Consumer and clinician perspectives on personalising breast cancer prevention information.

BACKGROUND: Personalised prevention of breast cancer has focused on women at very high risk, yet most breast cancers occur in women at average, or moderately increased risk (≤moderate risk). OBJECTIVES: To determine; 1) interest of women at ≤ moderate risk (consumers) in personalised information about breast cancer risk; 2) familial cancer clinicians' (FCCs) perspective on managing women at ≤ moderate risk, and; 3) both consumers' and FCCs reactions to iPrevent, a personalised breast cancer risk assessment and risk management decision support tool. METHODS: Seven focus groups on breast cancer risk were conducted with 49 participants; 27 consumers and 22 FCCs. Data were analysed thematically. RESULTS: Consumers reported some misconceptions, low trust in primary care practitioners for breast cancer prevention advice and frustration that they often lacked tailored advice about breast cancer risk. They expressed interest in receiving personalised risk information using iPrevent. FCCs reported an inadequate workforce to advise women at ≤ moderate risk and reacted positively to the potential of iPrevent to assist. CONCLUSIONS: While highlighting a potential role for iPrevent, several outstanding issues remain. For personalised prevention of breast cancer to extend beyond women at high risk, we must harness women's interest in receiving tailored information about breast cancer prevention and identify a workforce willing to advise women.

Prospective validation of the breast cancer risk prediction model BOADICEA and a batch-mode version BOADICEACentre.

BACKGROUND: Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm (BOADICEA) is a risk prediction algorithm that can be used to compute estimates of age-specific risk of breast cancer. It is uncertain whether BOADICEA performs adequately for populations outside the United Kingdom. METHODS: Using a batch mode version of BOADICEA that we developed (BOADICEACentre), we calculated the cumulative 10-year invasive breast cancer risk for 4176 Australian women of European ancestry unaffected at baseline from 1601 case and control families in the Australian Breast Cancer Family Registry. Based on 115 incident breast cancers, we investigated calibration, discrimination (using receiver-operating characteristic (ROC) curves) and accuracy at the individual level. RESULTS: The ratio of expected to observed number of breast cancers was 0.92 (95% confidence interval (CI) 0.76-1.10). The E/O ratios by subgroups of the participant's relationship to the index case and by the reported number of affected relatives ranged between 0.83 and 0.98 and all 95% CIs included 1.00. The area under the ROC curve was 0.70 (95% CI 0.66-0.75) and there was no evidence of systematic under- or over-dispersion (P=0.2). CONCLUSION: BOADICEA is well calibrated for Australian women, and had good discrimination and accuracy at the individual level.

Prospective study of breast cancer risk for mutation negative women from BRCA1 or BRCA2 mutation positive families.

Published studies have reached contradictory conclusions regarding breast cancer risk for women from families segregating a BRCA1 or BRCA2 mutation who do not carry the family-specific mutation. Accurate estimation of breast cancer risk is crucial for appropriate counselling regarding risk management. The aim of this study is to prospectively assess whether breast cancer risk for mutation negative women from families segregating BRCA1 or BRCA2 mutations is greater than for women in the general population. Eligible women were 722 first-, second- and third-degree relatives of a BRCA1 or BRCA2 mutation carrier from 224 mutation positive (128 BRCA1, 96 BRCA2) families, had no personal cancer history at baseline, and had been tested and found not to carry the family-specific mutation. Self-reported family history of cancer, preventive interventions and verified cancer diagnoses were collected at baseline, and every 3 years thereafter. Median follow-up was 6.1 years (range 0.1-12.4 years). Time at risk of breast cancer was censored at cancer diagnosis or risk-reducing surgery. Standardised incidence ratios (SIR) were estimated by comparing observed to population incidences of invasive breast cancer using Australian Cancer Incidence and Mortality Books. Six cases of invasive breast cancer were observed. The estimated SIRs were 1.14 (95% CI: 0.51-2.53) overall (n = 722), 1.29 (95% CI: 0.58-2.88) when restricted to first- and second-degree relatives of an affected mutation carrier (n = 442) and 0.48 (95% CI: 0.12-1.93) when restricted to those with no family history of breast cancer in the non-mutation carrying parental lineage (n = 424). There was no evidence that mutation negative women from families segregating BRCA1 or BRCA2 mutations are at increased risk of breast cancer. Despite this being the largest prospective cohort to assess this issue, moderately increased breast cancer risk (2-fold) cannot be ruled out.

Adequacy of risk-reducing gynaecologic surgery in BRCA1 or BRCA2 mutation carriers and other women at high risk of pelvic serous cancer.

The aim of this study was to describe the type of risk-reducing gynaecologic surgery (RRGS) and the extent of pathological evaluation being undertaken for Australasian women at high familial risk of pelvic serous cancer. Surgical and pathology reports were reviewed for women with BRCA1/BRCA2 mutations, or a family history of breast and ovarian cancer, who underwent RRGS between 1998 and 2008. "Adequate" surgery was defined as complete removal of all ovarian and extra-uterine fallopian tube tissue. "Adequate" pathology was defined as paraffin embedding of all removed ovarian and tubal tissue. Predictors of adequacy were assessed using logistic regression. There were 201 women, including 173 mutation carriers, who underwent RRGS. Of these, 91% had adequate surgery and 23% had adequate pathology. Independent predictors of adequate surgery were surgeon type (OR = 20; 95% CI 2-167; P = 0.005 for gynaecologic oncologists versus general gynaecologists), more recent surgery (OR = 1.33/year; 95% CI 1.07-1.67; P = 0.012) and younger patient age (OR = 0.93/year of age; 95% CI 0.87-0.99; P = 0.028). Independent predictors of adequate pathology were more recent surgery (OR = 1.26/year; 95% CI 1.06-1.49; P = 0.008) and surgeon type (OR = 3.1; 95% CI 1.4-6.7; P = 0.004 for gynaecologic oncologists versus general gynaecologists). Four serous ovarian cancers and one endometrioid endometrial cancer were detected during surgery or pathological examination. In conclusion Australasian women attending a specialist gynaecologic oncologist for RRGS are most likely to have adequate surgery and pathological examination. Additional education of clinicians and consumers is needed to ensure optimal surgery and pathology in these women.

Predictors of the use of complementary and alternative medicine (CAM) by women at high risk for breast cancer.

BACKGROUND: Few data exist regarding the use of complementary and alternative medicine (CAM) by unaffected women at high risk of breast cancer. METHODS: Self-reported CAM use by women from multiple-case breast cancer families was obtained by questionnaire. Factors associated with CAM use were assessed using multiple logistic regression. RESULTS: Of 892 women, 55% (n=489) used CAM, 6% (n=53) specifically to prevent cancer. CAM use was independently associated with tertiary education level (OR 2.56, 95% CI 1.83-3.58, p<0.001), greater physical activity (OR 1.05 per hour of physical activity/week, 95% CI 1.00-1.10, p=0.049), greater anxiety (OR 1.92, 95% CI 1.16-3.16, p=0.01), not currently smoking (OR 0.64, 95% CI 0.42-0.97, p=0.037) and lower perceived BC risk (OR 0.82 per 20 percentage points, 95% CI 0.72-0.94, p=0.005). CONCLUSIONS: The majority of high-risk women use CAM, but mostly for reasons other than cancer prevention. Most predictors of CAM use are consistent with the limited literature for women at high risk for cancer.

Risk-reducing surgery, screening and chemoprevention practices of BRCA1 and BRCA2 mutation carriers: a prospective cohort study.

This study prospectively evaluated the utilization of cancer risk management strategies in a multi-institutional cohort of BRCA1 and BRCA2 mutation carriers using a self-report questionnaire. Of 142 unaffected female mutation carriers, 70 (49%) had elected to receive their mutation result. Of those who knew their mutation result, 11% underwent bilateral mastectomy (BM), 29% had bilateral oophorectomy (BO), 78% performed regular breast self-examination (BSE), and 80%, 89%, 67%, and 0% had at least annual clinical breast examination (CBE), mammography, transvaginal ultrasound (TVU), and CA125, respectively. A further 20%, 7%, 0%, 21%, and 75%, respectively, reported never having had these tests. For women who elected not to receive their mutation result, 0% underwent BM, 6% underwent BO, and 77%, 42%, 56%, 7%, and 0% had regular BSE, CBE, mammography, TVU, and CA125, respectively. Only one woman used chemoprevention outside a clinical trial. Uptake of prophylactic surgery and screening was associated with knowing one's mutation status (for all behaviors except BSE), age (for BO and CBE) and residence (for mammography). In this cohort, the minority of mutation carriers utilized risk-reducing surgery or chemoprevention and a substantial minority were not undergoing regular cancer-screening tests.

The influence of increasing dialysis treatment time and reducing dry weight on blood pressure control in hemodialysis patients: a prospective study.

A good blood pressure control can be achieved with long hemodialysis sessions (dialysis center of Tassin, France). However, it is not well known whether a higher dialysis dose or a lower dry weight is responsible for this phenomenon. In a preliminary study, 21 hypertensive dialysis patients, dialyzed three times a week for 3-5 h, were randomized into three groups during a 3-month study period. In 6 patients, the dialysis treatment time was increased by 2 h, and the dry weight was gradually decreased (group 1). In 7 patients the dialysis treatment time was increased by 2 h without a change in dry weight (group 2). In 8 patients the dry weight was gradually lowered without changing the dialysis treatment time (group 3). Before and after the study, cardiac index and left ventricular mass index (echocardiography) and forearm vascular resistance (strain gauge plethysmography) were determined on a middialytic day. The blood pressure was assessed by 48-hour ambulatory monitoring. The antihypertensive medication was reduced when the postdialytic blood pressure became <130/80 mm Hg. The dry weight was reduced by 2.6 +/- 1.4 kg in group 1 and by 2.3 +/- 0.8 kg in group 3 (p < 0.05). The number of classes of antihypertensive medication was reduced from 3.3 to 1.8 in group 1 (NS), from 2.4 to 1.7 in group 2 (NS), and from 3.1 to 1.3 in group 3 (p < 0.05). The dose of the remaining antihypertensive drugs was reduced by 50% in group 1 (p < 0.05), by 32% in group 2 (NS), and by 72.2% in group 3 (p < 0.05). The interdialytic systolic blood pressure decreased significantly after increasing the dialysis time without changing the dry weight (group 2: 7 +/- 5 mm Hg; p < 0.05). The systolic blood pressure was also lower in the other patients groups: group 1: 13 +/- 26 mm Hg, group 3 : 7 +/- 16 mm Hg (NS). The pulse pressure decreased significantly in group 2 (7 +/- 5 mm Hg; p < 0.05) and in group 3 (6 +/- 7 mm Hg; p < 0.05) and tended to decrease in group 1 (11 +/- 12 mm Hg; p = 0.08). The diastolic blood pressure and the day-night blood pressure difference did not change significantly, nor did cardiac index and left ventricular mass index. The forearm vascular resistance tended to decrease in the patients on long dialysis sessions. This preliminary study suggests that the dialysis treatment time might have an independent beneficial effect on blood pressure control.

Screening for ovarian cancer using serum CA125 and vaginal examination: report on 2550 females.

This study was undertaken to assess the effectiveness of using serum CA125 and vaginal examination as a screening test for ovarian cancer in apparently healthy females. Two thousand five hundred and fifty healthy females aged 40 and over were recruited to participate in a screening study involving a questionnaire, serum CA125 measurement and vaginal examination. Females with either an elevated CA125 level or abnormal vaginal examination had a pelvic ultrasound performed as a secondary procedure. The positive predictive values of an elevated serum CA125 level, and a combination of CA125 level measurement and vaginal examination for ovarian cancer, were 1/100 and 1/3, respectively. The specificities of serum CA125 levels, vaginal examination and both in combination were 96.1%, 98.5% and 99.9%, respectively. In postmenopausal females the positive predictive values were improved with CA125 measurement alone, giving a positive predictive value of 1/24. Seventeen females underwent operative procedure as a result of the screening-only one of these was for an ovarian cancer. The combination of serum CA125 measurement and vaginal examination is not an effective screening test in the general population, although in postmenopausal females it does achieve acceptable specificities and positive predictive values.

Patterns of inheritance of ovarian cancer. An analysis from an ovarian cancer screening program.

BACKGROUND: A variety of inheritance patterns for familial ovarian cancer have been proposed including an autosomal dominant inheritance, a breast-ovary cancer syndrome and Lynch Cancer Family Syndrome (involving breast, bowel, ovary, and endometrial cancers). METHODS: Women participating in an ovarian cancer screening study completed a questionnaire concerning their family history of ovarian and other malignancies (in particular breast, bowel, and endometrial cancer). Confirmation of the diagnosis was sought when there was uncertainty. RESULTS: Two hundred forty women with a first-degree relative with ovarian cancer participated in the study. Nine percent of these women (representing 13 families) gave a definite history of two or more affected first-degree relatives. Two families had a pedigree consistent with an autosomal dominant inheritance. A breast-ovary cancer family and a Lynch cancer family syndrome were suspected in one family each, although 34% of all women gave a history of at least one other first-degree relative with either breast, bowel, or endometrial cancer. CONCLUSIONS: Only a small number of women with a family history of ovarian cancer fit into the recognized hereditary patterns. Difficulty in recognizing the inheritance patterns and the lack of definitive genetic markers poses problems in providing adequate counseling regarding screening and prophylactic oophorectomy.

Increased pulmonary response to inhaled endotoxin in lactating rats.

An important aspect of risk assessment is identification of subpopulations particularly susceptible to the effects of inhaled pollutants. The present study examined whether female rats were more sensitive during lactation to the acute pulmonary injury produced by inhaled endotoxin. Lactating and age-matched virgin female rats were exposed to aerosols of saline or endotoxin for 3 h and lavaged at 24 h after exposure. No significant differences in lactate dehydrogenase, beta-glucuronidase, total protein, and total cell and PMN counts were observed between virgin and lactating rats after exposure to saline. Each marker of pulmonary injury except beta-glucuronidase was 1.5- to 3-fold greater in lactating than in virgin female rats exposed to 29.6 micrograms/m3 endotoxin. PMNs (6-fold), total cell counts, and protein were also significantly increased (p < 0.05) in lactating rats exposed to 1.3 micrograms/m3 endotoxin, a concentration reported to occur in a number of agricultural settings. These results demonstrate that the physiologic state of lactation is associated with an increased sensitivity to the acute pulmonary injury produced by inhaled endotoxin and are consistent with previous work demonstrating a similar increased sensitivity to ozone exposure. The possibility of a similar pattern of enhanced response in analogous groups of humans merits examination.

The effect of the menstrual cycle on serum CA 125 levels: a population study.

OBJECTIVE: Our objective was to assess the effect of the menstrual cycle on CA 125 levels in a population study. STUDY DESIGN: Serum CA 125 was measured in 1478 women, with day of menstrual cycle noted in 574 women. Repeat examination was performed in women with elevated results, and 40 of these women were tracked by weekly examination of CA 125 levels. RESULTS: A significant difference was demonstrated when midcycle samples were compared with day 1 and day 28 samples (p < 0.05). In spite of this significance the difference was not clinically useful. Elevated serum CA 125 (> 35 U/ml) levels were present in 77 (5.2%) of the premenopausal women. A significant variation was demonstrable with higher CA 125 levels about the time of menstruation in 29 of the 40 women tracked. CONCLUSION: This study suggests that in the population as a whole the effect of the menstrual cycle on serum CA 125 is not clinically significant, but single elevated levels in an individual may represent menstrual fluctuation.

Enhanced inflammatory response to acute ozone exposure in rats during pregnancy and lactation.

Experimental evidence from several studies suggests that pregnant animals and women are more susceptible to oxidants than nonpregnant controls. In the study reported here, we sought to determine whether pregnant rats are more sensitive than age-matched virgin females to the inflammatory effects of ozone, a gaseous oxidant of considerable environmental significance. Rats at several stages of pregnancy and lactation, as well as age-matched virgin females, were exposed to 1 ppm ozone for 6 hr. Controls were sham-exposed to pure air for an identical period of time. Bronchoalveolar lavage was performed 24 hr after the beginning of exposure, and components of the lavage fluid considered to be indicators of inflammation were used to assess the severity of pulmonary inflammation. The results of this experiment showed that significantly enhanced sensitivity to ozone-induced pulmonary inflammation develops during pregnancy, is maintained during lactation, and disappears following lactation. Implicit in this pattern of differential sensitivity in rats is the possibility of a similar pattern of inflammatory response in analogous groups of humans as well as the potential for applicability to other oxidative pollutants.

Factors influencing serum CA 125 levels in normal women.

Serum CA 125 levels were studied in 2544 healthy women. Menopausal status and a history of hysterectomy were both highly significant influences on the CA 125 level (P less than .0001 for both factors). A history of hormone replacement therapy was also highly significant in reducing CA 125 levels (P = .002) in postmenopausal women. Other factors such as parity, history of unilateral oophorectomy or oral contraceptive usage, or family history of ovarian cancer were not significant influences when analysis of covariance was performed. When premenopausal women were assessed separately, age was significant (P = .04). The number of years since menopause did not influence CA 125 levels. Both hysterectomy and menopausal status have a clear effect on serum CA 125 levels and must be considered if serum CA 125 is to be used as a screening test.

Age-dependence of responses to acute ozone exposure in rats.

Previous work from this laboratory demonstrated that neonatal rats and postweanling rabbits are more sensitive to ozone-induced stimulation of pulmonary arachidonic acid (AA) metabolism than are young adults (Fundam. Appl. Toxicol. 15, 779.) In the study reported here, we have extended our initial investigation to include the influence of animal age on temporal aspects of pulmonary AA metabolism and several other responses to brief exposures to 1 ppm ozone. Rats of discrete ages ranging from 13 days to 16 weeks were exposed to 1 ppm ozone or to air for 2, 4, or 6 hr. Immediately following exposure the lungs were lavaged with six consecutive volumes of phosphate-buffered saline and the acellular fluid from the first lavage volume recovered was analyzed for its content of prostaglandin E2 (PGE2), protein, and lactate dehydrogenase. Leukocytes recovered by lavage were quantitated and characterized by viability and percentage of polymorphonuclear (PMN) cells. Several lines of evidence verified that PGE2 was produced by the lung as a consequence of ozone exposure and that its concentration in the fluid from the first lavage was a reasonably good index of pulmonary AA metabolism to prostanoids. We also demonstrated that the lavage process itself stimulates the lung, resulting in increased AA metabolism to prostanoids that were recovered in the second and following lavage volumes. The time course of PGE2 production by the ozone-exposed lung varied considerably with animal age. Neonatal rats 13 days of age were the most sensitive to ozone stimulation. At 2 hr of exposure, PGE2 concentration in the first lung lavage of these animals peaked at values approximately two orders of magnitude above controls and then decreased sharply with continued exposure. Adults and older neonates (18 days of age) were much less responsive to 2-hr exposures; however, continued exposure of these rats for up to 6 hr resulted in increasing PGE2 concentration in the first lung lavage. Other responses showed various degree of age dependence. The percentage of lavaged leukocytes that were nonviable (i.e., trypan blue-positive) showed a strong inverse correlation with animal age. In 13-day-old rats that were exposed for 6 hr, the percentage of dead leukocytes reached nearly 50%. In addition, sheets or clumps of dead cells that were judged to be epithelial cells were lavaged from these animals. Conversely, 16-week-old adult males exposed to ozone for 6 hr showed little evidence of damage to cells of the respiratory tract.(ABSTRACT TRUNCATED AT 400 WORDS)

Age-dependent effect of ozone on pulmonary eicosanoid metabolism in rabbits and rats.

Acute exposures to ozone have previously been shown to cause quantitative changes in the spectrum of arachidonic acid (AA) metabolites in lung lavage fluid. Since age appears to be an important variable in the toxicity of inhaled ozone, we investigated its effect on ozone-induced changes in pulmonary eicosanoid metabolism. Rats and rabbits ranging in age from neonates to young adults were exposed either to air or to 1 ppm ozone for 2 hr. Lung lavage fluid was collected within 1 hr following exposure and analyzed for its content of selected eicosanoids. In both species, there was a pronounced effect of age on ozone-induced pulmonary eicosanoid metabolism. Ozone-exposed animals at the youngest ages examined had severalfold greater amounts of two products of the cyclooxygenase pathway, prostaglandin E2 (PGE2) and prostaglandin F2 alpha (PGF2 alpha), than did age-matched controls. This effect lessened and eventually disappeared as the animals grew toward adulthood. In rabbits, ozone also induced increases in 6-keto-prostaglandin F1 alpha and thromboxane B2, but these changes were of lesser magnitude and evident only in the youngest rabbits exposed. There was no observed effect of ozone on lung lavage content of leukothriene B4. Indices of nonspecific pulmonary damage, i.e., protein concentration in lung lavage fluid and total number and viability of lavaged lung cells, were affected by ozone exposure, but not in an age-dependent manner that correlated with changes in pulmonary eicosanoid metabolism. In vitro ozone exposure of lung macrophages from naive rabbits of the same age range as those exposed in vivo demonstrated that ozone is capable of stimulating the elaboration of PGF2 alpha and especially PGE2. However, the increase in lavage fluid PGE2 and PGF2 alpha caused by ozone inhalation could not be attributed to macrophage metabolism conclusively since elaboration of PGE2 and PGF2 alpha by cultured macrophages was not enhanced by prior in vivo ozone exposure. In an ancillary study it was shown that 15-hydroxyprostaglandin dehydrogenase (PGDH) activity in rabbit lung homogenates was not affected by prior exposure to ozone, indicating that the increase in lung lavage fluid eicosanoids that occurred in these animals could not be explained by inhibition of PGDH.