Chantal Avila

Impact of Breast Cancer Subtypes and Treatment on Survival: An Analysis Spanning Two Decades

Background: We investigated the impact of breast cancer molecular subtypes and treatment on survival in a cohort of medically insured women followed for more than 20 years. Methods: We examined 934 female members of an integrated health care delivery system newly diagnosed with invasive breast cancer between 1988 and 1995 and followed them through 2008. Tumors were classified into four molecular subtypes on the basis of their expression profile: luminal A; luminal B; basal-like; and HER2-enriched. We followed women from the surgery date to death, health plan disenrollment, or studys end. HR and 95% confidence intervals (CI) were fit using Cox proportional hazards models adjusting for cancer treatments and tumor characteristics. Results: A total of 223 (23.9%) women died because of breast cancer during the 21-year study period. Compared with women with luminal A tumors, women with HER2-enriched (HR 2.56, 95% CI 1.53–4.29) and luminal B tumors (HR 1.96, 95% CI: 1.08–3.54) had roughly a two-fold increased adjusted risk of breast cancer mortality. In addition, the survival curves suggest that risk of late mortality persists in women with luminal A tumors. Conclusion: Among women with health care coverage, molecular subtypes were important predictors of breast cancer mortality. Women with HER2-enriched tumors and luminal B subtypes had the poorest survival despite adjusting for important covariates. Impact: In a cohort followed for more than 20 years, women with HER2-enriched tumors had worse survival, but interestingly, the survival curve for women with luminal A tumors continued to steadily decline after 10 years of follow-up. Cancer Epidemiol Biomarkers Prev; 21(10); 1848–55. ©2012 AACR.

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.

Long-term Safety of Radiotherapy and Breast Cancer Laterality in Older Survivors

Background: Although adjuvant radiotherapy (RT) following surgery for breast cancer improves overall survival, controversy exists about its long-term adverse impact on cardiovascular health in older survivors. Aim: To determine whether incident cardiovascular disease (CVD) is associated with RT and whether tumor laterality modifies this association. Methods: Women aged 65+ years diagnosed with stage I and II breast cancer between 1990 and 1994 were identified from three health plans. Women were followed through CVD outcomes, health plan disenrollment, death, or study end (December 31, 2004). The main independent variable was RT use. Adjusted HRs and 95% CIs were estimated using Cox proportional hazards models with time-dependent tamoxifen and RT use status. We adjusted for age, race, stage, estrogen receptor/progesterone receptor, hypertension, and diabetes. Results: In the full cohort (N = 806), RT was not associated with greater risk of CVD (maximum follow-up was 14 years). However, within the RT-exposed group (N = 340), women treated for left-side breast cancer had a significant increased risk of CVD outcomes (HR = 1.53, 95% CI: 1.06–2.21) compared with women with right-sided tumors. Conclusion: Laterality is critical to understanding the effect of RT on CVD. Studies of more contemporary cohorts of women treated with RT should incorporate this variable to determine whether the risk persists with refinements in the dosing and delivery of RT. Impact: As some irradiation to the heart is unavoidable even with refined modern RT techniques, continued effort is required to minimize such exposures, especially in older women with left-sided tumors. Cancer Epidemiol Biomarkers Prev; 20(10); 2120–6. ©2011 AACR.

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.

Effectiveness of aromatase inhibitors and tamoxifen in reducing subsequent breast cancer

Tamoxifen (TAM) has been prescribed for decades and aromatase inhibitors (AIs) have been used since the early 2000s in preventing subsequent breast cancer. However, outside of clinical trials, the effectiveness of AIs is not established. We examined the long‐term risk of subsequent breast cancer among survivors treated with TAM and AIs in a large health plan. The study included 22,850 survivors, diagnosed with initial breast cancer (stages 0–IV) from 1996 to 2006, and followed 13 years maximum. We compared the risk of subsequent breast cancer in those who used TAM and/or AIs versus nonusers (the reference group). Hazard ratios (HR) adjusted for patient, tumor, treatment, and health‐care characteristics were estimated using Cox models with time‐dependent drug use status. Women who used TAM/AIs had a large reduction in risk of subsequent breast cancer compared with nonusers. While confidence intervals (CI) for all hormone treatment groups overlapped, women with high adherence (medication possession ratio ≥80%) who used AIs exclusively and had positive ER or PR receptor status had the greatest risk reduction (HR = 0.34, 95% CI: 0.28–0.41), followed by those who switched from TAM to AIs (HR = 0.39, 95% CI: 0.30–0.49), and those who used TAM exclusively (HR = 0.42, 95% CI: 0.36–0.47). Women with high adherence had the greatest risk reduction in subsequent breast cancer, but the results were not substantially different from women who took the drugs less regularly. Compared with nonusers, the reduction in subsequent breast cancer risk ranged from 58% to 66% across the hormone treatment groups and degree of adherence.

Validation of AJCC TNM staging for breast tumors diagnosed before 2004 in cancer registries

PurposeAmerican Joint Committee on Cancer (AJCC) Tumor (T), Nodal (N), and Metastatic (M) staging is commonly used in clinical practice for treatment decisions, yet before 2004, Surveillance Epidemiology and End Results (SEER)-affiliated cancer registries did not routinely include TNM staging defined by AJCC criteria, reporting instead SEER Summary Staging.MethodsWe developed and validated an algorithm to determine AJCC TNM staging from Extent of Disease information for 17,133 female breast cancer cases diagnosed from 1988 to 2003 in the cancer registries of Kaiser Permanente Northern and Southern California. Test characteristics (percent agreement, Cohen’s kappa, sensitivity, specificity) were calculated to compare derived TNM with gold-standard TNM available in the registry.ResultsAgreement for TNM variables was excellent (range 0.91–1.00 for percent agreement and Cohen’s kappa). The sensitivity and specificity, respectively, of the algorithm for AJCC TNM Version 6 staging were as follows: Stage 0 (0.99, 1.00), Stage I (0.97, 0.98), Stage II (0.91, 0.96), Stage III (0.69, 0.99), and Stage IV (0.92, 1.00). Stage III had lower sensitivity due to reclassification of supraclavicular lymph node positivity from M1 (Stage IV) to N3 (Stage IIIC) in AJCC Version 6.ConclusionsDerived AJCC staging for breast tumors diagnosed before 2004 is feasible and accurate using cancer registry data.

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 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.

C-B2-03: 10-Year Safety of Radiotherapy Among Older Breast Cancer Survivors

Background Almost 75% of breast cancer patients worldwide are treated with adjuvant therapy, primarily radiotherapy (RT). However, little is known about the long-term effects on cardiovascular health, particularly in older women. Aims We studied nearly 800 women aged 65 years or older with early-stage breast cancer who received care through integrated health care plans to determine if cardiovascular disease (CVD) is associated with radiotherapy. Methods Design & Data Elements: The retrospective cohort study, Breast Cancer Treatment in Older Women (BOW), included 806 women aged 65+ years diagnosed with stage I–II breast cancer between 1990 & 1994. These women were treated with surgery (breast conserving surgery [BCS] or mastectomy) and followed through 12/31/2004. Exclusions: Participants with CVD disease at baseline; those who had chemotherapy; or underwent BCS only without radiation treatment (i.e., less than standard care). Data elements: Demographic, treatment, tumor and comorbidity data from medical records, automated membership databases & SEER-affiliated cancer registries. CVD outcomes: acute myocardial infarction, angina pectoris, pericarditis, valvular dysfunction, cardiomyopathy, dysrhthymia, congestive heart failure and stroke. Exposure: Completed radiation treatment (RT) Statistical analysis: Adjusted hazard ratios (HR) and 95% confidence intervals were estimated using Cox models with time dependent tamoxifen & radiotherapy use status. Covariates included age, year of diagnosis, race/ ethnicity, stage, ER/PR status, laterality, comorbidities & health plan. Results When comparing women who received RT with those who did not (full cohort, n=806), radiotherapy was not associated with greater risk of CVD after adjusting for multiple covariates including laterality (Table 2). However, within the subset exposed to RT (n=340), women treated for cancer of the left breast had a significant increase in CVD risk (HR=1.54, 1.07–2.23) compared with women treated with RT for the right breast. Conclusions Preliminary results demonstrate that RT to the left breast may be associated with greater CVD risk. Our next study, “Long-Term Survivorship in Older Women with Early Stage Breast Cancer”(BOWII), will follow these women for an additional 5 years. This study will collect a wider set of risk factors for CVD to further evaluate these findings (2RO1CA093772-05A2 R. Silliman).