Marilyn L. Kwan

Epidemiology of breast cancer subtypes in two prospective cohort studies of breast cancer survivors

IntroductionThe aim of this study was to describe breast tumor subtypes by common breast cancer risk factors and to determine correlates of subtypes using baseline data from two pooled prospective breast cancer studies within a large health maintenance organization.MethodsTumor data on 2544 invasive breast cancer cases subtyped by estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 (Her2) status were obtained (1868 luminal A tumors, 294 luminal B tumors, 288 triple-negative tumors and 94 Her2-overexpressing tumors). Demographic, reproductive and lifestyle information was collected either in person or by mailed questionnaires. Case-only odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using logistic regression, adjusting for age at diagnosis, race/ethnicity, and study origin.ResultsCompared with luminal A cases, luminal B cases were more likely to be younger at diagnosis (P = 0.0001) and were less likely to consume alcohol (OR = 0.74, 95% CI = 0.56 to 0.98), use hormone replacement therapy (HRT) (OR = 0.66, 95% CI = 0.46 to 0.94), and oral contraceptives (OR = 0.73, 95% CI = 0.55 to 0.96). Compared with luminal A cases, triple-negative cases tended to be younger at diagnosis (P ≤ 0.0001) and African American (OR = 3.14, 95% CI = 2.12 to 4.16), were more likely to have not breastfed if they had parity greater than or equal to three (OR = 1.68, 95% CI = 1.00 to 2.81), and were more likely to be overweight (OR = 1.82, 95% CI = 1.03 to 3.24) or obese (OR = 1.97, 95% CI = 1.03 to 3.77) if premenopausal. Her2-overexpressing cases were more likely to be younger at diagnosis (P = 0.03) and Hispanic (OR = 2.19, 95% CI = 1.16 to 4.13) or Asian (OR = 2.02, 95% CI = 1.05 to 3.88), and less likely to use HRT (OR = 0.45, 95% CI = 0.26 to 0.79).ConclusionsThese observations suggest that investigators should consider tumor heterogeneity in associations with traditional breast cancer risk factors. Important modifiable lifestyle factors that may be related to the development of a specific tumor subtype, but not all subtypes, include obesity, breastfeeding, and alcohol consumption. Future work that will further categorize triple-negative cases into basal and non-basal tumors may help to elucidate these associations further.

Environmental and Genetic Risk Factors for Childhood Leukemia: Appraising the Evidence

Childhood leukemia is the most common cause of malignancy under the age of 15, representing an annual incidence rate of 43 cases per million in the United States. Confirmed clinical and epidemiologic associations explain less than 10% of disease incidence, leaving 90% of cases with an unclear etiology. To effectively study leukemia in children, one must recognize that this disease has a multifactorial causal mechanism and a heterogeneous biological composition. In addition, the timing of environmental exposures and genetic changes related to disease risk must be considered. This review of both environmental and genetic risk factors for childhood leukemia evaluates the current published literature and synthesizes the available knowledge. Furthermore, attention is directed to expected sources of new advances and the compelling current issues that need to be addressed before further progress can be made. We discuss parental occupational exposures, air pollution, other chemical exposures such as household solvents and pesticides, radiation, dietary factors, immunological factors, socioeconomic status, and genetic susceptibility. We hope to provide the reader with an understanding of the challenge and promise that characterizes the current and future directions in childhood leukemia research.

Physical Activity and Risk of Recurrence and Mortality in Breast Cancer Survivors: Findings from the LACE Study

Introduction: Identifying modifiable factors that reduce the risk of recurrence and improve survival in breast cancer survivors is a pressing concern. The purpose of this study was to examine the association of physical activity following diagnosis and treatment with the risk of breast cancer recurrence and mortality and all-cause mortality in women with early-stage breast cancer. Materials and Methods: The sample consisted of 1,970 women from the Life After Cancer Epidemiology study, a prospective investigation of behavioral risk factors and health outcomes. Self-reported frequency and duration of work-related, household and caregiving, recreational, and transportation-related activities during the six months prior to enrollment were assessed. Outcomes were ascertained from electronic or paper medical charts. Hazard ratios and 95% confidence intervals were estimated from delayed entry Cox proportional hazards models. Results: Although age-adjusted results suggested that higher levels of physical activity were associated with reduced risk of recurrence and breast cancer mortality (P for trend = 0.05 and 0.07, respectively for highest versus lowest level of hours per week of moderate physical activity), these associations were attenuated after adjustment for prognostic factors and other confounding variables (P for trend = 0.36 and 0.26). In contrast, a statistically significant protective association between physical activity and all-cause mortality remained in multivariable analyses (hazard ratio, 0.66; 95% confidence interval, 0.42-1.03; P for trend = 0.04). Conclusions: These findings do not support a protective effect of physical activity on breast cancer recurrence or mortality but do suggest that regular physical activity is beneficial for breast cancer survivors in terms of total mortality. (Cancer Epidemiol Biomarkers Prev 2009;18(1):87–95)

Alcohol Consumption and Breast Cancer Recurrence and Survival Among Women With Early-Stage Breast Cancer: The Life After Cancer Epidemiology Study

PURPOSE To examine the association of alcohol consumption after breast cancer diagnosis with recurrence and mortality among early-stage breast cancer survivors. PATIENTS AND METHODS Patients included 1,897 LACE study participants diagnosed with early-stage breast cancer between 1997 and 2000 and recruited on average 2 years postdiagnosis, primarily from the Kaiser Permanente Northern California Cancer Registry. Alcohol consumption (ie, wine, beer, and liquor) was assessed at cohort entry using a food frequency questionnaire. Cox proportional hazards models were used to estimate hazard ratios (HR) and 95% CI with adjustment for known prognostic factors. RESULTS Two hundred ninety-three breast cancer recurrences and 273 overall deaths were ascertained after an average follow-up of 7.4 years. Nine hundred fifty-eight women (51%) were considered drinkers (> 0.5 g/d of alcohol), and the majority drank wine (89%). Drinking ≥ 6 g/d of alcohol compared with no drinking was associated with an increased risk of breast cancer recurrence (HR, 1.35; 95% CI, 1.00 to 1.83) and death due to breast cancer (HR, 1.51; 95% CI, 1.00 to 2.29). The increased risk of recurrence appeared to be greater among postmenopausal (HR, 1.51; 95% CI, 1.05 to 2.19) and overweight and obese women (HR, 1.60; 95% CI, 1.08 to 2.38). Alcohol intake was not associated with all-cause death and possibly associated with decreased risk of non-breast cancer death. CONCLUSION Consuming three to four alcoholic drinks or more per week after a breast cancer diagnosis may increase risk of breast cancer recurrence, particularly among postmenopausal and overweight/obese women, yet the cardioprotective effects of alcohol on non-breast cancer death were suggested.

Breast Cancer DNA Methylation Profiles Are Associated with Tumor Size and Alcohol and Folate Intake

Although tumor size and lymph node involvement are the current cornerstones of breast cancer prognosis, they have not been extensively explored in relation to tumor methylation attributes in conjunction with other tumor and patient dietary and hormonal characteristics. Using primary breast tumors from 162 (AJCC stage I–IV) women from the Kaiser Division of Research Pathways Study and the Illumina GoldenGate methylation bead-array platform, we measured 1,413 autosomal CpG loci associated with 773 cancer-related genes and validated select CpG loci with Sequenom EpiTYPER. Tumor grade, size, estrogen and progesterone receptor status, and triple negative status were significantly (Q-values <0.05) associated with altered methylation of 209, 74, 183, 69, and 130 loci, respectively. Unsupervised clustering, using a recursively partitioned mixture model (RPMM), of all autosomal CpG loci revealed eight distinct methylation classes. Methylation class membership was significantly associated with patient race (P<0.02) and tumor size (P<0.001) in univariate tests. Using multinomial logistic regression to adjust for potential confounders, patient age and tumor size, as well as known disease risk factors of alcohol intake and total dietary folate, were all significantly (P<0.0001) associated with methylation class membership. Breast cancer prognostic characteristics and risk-related exposures appear to be associated with gene-specific tumor methylation, as well as overall methylation patterns.

Breastfeeding and the Risk of Childhood Leukemia: A Meta-Analysis

Objectives. The authors used a meta-analytic technique to (1) quantify the evidence of an association between duration of breastfeeding and risk of childhood acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML), (2) assess the influence of socioeconomic status (SES) on any such associations, and (3) discuss the implications of these findings for the evaluation of whether breastfeeding reduces the risk of childhood leukemia. Methods. A fixed effects model was employed to systematically combine the results of 14 case-control studies addressing the effect of short-term (⩽6 months) and long-term (>6 months) breastfeeding on the risk of childhood ALL and/or AML. Subgroup analyses of studies that did and did not adjust for SES were also performed. Results. A significant, negative association was observed between long-term breastfeeding and both ALL risk (odds ratio [OR] = 0.76; 95% confidence interval [CI] 0.68, 0.84) and AML risk (OR=0.85; 95% CI 0.73, 0.98). Short-term breastfeeding was similarly protective for ALL and AML. Results for studies that adjusted and did not adjust for SES were not significantly different from the results for the 14 studies combined. Conclusions. This meta-analysis showed that both short-term and long-term breastfeeding reduced the risk of childhood ALL and AML, suggesting that the protective effect of breastfeeding might not be limited to ALL as earlier hypothesized. Potential bias introduced by different participation rates for case and control samples that differed in SES can be minimized by implementing larger case-control studies with SES-matched, population-based controls.

Risk factors for lymphedema in a prospective breast cancer survivorship study: the Pathways Study.

OBJECTIVE To determine the incidence of breast cancer-related lymphedema (BCRL) during the early survivorship period as well as demographic, lifestyle, and clinical factors associated with BCRL development. DESIGN The Pathways Study, a prospective cohort study of breast cancer survivors with a mean follow-up time of 20.9 months. SETTING Kaiser Permanente Northern California medical care program. PARTICIPANTS We studied 997 women diagnosed from January 9, 2006, through October 15, 2007, with primary invasive breast cancer and who were at least 21 years of age at diagnosis, had no history of any cancer, and spoke English, Spanish, Cantonese, or Mandarin. MAIN OUTCOME MEASURE Clinical indication for BCRL as determined from outpatient or hospitalization diagnostic codes, outpatient procedural codes, and durable medical equipment orders. RESULTS A clinical indication for BCRL was found in 133 women (13.3%), with a mean time to diagnosis of 8.3 months (range, 0.7-27.3 months). Being African American (hazard ratio, 1.93; 95% confidence interval, 1.00-3.72) or more educated (P for trend = .03) was associated with an increased risk of BCRL. Removal of at least 1 lymph node (hazard ratio, 1.04; 95% confidence interval, 1.02-1.07) was associated with an increased risk, yet no significant association was observed for type of lymph node surgery. Being obese at breast cancer diagnosis was suggestive of an elevated risk (hazard ratio, 1.43; 95% confidence interval, 0.88-2.31). CONCLUSIONS In a large cohort study, BCRL occurs among a substantial proportion of early breast cancer survivors. Our findings agree with those of previous studies on the increased risk of BCRL with removal of lymph nodes and being obese, but they point to a differential risk according to race or ethnicity.

Exercise in patients with lymphedema: a systematic review of the contemporary literature.

BackgroundControversy exists regarding the role of exercise in cancer patients with or at risk for lymphedema, particularly breast. We conducted a systematic review of the contemporary literature to distill the weight of the evidence and provide recommendations for exercise and lymphedema care in breast cancer survivors.MethodsPublications were retrieved from 11 major medical indices for articles published from 2004 to 2010 using search terms for exercise and lymphedema; 1,303 potential articles were selected, of which 659 articles were reviewed by clinical lymphedema experts for inclusion, yielding 35 articles. After applying exclusion criteria, 19 articles were selected for final review. Information on study design/objectives, participants, outcomes, intervention, results, and study strengths and weaknesses was extracted. Study evidence was also rated according to the Oncology Nursing Society Putting Evidence Into Practice® Weight-of-Evidence Classification.ResultsSeven studies were identified addressing resistance exercise, seven studies on aerobic and resistance exercise, and five studies on other exercise modalities. Studies concluded that slowly progressive exercise of varying modalities is not associated with the development or exacerbation of breast cancer-related lymphedema and can be safely pursued with proper supervision. Combined aerobic and resistance exercise appear safe, but confirmation requires larger and more rigorous studies.ConclusionsStrong evidence is now available on the safety of resistance exercise without an increase in risk of lymphedema for breast cancer patients. Comparable studies are needed for other cancer patients at risk for lymphedema.Implications for cancer survivorsWith reasonable precautions, it is safe for breast cancer survivors to exercise throughout the trajectory of their cancer experience, including during treatment.

NSAIDs and breast cancer recurrence in a prospective cohort study

ObjectiveWe examined the association between NSAID use and breast cancer recurrence in a prospective cohort of 2,292 early-stage breast cancer survivors diagnosed from 1997 to 2000 participating in the Life After Cancer Epidemiology (LACE) Study.MethodsFrom 2000 to 2002, mailed questionnaires were used to obtain information on aspirin, ibuprofen, and other NSAID use and subsequent breast cancer events. A total of 270 recurrences (local, regional, and distant disease and new primary breast cancers) were reported and verified by medical record review. Cox proportional hazard models were used to estimate rate ratios (RR) and 95% confidence intervals (CI), adjusting for age at diagnosis, race, cancer stage, tamoxifen treatment, chemotherapy use, body mass index, and cyclooxygenase-2 (COX2) inhibitor use.ResultsCurrent, regular use (at least three days per week at time of questionnaire administration) of ibuprofen (RR, 0.56; 95% CI, 0.32–0.98), but not aspirin (RR, 1.09; 95% CI, 0.74–1.61), was associated with a statistically significant decreased risk of breast cancer recurrence. The combination of ibuprofen and other non-aspirin NSAIDs such as naproxen and sulindac reflected a similar reduction in risk (RR, 0.56; 95% CI, 0.33–0.95). No association was found for the non-NSAID analgesic acetaminophen.ConclusionOur findings provide support for an inverse association between current, regular ibuprofen use and breast cancer recurrence.

Soy food intake after diagnosis of breast cancer and survival: an in-depth analysis of combined evidence from cohort studies of US and Chinese women

BACKGROUND Soy isoflavones have antiestrogenic and anticancer properties but also possess estrogen-like properties, which has raised concern about soy food consumption among breast cancer survivors. OBJECTIVE We prospectively evaluated the association between postdiagnosis soy food consumption and breast cancer outcomes among US and Chinese women by using data from the After Breast Cancer Pooling Project. DESIGN The analysis included 9514 breast cancer survivors with a diagnosis of invasive breast cancer between 1991 and 2006 from 2 US cohorts and 1 Chinese cohort. Soy isoflavone intake (mg/d) was measured with validated food-frequency questionnaires. HRs and 95% CIs were estimated by using delayed-entry Cox regression models, adjusted for sociodemographic, clinical, and lifestyle factors. RESULTS After a mean follow-up of 7.4 y, we identified 1171 total deaths (881 from breast cancer) and 1348 recurrences. Despite large differences in soy isoflavone intake by country, isoflavone consumption was inversely associated with recurrence among both US and Chinese women, regardless of whether data were analyzed separately by country or combined. No heterogeneity was observed. In the pooled analysis, consumption of ≥10 mg isoflavones/d was associated with a nonsignificant reduced risk of all-cause (HR: 0.87; 95% CI: 0.70, 1.10) and breast cancer-specific (HR: 0.83; 95% CI: 0.64, 1.07) mortality and a statistically significant reduced risk of recurrence (HR: 0.75; 95% CI: 0.61, 0.92). CONCLUSION In this large study of combined data on US and Chinese women, postdiagnosis soy food consumption of ≥10 mg isoflavones/d was associated with a nonsignificant reduced risk of breast cancer-specific mortality and a statistically significant reduced risk of recurrence.