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.
Buas MF, Gu H, Djukovic D, Zhu J, Drescher CW, Urban N, Raftery D, Li CI. Identification of novel candidate plasma metabolite biomarkers for distinguishing serous ovarian carcinoma and benign serous ovarian tumors. Gynecol Oncol. 2016;140(1)138-144.
OBJECTIVE: Serous ovarian carcinoma (OC) represents a leading cause of cancer-related death among U.S. women. Non-invasive tools have recently emerged for discriminating benign from malignant ovarian masses, but evaluation remains ongoing, without widespread implementation. In the last decade, metabolomics has matured into a new avenue for cancer biomarker development. Here, we sought to identify novel plasma metabolite biomarkers to distinguish serous ovarian carcinoma and benign serous ovarian tumor. METHODS: Using liquid chromatography-mass spectrometry, we conducted global and targeted metabolite profiling of plasma isolated at the time of surgery from 50 serous OC cases and 50 serous benign controls. RESULTS: Global lipidomics analysis identified 34 metabolites (of 372 assessed) differing significantly (P<0.05) between cases and controls in both training and testing sets, with 17 candidates satisfying FDR q<0.05, and two reaching Bonferroni significance. Targeted profiling of ~150 aqueous metabolites identified a single amino acid, alanine, as differentially abundant (P<0.05). A multivariate classification model built using the top four lipid metabolites achieved an estimated AUC of 0.85 (SD=0.07) based on Monte Carlo cross validation. Evaluation of a hybrid model incorporating both CA125 and lipid metabolites was suggestive of increased classification accuracy (AUC=0.91, SD=0.05) relative to CA125 alone (AUC=0.87, SD=0.07), particularly at high fixed levels of sensitivity, without reaching significance. CONCLUSIONS: Our results provide insight into metabolic changes potentially correlated with the presence of serous OC versus benign ovarian tumor and suggest that plasma metabolites may help differentiate these two conditions.
Urban N, Hawley S, Janes H, Karlan BY, Berg CD, Drescher CW, Manson JE, Palomares MR, Daly MB, Wactawski-Wende J, O'Sullivan MJ, Thorpe J, Robinson RD, Lane D, Li CI, Anderson GL. Identifying post-menopausal women at elevated risk for epithelial ovarian cancer. Gynecol Oncol. 2015 Nov;139(2):253-60.
OBJECTIVE: We developed and validated a hybrid risk classifier combining serum markers and epidemiologic risk factors to identify post-menopausal women at elevated risk for invasive fallopian tube, primary peritoneal, and ovarian epithelial carcinoma. METHODS: To select epidemiologic risk factors for use in the classifier, Cox proportional hazards analyses were conducted using 74,786 Women's Health Initiative (WHI) Observational Study (OS) participants. To construct a combination classifier, 210 WHI OS cases and 536 matched controls with serum marker measurements were analyzed; validation employed 143 cases and 725 matched controls from the WHI Clinical Trial (CT) with similar data. RESULTS: Analyses identified a combination risk classifier composed of two elevated-risk groups: 1) women with CA125 or HE4 exceeding a 98% specificity threshold; and 2) women with intact fallopian tubes, prior use of menopausal hormone therapy for at least two years, and either a first degree relative with breast or ovarian cancer or a personal history of breast cancer. In the WHI OS population, it classified 13% of women as elevated risk, identifying 30% of ovarian cancers diagnosed up to 7.8years post-enrollment (Hazard Ratio [HR]=2.6, p<0.001). In the WHI CT validation population, it classified 8% of women as elevated risk, identifying 31% of cancers diagnosed within 7years of enrollment (HR=4.6, p<0.001). CONCLUSION: CA125 and HE4 contributed significantly to a risk prediction classifier combining serum markers with epidemiologic risk factors. The hybrid risk classifier may be useful to identify post-menopausal women who would benefit from timely surgical intervention to prevent epithelial ovarian cancer.
Buas MF, Rho JH, Chai X, Zhang Y, Lampe PD, Li CI. Candidate early detection protein biomarkers for ER+/PR+ invasive ductal breast carcinoma identified using pre-clinical plasma from the WHI observational study. Breast Cancer Res Treat. 2015;153(2):445-454.
Estrogen receptor (ER)-positive/progesterone receptor (PR)-positive invasive ductal carcinoma accounts for ~45 % of invasive breast cancer (BC) diagnoses in the U.S. Despite reductions in BC mortality attributable to mammography screening and adjuvant hormonal therapy, an important challenge remains the development of clinically useful blood-based biomarkers for risk assessment and early detection. The objective of this study was to identify novel protein markers for ER+/PR+ ductal BC. A nested case-control study was conducted within the Women's Health Initiative observational study. Pre-clinical plasma specimens, collected up to 12.5 months before diagnosis from 121 cases and 121 matched controls, were equally divided into training and testing sets and interrogated using a customized antibody array targeting >2000 proteins. Statistically significant differences (P < 0.05) in matched case versus control signals were observed for 39 candidates in both training and testing sets, and four markers (CSF2, RYBP, TFRC, ITGB4) remained significant after Bonferroni correction (P < 2.03 × 10-5). A multivariate modeling procedure based on elastic net regression with Monte Carlo cross-validation achieved an estimated AUC of 0.75 (SD 0.06). Most candidates did not overlap with those described previously for triple-negative BC, suggesting sub-type specificity. Gene set enrichment analyses identified two GO gene sets as upregulated in cases-microtubule cytoskeleton and response to hormone stimulus (P < 0.05, q < 0.25). This study has identified a pool of novel candidate plasma protein biomarkers for ER+/PR+ ductal BC using pre-diagnostic biospecimens. Further validation studies are needed to confirm these candidates and assess their potential clinical utility for BC risk assessment/early detection.
Chen L, Malone KE, Li CI. Use of Antihypertensive Medications Not Associated with Risk of Contralateral Breast Cancer among Women Diagnosed with Estrogen Receptor-Positive Invasive Breast Cancer. Cancer Epidemiol Biomarkers Prev. 2015 Sep;24(9):1423-6.
BACKGROUND: Antihypertensive medications are widely used among adults in the United States, and there is some evidence that certain classes may affect the risk of adverse breast cancer outcomes, but their impact on risk of second primary contralateral breast cancer (CBC) is unclear. METHODS: We used data from a population-based nested case-control study consisting of 359 women diagnosed with both a first primary breast cancer and a second primary CBC and 691 control women diagnosed with only a single breast cancer and individually matched to cases. Multivariate conditional logistic regression was used to estimate ORs and 95% confidence intervals for risksassociated with ever, recency, and duration of use for various antihypertensive medications. RESULTS: No class of antihypertensive, including calcium channel blockers, β-blockers, angiotensin-converting enzyme (ACE) inhibitors, and diuretics, was associated with risk of second primary CBC. These results did not change materially in a sensitivity analysis restricted to women with a history of hypertension. CONCLUSION: Our findings do not support associations between use of various antihypertensives and CBC risk among women with estrogen receptor-positive breast cancer. IMPACT: The present study adds evidence to support the safety of commonly used antihypertensive medications among breast cancer survivors with respect to risk of second primary CBC.
Pepe MS, Li CI, Feng Z. Improving the quality of biomarker discovery research: the right samples and enough of them. Cancer Epidemiol Biomarkers Prev. 2015 Jun;24(6):944-50.
BACKGROUND: Biomarker discovery research has yielded few biomarkers that validate for clinical use. A contributing factor may be poor study designs. METHODS: The goal in discovery research is to identify a subset of potentially useful markers from a large set of candidates assayed on case and control samples. We recommend the PRoBE design for selecting samples. We propose sample size calculations that require specifying: (i) a definition for biomarker performance; (ii) the proportion of useful markers the study should identify (Discovery Power); and (iii) the tolerable number of useless markers amongst those identified (False Leads Expected, FLE). RESULTS: We apply the methodology to a study of 9,000 candidate biomarkers for risk of colon cancer recurrence where a useful biomarker has positive predictive value >/=30%. We find that 40 patients with recurrence and 160 without recurrence suffice to filter out 98% of useless markers (2% FLE) while identifying 95% of useful biomarkers (95% Discovery Power). Alternative methods for sample size calculation required more assumptions. CONCLUSIONS: Biomarker discovery research should utilize quality biospecimen repositories and include sample sizes that enable markers meeting prespecified performance characteristics for well-defined clinical applications to be identified. IMPACT: The scientific rigor of discovery research should be improved.
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;21(7):1764-71.
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;121(8):1279-86.
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.
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.