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1.  Breast Cancer Risk for Noncarriers of Family-Specific BRCA1 and BRCA2 Mutations: Findings From the Breast Cancer Family Registry 
Journal of Clinical Oncology  2011;29(34):4505-4509.
Purpose
Women with germline BRCA1 and BRCA2 mutations have five- to 20-fold increased risks of developing breast and ovarian cancer. A recent study claimed that women testing negative for their family-specific BRCA1 or BRCA2 mutation (noncarriers) have a five-fold increased risk of breast cancer. We estimated breast cancer risks for noncarriers by using a population-based sample of patients with breast cancer and their female first-degree relatives (FDRs).
Patients and Methods
Patients were women with breast cancer and their FDRs enrolled in the population-based component of the Breast Cancer Family Registry; patients with breast cancer were tested for BRCA1 and BRCA2 mutations, as were FDRs of identified mutation carriers. We used segregation analysis to fit a model that accommodates familial correlation in breast cancer risk due to unobserved shared risk factors.
Results
We studied 3,047 families; 160 had BRCA1 and 132 had BRCA2 mutations. There was no evidence of increased breast cancer risk for noncarriers of identified mutations compared with FDRs from families without BRCA1 or BRCA2 mutations: relative risk was 0.39 (95% CI, 0.04 to 3.81). Residual breast cancer correlation within families was strong, suggesting substantial risk heterogeneity in women without BRCA1 or BRCA2 mutations, with some 3.4% of them accounting for roughly one third of breast cancer cases.
Conclusion
These results support the practice of advising noncarriers that they do not have any increase in breast cancer risk attributable to the family-specific BRCA1 or BRCA2 mutation.
doi:10.1200/JCO.2010.34.4440
PMCID: PMC3236651  PMID: 22042950
2.  Changes in Health Status Among Aging Survivors of Pediatric Upper and Lower Extremity Sarcoma: A Report from the Childhood Cancer Survivor Study (CCSS) 
Objective
To evaluate health status and participation restrictions in childhood extremity sarcoma survivors.
Design
Members of the CCSS cohort with extremity sarcomas, who completed 1995, 2003 or 2007 questionnaires, were included.
Setting
Cohort Study of extremity sarcomas survivors.
Participants
Childhood cancer survivors diagnosed and treated between 1970–1986.
Interventions
Not applicable.
Main Outcome Measure
Prevalence rates for poor health status in six domains and five sub-optimal social participation categories were compared by tumor location and treatment exposure with generalized estimating equations adjusted for demographic/personal factors and time/age.
Results
Among 1094 survivors, median age at diagnosis 13 years (range 0–20), current age 33 years (range 10–53), 49% were male, 87.5% Caucasian, and 75% had lower extremity tumors. In adjusted models, when compared to upper extremity survivors, lower extremity survivors had increased risk of activity limitations but lower risk of not completing college. Compared to those who did not have surgery, those with limb-sparing (LS) and upper extremity amputations (UEA) were 1.6 times more likely to report functional impairment; while those with an above the knee amputation (AKA) were 1.9 times more likely to report functional impairment. Survivors treated with LS were 1.5 times more likely to report activity limitations. Survivors undergoing LS were more likely to report inactivity, incomes < $20,000, unemployment and no college degree. Those with UEA more likely reported inactivity, unmarried status and no college degree. Lastly, those with AKA more likely reported no college degree. Treatment with abdominal irradiation was associated with increased risk of poor mental health, functional impairment and activity limitation.
Conclusion
Treatment for lower extremity sarcomas is associated with a 50% increased risk for activity limitations; upper extremity survivors are at 10% higher risk for not completing college. Type of local control influences health status and participation restrictions. Both these outcomes decline with age.
doi:10.1016/j.apmr.2013.01.013
PMCID: PMC3913046  PMID: 23380347
upper extremity; lower extremity; sarcoma; survivors; childhood cancer
3.  Chemotherapy use and patient treatment preferences in advanced colorectal cancer: a prospective cohort study 
Cancer  2012;119(4):854-862.
BACKGROUND
Our objective was to determine how patient preferences guide the course of palliative chemotherapy for advanced colorectal cancer.
METHODS
Eligible patients with metastatic colorectal cancer (mCRC) were enrolled nationwide in a prospective, population-based cohort study. Data were obtained via medical record abstraction and patient surveys. Logistic regression was used to evaluate: patient characteristics associated with seeing medical oncology and receiving chemotherapy; and patient characteristics, beliefs and preferences associated with receiving >1 line of chemotherapy and receiving combination chemotherapy.
RESULTS
Among 702 patients with mCRC, 91% saw a medical oncologist, and among those, 82% received chemotherapy. Patients 65-75 and ≥75 years were less likely to see an oncologist, as were patients who were too sick to complete their own survey. In adjusted analyses patients ≥75 years and with moderate or severe comorbidity were less likely to receive chemotherapy, as were patients who were too sick to complete their own survey. Patients received chemotherapy even if they believed chemotherapy would not extend their life (90%), chemotherapy would not likely help with cancer-related problems (89%), or preferred treatment focusing on comfort even if it meant not living as long (90%). Older patients were less likely to receive combination first-line therapy. Patient preferences and beliefs were not associated with receipt of >1 line of chemotherapy or combination chemotherapy.
CONCLUSIONS
The majority of patients received chemotherapy even if they expressed negative or marginal preferences or beliefs regarding chemotherapy. Patient preferences and beliefs were not associated with intensity or number of chemotherapy regimens.
doi:10.1002/cncr.27815
PMCID: PMC3548062  PMID: 22972673
Colorectal cancer; decision making; patient preference; cohort studies; quality of healthcare
4.  Treatment and Mortality in Men with Localized Prostate Cancer: A Population-Based Study in California 
Purpose
To provide patients and physicians with population-based estimates of mortality from prostate cancer or other causes depending upon the primary treatment modality, stratified by patient age, tumor stage and grade.
Methods
We conducted a 10-year competing-risk analysis of 45,440 men diagnosed with clinically localized (T1 or T2) prostate cancer in California during 1995–1998. Information on patient characteristics, primary treatment and cause of death was obtained from the California Cancer Registry.
Results
In this population-based cohort, the most common primary treatment was surgery (40.4%), followed by radiotherapy (29.1%), conservative management (20.8%), and androgen deprivation therapy (ADT) monotherapy (9.8%). Prostate cancer mortality differed significantly (p < 0.0001) across treatment groups among patients <80 years at diagnosis with moderately or poorly differentiated disease; the 10-year disease-specific mortality rates were generally highest for men treated with ADT monotherapy [range: 3.3% (95% CI=0.8–12.5%) to 53.8% (95% CI=34.4–72.2%)], intermediate for men treated with conservative management [range: 1.7% (95% CI=0.7–4.6%) to 30.0% (95% CI=16.2–48.8%] or radiotherapy [range: 3.2% (95% CI=1.8–5.5%) to 18.3% (95% CI=15.1–22.0%)], and lowest for men treated with surgery [range: 1.2% (95% CI=0.8–1.7%) to 11.0% (95% CI=8.4–14.2%)].
Conclusion
The cause-specific mortality estimates provided by this observational study can help patients and physicians better understand the expected long-term outcomes of localized prostate cancer given the initial treatment choice and practice patterns in the general population.
PMCID: PMC3758138  PMID: 23997838
Prostate cancer; treatment; mortality; cohort study; California Cancer Registry
5.  Enrollment of Patients With Lung and Colorectal Cancers Onto Clinical Trials 
Journal of Oncology Practice  2012;9(2):e40-e47.
Both practice environment and patient clinical and demographic characteristics are associated with cancer clinical trial enrollment; simultaneous intervention may be required when trying to increase enrollment rates.
Purpose:
Only 2% to 5% of adult patients with cancer enroll onto clinical trials. We assessed simultaneously characteristics of patients and their physicians that may be independently associated with participation.
Methods:
CanCORS, a National Cancer Institute (NCI) –funded population-based observational cohort study of newly diagnosed patients with lung and colorectal cancers, sampled patients across five geographic areas, five health care delivery systems, and 15 Veterans Administration hospitals. We linked patient survey and medical record data with physician survey data to examine correlates of trial enrollment.
Results:
Among 9,901 patients, 5.3% enrolled onto trials. Of the 9,901 patients, we linked 6,506 patients to one medical oncologist, surgeon, or radiation oncologist (physicians, N = 1,325) who responded to the physician survey and was considered their primary cancer clinician decision maker. Patient age, race, disease stage, geographic region, and health insurance were independently associated with trial enrollment. Physician factors independently associated with patient trial enrollment were being a medical oncologist, practicing at an NCI-designated cancer center, taking the lead in discussing trials with patients, and receiving increased income from trial enrollment. After simultaneously adjusting for patient and physician characteristics, only being a physician practicing at an NCI-designated cancer center (odds ratio [OR], 1.65; 95% CI, 1.19 to 2.27) and patient female sex (OR, 1.36; 95% CI, 1.10 to 1.68), age > 70 versus < 50 years (OR, 0.28; 95% CI, 0.16 to 0.48), and advanced disease (OR, 1.85; 95% CI, 1.45 to 2.37) remained independently associated with trial enrollment.
Conclusion:
Both practice environment and patient clinical and demographic characteristics are associated with cancer clinical trial enrollment; simultaneous intervention may be required when trying to increase enrollment rates.
doi:10.1200/JOP.2012.000598
PMCID: PMC3595449  PMID: 23814523
6.  Quality of Cancer Care among Foreign-Born and US-Born Patients with Lung or Colorectal Cancer 
Cancer  2010;116(23):5497-5506.
Background
Disparities in care have been documented for foreign-born cancer patients in the US. However, limited data are available on lung and colorectal cancer. We assessed whether patient-reported quality and receipt of recommended care differed between US-born and foreign-born cancer patients.
Methods
We collected surveys and medical records for a population-based cohort including white, Hispanic, and Asian adults (2,205 US-born and 890 foreign-born) with lung or colorectal cancer diagnosed in California during 2003–2005. We used logistic regression to assess the association of nativity with patient-reported quality of care and receipt of recommended treatments (adjuvant chemotherapy for stage III colon cancer, adjuvant chemotherapy and radiation for stage II/III rectal cancer, and curative surgery for stage I/II non-small cell lung cancer). We also assessed whether language explained any differences in care by nativity.
Results
Overall, 46% of patients reported excellent care, but foreign-born patients were less likely than US-born patients to report excellent quality of care (adjusted odds ratio (AOR)=0.80, 95% confidence interval [CI]=0.65–1.00), a difference partly explained by language of survey, an indicator of English proficiency. Rates of recommended therapies ranged from 64% to 85%; foreign-born patients were less likely to receive chemotherapy and radiation for stage II/III rectal cancer (AOR=0.35, 95% CI=0.12–0.99). Rates of other treatments did not differ significantly by nativity.
Conclusions
Foreign-born cancer patients reported lower quality of care and were less likely to receive some cancer therapies than US-born. Better coordination of care and communication about cancer treatments and expanded use of interpreters may lessen these disparities.
doi:10.1002/cncr.25546
PMCID: PMC2974942  PMID: 20672356
lung cancer; colorectal cancer; recommended care; immigrants; satisfaction; quality; disparities; race/ethnicity; Hispanic; Asian
7.  The association of body mass index with mortality in the California Teachers Study 
Although underweight and obesity have been associated with increased risk of mortality, it remains unclear whether the associations differ by hormone therapy (HT) use and smoking. The authors examined the relationship between body mass index (BMI) and mortality within the California Teachers Study (CTS), specifically considering the impact of hormone therapy (HT) and smoking. The authors examined the associations of underweight and obesity with risks of all-cause and cause-specific mortality, among 115,433 women participating in the CTS, and specifically examined whether HT use or smoking modifies the effects of obesity. Multivariable Cox proportional hazards regression provided estimates of relative risks (RRs) and 95% confidence intervals (CIs). During follow up, 10,574 deaths occurred. All-cause mortality was increased for underweight (BMI < 18.5; adjusted relative risk [RR] = 1.33, 95% confidence interval [CI] =1.20–1.47) and obese participants (BMI ≥ 30: RR = 1.27, 95% CI = 1.19–1.37) relative to BMI of 18.5 – 24.9). Respiratory disease mortality was increased for underweight and obese participants. Death from any cancer, and breast cancer specifically, and cardiovascular disease was observed only for obese participants. The obesity and mortality association remained after stratification on HT and smoking. Obese participants remained at greater risk for mortality after stratification on menopausal hormone therapy and smoking. Obesity was associated with increased all-cause mortality, as well as death from any cancer (including breast), and cardiovascular and respiratory diseases. These findings help to identify groups at risk for BMI-related poor health outcomes.
doi:10.1002/ijc.25905
PMCID: PMC3246901  PMID: 21207419
9.  The potential value of sibling controls compared with population controls for association studies of lifestyle-related risk factors: an example from the Breast Cancer Family Registry 
Background A previous Australian population-based breast cancer case-control study found indirect evidence that control participation, although high, was not random. We hypothesized that unaffected sisters may provide a more appropriate comparison group than unrelated population controls.
Methods Three population-based case-control-family studies of breast cancer in women of white European origin were carried out by the Australian, Ontario and Northern California sites of the Breast Cancer Family Registry. We compared risk factors between 3643 cases, 2444 of their unaffected sisters and 2877 population controls and conducted separate case-control analyses based on population and sister controls using unconditional multivariable logistic regression.
Results Compared with sister controls, population controls were more highly educated, had an earlier age at menarche, fewer births, their first birth at a later age and their last birth more recently. The established breast cancer associations detected using sister controls, but not detected using population controls, were decreasing risk with each of later age at menarche, more births, younger age at first birth and greater time since last birth.
Conclusions Since participation of population controls might be unintentionally related to some risk factors, we hypothesize that sister controls could provide more valid relative risk estimates and be recruited at lower cost. Given declining study participation by population controls, this contention is highly relevant to epidemiologic research.
doi:10.1093/ije/dyr110
PMCID: PMC3204209  PMID: 21771852
Case-control; sister; breast cancer; lifestyle; risk factors
10.  Identification of BRCA1/2 Founder Mutations in Southern Chinese Breast Cancer Patients Using Gene Sequencing and High Resolution DNA Melting Analysis 
PLoS ONE  2012;7(9):e43994.
Background
Ethnic variations in breast cancer epidemiology and genetics have necessitated investigation of the spectra of BRCA1 and BRCA2 mutations in different populations. Knowledge of BRCA mutations in Chinese populations is still largely unknown. We conducted a multi-center study to characterize the spectra of BRCA mutations in Chinese breast and ovarian cancer patients from Southern China.
Methodology/Principal Findings
A total of 651 clinically high-risk breast and/or ovarian cancer patients were recruited from the Hong Kong Hereditary Breast Cancer Family Registry from 2007 to 2011. Comprehensive BRCA1 and BRCA2 mutation screening was performed using bi-directional sequencing of all coding exons of BRCA1 and BRCA2. Sequencing results were confirmed by in-house developed full high resolution DNA melting (HRM) analysis. Among the 451 probands analyzed, 69 (15.3%) deleterious BRCA mutations were identified, comprising 29 in BRCA1 and 40 in BRCA2. The four recurrent BRCA1 mutations (c.470_471delCT, c.3342_3345delAGAA, c.5406+1_5406+3delGTA and c.981_982delAT) accounted for 34.5% (10/29) of all BRCA1 mutations in this cohort. The four recurrent BRCA2 mutations (c.2808_2811delACAA, c.3109C>T, c.7436_7805del370 and c.9097_9098insA) accounted for 40% (16/40) of all BRCA2 mutations. Haplotype analysis was performed to confirm 1 BRCA1 and 3 BRCA2 mutations are putative founder mutations. Rapid HRM mutation screening for a panel of the founder mutations were developed and validated.
Conclusion
In this study, our findings suggest that BRCA mutations account for a substantial proportion of hereditary breast/ovarian cancer in Southern Chinese population. Knowing the spectrum and frequency of the founder mutations in this population will assist in the development of a cost-effective rapid screening assay, which in turn facilitates genetic counseling and testing for the purpose of cancer risk assessment.
doi:10.1371/journal.pone.0043994
PMCID: PMC3436879  PMID: 22970155
11.  Oral contraceptive use and survival in women with invasive breast cancer 
Background
Oral contraceptives (OCs) are widely used in the U.S. Although the relation between OC use and breast cancer incidence has been widely studied, the few studies examining associations between OC use prior to breast cancer diagnosis and survival are inconsistent.
Methods
Women with invasive breast cancer participating in the Women's Contraceptive and Reproductive Experiences (CARE) Study, a population-based case-control study (4565 women ages 35–64 years), and the California Teachers Study (CTS) cohort (3929 women ages 28–91 years) were followed for vital status. 1064 women died in the CARE Study (median follow-up, 8.6 years) and 523 died in the CTS (median follow-up, 6.1 years). Cox proportional hazards regression provided hazard rate ratio estimates (RRs) with 95% confidence intervals (CIs) for risk of death from any cause and from breast cancer.
Results
No association was observed for any OC use prior to diagnosis and all-cause mortality (CARE Study: RR=1.01 (95% CI=0.86–1.19); CTS: RR=0.84 (95% CI=0.67–1.05)). A decreased risk of all-cause mortality was observed in the CTS among women with more than 10 years of OC use (RR=0.67, 95% CI=0.47–0.96); however, no trend of decreasing risk with increasing OC duration was observed (P-trend=0.22), and no association was observed in the CARE study. No associations were observed for breast cancer-specific mortality.
Conclusions
OC use is not associated with all-cause or breast cancer-specific mortality among women with invasive breast cancer.
Impact
These two independent studies demonstrated no overall association between OC use and survival among women with breast cancer.
doi:10.1158/1055-9965.EPI-11-0022
PMCID: PMC3132273  PMID: 21551244
Oral contraceptives; breast cancer; survival; risk assessment
12.  Dietary phytocompounds and risk of lymphoid malignancies in the California Teachers Study cohort 
Cancer causes & control : CCC  2010;22(2):237-249.
Objective
We examined whether dietary intake of isoflavones, lignans, isothiocyanates, antioxidants, or specific foods rich in these compounds is associated with reduced risk of B-cell non-Hodgkin lymphoma (NHL), multiple myeloma (MM), or Hodgkin lymphoma (HL) in a large, prospective cohort of women.
Methods
Between 1995-1996 and December 31, 2007, among 110,215 eligible members of the California Teachers Study cohort, 536 women developed incident B-cell NHL, 104 developed MM, and 34 developed HL. Cox proportional hazards regression, with age as the time-scale, was used to estimate adjusted rate ratios (RRs) with 95% confidence intervals (CIs) for risk of lymphoid malignancies.
Results
Weak inverse associations with risk of diffuse large B-cell lymphoma were observed for isothiocyanates (RR for ≥12.1 vs. <2.7 mcM/day=0.67, 95% CI: 0.43-1.05) and an antioxidant index measuring hydroxyl radical absorbance capacity (RR for ≥2.2 vs. <0.9 μM Trolox equiv/g/day=0.68, 95% CI: 0.42-1.10; ptrend=0.08). Risk of other NHL subtypes, overall B-cell NHL, MM, or HL was not generally associated with dietary intake of isoflavones, lignans, isothiocyanates, antioxidants, or major food sources of these compounds.
Conclusions
Isoflavones, lignans, isothiocyanates, and antioxidant compounds are not associated with risk of most B-cell malignancies, but some phytocompounds may decrease risk of selected subtypes.
doi:10.1007/s10552-010-9692-5
PMCID: PMC3074494  PMID: 21107674
lymphoma; diet; isothiocyanates; antioxidants; cohort studies
13.  Accuracy of BRCA1/2 Mutation Prediction Models for Different Ethnicities and Genders: Experience in a Southern Chinese Cohort 
World Journal of Surgery  2012;36(4):702-713.
Background
BRCA1/2 mutation prediction models (BRCAPRO, Myriad II, Couch, Shattuck-Eidens, BOADICEA) are well established in western cohorts to estimate the probability of BRCA1/2 mutations. Results are conflicting in Asian populations. Most studies did not account for gender-specific prediction. We evaluated the performance of these models in a Chinese cohort, including males, before BRCA1/2 mutation testing.
Methods
The five risk models were used to calculate the probability of BRCA mutations in probands with breast and ovarian cancers; 267 were non-BRCA mutation carriers (247 females and 20 males) and 43 were BRCA mutation carriers (38 females and 5 males).
Results
Mean BRCA prediction scores for all models were statistically better for carriers than noncarriers for females but not for males. BRCAPRO overestimated the numbers of female BRCA1/2 mutation carriers at thresholds ≥20% but underestimated if <20%. BRCAPRO and BOADICEA underestimated the number of male BRCA1/2 mutation carriers whilst Myriad II underestimated the number of both male and female carriers. In females, BRCAPRO showed similar discrimination, as measured by the area under the receiver operator characteristic curve (AUC) for BRCA1/2 combined mutation prediction to BOADICEA, but performed better than BOADICEA in BRCA1 mutation prediction (AUC 93% vs. 87%). BOADICEA had the best discrimination for BRCA1/2 combined mutation prediction (AUC 87%) in males.
Conclusions
The variation in model performance underscores the need for research on larger Asian cohorts as prediction models, and the possible need for customizing these models for different ethnic groups and genders.
doi:10.1007/s00268-011-1406-y
PMCID: PMC3299960  PMID: 22290208
14.  Alcohol Consumption Over Time and Risk of Lymphoid Malignancies in the California Teachers Study Cohort 
American Journal of Epidemiology  2010;172(12):1373-1383.
Several previous studies found inverse associations between alcohol consumption and risk of non-Hodgkin lymphoma (NHL) and multiple myeloma. However, most studies were retrospective, and few distinguished former drinkers or infrequent drinkers from consistent nondrinkers. Therefore, the authors investigated whether history of alcohol drinking affected risks of NHL and multiple myeloma among 102,721 eligible women in the California Teachers Study, a prospective cohort study in which 496 women were diagnosed with B-cell NHL and 101 were diagnosed with multiple myeloma between 1995–1996 and December 31, 2007. Incidence rate ratios and 95% confidence intervals were estimated using Cox proportional hazards regression. Risk of all types of B-cell NHL combined or multiple myeloma was not associated with self-reported past consumption of alcohol, beer, wine, or liquor at ages 18–22 years, at ages 30–35 years, or during the year before baseline. NHL subtypes were inconsistently associated with alcohol intake. However, women who were former alcohol drinkers at baseline were at elevated risk of overall B-cell NHL (rate ratio = 1.46, 95% confidence interval: 1.08, 1.97) and follicular lymphoma (rate ratio = 1.81, 95% confidence interval: 1.00, 3.28). The higher risk among former drinkers emphasizes the importance of classifying both current and past alcohol consumption and suggests that factors related to quitting drinking, rather than alcohol itself, may increase B-cell NHL risk.
doi:10.1093/aje/kwq309
PMCID: PMC3105275  PMID: 20952595
alcohol drinking; cohort studies; lymphoma, non-Hodgkin; multiple myeloma
15.  Early dissemination of bevacizumab for advanced colorectal cancer: a prospective cohort study 
BMC Cancer  2011;11:354.
Background
We describe early dissemination patterns for first-line bevacizumab given for metastatic colorectal cancer treatment.
Methods
We analyzed patient surveys and medical records for a population-based cohort with metastatic colorectal cancer treated in multiple regions and health systems in the United States (US). Eligible patients were diagnosed with metastatic colorectal cancer and initiated first-line chemotherapy after US Food & Drug Administration (FDA) bevacizumab approval in February 2004. First-line bevacizumab therapy was defined as receiving bevacizumab within 8 weeks of starting chemotherapy for metastatic colorectal cancer. We evaluated factors associated with first-line bevacizumab treatment using logistic regression.
Results
Among 355 patients, 31% received first-line bevacizumab in the two years after FDA approval, including 26% of men, 41% of women, and 16% of those ≥ 75 years. Use rose sharply within 6 months after FDA approval, then plateaued. 20% of patients received bevacizumab in combination with irinotecan; 53% received it with oxaliplatin. Men were less likely than women to receive bevacizumab (adjusted OR 0.55; 95% CI 0.32-0.93; p = 0.026). Patients ≥ 75 years were less likely to receive bevacizumab than patients < 55 years (adjusted OR 0.13; 95% CI 0.04-0.46; p = 0.001).
Conclusions
One-third of eligible metastatic colorectal cancer patients received first-line bevacizumab shortly after FDA approval. Most patients did not receive bevacizumab as part of the regimen used in the pivotal study leading to FDA approval.
doi:10.1186/1471-2407-11-354
PMCID: PMC3174931  PMID: 21846341
16.  Parents’ Ages at Birth and Risk of Adult-onset Hematologic Malignancies Among Female Teachers in California 
American Journal of Epidemiology  2010;171(12):1262-1269.
Although advanced parental age at one's birth has been associated with increased risk of breast and prostate cancers, few studies have examined its effect on adult-onset sporadic hematologic malignancies. The authors examined the association of parents’ ages at women's births with risk of hematologic malignancies among 110,999 eligible women aged 22–84 years recruited into the prospective California Teachers Study. Between 1995 and 2007, 819 women without a family history of hematologic malignancies were diagnosed with incident lymphoma, leukemia (primarily acute myeloid leukemia), or multiple myeloma. Multivariable-adjusted Cox proportional hazards models provided estimates of relative risks and 95% confidence intervals. Paternal age was positively associated with non-Hodgkin lymphoma after adjustment for race and birth order (relative risk for age ≥40 vs. <25 years = 1.51, 95% confidence interval: 1.08, 2.13; P-trend = 0.01). Further adjustment for maternal age did not materially alter the association. By contrast, the elevated non-Hodgkin lymphoma risk associated with advanced maternal age (≥40 years) became null when paternal age was included in the statistical model. No association was observed for acute myeloid leukemia or multiple myeloma. Advanced paternal age may play a role in non-Hodgkin lymphoma etiology. Potential etiologic mechanisms include de novo gene mutations, aberrant paternal gene imprinting, or telomere/telomerase biology.
doi:10.1093/aje/kwq090
PMCID: PMC2915497  PMID: 20507900
cohort studies; hematologic neoplasms; leukemia, myeloid, acute; lymphoma, non-Hodgkin; maternal age; paternal age
17.  A novel de novo BRCA1 mutation in a Chinese woman with early onset breast cancer 
Familial Cancer  2011;10(2):233-237.
Germline mutations in the two breast cancer susceptibility genes, BRCA1 and BRCA2 account for a significant portion of hereditary breast/ovarian cancer. De novo mutations such as multiple exon deletion are rarely occurred in BRCA1 and BRCA2. During our mutation screening for BRCA1/2 genes to Chinese women with risk factors for hereditary breast/ovarian cancer, we identified a novel germline mutation, consisting of a deletion from exons 1 to 12 in BRCA1 gene, in a patient diagnosed with early onset triple negative breast cancer with no family history of cancer. None of her parents carried the mutation and molecular analysis showed that this novel de novo germline mutation resulted in down-regulation of BRCA1 gene expression.
Electronic supplementary material
The online version of this article (doi:10.1007/s10689-011-9429-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s10689-011-9429-y
PMCID: PMC3100488  PMID: 21404118
Breast cancer; BRCA1 gene; De novo mutation; Early onset
18.  Adverse Events Among the Elderly Receiving Chemotherapy for Advanced Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2009;28(4):620-627.
Purpose
To describe chemotherapy use and adverse events (AEs) for advanced-stage, non–small-cell lung cancer (NSCLC) in community practice, including descriptions according to variation by age.
Methods
We interviewed patients with newly diagnosed, stages IIIB and IV NSCLC in the population-based cohort studied by the Cancer Care Outcomes Research and Surveillance Consortium, and we abstracted the patient medical records. AEs were medical events occurring during chemotherapy. Using logistic regression, we assessed the association between age and chemotherapy; with Poisson regression, we estimated event rate ratios and adjusted the analysis for age, sex, ethnicity, radiation therapy, stage, histology, and presence and grade of 27 comorbidities.
Results
Of 1,371 patients, 58% (95% CI, 55% to 61%) received chemotherapy and 35% (95% CI, 32% to 38%) had AEs. After adjustment, 72% (95% CI, 65% to 79%) of those younger than 55 years and 47% (95% CI, 42% to 52%) of those age 75 years and older received chemotherapy. Platinum-based therapies were less common in the older-age groups. Pretreatment medical event rates were 18.6% for patients younger than 55 years and were only 9.2% for those age 75 years and older (adjusted rate ratio, 0.49; 95% CI, 0.26 to 0.91). In contrast, older adults were more likely to have AEs during chemotherapy. The adjusted rate ratios compared with age younger than 55 years were 1.70 for 65- to 74-year-olds (95% CI, 1.19 to 2.43) and 1.34 for those age 75 years and older (95% CI, 0.90 to 2.00).
Conclusion
Older patients who received chemotherapy had fewer pretherapy events than younger patients and were less likely to receive platinum-based regimens. Nevertheless, older patients had more adverse events during chemotherapy, independent of comorbidity. Potential implicit trade-offs between symptom management and treatment toxicity should be made explicit and additionally studied.
doi:10.1200/JCO.2009.23.8485
PMCID: PMC2815997  PMID: 20038726
19.  Assessing interactions between the associations of common genetic susceptibility variants, reproductive history and body mass index with breast cancer risk in the breast cancer association consortium: a combined case-control study 
Milne, Roger L | Gaudet, Mia M | Spurdle, Amanda B | Fasching, Peter A | Couch, Fergus J | Benítez, Javier | Arias Pérez, José Ignacio | Zamora, M Pilar | Malats, Núria | dos Santos Silva, Isabel | Gibson, Lorna J | Fletcher, Olivia | Johnson, Nichola | Anton-Culver, Hoda | Ziogas, Argyrios | Figueroa, Jonine | Brinton, Louise | Sherman, Mark E | Lissowska, Jolanta | Hopper, John L | Dite, Gillian S | Apicella, Carmel | Southey, Melissa C | Sigurdson, Alice J | Linet, Martha S | Schonfeld, Sara J | Freedman, D Michal | Mannermaa, Arto | Kosma, Veli-Matti | Kataja, Vesa | Auvinen, Päivi | Andrulis, Irene L | Glendon, Gord | Knight, Julia A | Weerasooriya, Nayana | Cox, Angela | Reed, Malcolm WR | Cross, Simon S | Dunning, Alison M | Ahmed, Shahana | Shah, Mitul | Brauch, Hiltrud | Ko, Yon-Dschun | Brüning, Thomas | Lambrechts, Diether | Reumers, Joke | Smeets, Ann | Wang-Gohrke, Shan | Hall, Per | Czene, Kamila | Liu, Jianjun | Irwanto, Astrid K | Chenevix-Trench, Georgia | Holland, Helene | Giles, Graham G | Baglietto, Laura | Severi, Gianluca | Bojensen, Stig E | Nordestgaard, Børge G | Flyger, Henrik | John, Esther M | West, Dee W | Whittemore, Alice S | Vachon, Celine | Olson, Janet E | Fredericksen, Zachary | Kosel, Matthew | Hein, Rebecca | Vrieling, Alina | Flesch-Janys, Dieter | Heinz, Judith | Beckmann, Matthias W | Heusinger, Katharina | Ekici, Arif B | Haeberle, Lothar | Humphreys, Manjeet K | Morrison, Jonathan | Easton, Doug F | Pharoah, Paul D | García-Closas, Montserrat | Goode, Ellen L | Chang-Claude, Jenny
Breast Cancer Research : BCR  2010;12(6):R110.
Introduction
Several common breast cancer genetic susceptibility variants have recently been identified. We aimed to determine how these variants combine with a subset of other known risk factors to influence breast cancer risk in white women of European ancestry using case-control studies participating in the Breast Cancer Association Consortium.
Methods
We evaluated two-way interactions between each of age at menarche, ever having had a live birth, number of live births, age at first birth and body mass index (BMI) and each of 12 single nucleotide polymorphisms (SNPs) (10q26-rs2981582 (FGFR2), 8q24-rs13281615, 11p15-rs3817198 (LSP1), 5q11-rs889312 (MAP3K1), 16q12-rs3803662 (TOX3), 2q35-rs13387042, 5p12-rs10941679 (MRPS30), 17q23-rs6504950 (COX11), 3p24-rs4973768 (SLC4A7), CASP8-rs17468277, TGFB1-rs1982073 and ESR1-rs3020314). Interactions were tested for by fitting logistic regression models including per-allele and linear trend main effects for SNPs and risk factors, respectively, and single-parameter interaction terms for linear departure from independent multiplicative effects.
Results
These analyses were applied to data for up to 26,349 invasive breast cancer cases and up to 32,208 controls from 21 case-control studies. No statistical evidence of interaction was observed beyond that expected by chance. Analyses were repeated using data from 11 population-based studies, and results were very similar.
Conclusions
The relative risks for breast cancer associated with the common susceptibility variants identified to date do not appear to vary across women with different reproductive histories or body mass index (BMI). The assumption of multiplicative combined effects for these established genetic and other risk factors in risk prediction models appears justified.
doi:10.1186/bcr2797
PMCID: PMC3046455  PMID: 21194473
20.  Family history of breast cancer and all-cause mortality after breast cancer diagnosis in the Breast Cancer Family Registry 
Background
Although having a family history of breast cancer is a well established breast cancer risk factor, it is not known whether it influences mortality after breast cancer diagnosis.
Methods
Subjects were 4,153 women with first primary incident invasive breast cancer diagnosed between 1991 and 2000, and enrolled in the Breast Cancer Family Registry through population-based sampling in Northern California, USA; Ontario, Canada; and Melbourne and Sydney, Australia. Cases were oversampled for younger age at diagnosis and/or family history of breast cancer. Carriers of germline mutations in BRCA1 or BRCA2 were excluded. Cases and their relatives completed structured questionnaires assessing breast cancer risk factors and family history of cancer. Cases were followed for a median of 6.5 years, during which 725 deaths occurred. Cox proportional hazards regression was used to evaluate associations between family history of breast cancer at the time of diagnosis and risk of all-cause mortality after breast cancer diagnosis, adjusting for established prognostic factors.
Results
The hazard ratios for all-cause mortality were 0.98 (95% confidence interval [CI]=0.84-1.15) for having at least one first- or second-degree relative with breast cancer, and 0.85 (95% CI=0.70-1.02) for having at least one first-degree relative with breast cancer, compared with having no such family history. Estimates did not vary appreciably when stratified by case or tumor characteristics.
Conclusions
Family history of breast cancer is not associated with all-cause mortality after breast cancer diagnosis for women without a known germline mutation in BRCA1 or BRCA2. Therefore, clinical management should not depend on family history of breast cancer.
doi:10.1007/s10549-008-0255-3
PMCID: PMC2728159  PMID: 19034644
breast cancer; survival; mortality; family history
21.  Pre-diagnosis reproductive factors and all-cause mortality for women with breast cancer in the Breast Cancer Family Registry 
Studies have examined the prognostic relevance of reproductive factors prior to breast cancer (BC) diagnosis, but most have been small and overall their findings inconclusive. Associations between reproductive risk factors and all-cause mortality after BC diagnosis were assessed using a population-based cohort of 3,107 women of white European ancestry with invasive BC (1,130 from Melbourne and Sydney, Australia; 1,441 from Ontario, Canada; and 536 from Northern California, USA). During follow-up with a median of 8.5 years, 567 deaths occurred. At recruitment, questionnaire data were collected on oral contraceptive use, number of full-term pregnancies, age at first full-term pregnancy, time from last full-term pregnancy to BC diagnosis, breastfeeding, age at menarche and menopause and menopausal status at BC diagnosis. Hazard ratios (HR) for all-cause mortality were estimated using Cox proportional hazards models with and without adjustment for age at diagnosis, study center, education and body mass index. Compared with nulliparous women, those who had a child up to 2 years, or between 2 to 5 years, prior to their BC diagnosis were more likely to die. The unadjusted HR estimates were 2.75 (95%CI=1.98–3.83, p<0.001) and 2.20 (95%CI=1.65–2.94, p<0.001), respectively, and the adjusted estimates were 2.25 (95%CI=1.59–3.18, p<0.001) and 1.82 (95%CI=1.35–2.46, p<0.001), respectively). When evaluating the prognosis of women recently diagnosed with BC, the time since last full-term pregnancy should be routinely considered along with other established host and tumor prognostic factors, but consideration of other reproductive factors may not be warranted.
doi:10.1158/1055-9965.EPI-08-1014
PMCID: PMC2746957  PMID: 19505912
Breast cancer; survival; reproductive; outcome; pregnancy
22.  Performance of Prediction Models for BRCA Mutation Carriage in Three Racial/Ethnic Groups: Findings from the Northern California Breast Cancer Family Registry 
Purpose
Patients with early-onset breast and/or ovarian cancer frequently wish to know if they inherited a mutation in one of the cancer susceptibility genes, BRCA1 or BRCA2. Accurate carrier prediction models are needed to target costly testing. Two widely used models, BRCAPRO and BOADICEA, were developed using data from non-Hispanic Whites (NHW), but their accuracies have not been evaluated in other racial/ethnic populations.
Methods
We evaluated the BRCAPRO and BOADICEA models in a population-based series of African-American, Hispanic and NHW breast cancer patients tested for BRCA1 and BRCA2 mutations. We assessed model calibration by evaluating observed versus predicted mutations and attribute diagrams, and model discrimination using areas under receiver operating characteristic curves (AUCs).
Results
Both models were well-calibrated within each racial/ethnic group, with some exceptions. BOADICEA over-predicted mutations in African Americans and older NHWs, and BRCAPRO under-predicted in Hispanics. In all racial/ethnic groups, the models over-predicted in cases whose personal and family histories indicated greater than 80% probability of carriage. The two models showed similar discrimination in each racial/ethnic group, discriminating least well in Hispanics. For example, BRCAPRO’s AUCs were 83% (95% confidence interval 63–93%) for NHWs, compared to 74% (59–85%) for African Americans and 58% (45–70%) for Hispanics.
Conclusions
The models’ poor performance for Hispanics may be due to model misspecification in this racial/ethnic group. However, it also may reflect racial/ethnic differences in the distributions of personal and family histories among breast cancer cases in the Northern California population.
doi:10.1158/1055-9965.EPI-08-1090
PMCID: PMC2706699  PMID: 19336551
African-American; BOADICEA; BRCA mutation; BRCAPRO; breast cancer; carrier prediction models; Hispanic; two-stage sampling
23.  Low level alcohol intake, cigarette smoking and risk of breast cancer in Asian-American women 
Studies have shown that breast cancer incidence rates among Asian migrants to the United States approach U.S. incidence rates over several generations, implicating potentially modifiable exposures such as moderate alcohol use that has been linked to excess breast cancer risk in other populations. The goal of this study was to investigate the effect of alcohol intake, primarily low levels, on breast cancer risk in Asian-American women and explore whether smoking and alcohol contributed to the in breast cancer incidence rates observed among Asian migrants to the United States. Study subjects in this population-based case-control study included 597 incident cases of breast cancer of Chinese, Japanese, and Filipino ethnicity living in San Francisco-Oakland, Los Angeles, and Oahu, Hawaii and 966 population controls frequency matched on age, ethnicity, and area of residence. The fraction of smokers and drinkers was significantly higher in women born in Western compared with Eastern countries. However, breast cancer risk was not significantly associated with smoking (odds ratio (OR) = 1.2, 95% confidence interval (95% CI) = 0.9–1.6) or alcohol drinking (OR = 0.9, 95% CI = 0.7–1.1) in this population of low consumers of alcohol (median intake among drinkers in grams per day was 0.48 for cases and 0.40 for controls). These data suggest that low alcohol intake is not related to increased breast cancer risk in Asian-American women and that neither alcohol nor cigarette use contributed to the elevated risks in Asian-American women associated with migration patterns and Westernization.
doi:10.1007/s10549-009-0464-4
PMCID: PMC2808456  PMID: 19597702
Breast cancer; Alcohol drinking; Cigarette smoking; Asian-American; Epidemiology
24.  Lung cancer incidence in never-smokers 
Purpose
Lung cancer is a leading cause of cancer death worldwide. While smoking remains the predominant cause of lung cancer, lung cancer in never-smokers is an increasingly prominent public health issue. Data on this topic, particularly lung cancer incidence rates in never-smokers, however, are limited.
Methods
We review the existing literature on lung cancer incidence and mortality rates among never-smokers and present new data regarding rates in never-smokers from large, population-based cohorts: 1) Nurses’ Health Study, 2) Health Professionals Follow-up Study, 3) California Teachers Study, 4) Multiethnic Cohort Study, 5) Swedish Lung Cancer Register in the Uppsala/Örebro region, and the 6) First National Health and Nutrition Examination Survey Epidemiologic Follow-up Study.
Results
Truncated age-adjusted incidence rates of lung cancer among never-smokers aged 40 to 79 years in these six cohorts ranged from 14.4 to 20.8 per 100,000 person-years in women and 4.8 to 13.7 per 100,000 person-years in men, supporting earlier observations that women are more likely than men to have non-smoking-associated lung cancer. The distinct biology of lung cancer in never-smokers is apparent in differential responses to epidermal growth factor receptor inhibitors and an increased prevalence of adenocarcinoma histology in never-smokers.
Conclusion
Lung cancer in never-smokers is an important public health issue needing further exploration of its incidence patterns, etiology, and biology.
doi:10.1200/JCO.2006.07.2983
PMCID: PMC2764546  PMID: 17290054
25.  Performance of BRCA1/2 Mutation Prediction Models in Asian Americans 
Journal of Clinical Oncology  2008;26(29):4752-4758.
Purpose
There are established differences in breast cancer epidemiology between Asian and white individuals, but little is known about hereditary breast cancer in Asian populations. Although increasing numbers of Asian individuals are clinically tested for BRCA1/2 mutations, it is not known whether computer models that predict mutations work accurately in Asian individuals. We compared the performance in Asian and white individuals of two widely used BRCA1/2 mutation prediction models, BRCAPRO and Myriad II.
Patients and Methods
We evaluated BRCAPRO and Myriad II in 200 Asian individuals and a matched control group of 200 white individuals who were tested for BRCA1/2 mutations at four cancer genetics clinics, by comparing numbers of observed versus predicted mutation carriers and by evaluating area under the receiver operating characteristic curve (AUC) for each model.
Results
BRCAPRO and Myriad II accurately predicted the number of white BRCA1/2 mutation carriers (25 observed v 24 predicted by BRCAPRO; 25 predicted by Myriad II, P ≥ .69), but underpredicted Asian carriers by two-fold (49 observed v 25 predicted by BRCAPRO; 26 predicted by Myriad II; P ≤ 3 × 10−7). For BRCAPRO, this racial difference reflects substantial underprediction of Asian BRCA2 mutation carriers (26 observed v 4 predicted; P = 1 × 10−30); for Myriad II, separate mutation predictions were not available. For both models, AUCs were nonsignificantly lower in Asian than white individuals, suggesting less accurate discrimination between Asian carriers and noncarriers.
Conclusion
Both BRCAPRO and Myriad II underestimated the proportion of BRCA1/2 mutation carriers, and discriminated carriers from noncarriers less well, in Asian compared with white individuals.
doi:10.1200/JCO.2008.16.8310
PMCID: PMC2653135  PMID: 18779604

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