Cancer Epidemiology Research Cooperative (CERC)
Program in Epidemiology
Division of Public Health Sciences
Dr. Li is a Full Member in the Division of Public Health Sciences at the Fred Hutchinson Cancer Research Center (FHCRC) and is a Research Associate 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.
Research Interests
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.
Current Studies
The BRAVO Study
The INSIGHT Study
The REACH Study
The SHARE Study
Recent Publications
Amon LM, Pitteri SJ, Li CI, McIntosh MW, Ladd J, Disis ML, Porter PL, Wong CH, Zhang Q, Prentice RL, Lampe PD, Hanash SM. Concordant release of glycolysis proteins into the plasma preceding a diagnosis of ER+ breast cancer. Cancer Res 2012 [In press]
Although the identification of peripheral blood biomarkers would enhance early detection strategies for breast cancer, the discovery of protein markers has been challenging. In this study, we sought to identify coordinated changes in plasma proteins associated with breast cancer based on large scale quantitative mass spectrometry. We analyzed plasma samples collected up to 74 weeks prior to diagnosis from 420 ER+ cases and matched controls enrolled in the Women's Health Initiative cohort. A gene set enrichment analysis was applied to 467 quantified proteins linking their corresponding genes to particular biological pathways. Based upon differences in the concentration of individual proteins, glycolysis pathway proteins exhibited a statistically significant difference between cases and controls. In particular, the enrichment was observed among cases in which blood was drawn closer to diagnosis (effect size for the 0-38 weeks pre-diagnostic group: 1.91; p-value:8.3E-05). Analysis of plasmas collected at the time of diagnosis from an independent set of cases and controls confirmed upregulated levels of glycolysis proteins among cases relative to controls. Together, our findings indicate that the concomitant release of glycolysis proteins into the plasma is a pathophysiological event that precedes a diagnosis of ER+ breast cancer.
Li CI, Beaber EF, Tang MT, Porter PL, Daling JR, Malone KE. Effect of depo-medroxyprogesterone acetate on breast cancer risk among women 20-44 years of age. Cancer Res 2012 [In press]
Depo-medroxyprogesterone acetate (DMPA) is an injectable contraceptive that contains the same progestin as the menopausal hormone therapy regimen found to increase breast cancer risk among postmenopausal women in the Women's Health Initiative clinical trial. However, few studies have evaluated the relationship between DMPA use and breast cancer risk. Here we conducted a population-based case-control study among 1028 women 20-44 years of age to assess the association between DMPA use and breast cancer risk. Detailed information on DMPA use and other relevant covariates was obtained through structured interviewer administered in-person questionnaires, and unconditional logistic regression was used to evaluate associations between various aspects of DMPA use and breast cancer risk. We found that recent DMPA use for 12 months or longer was associated with a 2.2-fold (95% CI: 1.2-4.2) increased risk of invasive breast cancer. This risk did not vary appreciably by tumor stage, size, hormone receptor expression, or histological subtype. Although breast cancer is rare among young women and the elevated risk of breast cancer associated with DMPA appears to dissipate after discontinuation of use, our findings emphasize the importance of identifying the potential risks associated with specific forms of contraceptives given the number of available alternatives.
Phipps AI, Buist DS, Malone KE, Barlow WE, Porter PL, Kerlikowske K, O'Meara ES, Li CI. Breast density, body mass index, and risk of tumor marker-defined subtypes of breast cancer. Ann Epidemiol 2012 [In press]
Breast density and body mass index (BMI) are correlated attributes and are both potentially modifiable risk factors for breast cancer. However, relationships between these factors and risk of molecularly-defined subtypes of breast cancer have not been established. We used breast density and BMI data collected by the Breast Cancer Surveillance Consortium from 1,054,466 women ages 40 to 84 years receiving mammography, including 13,797 women subsequently diagnosed with breast cancer. Cases were classified into three groups on the basis of expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2:1) ER-positive (ER+, n = 10,026), 2) HER2-expressing (ER-negative/PR-negative/HER2-positive, n = 308), or triple-negative (ER-negative/PR-negative/HER2-negative, n = 705). Using Cox regression, we evaluated subtype-specific associations with breast density and BMI. Breast density was similarly positively associated with risk of all subtypes, especially among women ages 40 to 64 years. BMI was positively associated with risks of ER+ and triple-negative breast cancer in women ages 50 to 84 who were not users of hormone therapy. Breast density is positively associated with breast cancer risk, regardless of disease subtype. Associations with BMI appear to vary more by breast cancer subtype. Additional studies are needed to confirm and further characterize risk factors for HER2-expressing and triple-negative breast cancer.
Livaudais JC, Hershman DL, Habel L, Kushi L, Gomez SL, Li CI, Neugut AI, Fehrenbacher L, Thompson B, Coronado GD. Racial/ethnic differences in initiation of adjuvant hormonal therapy among women with hormone receptor-positive breast cancer. Breast Cancer Res Treat 2012;131:607-617.
Mortality after breast cancer diagnosis is known to vary by race/ethnicity even after adjustment for differences in tumor characteristics. As adjuvant hormonal therapy decreases risk of recurrence and increases overall survival among women with hormone receptor-positive tumors, treatment disparities may play a role. We explored racial/ethnic differences in initiation of adjuvant hormonal therapy, defined as two or more prescriptions for tamoxifen or aromatase inhibitor filled within the first year after diagnosis of hormone receptor-positive localized or regional-stage breast cancer. The sample included women diagnosed with breast cancer enrolled in Kaiser Permanente Northern California (KPNC). Odds ratios [OR] and 95% confidence intervals [CI] compared initiation by race/ethnicity (Hispanic, African American, Chinese, Japanese, Filipino, and South Asian vs. non-Hispanic White [NHW]) using logistic regression. Covariates included age and year of diagnosis, area-level socioeconomic status, co-morbidities, tumor stage, histology, grade, breast cancer surgery, radiation and chemotherapy use. Our sample included 13,753 women aged 20-79 years, diagnosed between 1996 and 2007, and 70% initiated adjuvant hormonal therapy. In multivariable analysis, Hispanic and Chinese women were less likely than NHW women to initiate adjuvant hormonal therapy ([OR] = 0.82; [CI] 0.71-0.96 and [OR] = 0.78; [CI] 0.63-0.98, respectively). Within an equal access, insured population, lower levels of initiation of adjuvant hormonal therapy were found for Hispanic and Chinese women. Findings need to be confirmed in other insured populations and the reasons for under-initiation among these groups need to be explored.
Kwon S, Lazo-Escalante M, Villaran MV, Li CI. Relationship between interpregnancy interval and birth defects in Washington State. J Perinatol 2012; 32:45-50.
Interpregnancy interval (IPI) influences numerous adverse perinatal outcomes. IPI's impact on birth defects is unclear. We conducted a population-based case-control study, using 1998 to 2008 administrative data from Washington State. A total of 10 772 cases, women whose second of two births resulted in an infant with a birth defect, were compared with 32 310 controls, women whose second of two births did not result in an infant with a birth defect. Compared with mothers with an IPI between 18 to 23 months, those with an IPI <6 months or 60 months had elevated risks of delivering an infant with a birth defect (odds ratio=1.15, 95% confidence interval: 1.03 to 1.28, and odds ratio=1.15, 95% confidence interval: 1.04 to 1.26, respectively). We observed a J-shaped relationship between IPI and risk of having an infant with a birth defect. As this is one of the first studies to evaluate this association, confirmatory studies are needed.
Monsees GM, Malone KE, Tang MT, Newcomb PA, Li CI. Bisphosphonate use after estrogen receptor-positive breast cancer and risk of contralateral breast cancer. J Natl Cancer Inst 2011; 103:1752-1760.
A growing body of evidence suggests that nitrogenous bisphosphonates may reduce the risk of developing a first breast cancer and may prevent metastases among breast cancer survivors. However, their impact on risk of second primary contralateral breast cancer is uncertain. Within a nested case-control study among women diagnosed with a first primary estrogen receptor-positive invasive breast cancer at ages 40-79 years, we assessed the association between post-diagnostic bisphosphonate use and risk of second primary contralateral breast cancer. We used multivariable-adjusted conditional logistic regression to estimate odds ratios (ORs) and 95% confidence intervals (CIs) comparing 351 contralateral breast cancer case subjects with 662 control subjects (ie, breast cancer patients not diagnosed with contralateral breast cancer) who were incidence density-matched on county; race/ethnicity; and age at, year of, and stage at first breast cancer diagnosis. We performed sensitivity analyses with respect to bisphosphonate type and confounding by indication. All statistical tests were two-sided. Current use of any nitrogenous bisphosphonate and use specifically of alendronate were both associated with reduced risks of contralateral breast cancer compared with never use (OR = 0.41, 95% CI = 0.20 to 0.84 and OR = 0.39, 95% CI = 0.18 to 0.88, respectively). The risk of contralateral breast cancer further declined with longer durations of bisphosphonate use among current users (P(trend) = .03). Results were similar in analyses restricted to patients with a history of osteoporosis or osteopenia. Bisphosphonate use was associated with a substantial reduction in risk of contralateral breast cancer. If this finding is confirmed in additional studies, nitrogenous bisphosphonate therapy may be a feasible approach for contralateral breast cancer risk reduction.
Li CI. Discovery and validation of breast cancer early detection biomarkers in preclinical samples. Horm Cancer 2011; 2:125-131.
Despite the widespread use of mammography for breast cancer screening, breast cancer remains the most common cause of cancer-related mortality among women worldwide. The identification of blood-based biomarkers useful for the early detection of breast cancer could have a major impact on reducing breast cancer disease burden by identifying cancers early when they are most treatable. We conducted a series of large-scale proteomic discovery and validation studies using preclinical samples from the Women's Health Initiative Observational Study prospective cohort. Of the 503 proteins quantified in experiments conducted on samples from ER(+) breast cancer patients and matched controls, 57 differentiated cases from controls. The seven candidates were assessed in an independent validation set with a commercially available ELISA assay. We confirmed that one of these candidates, epidermal growth factor receptor (EGFR), was elevated in cases versus controls. Compared to women in the lowest EGFR quartile, those in the highest quartile has a 2.90-fold (p = 0.0005) increased risk of developing breast cancer. An interaction with use of menopausal hormone therapy was observed such that among current estrogen plus progestin users, those in the highest EGFR quartile had a 9.04-fold (p = 0.0004) increased risk of developing breast cancer. While the performance of EGFR in terms of sensitivity and specificity is insufficient for it to be used on its own clinically, the formal validation of EGFR suggests that there may indeed be changes in the plasma proteome prior to the clinical diagnosis of breast cancer that are detectable and of potential clinical utility.
Phipps AI, Chlebowski RT, Prentice R, McTiernan A, Stefanick ML, Wactawski-Wende J, Kuller LH, Adams-Campbell LL, Lane D, Vitolins M, Kabat GC, Rohan TE, Li CI. Body size, physical activity, and risk of triple-negative and estrogen receptor-positive breast cancer. Cancer Epidemiol Biomarkers Prev 2011; 20:454-463.
Triple-negative breast cancer, characterized by a lack of hormone receptor and HER2 expression, is associated with a particularly poor prognosis. Focusing on potentially modifiable breast cancer risk factors, we examined the relationship between body size, physical activity, and triple-negative disease risk. Using data from 155,723 women enrolled in the Women's Health Initiative (median follow-up, 7.9 years), we assessed associations between baseline body mass index (BMI), BMI in earlier adulthood, waist and hip circumference, waist-hip ratio, recreational physical activity, and risk of triple-negative (n = 307) and estrogen receptor-positive (ER(+), n = 2,610) breast cancers. Women in the highest versus lowest BMI quartile had 1.35-fold (95% CI, 0.92-1.99) and 1.39-fold (95% CI, 1.22-1.58) increased risks of triple-negative and ER(+) breast cancers, respectively. Waist and hip circumferences were positively associated with risk of ER(+) breast cancer (P(trend) = 0.01 for both measures) but were not associated with triple-negative breast cancer. Compared with women who reported no recreational physical activity, women in the highest activity tertile had similarly lower risks of triple-negative and ER(+) breast cancers (HR = 0.77; 95% CI, 0.51-1.13; and HR = 0.85; 95% CI, 0.74-0.98, respectively). Despite biological and clinical differences, triple-negative and ER(+) breast cancers are similarly associated with BMI and recreational physical activity in postmenopausal women. The biological mechanisms underlying these similarities are uncertain and these modest associations require further investigation. Impact: If confirmed, these results suggest potential ways postmenopausal women might modify their risk of both ER(+) and triple-negative breast cancers.
Kabat GC, Kim M, Phipps AI, Li CI, Messina CR, Wactawski-Wende J, Kuller L, Simon MS, Yasmeen S, Wassertheil-Smoller S, Rohan TE. Smoking and alcohol consumption in relation to risk of triple-negative breast cancer in a cohort of postmenopausal women. Cancer Causes Control 2011; 22:775-783.
Little is known about the risk factors for triple-negative breast cancer (TNBC), which has a worse prognosis compared to hormone receptor-positive breast cancer. We examined the association of smoking and alcohol intake with TNBC and estrogen receptor-positive (ER+) breast cancer. Among 148,030 women enrolled in the Women's Health Initiative, 300 TNBC cases and 2,479 ER+ cases were identified over a median of 8.0 years of follow-up. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Cigarette smoking was not associated with TNBC, whereas drinkers had reduced risk compared to never drinkers. In contrast, both exposures showed slight positive associations with ER+ breast cancer: for women with ≥40 pack-years of smoking, the HR was 1.24, 95% CI 1.06-1.44; for women consuming ≥7 servings of alcohol per week, the HR was 1.26, 95% CI 1.06-1.50. Intakes of wine and hard liquor were also significantly positively associated with ER+ breast cancer. These findings from a large cohort of postmenopausal women suggest that smoking and alcohol consumption are not associated with increased risk of TNBC, but may be modestly associated with increased risk of ER+ breast cancer.
Phipps AI, Chlebowski RT, Prentice R, McTiernan A, Wactawski-Wende J, Kuller LH, Adams-Campbell LL, Lane D, Stefanick ML, Vitolins M, Kabat GC, Rohan TE, Li CI. Reproductive history and oral contraceptive use in relation to risk of triple-negative breast cancer. J Natl Cancer Inst 2011; 103:470-477.
Triple-negative (ie, estrogen receptor [ER], progesterone receptor, and HER2 negative) breast cancer occurs disproportionately among African American women compared with white women and is associated with a worse prognosis than ER-positive (ER+) breast cancer. Hormonally mediated risk factors may be differentially related to risk of triple-negative and ER+ breast cancers. Using data from 155 723 women enrolled in the Women's Health Initiative, we assessed associations between reproductive and menstrual history, breastfeeding, oral contraceptive use, and subtype-specific breast cancer risk. We used Cox regression to evaluate associations with triple-negative (N = 307) and ER+ (N = 2610) breast cancers and used partial likelihood methods to test for differences in subtype-specific hazard ratios (HRs). Reproductive history was differentially associated with risk of triple-negative and ER+ breast cancers. Nulliparity was associated with decreased risk of triple-negative breast cancer (HR = 0.61, 95% confidence interval [CI] = 0.37 to 0.97) but increased risk of ER+ breast cancer (HR = 1.35, 95% CI = 1.20 to 1.52). Age-adjusted absolute rates of triple-negative breast cancer were 2.71 and 1.54 per 10 000 person-years in parous and nulliparous women, respectively; by comparison, rates of ER+ breast cancer were 21.10 and 28.16 per 10 000 person-years in the same two groups. Among parous women, the number of births was positively associated with risk of triple-negative disease (HR for three births or more vs one birth = 1.46, 95% CI = 0.82 to 2.63) and inversely associated with risk of ER+ disease (HR = 0.88, 95% CI = 0.74 to 1.04). Ages at menarche and menopause were modestly associated with risk of ER+ but not triple-negative breast cancer; breastfeeding and oral contraceptive use were not associated with either subtype. The association between parity and breast cancer risk differs appreciably for ER+ and triple-negative breast cancers. These findings require further confirmation because the biological mechanisms underlying these differences are uncertain.
Huang Y, Malone KE, Cushing-Haugen KL, Daling J, Li CI. Relationship between menopausal symptoms and risk of postmenopausal breast cancer. Cancer Epidemiol Biomarkers Prev 2011; 20:379-388.
Prior studies indicate that women with menopausal symptoms have lower estrogen levels as they go through menopause compared to women who do not experience them. Given the central role of hormones in the etiology of breast cancer, a link between menopausal symptoms and breast cancer is plausible. However, no prior studies have evaluated the association between menopausal symptoms and breast cancer risk. Utilizing data from a population-based case-control study we examined associations between menopausal symptoms and risks of different histologic types of breast cancer among postmenopausal women. We calculated multivariate adjusted odds ratios (OR) using polytomous logistic regression and evaluated several potential effect modifiers. Women who ever experienced menopausal symptoms had lower risks of invasive ductal carcinoma [IDC, OR=0.5; 95% confidence interval (CI): 0.3-0.7], invasive lobular carcinoma (ILC, OR=0.5; 95% CI: 0.3-0.8), and invasive ductal-lobular carcinoma (IDLC, OR=0.7; 95% CI: 0.4-1.2), and these reductions in risk were independent of recency and timing of hormone therapy use, age at menopause, and body mass index. Increasing intensity of hot flashes among women who ever experienced hot flashes was also associated with decreasing risks of all three breast cancer subtypes (p-values for trend all ≤0.017). This is the first study to report that women who ever experienced menopausal symptoms have a substantially reduced risk of breast cancer, and that severity of hot flashes is also inversely associated with risk. Impact: If confirmed, these findings could enhance our understanding of breast cancer etiology and factors potentially relevant to prevention.
Phipps AI, Buist DS, Malone KE, Barlow WE, Porter PL, Kerlikowske K, Li CI. Reproductive history and risk of three breast cancer subtypes defined by three biomarkers. Cancer Causes Control 2011; 22:399-405.
Breast cancer subtypes defined by estrogen receptor (ER), progesterone receptor (PR), and HER2 expression are biologically distinct and thus, may have distinct etiologies. In particular, it is plausible that risk factors operating through hormonal mechanisms are differentially related to risk of such tumor subtypes. Using data from the Breast Cancer Surveillance Consortium, we explored associations between reproductive history and three breast cancer subtypes. Data on parity and age at first birth were collected from 743,623 women, 10,896 of whom were subsequently diagnosed with breast cancer. Cases were classified into three subtypes based on tumor maker expression: (1) ER positive (ER+, N = 8,203), (2) ER negative/PR negative/HER2 positive (ER-/PR-/HER2+, N = 288), or (3) ER-, PR-, and HER2-negative (triple-negative, N = 645). Associations with reproductive history, evaluated using Cox regression, differed significantly across tumor subtypes. Nulliparity was most strongly associated with risk of ER+ breast cancer [hazard ratio (HR) = 1.31, 95% confidence interval (CI): 1.23-1.39]; late age at first birth was most strongly associated with risk of ER-/PR-/HER2+ disease (HR = 1.83, 95% CI: 1.31-2.56). Neither parity nor age at first birth was associated with triple-negative breast cancer. In contrast to ER+ and ER-/PR-/HER2+ subtypes, reproductive history does not appear to be a risk factor for triple-negative breast cancer.
Ooi SL, Martinez ME, Li CI. Disparities in breast cancer characteristics and outcomes by race/ethnicity. Breast Cancer Res Treat 2011; 127:729-738.
Disparities in breast cancer stage and mortality by race/ethnicity in the United States are persistent and well known. However, few studies have assessed differences across racial/ethnic subgroups of women broadly defined as Hispanic, Asian, or Pacific Islander, particularly using more recent data. Using data from 17 population-based cancer registries in the Surveillance, Epidemiology, and End Results (SEER) program, we evaluated the relationships between race/ethnicity and breast cancer stage, hormone receptor status, treatment, and mortality. The cohort consisted of 229,594 women 40-79 years of age diagnosed with invasive breast carcinoma between January 2000 and December 2006, including 176,094 non-Hispanic whites, 20,486 Blacks, 15,835 Hispanic whites, 14,951 Asians, 1,224 Pacific Islanders, and 1,004 American Indians/Alaska Natives. With respect to statistically significant findings, American Indian/Alaska Native, Asian Indian/Pakistani, Black, Filipino, Hawaiian, Mexican, Puerto Rican, and Samoan women had 1.3-7.1-fold higher odds of presenting with stage IV breast cancer compared to non-Hispanic white women. Almost all groups were more likely to be diagnosed with estrogen receptor-negative/progesterone receptor-negative (ER-/PR-) disease with Black and Puerto Rican women having the highest odds ratios (2.4 and 1.9-fold increases, respectively) compared to non-Hispanic whites. Lastly, Black, Hawaiian, Puerto Rican, and Samoan patients had 1.5-1.8-fold elevated risks of breast cancer-specific mortality. Breast cancer disparities persist by race/ethnicity, though there is substantial variation within subgroups of women broadly defined as Hispanic or Asian. Targeted, multi-pronged interventions that are culturally appropriate may be important means of reducing the magnitudes of these disparities.
