identifying subsequent BC (recurrence or second primary) using a cohort of 17,245 women diagnosed with early-stage BC from 2 health plans. We used a combination of information from pathology report reviews and an automated data algorithm to identify subsequent BC (for those lesions without pathologic confirmation). Test characteristics were determined for a developmental (N=175) and test (N=500) set. Results:Sensitivity and specificity of our hybrid approach were robust [96.7% (87.6%–99.4%) and 92.1% (85.1%–96.1%), respectively] in the developmental set. In the test set, the sensitivity, specificity, and negative predictive value were also high [96.9% (88.4%–99.5%), 92.4% (89.4%–94.6%), and 99.5% (98.0%–99.0%), respectively]. The positive predictive value was lower (65.6%, 55.2%–74.8%). Chart review was required for 10.9% of the 17,245 women; 2946 (17.0%) women developed subsequent BC over a 14-year period. The date of subsequent BC identified by the algorithm was concordant with full chart reviews. Conclusions:We developed an efficient and effective hybrid approach that decreased the number of charts needed to be manually reviewed by approximately 90%, to determine subsequent BC occurrence and disease-free survival time.

Medication adherence, molecular monitoring, and clinical outcomes in patients with chronic myelogenous leukemia in a large HMO

OBJECTIVE Our objective was to examine the association between adherence to tyrosine kinase inhibitors (TKIs) and molecular monitoring and the risk of disease progression or mortality among patients with chronic phase chronic myeloid leukemia (CML). DESIGN We assembled a retrospective cohort of patients with CML (chronic phase, no prior cancer history, and confirmed to be Philadelphia chromosome positive) using data from electronic health records and chart reviews. Medication possession ratio (MPR) was used to measure drug adherence. SETTING A large, community-based, integrated health plan in Southern California. PARTICIPANTS The cohort consisted of 245 adult patients (≥18 years old) with Philadelphia positive chronic phase CML diagnosed from 2001 to 2012 and followed through 2013. MAIN OUTCOME MEASURES In survival analyses, we examined the association of TKI adherence (MPR) and polymerase chain reaction (PCR) monitoring test frequency with the composite clinical outcome, progression to accelerated phase disease-blast crisis or mortality (progression-free survival). The cohort was followed for a maximum of 13 years (median 4.6 years). RESULTS Over 90% of the cohort initiated TKI therapy within 3 months of diagnosis, and the mean MPR was 88% (SD 18%). Virtually all patients (96%) started on imatinib. The rates of progression to accelerated phase-blast crisis and mortality were lower in patients with greater TKI adherence (20.4/1000 person-years) versus lower adherence (27.0/1000 person-years). Patients who underwent PCR monitoring had a significantly reduced risk of progression or mortality, which was seen in patients with high and low TKI adherence status from both the groups (hazard ratio [HR] 0.07 [95% CI 0.03-0.19 if MPR >90%] and HR 0.70 [95% CI 0.02-0.21 if MPR<90%]). CONCLUSION Our results suggest that close clinical monitoring, which includes PCR monitoring in patients with high and low TKI drug adherence, is associated with a lower risk of progression or mortality.

Abstract P2-09-04: Implementation of next generation cancer gene panel testing in a large HMO

Background: Next generation cancer gene panel testing is fairly new in clinical practice. Little is known about the diagnostic yield of multigene cancer panel testing in community based hospitals. Objective: To describe characteristics of a diverse cohort who underwent high/moderate risk multigene panel testing for either a personal or a family history of cancer in a large health plan, and report the proportion of pathogenic/likely pathogenic variants (PV/LPV) and variants of unknown clinical significance (VUS) by race/ethnicity. Methods: Subjects included all 586 female patients who were referred for genetic counseling and underwent multigene panel testing between July 2014 and January 2015. Based on a literature review, the custom-designed high/moderate risk gene panel included 20 cancer susceptibility genes (described below). All tests were performed by the same commercial laboratory (GeneDx). Results: Of the 586 women, 78 (13.3%) tested positive PV/LPV316 (53.9%) tested negative; and 192 (32.8%) carried one or more VUS. Age at testing ranged from 22-81 years (median 50 years). More women with PV/LPV results tended to be obese than those who tested negative (39.7% vs. 31.2%), and had greater comorbidity (Charlson Index of >3, 35.9% vs. 33.2%). Of 586 women, 305 (52.0%) had a cancer diagnosis, mainly first primary breast cancer (n=290, 95.1%), while some also had a second primary breast cancer (n=67, 11.4%). Of the 305 women with cancer, 131 (42.9%) were diagnosed prior to the multigene testing implementation (1987-2013), while 174 (57.1%) were diagnosed after implementation. The cohort was diverse in terms of race/ethnicity: Western/Northern European (31.2%), Latina/Caribbean (30.0%), Asian (14.8%), African-American (7.2%), Ashkenazi Jewish (6.3%), Native American (5.9%), and other (14.9%) (percent exceeds 100% due to mixed race/ethnicity). Of the 192 women who carried a VUS, 60.4% were Western/Northern European, and 46.4% were Latina/Caribbean. Pathogenic or likely pathogenic mutations were higher in Latina /Caribbean women (37.2%), followed by Western/Northern European (26.7%), and African (10.3%). We identified a total of 84 pathogenic mutations among the 78 women with PV/LPV in the following genes: BRCA1 (n=22), BRCA2 (n=17), MUTYH (n=16; all heterozygous), CHEK2 (n=9), ATM (n=4), PALB2 (n=4), PMS2 (n=3), MLH1 (n=2), VHL (n=2), and one mutation in each of the following genes: APC, CDH1, PTEN, TP53, and STK11. VUS were detected in 192 patients (32.7%) of the 586 tested. VUS in ATM (n=57), APC (n=32) and CHEK2 (n=25) comprised 59.4% of all VUS detected. Discussion: The large percent of VUS was surprising, given that our panel included only high/moderate risk cancer genes. The over-representation of BRCA1/2 among all mutations (45.1%) likely reflected a greater proportion of patients referred for genetic counseling with a personal and/or family breast cancer history. Given that 35% of our positive results were dominant-acting pathogenic or suspected pathogenic mutations, our results suggest that multigene cancer panel testing is an appropriate method for detecting germline mutations in a high-risk cohort in a managed care setting. Citation Format: Haque R, Alvarado M, Ahmed SA, Chung J, Tiller GE. Implementation of next generation cancer gene panel testing in a large HMO. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-09-04.

Abstract PD4-2: Cardiovascular toxicity following aromatase inhibitor use in 13,273 survivors cared for in a HMO

Background Aromatase inhibitors (AIs) reduce breast cancer incidence in primary prevention trials (MAP3, IBIS2). However, controversy regarding AI’s influence on cardiovascular disease (MI, angina, and cardiac failure) (Amir et al JNCI 2011) could limit use in prevention settings. Methods We assembled a cohort of 13,273 postmenopausal breast cancer patients initially CVD (cardiovascular disease)-free at diagnosis in a large managed care organization. Women were diagnosed 1991-2010, and followed through 2012. The outcome, CVD risk was compared across endocrine treatments (AI, tamoxifen [TAM], both, or neither). Information on demographics, comorbidity (diabetes, hypertension, etc.), and covariate medications (antihyperlipidemics, antihypertensives, and other CVD drugs) were available from electronic medical records. We conducted Cox models using time-dependent endocrine drug use variables adjusted for age, demographics, comorbidity, and CVD drug use, cancer treatment, tumor characteristics and tumor laterality. Results Among the 13,273 cohort, postmenopausal women who used AIs exclusively had a similar risk of ischemic disease (HR=0.97, 95% CI: 0.78-1.22) and stroke (HR=0.97, 95% CI: 0.70-1.33) versus those who used TAM only (HR=1.00, reference). However, women who used AIs only had a higher risk of other CVD disease combined (CHF, cardiomyopathy, dysrthymia, valvular dysfunction, pericarditis) (HR=1.26, 95% CI: 1.11-1.43) than those exposed to TAM only. The risk of other CVD disease was greater among women exposed to sequential TAM and AI treatment. The results are based on 3,711 CVD events occurring in 72,886 woman-years of follow-up. Based on a subset of 7,982 patients who underwent breast irradiation, the risk of CVD overall was greater among women who used AIs only and received left-sided irradiation (HR=1.21, 95% CI: 1.02-1.44). Discussion These results indicate that variation exists in the type of CVD events that occur in breast cancer patients receiving AIs in comparison to tamoxifen users. For example, the risk of ischemic disease or stroke was not elevated in those who used AIs only versus TAM users. However, overall CVD events were greater in women who used AIs only (or sequentially after TAM), especially if they received left-sided breast irradiation. While these observational study results require cautious interpretation, they provide a basis for comparing the benefits and risks of endocrine treatments. Citation Format: Reina Haque, Joanne E Schottinger, Jiaxiao Shi, Joanie Chung, Chantal Avila, Britta Amundsen, Rowan T Chlebowski. Cardiovascular toxicity following aromatase inhibitor use in 13,273 survivors cared for in a HMO [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr PD4-2.

Abstract P3-07-05: Bisphosphonate use after primary breast cancer and risk of contralateral breast cancer using pharmacy data

Background: It is not clear if bisphosphonates (BP) are associated with improved breast cancer prognosis in women with early breast cancer. Clinical trials have reported mixed results, yet BPs may be most beneficial in patients with low estrogen levels. However, BPs and risk of second (contralateral) breast cancer has been minimally studied. We examined the association of oral BP use (ever/never and duration) on risk of contralateral breast cancer (CBC) in 17,224 women with early stage breast cancer treated with tamoxifen. Materials and Methods: A cohort was assembled of women diagnosed with their first primary breast cancer (Stage 0, I, II) from 1996 to 2007 on tamoxifen and followed through 31 December 2009 at Kaiser Permanente Northern and Southern California. Demographic, tumor, pharmacy, and cancer treatment information was extracted from electronic medical records and SEER-affiliated cancer registries at each site. Second (contralateral) tumors were identified from the cancer registries. Detailed information on oral BP use (before and after initial breast cancer diagnosis) was obtained from pharmacy databases. A record of >90 days supply was considered the minimum exposure. Initiation and duration of post-diagnosis use was categorized as 1) non-use (≤90 days supply) and use (>90 days supply) and 2) non-use (≤90 days supply), 91 days– Results: Over a mean (SD) follow-up of 6.4 (6.3) years, 586 women (3.4%) were diagnosed with CBC after their initial breast cancer diagnosis. Around 19.2% (n = 3303) of the cohort used a BP post-initial breast cancer diagnosis (>93% alendronate). To minimize confounding by indication, all models were adjusted for prior use of BPs before breast cancer diagnosis (n = 1047, 6.1%) and excluded women with prior 5-year history of osteopenia, osteoporosis, and fractures (n = 1808, 10.5%). Compared to non-users, ever use (>90 days supply) was associated with a modestly lower CBC risk (HR = 0.80; 95% CI: 0.61, 1.16). However, stratified analyses by age at breast cancer diagnosis ( Discussion: While we found modestly lower CBC risk with BP use after diagnosis of primary breast cancer, the protective effects were perhaps confined to older women compared with younger women. Next steps include adding BMD to further explore confounding by indication and examining BP use and breast cancer recurrence and mortality. Citation Information: Cancer Res 2012;72(24 Suppl):Abstract nr P3-07-05.