The origins of breast cancer associated with mammographic density: a testable biological hypothesis.

BACKGROUND: Our purpose is to develop a testable biological hypothesis to explain the known increased risk of breast cancer associated with extensive percent mammographic density (PMD), and to reconcile the apparent paradox that although PMD decreases with increasing age, breast cancer incidence increases. METHODS: We used the Moolgavkar model of carcinogenesis as a framework to examine the known biological properties of the breast tissue components associated with PMD that includes epithelium and stroma, in relation to the development of breast cancer. In this model, normal epithelial cells undergo a mutation to become intermediate cells, which, after further mutation, become malignant cells. A clone of such cells grows to become a tumor. The model also incorporates changes with age in the number of susceptible epithelial cells associated with menarche, parity, and menopause. We used measurements of the radiological properties of breast tissue in 4454 healthy subjects aged from 15 to 80+ years to estimate cumulative exposure to PMD (CBD) in the population, and we examined the association of CBD with the age-incidence curve of breast cancer in the population. RESULTS: Extensive PMD is associated with a greater number of breast epithelial cells, lobules, and fibroblasts, and greater amounts of collagen and extracellular matrix. The known biological properties of these tissue components may, singly or in combination, promote the acquisition of mutations by breast epithelial cells specified by the Moolgavkar model, and the subsequent growth of a clone of malignant cells to form a tumor. We also show that estimated CBD in the population from ages 15 to 80+ years is closely associated with the age-incidence curve of breast cancer in the population. CONCLUSIONS: These findings are consistent with the hypothesis that the biological properties of the breast tissue components associated with PMD increase the probability of the transition of normal epithelium to malignant cells, and that the accumulation of mutations with CBD may influence the age-incidence curve of breast cancer. This hypothesis gives rise to several testable predictions.

Socio-economic deprivation: a significant determinant affecting stage of oral cancer diagnosis and survival.

BACKGROUND: Many factors contribute to socioeconomic status (SES), yet in most survival studies only income is used as a measure for determining SES. We used a complex, composite, census-based metric for socioeconomic deprivation to better distinguish individuals with lower SES and assess its impact on survival and staging trends of oral cancers. METHODS: Oropharyngeal (OPC) and oral cavity cancer (OCC) cases were identified from the British Columbia cancer registry between 1981-2009 and placed into affluent and deprived neighborhoods using postal codes linked to VANDIX (a composite SES index based on 7 census variables encompassing income, housing, family structure, education, and employment). Stage and cancer-specific survival rates were examined by sex, SES, and time period. RESULTS: Approximately 50 % of OPC and OCC cases of both sexes resided in SES deprived neighborhoods. Numbers of cases have increased in recent years for all but OCC in men. The deprivation gap in survival between affluent and deprived neighborhoods widened in recent years for OPC and OCC in men, while decreasing for OPC and increasing slightly for OCC in women. Greater proportions of OCC cases were diagnosed at later stage disease for both sexes residing in deprived neighborhoods, a trend not seen for OPC. CONCLUSION: SES remains a significant independent determinant of survival for both OPC and OCC when using a composite metric for SES. OPC survival rates among men have improved, albeit at slower rates in deprived communities. OCC screening programs need to be targeted towards SES-deprived neighborhoods where greater proportions of cases were diagnosed at a later stage and survival rates have significantly worsened in both sexes.

Mammographic features associated with interval breast cancers in screening programs.

INTRODUCTION: Percent mammographic density (PMD) is associated with an increased risk of interval breast cancer in screening programs, as are younger age, pre-menopausal status, lower body mass index and hormone therapy. These factors are also associated with variations in PMD. We have examined whether these variables influence the relative frequency of interval and screen-detected breast cancer, independently or through their associations with PMD. We also examined the association of tumor size with PMD and dense and non-dense areas in screen-detected and interval breast cancers. METHODS: We used data from three case-control studies nested in screened populations. Interval breast cancer was defined as invasive breast cancer detected within 12 months of a negative mammogram. We used a computer-assisted method of measuring the dense and total areas of breast tissue in the first (baseline) mammogram taken at entry to screening programs and calculated the non-dense area and PMD. We compared these mammographic features, and other risk factors at baseline, in women with screen-detected (n = 718) and interval breast cancer (n = 125). RESULTS: In multi-variable analysis, the baseline characteristics of younger age, greater dense area and smaller non-dense mammographic area were significantly associated with interval breast cancer compared to screen-detected breast cancer. Compared to screen-detected breast cancers, interval cancers had a larger maximum tumor diameter within each mammographic measure. CONCLUSIONS: Age and the dense and non-dense areas in the baseline mammogram were independently associated with interval breast cancers in screening programs. These results suggest that decreased detection of cancers caused by the area of dense tissue, and more rapid growth associated with a smaller non-dense area, may both contribute to risk of interval breast cancer. Tailoring screening to individual mammographic characteristics at baseline may reduce the number of interval cancers.

Cost-effectiveness of annual versus biennial screening mammography for women with high mammographic breast density.

OBJECTIVES: The sensitivity of screening mammography is much lower among women who have dense breast tissue, compared with women who have largely fatty breasts, and they are also at much higher risk of developing the disease. Increasing mammography screening frequency from biennially to annually has been suggested as a policy option to address the elevated risk in this population. The purpose of this study was to assess the cost-effectiveness of annual versus biennial screening mammography among women aged 50-79 with dense breast tissue. METHODS: A Markov model was constructed based on screening, diagnostic, and treatment pathways for the population-based screening and cancer care programme in British Columbia, Canada. Model probabilities and screening costs were calculated from screening programme data. Costs for breast cancer treatment were calculated from treatment data, and utility values were obtained from the literature. Incremental cost-effectiveness was expressed as cost per quality adjusted life year (QALY), and probabilistic sensitivity analysis was conducted. RESULTS: Compared with biennial screening, annual screening generated an additional 0.0014 QALYs (95% CI: -0.0480-0.0359) at a cost of $819 ($ = Canadian dollars) per patient (95% CI: 506-1185), resulting in an incremental cost effectiveness ratio of $565,912/QALY. Annual screening had a 37.5% probability of being cost-effective at a willingness-to-pay threshold of $100,000/QALY. CONCLUSION: There is considerable uncertainty about the incremental cost-effectiveness of annual mammography. Further research on the comparative effectiveness of screening strategies for women with high mammographic breast density is warranted, particularly as digital mammography and density measurement become more widespread, before cost-effectiveness can be reevaluated.

Population-based incidence trends of oropharyngeal and oral cavity cancers by sex among the poorest and underprivileged populations.

BACKGROUND: Oral cancer is an important health issue, with changing incidence in many countries. Oropharyngeal cancer (OPC, in tonsil and oropharygeal areas) is increasing, while oral cavity cancer (OCC, other sites in the mouth) is decreasing. There is the need to identify high risk groups and communities for further study and intervention. The objective of this study was to determine how the incidence of OPC and OCC varied by neighbourhood socioeconomic status (SES) in British Columbia (BC), including the magnitude of any inequalities and temporal trends. METHODS: ICDO-3 codes were used to identify OPC and OCC cases in the BC Cancer Registry from 1981-2010. Cases were categorized by postal codes into SES quintiles (q1-q5) using VANDIX, which is a census-based, multivariate weighted index based on neighbourhood average household income, housing tenure, educational attainment, employment and family structure. Age-standardized incidence rates were determined for OPC and OCC by sex and SES quintiles and temporal trends were then examined. RESULTS: Incidence rates are increasing in both men and women for OPC, and decreasing in men and increasing in women for OCC. This change is not linear or proportionate between different SES quintiles, for there is a sharp and dramatic increase in incidence according to the deprivation status of the neighbourhood. The highest incidence rates in men for both OPC and OCC were observed in the most deprived SES quintile (q5), at 1.7 times and 2.2 times higher, respectively, than men in the least deprived quintile (q1). For OPC, the age-adjusted incidence rates significantly increased in all SES quintiles with the highest increase observed in the most deprived quintile (q5). Likewise, the highest incidence rates for both OPC and OCC in women were observed in the most deprived SES quintile (q5), at 2.1 times and 1.8 times higher, respectively, than women in the least deprived quintile (q1). CONCLUSION: We report on SES disparities in oral cancer, emphasizing the need for community-based interventions that address access to medical care and the distribution of educational and health promotion resources among the most SES deprived communities in British Columbia.

Mammographic density phenotypes and risk of breast cancer: a meta-analysis.

BACKGROUND: Fibroglandular breast tissue appears dense on mammogram, whereas fat appears nondense. It is unclear whether absolute or percentage dense area more strongly predicts breast cancer risk and whether absolute nondense area is independently associated with risk. METHODS: We conducted a meta-analysis of 13 case-control studies providing results from logistic regressions for associations between one standard deviation (SD) increments in mammographic density phenotypes and breast cancer risk. We used random-effects models to calculate pooled odds ratios and 95% confidence intervals (CIs). All tests were two-sided with P less than .05 considered to be statistically significant. RESULTS: Among premenopausal women (n = 1776 case patients; n = 2834 control subjects), summary odds ratios were 1.37 (95% CI = 1.29 to 1.47) for absolute dense area, 0.78 (95% CI = 0.71 to 0.86) for absolute nondense area, and 1.52 (95% CI = 1.39 to 1.66) for percentage dense area when pooling estimates adjusted for age, body mass index, and parity. Corresponding odds ratios among postmenopausal women (n = 6643 case patients; n = 11187 control subjects) were 1.38 (95% CI = 1.31 to 1.44), 0.79 (95% CI = 0.73 to 0.85), and 1.53 (95% CI = 1.44 to 1.64). After additional adjustment for absolute dense area, associations between absolute nondense area and breast cancer became attenuated or null in several studies and summary odds ratios became 0.82 (95% CI = 0.71 to 0.94; P heterogeneity = .02) for premenopausal and 0.85 (95% CI = 0.75 to 0.96; P heterogeneity < .01) for postmenopausal women. CONCLUSIONS: The results suggest that percentage dense area is a stronger breast cancer risk factor than absolute dense area. Absolute nondense area was inversely associated with breast cancer risk, but it is unclear whether the association is independent of absolute dense area.

Genetic polymorphisms at TIMP3 are associated with survival of adenocarcinoma of the gastroesophageal junction.

The poor survival of adenocarcinomas of the gastroesophageal junction (GEJ) makes them clinically important. Discovery of host genetic factors that affect outcome may guide more individualized treatment. This study tests whether constitutional genetic variants in matrix metalloproteinases (MMP) and tissue inhibitors of metalloproteinases (TIMP) genes are associated with outcome of GEJ adenocarcinoma. Single nucleotide polymorphisms (SNPs) at four TIMP (TIMP1-4) and three MMP genes (MMP2, MMP7 and MMP9) were genotyped in DNA samples from a prospective cohort of patients with primary adenocarcinoma of the GEJ admitted to the British Columbia Cancer Agency. Cox proportional hazards regression, with adjustment for patient, disease and treatment variables, was used to estimate the association of SNPs with survival. Genotypes for 85 samples and 48 SNPs were analyzed. Four SNPs across TIMP3, (rs130274, rs715572, rs1962223 and rs5754312) were associated with survival. Interaction analyses revealed that the survival associations with rs715572 and rs5754312 are specific and significant for 5FU+cisplatin treated patients. Sanger sequencing of the TIMP3 coding and promoter regions revealed an additional SNP, rs9862, also associated with survival. TIMP3 genetic variants are associated with survival and may be potentially useful in optimizing treatment strategies for individual patients.

Gender- and ethnicity-specific survival trends of oral cavity and oropharyngeal cancers in British Columbia.

INTRODUCTION: A shift in etiology of oral cancers has been associated with a rise in incidence for oropharyngeal cancers (OPC) and decrease for oral cavity cancers (OCC); however, there is limited information about population-based survival trends. We report epidemiological transitions in survival for both OPC and OCC from a population-based cancer registry, focusing upon gender and ethnic differences. METHODS: All primary oral cancers diagnosed between 1980 and 2005 were identified from the British Columbia Cancer Registry and regrouped into OPC and OCC by topographical subsites, time periods (1980-1993 and 1994-2005), stage at diagnosis, and ethnicity. Cases were then followed up to December 2009. Using gender-based analysis, actuarial life tables were used to calculate survival rates, which were compared using Kaplan-Meier curves and log-rank tests. RESULTS: For OPC, survival improved, significant for tonsil and base of tongue in men and marginally significant at base of tongue in women. This improvement occurred in spite of an increase in late-stage diagnosis for OPC in both genders. Interestingly, there was no difference in survival for early- and late-stage disease for OPC in men. For OCC, there was a decrease in survival for floor of mouth cancers in both genders although significant in women only. South Asians had the poorest survival for OCC in both genders. CONCLUSION: Survival for OPC improved, more dramatically in men than women, in spite of late-stage diagnosis and increasing nodal involvement. Given the poor survival rates and need for early detection, targeted OCC screening programs are required for South Asians.

Mammographic density, response to hormones, and breast cancer risk.

BACKGROUND: Percent mammographic density (PMD) is a strong risk factor for breast cancer that changes in response to changes in hormone exposure. We have examined the magnitude of the association of hormone exposure with PMD according to subsequent breast cancer risk. METHODS: In three case-control studies, with 1,164 patient cases and 1,155 controls nested in cohorts of women screened with mammography, we examined the association of PMD measured in the baseline mammogram with risk of breast cancer in the following 1 to 8 years (mean, 3 years), according to use of oral contraceptives (OCs) in premenopausal women, menopause, and hormone therapy (HT) in postmenopausal women. All statistical comparisons are adjusted for age and other risk factors. RESULTS: In premenopausal women who later developed breast cancer (patient cases), PMD was 5.3% greater in past users of OCs than in nonusers (P = .06). In controls, OC users had 2% less density than nonusers (P = .44; test for interaction P = .06). The difference in PMD between premenopausal and postmenopausal women for patient cases was 8.5% (P < .001) and for controls, 3.9% (P = .01; test for interaction P = .03). In postmenopausal women, PMD was 6% greater in patients who used HT than in never users (P < .001). Controls who used HT had 1.6% greater PMD (P = .26) than never users (test for interaction P = .001). Differences in PMD resulted mainly from differences in the dense area of the mammogram. CONCLUSION: Differences in PMD associated with differences in hormone exposure were greater in women who later developed breast cancer than in controls in each of the hormone exposures examined.

A randomized trial of dietary intervention for breast cancer prevention.

Epidemiologic data and animal experiments suggest that dietary fat may influence risk of breast cancer. To determine whether intervention with a low-fat, high-carbohydrate diet would reduce breast cancer incidence in women at increased risk of the disease, we carried out a randomized controlled trial in Canada. We recruited 4,690 women with extensive mammographic density and randomized them to an intervention group or a comparison group. The intervention group received intensive dietary counseling to reduce fat intake to a target of 15% of calories and increase carbohydrate to 65% of calories. Dietary intakes were assessed throughout using food records. Subjects were followed for at least 7 years and for an average of 10 years. The main outcome was invasive breast cancer. Percentage of calories from fat in the intervention group decreased from 30% at baseline to 20% after randomization and remained 9% to 10% lower than the comparison group throughout. There were 118 invasive breast cancers in the intervention group and 102 in the comparison group [adjusted hazard ratio = 1.19 (95% CI: 0.91-1.55)]. Analysis of food records showed that fat intake at baseline and after randomization was not associated with total breast cancer incidence. Greater weight and lower carbohydrate intake at baseline and after randomization were associated with an increased risk of estrogen receptor (ER)-positive breast cancer. Our findings suggest that a sustained reduction in dietary fat intake did not reduce risk of breast cancer in women with extensive mammographic density. Weight and carbohydrate intakes were associated with risk of ER-positive breast cancer.

Trends in oropharyngeal and oral cavity cancer incidence of human papillomavirus (HPV)-related and HPV-unrelated sites in a multicultural population: the British Columbia experience.

BACKGROUND: There is a growing recognition of the involvement of human papilloma virus infection in the etiology of head and neck cancers at some sites, mainly the base of the tongue, tonsils, and other oropharynx (hereafter termed oropharyngeal cancer). Other oral sites (hereafter termed oral cavity cancer [OCC]) show a stronger association with tobacco and alcohol. Little is known about the ethnic variation in incidence for these cancers. This study determined incidence rates of OCC and oropharyngeal cancer among South Asian, Chinese, and the general population in British Columbia, Canada. METHODS: Patients with OCC and oropharyngeal cancer diagnosed from 1980 to 2006 were identified through the British Columbia cancer registry, and surname lists were used to establish ethnicity. Age-adjusted incidence rates were determined for these cancers by sex, topographical site, and ethnicity, and temporal trends were examined. RESULTS: Age-adjusted incidence rates have been decreasing for OCC and increasing for oropharyngeal cancer in the general population for both sexes, with men having higher incidence rates than women. Ethnic differences were found, with the highest age-adjusted incidence rates for OCC for men in South Asians and for women in Chinese, and with the highest age-adjusted incidence rates for oropharyngeal cancer for men in Chinese and for women in the general population. Differences were also found for OCC topographical sites by sex and ethnicity. CONCLUSIONS: The incidence of oropharyngeal cancer has now surpassed OCC in the British Columbia male population. Ethnic minorities are at higher risk than the general population for both OCC and oropharyngeal cancer for men, and for OCC for women.

Areca nut and betel quid chewing among South Asian immigrants to Western countries and its implications for oral cancer screening.

The South Asian community is the largest and one of the fastest growing minority groups in Canada, according to the 2006 census. These immigrants bring to Canada talents and skills that can promote Canada's economy and cultural diversity, but they also bring lifestyle habits that may lead to serious health issues. Chewing areca nut and betel quid (paan, with and without tobacco) is a known risk factor for oral cancer. This habit is common in the Indo-Canadian population, as evidenced by its sales in local Indian markets and restaurants. In this article, we present an overview of the sociocultural beliefs, knowledge and practices regarding betel quid/areca nut chewing, and discuss its implications for oral cancer screening among this immigrant population.

Feasibility of self-collection of specimens for human papillomavirus testing in hard-to-reach women.

To study the feasibility of self-collected specimens for testing human papillomavirus (HPV) status among hard-to-reach women, outreach nurses recruited women in women's centres, shelters and alleys in Vancouver's Downtown Eastside. Of the 151 participants for whom samples were available, 43 (28.5%) tested positive for high-risk HPV. Outreach nurses were able to recontact 81.4% of the participants who tested positive and referred them for further testing. About 14% (21/151) of participants had never received a Papanicolaou smear in British Columbia, as compared with 8.3% (608/7336) of women in the BC general population (p < 0.05). This difference suggests that self-collection of specimens for HPV testing is a feasible method to reach women who have not previously participated in cervical cancer screening programs.

Mammographic density and the risk and detection of breast cancer.

BACKGROUND: Extensive mammographic density is associated with an increased risk of breast cancer and makes the detection of cancer by mammography difficult, but the influence of density on risk according to method of cancer detection is unknown. METHODS: We carried out three nested case-control studies in screened populations with 1112 matched case-control pairs. We examined the association of the measured percentage of density in the baseline mammogram with risk of breast cancer, according to method of cancer detection, time since the initiation of screening, and age. RESULTS: As compared with women with density in less than 10% of the mammogram, women with density in 75% or more had an increased risk of breast cancer (odds ratio, 4.7; 95% confidence interval [CI], 3.0 to 7.4), whether detected by screening (odds ratio, 3.5; 95% CI, 2.0 to 6.2) or less than 12 months after a negative screening examination (odds ratio, 17.8; 95% CI, 4.8 to 65.9). Increased risk of breast cancer, whether detected by screening or other means, persisted for at least 8 years after study entry and was greater in younger than in older women. For women younger than the median age of 56 years, 26% of all breast cancers and 50% of cancers detected less than 12 months after a negative screening test were attributable to density in 50% or more of the mammogram. CONCLUSIONS: Extensive mammographic density is strongly associated with the risk of breast cancer detected by screening or between screening tests. A substantial fraction of breast cancers can be attributed to this risk factor.

Body size, mammographic density, and breast cancer risk.

BACKGROUND: Greater weight and body mass index (BMI) are negatively correlated with mammographic density, a strong risk factor for breast cancer, and are associated with an increased risk of breast cancer in postmenopausal women, but with a reduced risk in premenopausal women. We have examined the associations of body size and mammographic density on breast cancer risk. METHOD: We examined the associations of body size and the percentage of mammographic density at baseline with subsequent risk of breast cancer among 1,114 matched case-control pairs identified from three screening programs. The effect of each factor on risk of breast cancer was examined before and after adjustment for the other, using logistic regression. RESULTS: In all subjects, before adjustment for mammographic density, breast cancer risk in the highest quintile of BMI, compared with the lowest, was 1.04 [95% confidence interval (CI), 0.8-1.4]. BMI was associated positively with breast cancer risk in postmenopausal women, and negatively in premenopausal women. After adjustment for density, the risk associated with BMI in all subjects increased to 1.60 (95% CI, 1.2-2.2), and was positive in both menopausal groups. Adjustment for BMI increased breast cancer risk in women with 75% or greater density, compared with 0%, increased from 4.25 (95% CI, 1.6-11.1) to 5.86 (95% CI, 2.2-15.6). CONCLUSION: BMI and mammographic density are independent risk factors for breast cancer, and likely to operate through different pathways. The strong negative correlated between them will lead to underestimation of the effects on risk of either pathway if confounding is not controlled.

Mammographic density as a surrogate marker for the effects of hormone therapy on risk of breast cancer.

BACKGROUND: Some types of hormone therapy increase both risk of breast cancer and mammographic density, a risk factor for the disease, suggesting that mammographic density may be a surrogate marker for the effects of hormones on risk of breast cancer. This research was undertaken to determine whether the effect of hormone therapy on breast cancer risk is mediated by its effect on mammographic density. METHODS: Individually matched cases and controls from three nested case-control studies in breast screening populations were studied. Cases had developed invasive breast cancer at least 12 months after the initial screen. Information was collected on hormone use and other risk factors at the time of the baseline mammogram, and percent density was measured by a computer-assisted method. RESULTS: There were 1,748 postmenopausal women, of whom 426 (24.4%) were using hormones at the time of their initial screening mammogram. Current use of hormone therapy was associated with an increased risk of breast cancer (odds ratio, 1.26; 95% confidence interval, 1.0-1.6) that was little changed by adjustment for percent density in the baseline mammogram (odds ratio, 1.19; 95% confidence interval, 0.9-1.5). Percent density in the baseline mammogram was among cases greater in current users of hormones that in never-users (difference = 5.0%, P < 0.001), but the difference was smaller and nonsignificant in controls (difference = 1.6%, P = 0.3). CONCLUSION: Although the effects of hormone therapy on mammographic density were greater in cases than controls, we did not find evidence that these effects were causally related to risk of breast cancer.

Toluidine blue staining identifies high-risk primary oral premalignant lesions with poor outcome.

There is a pressing need for the development of visual aids that will facilitate the detection of oral premalignant lesions (OPLs) with a high-risk of progression. Preliminary data suggest that toluidine blue stain may be preferentially retained by OPLs with high-risk molecular clones. In this study, we monitored OPLs from 100 patients without any history of oral cancer for an average of 44 months in order to evaluate the association of toluidine blue status with clinicopathologic risk factors, molecular patterns (microsatellite analysis on seven chromosome arms: 3p, 9p, 4q, 8p, 11q, 13q, and 17p) and outcome. Toluidine blue-positive staining correlated with clinicopathologic risk factors and high-risk molecular risk patterns. Significantly, a >6-fold elevation in cancer risk was observed for toluidine blue-positive lesions, with positive retention of the dye present in 12 of the 15 lesions that later progressed to cancer (P = 0.0008). This association of toluidine blue status with risk factors and outcome was evident even when the analysis was restricted to OPLs with low-grade or no dysplasia. Our results suggest the potential use of toluidine blue in identifying high-risk OPLs.

Translation challenges of cross-cultural research and program development.

PURPOSE: Translation of cross-cultural surveys and programs pose unique challenges. This paper identifies potential pitfalls of current translation guidelines and presents solutions employed for one project. METHODS: We followed current guidelines for translation of survey instruments including forward and back translation, and also utilized qualitative methods to decenter survey questions. In addition, our project adapted translation by committee with a core translation team of bilingual/trilingual investigators and staff members with diverse skills and complementary degrees of proficiency in the languages and dialects of interest. PRINCIPAL FINDINGS: This approach resulted with a mechanism for emic equivalence, identifying and resolving dialectic and sociolinguistic concerns, selecting appropriate written Chinese styles, and providing appropriate linguistic training to interviewers. CONCLUSIONS: An understanding of the history of a people and its ramifications for the language are important components of the translation process. Allocation of appropriate time, resources, and skills are critical to the successful development of valid cross-cultural survey instruments and effective programs.