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.
Mirus J, Zhang Y, Li CI, Lokshin AE, Prentice RL, Lampe PD, Hingorani SR. Cross-species antibody microarray interrogation identifies a 3-protein panel of plasma biomarkers for the early detection of pancreas cancer. Clin Cancer Res 2015 Jan 14. In press.
Purpose: Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer death in the United States and its incidence is on the rise. Advanced disease is nearly uniformly lethal, emphasizing the need to identify PDA at its earliest stages. To discover early biomarkers of PDA, we evaluated the circulating proteome in murine preinvasive and invasive plasma samples and human pre-diagnostic and diagnostic samples. Experimental Design: Using a customized antibody microarray platform containing >4000 features, we interrogated plasma samples spanning preinvasive and invasive disease from a highly faithful mouse model of PDA. In parallel, we mined pre-diagnostic plasma from women in the Women's Health Initiative (WHI) who would later succumb to PDA together with matched, cancer-free control samples. Samples collected after an establishing diagnosis of PDA were also interrogated to further validate markers. Results: We identified ERBB2 and TNC in our cross-species analyses and multiple antibodies identified ESR1 in pre-diagnostic plasma from people that succumb to PDA. This 3-marker panel had an AUC of 0.86 (0.76-0.96, 95% confidence interval (CI)) for the diagnostic cohort that increased to 0.97 (0.92-1.0, 95% CI) with CA19-9 included. The 3-marker panel also had an AUC of 0.68 (0.58-0.77, 95% CI) for the pre-diagnostic cohort. Conclusions: We identified potential disease detection markers in plasma up to 4 years prior to death from PDA with superior performance to CA19-9. These markers might be especially useful in high-risk cohorts to diagnose early, resectable disease, particularly in patients that do not produce CA19-9.
Rosenberg AR, Kroon L, Chen L, Li CI, Jones B. Insurance status and risk of cancer mortality among adolescents and young adults. Cancer. 2014 Dec 9. In press.
BACKGROUND: Adolescents and young adults with cancer have inferior survival outcomes compared with younger pediatric patients and older adult patients. Lack of insurance may partly explain this disparity. The objective of this study was to identify associations between insurance status and both advanced-stage cancer and cancer-specific mortality. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) 18 registries, 57,981 patients ages 15 to 39 years were identified who were diagnosed between 2007 and 2010 and had complete insurance and staging information. Multinomial logistic regression models were used to identify associations between insurance type and disease stage, with the models adjusted for sex, age, and race. Cox proportional hazards models were used to estimate cancer-specific mortality. RESULTS: Overall, 84% of patients were aged ≥25 years, 64% were women, and 79% were privately insured. Compared with patients who had private insurance, those who had nonprivate insurance tended to present with more advanced-stage disease and to die more quickly and more commonly from their cancer. Patients ages 25 to 39 years who had Medicaid coverage or no insurance had 3.2 times and 2.4 times higher odds of having stage IV disease, respectively, than privately insured patients (95% confidence interval [CI], 3.0-3.5 times higher odds and 2.1-2.6 times higher odds, respectively). Among those with stage I/II and III/IV cancers, the risk of death was 2.9 times greater (95% CI, 2.2-3.9 times greater) and 1.7 times greater (95% CI, 1.5-1.9 times greater), respectively, than the risk for privately insured patients. Patients who died from stage III/IV cancers survived at least 2 months longer if they had private insurance. CONCLUSIONS: Among young adults, insurance status is independently associated with advanced-stage cancer and the risk of death from cancer, even for patients who have low-stage disease. Broader insurance coverage and access to health care may improve some of the disparate outcomes of adolescents and young adults with cancer.
Lowry SJ, Malone KE, Cushing-Haugen KL, Li CI. The risk of breast cancer associated with specific patterns of migraine history. Cancer Causes Control. 2014 Dec;25(12):1707-15.
PURPOSE: Studies have suggested that a history of migraines may be associated with a lower risk of some types of breast cancer, though biological mechanisms are unclear. Identifying specific characteristics of migraines which are most strongly associated with breast cancer risk could improve our understanding of this relationship. METHODS: We ascertained specific characteristics of women's migraine histories (severity, timing features, and presence of migraine aura). We used polytomous logistic regression to estimate the risk of ER+ ductal, ER- ductal, ER+ lobular, and ER+ ductal-lobular breast cancer associated with self-reported characteristics of migraine history. A total of 715 breast cancer cases (276 ER+ ductal, 46 ER- ductal, 191 ER+ lobular, and 202 ER+ ductal-lobular) and 376 controls ages 55-74 years were included in this population-based case-control study. RESULTS: Compared to women without a migraine history, women with a >30-year history of migraines had a 60 % (95 % CI 0.2-0.6) lower risk of ER+ ductal breast cancer; those who had their first migraine before age 20 had 50 % lower risks of ER+ ductal and ER+ lobular breast cancer (both 95 % CIs 0.3-0.9), and women who experienced migraine with aura had 30 % (95 % CI 0.5-0.98) and 40 % (95 % CI 0.4-0.9) lower risks of ER+ ductal and ER+ lobular breast cancer, respectively. CONCLUSION: The lower risk of ER+ breast cancer associated with migraine appears to be limited to those women with early onset or long duration of migraine history, or those who experienced migraine with aura. This expands our understanding of the relationship between migraine and breast cancer and provides additional insight into potential underlying biological mechanisms.
Phipps AI, Li CI. Breastfeeding and triple-negative breast cancer: potential implications for racial/ethnic disparities. J Natl Cancer Inst. 2014;106: pii: dju281.
Chen L, Malone KE, Li CI. Bra Wearing Not Associated with Breast Cancer Risk: A Population-Based Case-Control Study. Cancer Epidemiol Biomarkers Prev. 2014;23(10):2181-5.
Despite the widespread use of bras among U.S. women and concerns in the lay media that bra wearing may increase breast cancer risk, there is a scarcity of credible scientific studies addressing this issue. The goal of the study was to evaluate the relationship between various bra-wearing habits and breast cancer risk among postmenopausal women. We conducted a population-based case-control study of breast cancer in the Seattle-Puget Sound metropolitan area that compared 454 invasive ductal carcinoma (IDC) cases and 590 invasive lobular carcinoma (ILC) cases diagnosed between 2000 and 2004 with 469 control women between 55 to 74 years of age. Information on bra-wearing habits and other breast cancer risk factors was collected from study participants through in-person interviews. Multivariate adjusted odds ratios (OR) and their associated 95% confidence intervals (CI) were estimated using polytomous logistic regression. No aspect of bra wearing, including bra cup size, recency, average number of hours/day worn, wearing a bra with an underwire, or age first began regularly wearing a bra, was associated with risks of either IDC or ILC. Our results did not support an association between bra wearing and increased breast cancer risk among postmenopausal women.
Chen L, Linden HM, Anderson BO, Li CI. Trends in 5-year survival rates among breast cancer patients by hormone receptor status and stage. Breast Cancer Res Treat. 2014;147(3):609-16.
Improvement in breast cancer survival has been observed in recent decades in the U.S., but it is unclear if similar survival gains are consistent across breast cancer subtypes, especially with regards to more advanced stages of the disease. Data were from 13 population-based cancer registries participating in the surveillance, epidemiology, and end results (SEER) program, consisting of women between 20 and 79 years of age diagnosed with invasive breast cancer between 1992 and 2008. 2-year (1992-2008) and 5-year (1992-2006) breast cancer cause-specific survival rates were calculated and stratified by estrogen receptor (ER)/progesterone receptor (PR) status, stage, and race. Annual percent changes in survival rates were assessed. From 1992 through 1998-1999, 5- and 2-year cause-specific survival rates significantly improved across ER+/PR+, ER-/PR-, and ER+/PR- subtypes, with an annual increase ranging from 0.5 to 1.0 % in the 5-year rates. From 1998-1999 to 2006, different patterns were observed by ER/PR subtypes with survival rates slightly improving for ER+/PR+, continuing to improve at a rate of 0.5 % per year for ER-/PR-, and dropping 0.3 % annually for ER+/PR-. No significant survival gains were experienced by patients with ER-/PR+ cancer during the study period. In terms of advanced diseases, greatest annual increases in survival rates were seen for patients with stage III-IV ER+/PR+ and ER-/PR-tumors but less progress was observed for advanced ER+/PR- breast cancers. Steady improvements in survival rates for breast cancer have been achieved over the past several decades. However, 5-year survival rates for stage IV disease remained dismally below 20 % for most ER/PR subtypes.
Beaber EF, Buist DS, Barlow WE, Malone KE, Reed SD, Li CI. Recent Oral Contraceptive Use by Formulation and Breast Cancer Risk among Women 20 to 49 Years of Age. Cancer Res;74(15):4078-89.
Previous studies of oral contraceptives and breast cancer indicate that recent use slightly increases risk, but most studies relied on self-reported use and did not examine contemporary oral contraceptive formulations. This nested case-control study was among female enrollees in a large U.S. integrated health care delivery system. Cases were 1,102 women ages 20 to 49 years diagnosed with invasive breast cancer from 1990 to 2009. Controls were randomly sampled from enrollment records (n = 21,952) and matched to cases on age, year, enrollment length, and medical chart availability. Detailed oral contraceptive use information was ascertained from electronic pharmacy records and analyzed using conditional logistic regression, ORs, and 95% confidence intervals (CI). Recent oral contraceptive use (within the prior year) was associated with an increased breast cancer risk (OR, 1.5; 95% CI, 1.3-1.9) relative to never or former OC use. The association was stronger for estrogen receptor-positive (ER(+); OR, 1.7; 95% CI, 1.3-2.1) than estrogen receptor-negative (ER(-)) disease (OR, 1.2, 95% CI, 0.8-1.8), although not statistically significantly different (P = 0.15). Recent use of oral contraceptives involving high-dose estrogen (OR, 2.7; 95% CI, 1.1-6.2), ethynodiol diacetate (OR, 2.6; 95% CI, 1.4-4.7), or triphasic dosing with an average of 0.75 mg of norethindrone (OR, 3.1; 95% CI, 1.9-5.1; Pheterogeneity compared with using other oral contraceptives = 0.004) was associated with particularly elevated risks, whereas other types, including low-dose estrogen oral contraceptives, were not (OR, 1.0; 95% CI, 0.6-1.7). Our results suggest that recent use of contemporary oral contraceptives is associated with an increased breast cancer risk, which may vary by formulation. If confirmed, consideration of the breast cancer risk associated with different oral contraceptive types could impact discussions weighing recognized health benefits and potential risks.
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;145(2):481-489.
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;145(2):439-447.
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;23(5):755-764.
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;120(10);1548-56.
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.