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.
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. [In press]
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.
Sawyers CL, Abate-Shen C, Anderson KC, Barker A, Baselga J, Berger NA, Foti M, Jemal A, Lawrence TS, Li CI, Mardis ER, Neumann PJ, Pardoll DM, Prendergast GC, Reed JC, Weiner GJ; AACR Cancer Progress Report Writing Committee. AACR Cancer Progress Report 2013. Clin Cancer Res 2013. [In press]
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.
Livaudais JC, Lacroix AZ, Chlebowski RT, Li CI, Habel LA, Simon MS, Thompson B, Erwin DO, Hubbell FA, Coronado G. Racial/ethnic differences in use and duration of adjuvant hormonal therapy for breast cancer in the Women's Health Initiative. Cancer Epidemiol Biomarkers Prev 2013; 22:365-373.
BACKGROUND: Five-year breast cancer survival rates are lower among Hispanic and African American women than among Non-Hispanic White (NHW) women. Differences in breast cancer treatment likely play a role. Adjuvant hormonal therapies increase overall survival among women with hormone receptor-positive breast cancer. METHODS: We examined racial/ethnic differences in use and duration of adjuvant hormonal therapy among 3,588 postmenopausal women enrolled in the Women's Health Initiative (WHI) Extension Study. Women diagnosed with hormone receptor-positive localized or regional stage breast cancer after study enrollment were surveyed between September 2009 and August 2010 and asked to recall prior use and duration of adjuvant hormonal breast cancer therapy. Odds ratios [OR] comparing self-reported use and duration by race/ethnicity (Hispanic, African American, Asian/Pacific Islander vs. NHW) were estimated using multivariable-adjusted logistic regression. RESULTS: Of the 3,588 women diagnosed from 1994-2009; 3,039 (85%) reported any use of adjuvant hormonal therapy and 67% of women reporting ever-use who were diagnosed prior to 2005 reported using adjuvant hormonal therapy for the optimal duration of ≥5 years. In adjusted analysis, no statistically significant differences in use or duration by race/ethnicity were observed. CONCLUSIONS: This study did not find significant differences in use or duration of use of adjuvant hormonal therapy by race/ethnicity. Impact: Findings should be confirmed in other population-based samples and potential reasons for discontinuation of therapy across all racial/ethnic groups should be explored.
Ladd JJ, Chao T, Johnson MM, Qiu J, Chin A, Israel R, Pitteri SJ, Mao J, Wu M, Amon LM, McIntosh MW, Li CI, Prentice R, Disis NL, Hanash SM. Autoantibody signatures involving glycolysis and splicesome proteins precede a diagnosis of breast cancer among post-menopausal women. Cancer Res 2012; 73:1502-1513.
We assessed the autoantibody repertoire of a mouse model engineered to develop breast cancer and the repertoire of autoantibodies in plasmas collected at a pre-clinical time point and at the time of clinical diagnosis of breast cancer. In seeking to identify common pathways, networks and protein families associated with the humoral response, we elucidated the dynamic nature of tumor antigens and autoantibody interactions. Lysate proteins from an immortalized cell line from an MMTV-neu mouse model and from MCF7 human breast cancers were spotted onto nitrocellulose microarrays and hybridized with mouse and human plasma samples, respectively. Ig-based plasma immunoreactivity against glycolysis and spliceosome proteins was a predominant feature observed both in tumor bearing mice and in pre-diagnostic human samples. Interestingly, autoantibody reactivity was more pronounced further away than closer to diagnosis. We provide evidence for dynamic changes in autoantibody reactivity with tumor development and progression thatmay depend in part on the extent of antigen-antibody interactions.
Saltzman BS, Weiss NS, Sieh W, Fitzpatrick AL, McTiernan A, Daling JR, Li CI. Use of antihypertensive medications and breast cancer risk. Cancer Causes Control 2013; 24:365-371.
PURPOSE: Use of specific antihypertensive medications (AHTs) has been hypothesized to increase breast cancer risk, but results across published studies are inconsistent. METHODS: We re-evaluated the relationship between AHT use and breast cancer risk in a prospective cohort of 3,201 women ≥65 years of age at recruitment now with more than double the length of follow-up (12 vs. 5 years) and substantially more breast cancer diagnoses (188 compared with 75 cases). We estimated the association between AHT use overall as well as use of specific formulations (based on data collected annually) and breast cancer risk using multivariate-adjusted Cox regression. RESULTS: Compared with women who reported no use of AHTs, women who had used calcium channel blockers (CCB) within the past two years had a 1.6-fold increased risk of breast cancer (95 % confidence interval (CI): 1.0-2.5), and in particular, recent users of immediate-release CCBs had a 2.4-fold increased risk (95 % CI: 1.3-4.5). Neither ever nor recent use of any other type of AHT was associated with breast cancer risk. CONCLUSIONS: While the observed association between immediate-release CCBs and breast cancer risk is based on a small sample size and needs to be interpreted cautiously, this result is consistent with others in the literature. However, given declines in use of these preparations in favor of sustained-release CCBs, which was not related to risk, the potential clinical and public health impact of this association is limited. This study also adds to the evidence that other commonly used AHTs are not strongly related to breast cancer risk.
Calip GS, McDougall JA, Wheldon MC, Li CI, De Roos AJ. Evaluation of seasonality in the diagnosis of acute myeloid leukaemia among adults in the United States, 1992-2008. Br J Haematol 2013; 160:343-350.
Recent studies have suggested seasonal variation in the diagnosis of acute myeloid leukaemia (AML), and the aetiological role seasonal factors may play in this group of haematological neoplasms remains unclear. We evaluated potential seasonality of AML diagnosis among adults. Cases included were ascertained from the Surveillance, Epidemiology, and End Results (SEER) 13 registries from 1992-2008. Chi-square analysis for heterogeneity and multiple Poisson regression using parametric harmonic modelling and bootstrap testing were used to detect possible monthly variation. Months of peak diagnoses were December and January, although some variation was present by sex and age. Heterogeneity across months was statistically significant (P < 0·001). In stratified analyses, monthly variation was detected only among males (P = 0·009) and in cases aged 65 years and older (P = 0·031). Poisson regression found no seasonal effect among all cases when fit to the sinusoidal model (P = 0·110). However, similar variation among males (P = 0·009) and cases aged 65 years and older (P = 0·018) was present. There is growing evidence of seasonality in AML diagnosis, particularly among older persons and men. Investigation of specific seasonal risk factors would be informative in explaining the aetiology behind the observed variation.
Li CI, Beaber EF, Tang MT, Porter PL, Daling JR, Malone KE. Reproductive factors and risk of estrogen receptor positive, triple-negative, and HER2-neu overexpressing breast cancer among women 20-44 years of age. Breast Cancer Res Treat 2013; 137:579-587.
Aspects of reproductive history are among the most well-established breast cancer risk factors. However, relatively little is known about how they influence risk of different molecular subtypes of breast cancer, particularly among younger women. Using data from a population-based case-control study of women 20-44 years of age, we assessed the relationships between various reproductive factors and risk of estrogen receptor positive (ER+), triple-negative, and HER2-overexpressing breast cancers. Detailed reproductive histories were obtained through structured interviewer administered in-person questionnaires. Reproductive histories among control women (n = 941) were compared to those of ER+ cases (n = 781), triple-negative cases (n = 180), and HER2-overexpressing cases (n = 60) using polytomous logistic regression. Age at menarche, parity, and number of full-term pregnancies were similarly associated with risk of all three breast cancer subtypes. In contrast, age at first live birth, the interval between age at menarche and age at first birth, and breastfeeding were inversely associated with risk of triple-negative breast cancer (P values for trend 0.002, 0.006 and 0.018, respectively), but were not associated with risk of ER+ or HER2-overexpressing cancers. A strong inverse association between breastfeeding and risk of triple-negative breast cancer has now been consistently observed across numerous studies, and at present it is the most well-established protective factor for this aggressive and lethal form of breast cancer. Further studies clarifying the biological mechanisms underlying this relationship and confirming our results with respect to age at first birth and the interval between age at menarche and age at first birth are needed.
Semmens EO, Kopecky KJ, Grant E, Mathes RW, Nishi N, Sugiyama H, Moriwaki H, Sakata R, Soda M, Kasagi F, Yamada M, Fujiwara S, Akahoshi M, Davis S, Kodama K, Li CI. Relationship between anthropometric factors, radiation exposure, and colon cancer incidence in the Life Span Study cohort of atomic bomb survivors. Cancer Causes Control 2013; 24:27-37.
We examined colon cancer risk in atomic bomb survivors to investigate whether excess body weight after the bombings alters sensitivity to radiation effects. Of the 56,064 Japanese atomic bomb survivors with follow-up through 2002 with self-reported anthropometric data obtained from periodic mail surveys, 1,142 were diagnosed with colon cancer. We evaluated the influence of body mass index (BMI) and height on radiation-associated colon cancer risk using Poisson regression. We observed a similar linear dose-response relationship for the 56,064 subjects included in our analysis and the entire cohort of Japanese atomic bomb survivors [excess relative risk (ERR) per Gray (Gy) = 0.53, 95 % confidence interval (CI) 0.25-0.86]. Elevation in earliest reported BMI, BMI reported closest to colon cancer diagnosis, and time-varying BMI were associated with an elevated risk of colon cancer [relative risk (RR) per 5 kg/m(2) increase in BMI = 1.14, 95 % CI 1.03-1.26; RR = 1.16, 95 % CI 1.05-1.27; and RR = 1.15, 95 % CI 1.04-1.27, respectively]. Height was not significantly related to colon cancer risk. Inclusion of anthropometric variables in models had little impact on radiation risk estimates, and there was no evidence that sensitivity to the effect of radiation on colon cancer risk depended on BMI. Radiation exposure and BMI are both risk factors for colon cancer. BMI at various times after exposure to the atomic bombings does not significantly influence the relationship between radiation dose and colon cancer risk, suggesting that BMI and radiation impact colon cancer risk independently of each other.
Saltzman BS, Malone KE, McDougall JA, Daling JR, Li CI. Estrogen receptor, progesterone receptor, and HER2-neu expression in first primary breast cancers and risk of second primary contralateral breast cancer. Breast Cancer Res Treat 2012; 135:849-855.
Breast cancer survivors have a 60 % higher risk of developing a second primary asynchronous contralateral breast cancer (CBC) compared to women's risk of developing a first primary breast cancer (FBC). However, little is known about how expression of tumor markers in first breast cancers influences CBC risk. We conducted a population-based nested case-control study among women 20-74 years of age diagnosed with a first breast cancer between 1996 and 2008 in western Washington State to evaluate the association between their tumor's estrogen receptor (ER), progesterone receptor (PR) and HER2-neu (HER2) expression, and risk of CBC. The study included 482 cases diagnosed with both a FBC and a CBC and 1,506 control women diagnosed only once with breast cancer identified through our local Surveillance, Epidemiology and End Results (SEER) cancer registry. Compared to the women whose FBC was ER+/PR+, those with ER-/PR- first tumors had a 1.6-fold (95 % confidence interval (CI): 1.2-2.3) increased risk of developing a CBC. When evaluated by joint ER/PR/HER2 status, compared to women with ER+/HER2- first cancers, those with HER2-overexpressing (ER-/HER2+) and triple-negative disease (ER-/PR-/HER2-) had 2.0-fold (95 % CI: 1.1-3.8) and 1.4-fold (95 % CI: 0.9-2.3) elevated risks of developing CBC, respectively. Beyond the known higher risks of mortality among patients diagnosed with more aggressive BC subtypes, here, we observe that they may also have increased risks of developing CBC.
Phipps AI, Anderson GL, Cochrane BB, Li CI, Wactawski-Wende J, Ho GY, O'Sullivan MJ, Newcomb PA. Migraine history, nonsteroidal anti-inflammatory drug use, and risk of postmenopausal endometrial cancer. Horm Cancer 2012; 3:240-248.
Endometrial cancer is primarily a hormonally mediated disease. As such, factors that mediate or reflect exposure to estrogens, or that mediate response to such exposure, may plausibly be associated with endometrial cancer risk. History of migraines, another hormonally mediated condition, has recently been associated with a reduced risk of hormone receptor-positive breast cancer; however, the relationship between migraines and endometrial cancer has not previously been explored. We evaluated the relationship between migraine history and endometrial cancer risk in postmenopausal women, considering also the potential impact of nonsteroidal anti-inflammatory drug (NSAID) use, given the relationship of NSAIDs to hormones and to migraine history. We identified 93,384 women participating in the Women's Health Initiative prospective cohort who had an intact uterus at the time of study entry. Using Cox proportional hazards regression, we assessed risk of endometrial cancer during study follow-up according to history of migraines and according to current NSAID use at the time of study entry, adjusting for age, study arm, race, and hormone therapy use. We also evaluated interaction in these associations by body mass index. Having a history of migraines was not associated with endometrial cancer risk [hazard ratio (HR) = 0.91, 95 % confidence interval (CI) = 0.75-1.11], regardless of body mass index (BMI) or NSAID use status. Similarly, current NSAID use was not associated with endometrial cancer risk (HR = 1.01, 95 % CI = 0.88-1.16), regardless of BMI. Migraine history and NSAID use do not appear to be associated with risk of endometrial cancer.
Li CI, Mirus JE, Zhang Y, Ramirez AB, Ladd JJ, Prentice RL, McIntosh MW, Hanash SM, Lampe PD. Discovery and preliminary confirmation of novel early detection biomarkers for triple-negative breast cancer using preclinical plasma samples from the Women's Health Initiative observational study. Breast Cancer Res Treat 2012;135:611-618.
Triple-negative breast cancer is a particularly aggressive and lethal breast cancer subtype that is more likely to be interval-detected rather than screen-detected. The purpose of this study is to discover and initially validate novel early detection biomarkers for triple-negative breast cancer using preclinical samples. Plasma samples collected up to 17 months before diagnosis from 28 triple-negative cases and 28 matched controls from the Women's Health Initiative Observational Study were equally divided into a training set and a test set and interrogated by a customized antibody array. Data were available on 889 antibodies; in the training set, statistically significant differences in case versus control signals were observed for 93 (10.5 %) antibodies at p < 0.05. Of these 93 candidates, 29 were confirmed in the test set at p < 0.05. Areas under the curve for these candidates ranged from 0.58 to 0.79. With specificity set at 98 %, sensitivity ranged from 4 to 68 % with 20 candidates having a sensitivity >/=20 % and 6 having a sensitivity >/=40 %. In an analysis of KEGG gene sets, the pyrimidine metabolism gene set was upregulated in cases compared to controls (p = 0.004 in the testing set) and the JAK/Stat signaling pathway gene set was downregulated (p = 0.003 in the testing set). Numerous potential early detection biomarkers specific to triple-negative breast cancer in multiple pathways were identified. Further research is required to followup on promising candidates in larger sample sizes and to better understand their potential biologic importance as our understanding of the etiology of triple-negative breast cancer continues to grow.
Phipps AI, Scoggins J, Rossing MA, Li CI, Newcomb PA. Temporal trends in incidence and mortality rates for colorectal cancer by tumor location: 1975-2007. Am J Public Health 2012; 102:1791-1797.
We evaluated changes in colorectal cancer (CRC) incidence and mortality by anatomic site to assess the possible impact of CRC screening. Using data from 9 Surveillance, Epidemiology, and End Results cancer registries, we estimated trends in 1975-2007 CRC incidence and 1985-2007 incidence-based mortality. We evaluated trends separately for proximal and distal CRC, overall and by stage, tumor site, and race. Between 1975 and 2007, 323 237 adults in the study area were diagnosed with CRC. For most tumor and population subgroups, incidence rates increased between 1975 and 1985 and subsequently declined markedly. Declines were most rapid between 1999 and 2007 and were greater for distal than proximal CRC. Declines in incidence were greater for White than Black adults and greatest for regional-stage disease. There was little difference in trends across subsites within the proximal and distal colorectum. Declines in incidence-based mortality mirrored those for incidence. Recent declines in CRC incidence and mortality are greater for distal than proximal CRC. Differing trends across populations may reflect variations in screening prevalence; distinct trends by tumor characteristics likely reflect differences in screening efficacy.