Dr. Li is the co-Program Head of the Translational Research Program (TRP) and a Full Member in the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center (FHCRC), and is a Research Professor in the Department of Epidemiology at the University of Washington. He received his MD from the University of California, San Francisco, and his PhD in Epidemiology from the University of Washington. At FHCRC, Dr. Li works in the Cancer Epidemiology Research Cooperative (CERC), which is in FHCRC's Program in Epidemiology.
Dr. Li's research interests lie principally in the field of breast cancer and understanding factors related to its etiology and outcomes using a multidisciplinary approach. Currently, he is working on projects aimed at identifying novel biomarkers that could be used for the early detection of breast cancer, evaluating risk factors for different types of breast cancer, identifying predictors of poor outcomes among breast cancer survivors, and assessing disparities in cancer stage, treatment and survival by race/ethnicity.
Li CI, Daling JR, Haugen KL, Tang MT, Porter PL, Malone KE. Use of menopausal hormone therapy and risk of ductal and lobular breast cancer among women 55-74 years of age. Breast Cancer Res Treat. 2014. [Epub ahead of print]
The Women's Health Initiative (WHI) randomized trials found that use of combined estrogen and progestin menopausal hormone therapy (CHT) increases breast cancer risk, but use of unopposed estrogen hormone therapy (EHT) does not. However, several questions regarding the impact of hormone use on risk of different types of breast cancer and what thresholds of use confer elevations in risk remain. We conducted a population-based case-control study among women 55-74 years of age to assess the association between menopausal hormone use and risk of invasive ductal and invasive lobular breast carcinomas. Associations were evaluated using polytomous logistic regression and analyses included 880 ductal cases, 1,027 lobular cases, and 856 controls. Current EHT and CHT use were associated with 1.6-fold [95 % confidence interval (CI): 1.1-2.2] and 2.3-fold (95 % CI: 1.7-3.2) increased risks of lobular breast cancer, respectively, but neither was associated with risk of ductal cancer. Lobular cancer risk was increased after 9 years of EHT use, but after only 3 years of CHT use. Evidence across more than a dozen studies indicates that lobular carcinoma is the type of breast cancer most strongly influenced by menopausal hormones. Here, we characterize what thresholds of duration of use of both EHT and CHT that confer elevations in risk. Despite the rapid decline in hormone therapy use the WHI results were published, study of the hazards associated with these medications remains relevant given the estimated 38 million hormone therapy prescriptions that are still filled in the United States annually.
Pocobelli G, Newcomb PA, Li CI, Cook LS, Barlow WE, Weiss NS. Fatal breast cancer risk in relation to use of unopposed estrogen and combined hormone
therapy. Breast Cancer Res Treat. 2014 Mar 27. [Epub ahead of print]
Use of combined hormone therapy (CHT) is associated with increased breast cancer incidence, but it is unclear whether this translates into increased breast cancer mortality. To address this question, we conducted a population-based nested case-control study in Saskatchewan, Canada, where a population-based prescription drug database has existed since 1975. We evaluated fatal breast cancer risk in relation to recency and duration of use of CHT and unopposed estrogen hormone therapy (EHT). A total of 1,288 cases and 12,535 controls were included in the analyses. Exclusive use of EHT was not associated with fatal breast cancer risk, either overall or within categories of recency or duration [odds ratio (OR) for current vs. never use = 1.1; 95 % confidence interval (CI) 0.8-1.3]. Use of CHT (includes women who had also used EHT) was also not associated with fatal breast cancer risk (OR for current vs. never use = 0.9; 95 % CI 0.7-1.3), except for a suggestion of an increased risk with current long-term use. Consistent with prior studies, we observed no increased risk of fatal breast cancer associated with use of EHT. To date only a few studies have evaluated fatal breast cancer risk in relation to use of CHT, and collectively the results are inconsistent.
Beaber EF, Malone KE, Tang MT, Barlow WE, Porter PL, Daling JR, Li CI. Oral Contraceptives and Breast Cancer Risk Overall and by Molecular Subtype Among Young Women. Cancer Epidemiol Biomarkers Prev. 2014. [Epub ahead of print]
BACKGROUND: Evidence suggests that recent oral contraceptive (OC) use is associated with a small increased breast cancer risk; yet risks associated with contemporary OC preparations and by molecular subtype are not well characterized.
METHODS: We conducted a population-based case-control study of invasive breast cancer among women ages 20 to 44 residing in the Seattle-Puget Sound area from 2004 to 2010 (985 cases and 882 controls). We collected information on contraceptive use and participant characteristics via an in-person interview. Multivariable-adjusted logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI).
RESULTS: Lifetime duration of OC use for ≥15 years was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.1-2.2). Current OC use (within 1 year of reference date) for ≥5 years was associated with an increased risk (OR, 1.6; 95% CI, 1.1-2.5) and there were no statistically significant differences in risk by OC preparation. Risk magnitudes were generally greater among women ages 20 to 39, and for estrogen receptor-negative (ER(-)) and triple-negative breast cancer (current use for ≥5 years among ages 20-39: ER(-) OR, 3.5; 95% CI, 1.3-9.0; triple-negative OR, 3.7; 95% CI, 1.2-11.8), although differences between groups were not statistically significant.
CONCLUSIONS: Long-term use of contemporary OCs and current use for ≥5 years was associated with an increased breast cancer risk among women ages 20 to 44. Risk may be greater among younger women and for ER(-) and triple-negative breast cancer, but these findings require confirmation.
IMPACT: Continued surveillance and pooled analyses of OC use and breast cancer risk by molecular subtype are needed as OC preparations evolve.
Kawai M, Malone KE, Tang MT, Li CI. Height, body mass index (BMI), BMI change, and the risk of estrogen receptor-positive, HER2-positive, and triple-negative breast cancer among women ages 20 to 44 years. Cancer. 2014. [Epub ahead of print]
BACKGROUND: The evidence regarding correlations between various anthropometric characteristics and breast cancer risk among young women is mixed, and few studies have assessed these associations by subtype.
METHODS: This was a population-based, case-control study of 779 women with estrogen receptor (ER)-positive breast cancer; 182 women with ER-negative/human epidermal growth factor-2 (HER2)-negative/progesterone receptor-negative (triple-negative [TN]) breast cancer; and 60 women with ER-negative/HER2-overexpressing, invasive breast cancer ages 20 to 44 years who were diagnosed from 2004 to 2010 in the Seattle-Puget Sound metropolitan area; as well as 939 cancer-free controls. Associations between height and body mass index (BMI) at different time points in relation to breast cancer risk were assessed using polytomous logistic regression.
RESULTS: Height, BMI at age 18 years, and BMI at the reference date were not related to the risks of ER-positive, TN, or HER2-overexpressing breast cancer. Changes in BMI from age 18 years to the reference date were not related to the risk of either ER-positive or HER2-overexpressing breast cancer. However, compared with women who had a BMI change from 0 to 4.9 kg/m(2) from age 18 years to the reference date, those who experienced a BMI increase ≥10 kg/m(2) during the same interval had a 2.0-fold (95% confidence interval, 1.2-fold to 3.3-fold increase) increased risk of TN breast cancer. For women with ER-positive disease, there was some evidence that parity modified the effect of BMI change (Pinteraction = .002), because a BMI increase of ≥10 kg/m(2) was associated with a reduced risk of ER-positive disease only among nulliparous women (odds ratio, 0.3; 95% confidence interval, 0.2-0.6).
Pepe MS, Janes H, Li CI. Net risk reclassification p values: valid or misleading? J Natl Cancer Inst. 2014 Apr 1;106(4):dju041.
BACKGROUND: The Net Reclassification Index (NRI) and its P value are used to make conclusions about improvements in prediction performance gained by adding a set of biomarkers to an existing risk prediction model. Although proposed only 5 years ago, the NRI has gained enormous traction in the risk prediction literature. Concerns have recently been raised about the statistical validity of the NRI.
METHODS: Using a population dataset of 10000 individuals with an event rate of 10.2%, in which four biomarkers have no predictive ability, we repeatedly simulated studies and calculated the chance that the NRI statistic provides a positive statistically significant result. Subjects for training data (n = 420) and test data (n = 420 or 840) were randomly selected from the population, and corresponding NRI statistics and P values were calculated. For comparison, the change in the area under the receiver operating characteristic curve and likelihood ratio statistics were calculated.
RESULTS: We found that rates of false-positive conclusions based on the NRI statistic were unacceptably high, being 63.0% in the training datasets and 18.8% to 34.4% in the test datasets. False-positive conclusions were rare when using the change in the area under the curve and occurred at the expected rate of approximately 5.0% with the likelihood ratio statistic.
CONCLUSIONS: Conclusions about biomarker performance that are based primarily on a statistically significant NRI statistic should be treated with skepticism. Use of NRI P values in scientific reporting should be halted.
Brauer HA, D'Arcy M, Libby TE, Thompson HJ, Yasui YY, Hamajima N, Li CI, Troester MA, Lampe PD. Dermcidin expression is associated with disease progression and survival among breast cancer patients. Breast Cancer Res Treat. 2014 Apr;144(2):299-306.
Improved diagnostic screening has led to earlier detection of many tumors, but screening may still miss many aggressive tumor types. Proteomic and genomic profiling studies of breast cancer samples have identified tumor markers that may help improve screening for more aggressive, rapidly growing breast cancers. To identify potential blood-based biomarkers for the early detection of breast cancer, we assayed serum samples via matrix-assisted laser desorption ionization-time of flight mass spectrometry from a rat model of mammary carcinogenesis. We found elevated levels of a fragment of the protein dermcidin (DCD) to be associated with early progression of N-methylnitrosourea-induced breast cancer, demonstrating significance at weeks 4 (p = 0.045) and 5 (p =0.004), a time period during which mammary pathologies rapidly progress from ductal hyperplasia to adenocarcinoma. The highest serum concentrations were observed in rats bearing palpable mammary carcinomas. Increased DCD was also detected with immunoblotting methods in 102 serum samples taken from women just prior to breast cancer diagnosis. To validate these findings in a larger population, we applied a 32-gene in vitro DCD response signature to a dataset of 295 breast tumors and assessed correlation with intrinsic breast cancer subtypes and overall survival. The DCD-derived gene signature was significantly associated with subtype (p < 0.001) and poorer overall survival [HR (95 % CI) = 1.60 (1.01-2.51), p = 0.044]. In conclusion, these results present novel evidence that DCD levels may increase in early carcinogenesis, particularly among more aggressive forms of breast cancer.
Kawai M, Malone KE, Tang MT, Li CI. Active smoking and the risk of estrogen receptor-positive and triple-negative breast cancer among women ages 20 to 44 years. 2014 Apr 1;120(7):1026-34.
BACKGROUND: Evidence regarding the correlation between smoking and breast cancer among young women is mixed, and previous studies have not assessed whether smoking is associated differentially with risks of the major breast cancer subtypes.
METHODS: This was a population-based, case-control study of 778 women with estrogen receptor (ER)-positive breast cancers and 182 women with ER-negative, progesterone receptor-negative, and human epidermal growth factor receptor 2-negative (triple-negative [TN]), invasive breast cancers ages 20 to 44 years who were diagnosed from 2004 to 2010 in the Seattle-Puget Sound metropolitan area. A control group of 938 cancer-free women also was included. Associations between various aspects of smoking history and the risks of ER-positive and TN breast cancer were assessed using polytomous logistic regression.
RESULTS: Ever-smokers had a 1.3-fold increased risk (95% confidence interval [CI], 1.1-fold to 1.7-fold increased risk) of breast cancer overall; and, when stratified by cancer subtype, they had a 1.4-fold increased risk (95% CI, 1.1-fold to 1.8-fold increased risk) of ER-positive breast cancer, but there was no elevation in their risk of TN disease (odds ratio, 1.1; 95% CI, 0.7-1.6). Current/recent smokers with a ≥10 pack-year history of smoking had a 1.6-fold increased risk (95% CI, 1.1-fold to 2.4-fold increased risk) of ER-positive breast cancer but had no increase in their risk of TN breast cancer (odds ratio, 1.0; 95% CI, 0.5-1.9).
CONCLUSIONS: The current results suggested that young women who are current/recent smokers with high pack-year histories may have an increased risk of ER-positive breast cancer but not TN breast cancer. Although this association was modest, the findings suggest that an increased risk of ER-positive breast cancer may be another health risk incurred by young women who smoke.
Kaplan HG, Malmgren JA, Li CI, Calip GS. Age related risk of myelodysplastic syndrome and acute myeloid leukemia among breast cancer survivors. Breast Cancer Res Treat 2013;142(3):629-36.
Increased incidence of acute myeloid leukemia (AML) has been identified among breast cancer (BC) survivors but measurement has not included myelodysplastic syndrome (MDS). Our aim is to identify age and stage related MDS/AML incidence post BC diagnosis. We used the 2001-2009 Surveillance, Epidemiology, and end results (SEER) database to identify first primary stage I-III BC patients. Subsequent MDS or AML diagnosis was identified with observed rates compared to expected MDS/AML incidence in the general population. Age adjusted observed/expected rate ratios and 95 % confidence intervals (CI) were calculated. The unadjusted all age and stage MDS/AML incidence rate was .15 % (470/306,691) with a progressively higher rate by age (age 20-49 = .11, age 50-64 = .14, age 65+ =.21, and age 75+ =.18) and stage (stage I = .11, stage II = .18, and stage III = .22). Compared to the general population, BC patients had a 2.75-fold [95 % CI 2.51-3.00] increased relative risk of being diagnosed with MDS/AML. Young age survivors had highest relative risk [age 20-49: relative risk (RR) = 10.60 (95 % CI 8.57-12.93); age 50-64: 5.96 (95 % CI 5.13, 6.88); age 65-74 year-olds: 2.94 (95 % CI 2.45, 3.50); and age ≥75 year-olds: 1.28 (95 % CI 1.03, 1.56)]. Separately MDS relative risk was highest among young women [30.44 (95 % CI = 19.63, 44.62)]. MDS/AML relative risk increased from 1.87 to 5.66 for stage I-III. Conclusions: Myelodysplastic syndrome and acute myeloid leukemia relative risk is substantially elevated among breast cancer survivors especially those aged 20-49. While the actual number is small, MDS/AML is a serious disease. More research is needed to identify the treatments that put women at risk and find less leukemogenic options, especially for young women.
Li CI, Daling JR, Tang MT, Haugen KL, Porter PL, Malone KE. Use of Antihypertensive Medications and Breast Cancer Risk Among Women Aged 55 to
74 Years. JAMA Intern Med 2013;173:1629-37.
IMPORTANCE Antihypertensive agents are the most commonly prescribed class of medications in the United States. Evidence regarding the relationship between different types of antihypertensives and breast cancer risk is sparse and inconsistent, and prior studies have lacked the capacity to assess impacts of long-term use. OBJECTIVE To evaluate associations between use of various classes of antihypertensive medications and risks of invasive ductal and invasive lobular breast cancers among postmenopausal women. DESIGN, SETTING, AND PARTICIPANTS Population-based case-control study in the 3-county Seattle-Puget Sound metropolitan area. Participants were women aged 55 to 74 years, 880 of them with invasive ductal breast cancer, 1027 with invasive lobular breast cancer, and 856 with no cancer serving as controls. EXPOSURES Recency and duration of use of antihypertensive medications. MAIN OUTCOMES AND MEASURES Risks of invasive ductal and invasive lobular breast cancers. RESULTS Current use of calcium-channel blockers for 10 or more years was associated with higher risks of ductal breast cancer (odds ratio [OR], 2.4; 95% CI, 1.2-4.9) (P = .04 for trend) and lobular breast cancer (OR, 2.6; 95% CI, 1.3-5.3) (P = .01 for trend). This relationship did not vary appreciably by type of calcium-channel blocker used (short-acting vs long-acting, dihydropyridines vs non-dihydropyridines). In contrast, use of diuretics, β-blockers, and angiotensin II antagonists were not associated with risk. CONCLUSIONS AND RELEVANCE While some studies have suggested a positive association between calcium-channel blocker use and breast cancer risk, this is the first study to observe that long-term current use of calcium-channel blockers in particular are associated with breast cancer risk. Additional research is needed to confirm this finding and to evaluate potential underlying biological mechanisms.
McDougall JA, Malone KE, Daling JR, Cushing-Haugen KL, Porter PL, Li CI. Long-Term Statin Use and Risk of Ductal and Lobular Breast Cancer among Women 55 to 74 Years of Age. Cancer Epidemiol Biomarkers Prev 2013; 22:1529-1537.
BACKGROUND: Mechanistic studies largely support the chemopreventive potential of statins. However, results of epidemiologic studies investigating statin use and breast cancer risk have been inconsistent and lacked the ability to evaluate long-term statin use. METHODS: We used data from a population-based case-control study of breast cancer conducted in the Seattle-Puget Sound region to investigate the relationship between long-term statin use and breast cancer risk. Nine hundred sixteen invasive ductal carcinoma (IDC) and 1,068 invasive lobular carcinoma (ILC) cases in patients 55 to 74 years of age diagnosed between 2000 and 2008 were compared with 902 control women. All participants were interviewed in-person and data on
hypercholesterolemia and all episodes of lipid-lowering medication use were collected through a structured questionnaire. We assessed the relationship
between statin use and IDC and ILC risk using polytomous logistic regression. RESULTS: Current users of statins for 10 years or longer had a 1.83-fold
increased risk of IDC [95% confidence interval (CI): 1.14-2.93] and a 1.97-fold increased risk of ILC (95% CI: 1.25-3.12) compared with never users of statins. Among women diagnosed with hypercholesterolemia, current users of statins for 10 years or longer had more than double the risk of both IDC (OR: 2.04, 95% CI: 1.17-3.57) and ILC (OR: 2.43, 95% CI: 1.40-4.21) compared with never users. CONCLUSION: In this contemporary population-based case-control study, long-term use of statins was associated with increased risks of both IDC and ILC. IMPACT: Additional studies with similarly high frequencies of statin use for various durations are needed to confirm this novel finding.