PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2.

BACKGROUND: Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!. METHODS: The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes. RESULTS: All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS. CONCLUSION: Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.

A population-based validation of the prognostic model PREDICT for early breast cancer.

INTRODUCTION: Predict (www.predict.nhs.uk) is a prognostication and treatment benefit tool developed using UK cancer registry data. The aim of this study was to compare the 10-year survival estimates from Predict with observed 10-year outcome from a British Columbia dataset and to compare the estimates with those generated by Adjuvant! (www.adjuvantonline.com). METHOD: The analysis was based on data from 3140 patients with early invasive breast cancer diagnosed in British Columbia, Canada, from 1989-1993. Demographic, pathologic, staging and treatment data were used to predict 10-year overall survival (OS) and breast cancer specific survival (BCSS) using Adjuvant! and Predict models. Predicted outcomes from both models were then compared with observed outcomes. RESULTS: Calibration of both models was excellent. The difference in total number of deaths estimated by Predict was 4.1 percent of observed compared to 0.7 percent for Adjuvant!. The total number of breast cancer specific deaths estimated by Predict was 3.4 percent of observed compared to 6.7 percent for Adjuvant! Both models also discriminate well with similar AUC for Predict and Adjuvant! respectively for both OS (0.709 vs 0.712) and BCSS (0.723 vs 0.727). Neither model performed well in women aged 20-35. CONCLUSION: In summary Predict provided accurate overall and breast cancer specific survival estimates in the British Columbia dataset that are comparable with outcome estimates from Adjuvant! Both models appear well calibrated with similar model discrimination. This study provides further validation of Predict as an effective predictive tool following surgery for invasive breast cancer.

Descriptive epidemiology of skin cancer on Aruba: 1980-1995.

BACKGROUND: An epidemiology unit was established in Aruba in 1994. The primary focus was the development of an infrastructure for both surveillance and health information data systems. This effort resulted in the first analysis of available skin cancer data. METHODS: A retrospective study of cancer and particularly skin cancer cases at the local histopathology laboratory for the period 1980-1995 was performed. All available records with a cancer diagnosis were evaluated. RESULTS: During the study period, an increase in age-adjusted rates for both men and women was observed for basal cell carcinomas and squamous cell carcinomas. No temporal trend was discerned for malignant melanoma or other skin cancers because the numbers of cases were small. Lesions were most often seen on the nose, face, and arm. Dermatologists provided the majority of skin cancer diagnoses and demonstrated the greatest diagnostic accuracy. CONCLUSIONS: The presence of a central histopathology laboratory may provide small island states, like Aruba, with important public health data. This first description of Aruba's skin cancer epidemiology provides information that may be utilized for future public health action.

Cancer in the mothers and siblings of testicular cancer patients.

Some families seem to have an increased risk of several different cancers and a reduced risk of others. Either genetic predisposition or a shared environment may explain this familial clustering, and the type of cause can affect how family members should be advised. We used data from a case-control study to examine the risk of cancer in the mother, sisters and brothers of men with testicular cancer. Our results show a significant relative risk (RR=1.7; 95% confidence interval (CI): 1.05-2.6) of cancer for sisters of testicular cancer patients in comparison with the sisters of controls. When data were combined for brothers and sisters, the RR for all cancers was 1.53 (CI: 1.1-2.3). Despite the limitations of our data, there is evidence for cancer clustering in the families of testicular cancer patients. Unfortunately, the evidence is consistent with either a genetic or environmental etiology.

A computer model to simulate family history of breast/ovarian cancer in BRCA1 mutation carriers.

The BRCA1 gene and its relationship to family history of breast/ovarian cancer are difficult to study in a population because of practical and ethical issues. The paucity of information on BRCA1 in the general population was a major theme in a recent review of genetic testing in Canada. We develop a simulation model to mimic genetic inheritance and cancer incidence in the family of someone with a germline BRCA1 mutation. Given someone's age and family structure, our model simulates his or her family history in three steps: (1) determine which family members have the mutation, (2) determine the ages of family members and (3) determine which family members have breast/ovarian cancer. Each step involves random variation. Some parameters in our model are estimated using local (British Columbia, Canada) population data. The breast/ovarian cancer risk associated with BRCA1 mutations is estimated using values published in the literature. An example is provided to illustrate the model's application. The model incorporates results from genetics, demography and epidemiology, but requires several additional assumptions. Research to address these assumptions is recommended.

Broad-spectrum sunscreen use and the development of new nevi in white children: A randomized controlled trial.

CONTEXT: High nevus density is a risk factor for cutaneous malignant melanoma. Melanocytic nevi originate in childhood and are largely caused by solar exposure. OBJECTIVE: To determine whether use of broad-spectrum, high-sun protection factor (SPF) sunscreen attenuates development of nevi in white children. DESIGN: Randomized trial conducted June 1993 to May 1996. SETTING AND PARTICIPANTS: A total of 458 Vancouver, British Columbia, schoolchildren in grades 1 and 4 were randomized in 1993. After exclusion of nonwhite children and those lost to follow-up or with missing data, 309 children remained for analysis. Each child's nevi were enumerated at the start and end of the study in 1996. INTERVENTION: Parents of children randomly assigned to the treatment group (n=222) received a supply of SPF 30 broad-spectrum sunscreen with directions to apply it to exposed sites when the child was expected to be in the sun for 30 minutes or more. Children randomly assigned to the control group (n=236) received no sunscreen and were given no advice about sunscreen use. MAIN OUTCOME MEASURE: Number of new nevi acquired during the 3 years of the study, compared between treatment and control groups. RESULTS: Children in the sunscreen group developed fewer nevi than did children in the control group (median counts, 24 vs 28; P=.048). A significant interaction was detected between freckling and study group, indicating that sunscreen use was much more important for children with freckles than for children without. Modeling of the data suggests that freckled children assigned to a broad-spectrum sunscreen intervention would develop 30% to 40% fewer new nevi than freckled children assigned to the control group. CONCLUSIONS: Our data indicate that broad-spectrum sunscreens may attenuate the number of nevi in white children, especially if they have freckles. JAMA. 2000.

Childhood cancer in the offspring of male sawmill workers occupationally exposed to chlorophenate fungicides.

The objective of this study was to determine whether paternal occupational exposure to chlorophenol fungicides and their dioxin contaminants is associated with childhood cancer in the offspring of sawmill workers. We used data from 23,829 British Columbian sawmill workers employed for at least 1 continuous year between 1950 and 1985 in 11 sawmills that used chlorophenates. Probabilistic linkage of the sawmill worker cohort to the provincial marriage and birth files produced an offspring cohort of 19,674 children born at least 1 year after the initiation of employment in the period 1952-1988. We then linked the offspring cohort to the British Columbia Cancer Registry. We included all malignancies in cases younger than 20 years of age that appeared on the cancer registry between 1969 and 1993. We calculated standardized incidence ratios (SIRs) using the British Columbia population as a reference. A nested case-control analysis assessed the effects of paternal cumulative exposure and windows of exposure on the risk of developing cancer in the offspring. We identified 40 cases of cancer during 259,919 person-years of follow-up. The all-cancer SIR was 1.0 [95% confidence interval (CI), 0.7-1.4]; the SIR for leukemia was 1.0 (CI, 0.5-1.8); and the SIR for brain cancer was 1.3 (CI, 0.6-2.5). The nested case-control analysis showed slightly increased risks in the highest categories of chlorophenol exposure, although none was statistically significant. Our analyses provide little evidence to support a relationship between the risk of childhood cancer and paternal occupational exposure to chlorophenate fungicides in British Columbian sawmills.

Sunlight exposure, hat use, and squamous cell skin cancer on the head and neck.

BACKGROUND: Sunlight is the environmental exposure most often associated with squamous cell cancer (SCC) of the skin. It can be difficult to quantify the sunlight exposure of the skin because of the different types of clothing that may be worn. The problem is simplified for studies of SCC on the skin of the head and neck, where a hat is the only type of clothing that needs to be considered. OBJECTIVE: The purpose of the study was to determine the risk for SCC of sunlight exposure on the skin of the head and neck, and the protective effect, if any, associated with wearing a hat. METHODS: A case-control study of squamous cell carcinoma of the skin was conducted amongst men in the province of Alberta, Canada. Analysis was restricted to only those cases where cancer occurred on the head or neck, and their age and sex matched controls. RESULTS: Ethnicity, non-sunexposed skin colour, and hair colour each significantly affected the SCC risk. An increased SCC risk was also associated with greater cumulative sunlight exposure and with sunburns experienced during the ages 5 to 15 years. The risk associated with sunlight exposure was significantly elevated in men who reported that they had always or usually worn a hat. CONCLUSION: As observed in previous studies, SCC on the skin of the head and neck is associated with host pigmentation, sunburns occurring in childhood, and sunlight exposure during adulthood. The risk observed for wearing a hat may be due to bias or confounding; however, hats remain an unproven means of protection against SCC on the skin of the head and neck.

Effect of acetylsalicylic acid on radiation and cosmetic results after conservative surgery for early breast cancer: a randomized trial.

BACKGROUND AND PURPOSE: Acetylsalicylic acid (ASA) can reduce the incidence of stroke and myocardial infarction by inhibiting platelet-fibrin thrombi in small blood vessels. To determine if ASA could reduce late effects of radiation therapy mediated by damage to small blood vessels, a prospective, placebo-controlled, double-blind trial was conducted in women with early breast cancer, receiving radiotherapy to the conserved breast. MATERIALS AND METHODS: Cosmetic outcome and late radiotherapy effects were recorded prospectively for 186 women with T1 or T2, pathologically node-negative breast cancer treated with breast conservation and randomized to receive ASA (325 mg daily) or placebo for 1 year from the start of radiation therapy. Radiation was a tangent pair to the breast alone delivering a modal dose of 44 Gy in 16 daily fractions in 22-25 days. RESULTS: Median follow-up is 6.5 years. The use of ASA has not had any effect on the acute (erythema, edema or discomfort) or late (induration, telangiectasia) effects of radiotherapy (all P > 0.10), the patients' or physicians' assessment of the cosmetic outcome (all P > 0.25) or rates of breast recurrence (P > 0.25). CONCLUSION: ASA cannot be recommended to improve the outcome of radiotherapy complementing breast conserving surgery.

Late cosmetic results of short fractionation for breast conservation.

BACKGROUND AND PURPOSE: The number of fractions of radiation therapy (RT) used after breast conserving surgery varies widely and accounts for a significant proportion of the workload in a modern radiotherapy department. Internationally, 'standard' therapy ranges from 3 to 7 weeks of daily treatment with or without a boost. Short RT schedules have the attraction of reducing workload but raise concern about an increased risk of late effects and poorer cosmetic outcome. MATERIALS AND METHODS: In a randomized trial, 186 women with T1 or T2, pathologically node-negative breast cancer had cosmetic and various normal tissue effects data collected prospectively. The breast RT prescription was 44 Gy in 16 daily fractions to a tangent pair. RESULTS: Median follow-up is 6.7 years. Actuarial 5-year breast recurrence was 6%. Overall cosmetic results at 5 years were good or excellent in 89% and 96% as reported by physicians and patients, respectively, and were stable between 2 and 5 years. Breast discomfort, erythema, edema and induration were related to both surgery and RT. At 5 years, 20% had breast discomfort, 18% had induration, 6% had erythema and 3% had some degree of breast edema. Fewer patients had these effects at 5 years than immediately after primary surgery. The presence of induration prior to starting RT was associated with a greater likelihood of breast induration 3 or more years following RT (P = 0.02). Thirteen percent of patients, generally those with large breasts, developed mild inframammary telangiectasia by 5 years. CONCLUSIONS: Results are comparable to those reported from centers employing more conventional fractionation. Short fractionation produces acceptable cosmetic results for the majority of women if there are no contraindications to RT and in the absence of significant post-operative breast induration.

Chemical exposures, medical history, and risk of squamous and basal cell carcinoma of the skin.

The role of non-sunlight-related risk factors for squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) of the skin was investigated in a population-based, case-control study conducted among males in Alberta, Canada. In total, 180 SCC and 226 BCC cases and 406 randomly selected male controls, frequency matched by 5-year age groups to the cases, were interviewed by trained personnel using a standardized etiological questionnaire. Data were analyzed using conditional logistic regression techniques. After adjustment for age, skin and hair color, mother's ethnic origin, and sunlight exposure, elevated risks for SCC were seen in subjects exposed to insecticides [odds ratio (OR), highest tertile, 2.8; 95% confidence interval (CI), 1.4-5.6], herbicides (OR, highest tertile, 3.9; 95% CI, 2.2-6.9), and fungicides and seed treatments (OR, highest tertile, 2.4; 95% CI, 1.4-4.0), as well petroleum products, grease, and several other exposures. Elevated risks of BCC were seen in subjects exposed to fiberglass dust (OR, 2.0; 95% CI, 1.0-3.9) and dry cleaning agents (OR, 4.6 95% CI, 1.1-19.7). Prior nondiagnostic X-ray treatment for skin conditions increased risk of both cancers. Although solar UV radiation is known to be the major environmental exposure causing nonmelanocytic skin cancer, results of this study suggest that nonsolar factors may also be important.

Non-solar ultraviolet radiation and the risk of basal and squamous cell skin cancer.

A case-control study of non-melanocytic skin cancer was conducted among men in the province of Alberta, Canada. Two hundred and twenty-six cases of basal cell carcinoma (BCC), 180 cases of squamous cell carcinoma (SCC) and 406 age-matched controls provided information concerning skin pigmentation, occupational history, recreational activity, exposure to sunlight and sources of non-solar ultraviolet radiation (NSUVR) and other potential risk factors. Our analyses show no evidence of elevated risk for BCC or SCC among subjects exposed to various types of NSUVR. This is in opposition to studies of melanoma that have shown elevated risks for exposure to fluorescent lighting, sunlamps and sunbeds.

Sunlight exposure, pigmentary factors, and risk of nonmelanocytic skin cancer. I. Basal cell carcinoma.

BACKGROUND AND DESIGN: Basal cell carcinoma (BCC) of the skin is the most common neoplasm in white populations, and solar radiation is generally accepted to be the dominant environmental risk factor for this disease. However, little information is available on the nature of the relationship between BCC and sunlight. The purpose of this study was to evaluate the nature of the relationship between sunlight exposure, pigmentary factors, and BCC of the skin. A population-based case-control study of 226 male patients with BCC diagnosed from January 1, 1983, through December 31, 1984, and 406 randomly selected male control subjects was conducted in Alberta, Canada. The study was conducted using a standardized questionnaire, administered in person by trained interviewers. Data were analyzed using conditional logistic regression methods. RESULTS: After controlling for other host and pigmentary factors, the risk of BCC was increased in subjects with light skin color and those who freckled in childhood. A history of severe sunburn in childhood also increased risk. Subjects of southern European ethnic origin were at significantly lower risk of BCC. Surprisingly, no association was seen between mean annual cumulative summer sunlight exposure and risk of BCC. A significantly increased risk of BCC was seen in subjects with increased recreational sunlight exposure in adolescence and childhood (age, 0 to 19 years), although an inverse relationship was seen with lifetime recreation exposure. The relationship with childhood sun exposure was most pronounced among sun-sensitive subjects whose skin tended to burn rather than tan in the sun. CONCLUSIONS: The lack of association between cumulative sun exposure and BCC contradicts conventional wisdom about the cause of this tumor, and the increased risk with sun exposure at age 0 to 19 years suggests that childhood and adolescence may be critical periods for establishing adult risk for BCC.

Sunlight exposure, pigmentation factors, and risk of nonmelanocytic skin cancer. II. Squamous cell carcinoma.

INTRODUCTION AND DESIGN: Squamous cell carcinoma of the skin (SCC), a common cancer in white populations, is related to sunshine exposure; however, relatively little information is available on how timing and character of exposure affect the relationship. The purpose of this study was to investigate the nature of the relationship of SCC to individual solar UV exposure after control for phenotype and pigmentary factors. All newly diagnosed cases of SCC were in men aged 25 through 79 years, ascertained in the province of Alberta from January 1, 1983, through December 31, 1984, who were approached for participation; 80% completed a standardized etiologic interview that was conducted in their homes by a trained interviewer. Control subjects were chosen at random from the Alberta Health Care Insurance Plan subscribers list, matched only by sex (male) and age (within a 5-year age group). The response rate among controls was 71%. RESULTS: Subjects with pale skin and red hair had an elevated risk of SCC. Subjects whose mother was of southern European ancestry had a reduced risk of SCC. After accounting for pigmentary factors, no association was seen between risk of SCC and cumulative lifetime sun exposure. However, a strong trend toward increasing risk was seen with increasing chronic occupational sun exposure in the 10 years prior to diagnosis. CONCLUSION: The results suggest that recent sun exposure (in the 10 years prior to diagnosis) may be important in accounting for individual risk of SCC.

Adjuvant systemic therapy and survival after breast cancer.

BACKGROUND AND METHODS: We examined the effect of adjuvant systemic therapy on survival after breast cancer among the residents of the Canadian province of British Columbia. Data on survival were collected for all women in whom breast cancer was diagnosed in British Columbia during each of three calendar years chosen to represent different province-wide treatment recommendations: 1974, when no adjuvant systemic therapy was recommended; 1980, when adjuvant chemotherapy was recommended only for premenopausal women with node-positive disease; and 1984, when adjuvant chemotherapy was also recommended for premenopausal women with node-negative disease and lymphatic, vascular, or neural invasion and tamoxifen was recommended for postmenopausal women with involved lymph nodes or lymphatic, vascular, or neural invasion unless their tumors were negative for estrogen receptors. RESULTS: For women less than 50 years of age, disease-specific survival at seven years (i.e., with censoring of data on women who died from causes other than breast cancer) improved from 65.2 to 76.3 percent between 1974 and 1984 (P = 0.008), and overall survival improved from 64.8 to 74.6 percent (P = 0.02). For women from 50 through 89 years of age, disease-specific survival at seven years improved from 62.5 to 70.4 percent between 1980 and 1984 (P = 0.001), and overall survival improved from 53.9 to 58.3 percent (P = 0.05). The timing of the improvements in survival correlated with the introduction of adjuvant systemic therapy in each group. CONCLUSIONS: Survival among women with breast cancer improved significantly in a geographically defined population during the period when adjuvant systemic therapy became widely used.

Shell Growth and Viability Differences Between the Marine Mussels Mytilus edulis (L.), Mytilus galloprovincialis (Lmk.), and Their Hybrids From Two Sympatric Populations in S.W. England.

Mussels were collected at high and low shore locations from two Mytilus edulis/Mytilus galloprovincialis populations, Croyde Bay and Whitsand Bay, in S.W. England. Genotype-dependent length-at-age values were determined. At high and low shore locations at both sites, M. edulis-like mussels had significantly smaller length-at-age values than M. galloprovincialis-like and putative F1 hybrid individuals. The putative F1 hybrids exhibited length-at-age values between those of the parental types, but much closer to those of M. galloprovincialis-like rather than M. edulis-like individuals. Genotype frequencies as a function of age were determined and relative viability coefficients estimated from comparisons of genotype frequencies of young versus old mussels. At high and low shore locations at both sites, the relative viability coefficient of M. galloprovincialis-like individuals was greater than that of M. edulis-like mussels. Putative F1 hybrids at both sites had relative viability coefficients intermediate between those of the parental types. These data indicate that the length-dependent variation in allozyme frequencies that characterizes sympatric populations can be attributed to a small but significant genotype-dependent difference in length-at-age values, but mostly to large and highly significant differences in viability.

Survey of lead, cadmium and fluoride in human milk and correlation of levels with environmental and food factors.

Lead, cadmium and fluoride were determined in 210 samples of human milk and the mean and median levels and ranges found were 1.04 and 0.55 ng/g (range less than 0.05-15.8 ng/g) for lead, 0.08 and 0.06 ng/g (range less than 0.002-4.05 ng/g) for cadmium, and 7.08 and less than 4 ng/g (range less than 2-97 ng/g) for fluoride. For mothers taking no fluoride supplements and living in communities with fluoride (1 microgram/g) in the drinking-water, the mean fluoride level was 9.8 ng/g. Where no fluoride was present in the drinking-water, the mean level was 4.4 ng/g. Geometric means for all non-zero lead, cadmium and fluoride concentrations were 0.566, 0.063 and 12 ng/g, respectively. Statistical correlation of levels with some dietary and environmental factors showed that lead levels were most strongly correlated with the age of the house (P less than 0.001), with maternal exposure to heavy traffic for more than 5 yr (P = 0.011), and with coffee consumption (P = 0.034). Fluoride levels correlated strongly (P = 0.007) with the presence of fluoride in the drinking-water. Cadmium levels correlated strongly with exposure to cigarette smoke (P = 0.005 if the mother smoked and P = 0.003 if the father smoked and the mother did not smoke).