Jane Warwick

The Gothenburg Breast Screening Trial

Although there is evidence for a reduction in breast carcinoma mortality with mammographic screening, some doubts have been expressed, and there is still uncertainty regarding the age specific effects.

Tamoxifen-Induced Reduction in Mammographic Density and Breast Cancer Risk Reduction: A Nested Case–Control Study

BACKGROUND Mammographic breast density is a strong risk factor for breast cancer. Tamoxifen, which reduces the risk of breast cancer in women at high risk, also reduces mammographic breast density. However, it is not known if tamoxifen-induced reductions in breast density can be used to identify women who will benefit the most from prophylactic treatment with this drug. METHODS We conducted a nested case-control study within the first International Breast Cancer Intervention Study, a randomized prevention trial of tamoxifen vs placebo. Mammographic breast density was assessed visually and expressed as a percentage of the total breast area in 5% increments. Case subjects were 123 women diagnosed with breast cancer at or after their first follow-up mammogram, which took place 12-18 months after trial entry, and control subjects were 942 women without breast cancer. Multivariable logistic regression was used to adjust for other risk factors. All statistical tests were two-sided. RESULTS In the tamoxifen arm, 46% of women had a 10% or greater reduction in breast density at their 12- to 18-month mammogram. Compared with all women in the placebo group, women in the tamoxifen group who experienced a 10% or greater reduction in breast density had 63% reduction in breast cancer risk (odds ratio = 0.37, 95% confidence interval = 0.20 to 0.69, P = .002), whereas those who took tamoxifen but experienced less than a 10% reduction in breast density had no risk reduction (odds ratio = 1.13, 95% confidence interval = 0.72 to 1.77, P = .60). In the placebo arm, there was no statistically significant difference in breast cancer risk between subjects who experienced less than a 10% reduction in mammographic density and subjects who experienced a greater reduction. CONCLUSION The 12- to 18-month change in mammographic breast density is an excellent predictor of response to tamoxifen in the preventive setting.

Treatment of post-transplant premalignant skin disease: a randomized intrapatient comparative study of 5-fluorouracil cream and topical photodynamic therapy.

Background  Organ transplant recipients (OTR) are at high risk of developing nonmelanoma skin cancer and premalignant epidermal dysplasia (carcinoma in situ/ Bowens disease and actinic keratoses). Epidermal dysplasia is often widespread and there are few comparative studies of available treatments.

Correcting for Lead Time and Length Bias in Estimating the Effect of Screen Detection on Cancer Survival

Determination of survival time among persons with screen-detected cancer is subject to lead time and length biases. The authors propose a simple correction for lead time, assuming an exponential distribution of the preclinical screen-detectable period. Assuming two latent categories of tumors, one of which is more prone to screen detection and correspondingly less prone to death from the cancer in question, the authors have developed a strategy of sensitivity analysis for various magnitudes of length bias. Here they demonstrate these methods using a series of 25,962 breast cancer cases (1988-2004) from the West Midlands, United Kingdom.

Parathyroid hormone related protein and skeletal morbidity in breast cancer

The presence of parathyroid hormone related protein (PTHRP) in human breast cancers has been assessed by immunohistochemistry using a polyclonal antiserum specific for the mid-region sequence 37-67 in an immunoperoxidase technique. The primary tumours from 155 normocalcaemic, consecutive women with early breast cancer who had been followed up for a minimum of 5 years were assessed. Dewaxed paraffin sections of formalin fixed tissue was used throughout. Positive PTHRP staining was detected in 56% of the cancers and was unrelated to standard prognostic factors, recurrence or survival. However, PTHRP positivity was related to the development of bone metastases (P less than or equal to 0.03) and hypercalcaemic episodes. PTHRP is implicated as the humoral factor responsible for hypercalcaemia associated with breast cancer and tumour positivity may be a useful predictor of which women will develop bone metastases.

Azathioprine treatment photosensitizes human skin to ultraviolet A radiation

Background  Azathioprine is used to treat a variety of conditions and to prevent graft rejection in organ transplant recipients (OTRs).

Overdiagnosis in screening: is the increase in breast cancer incidence rates a cause for concern?

OBJECTIVES To estimate the degree of overdiagnosis of breast cancer in a mammographic screening programme. SETTING A mammography service screening programme in Florence, Italy. METHODS We studied the incidence of breast cancer in Florence between 1990 and 1999, following the introduction of screening in 1990. Incidence of breast cancer in this period was compared with incidence between 1985 and 1989, before the introduction of screening. It was necessary to estimate the number of cancers that would have arisen in the absence of screening, but after the end of followup (31 December 1999), so that these were not misclassified as overdiagnosed tumours. Around 60,000 women aged 50-69 were invited for screening during the period of study. RESULTS There were 2780 breast cancers diagnosed during the period of study (2626 were invasive). There was no significant evidence of overdiagnosis of invasive cancers. When invasive and in situ cancers were considered together, around 5% of cases were overdiagnosed. CONCLUSIONS There is a small amount of overdiagnosis of ductal carcinoma in situ in mammography screening; however, this should not deter women from being screened. Training and practice in mammographic screening should emphasise detection of small, invasive lesions. Research into the natural history and treatment of the disease should aim at minimising overtreatment of those in situ lesions that are less likely to progress to invasive disease.

Molecular subtyping of DCIS: heterogeneity of breast cancer reflected in pre-invasive disease

Background:Molecular profiling has identified at least four subtypes of invasive breast carcinoma, which exhibit distinct clinical behaviour. There is good evidence now that DCIS represents the non-obligate precursor to invasive breast cancer and therefore it should be possible to identify similar molecular subtypes at this stage. In addition to a limited five-marker system to identify molecular subtypes in invasive breast cancer, it is evident that other biological molecules may identify distinct tumour subsets, though this has not been formally evaluated in DCIS.Methods:Tissue microarrays were constructed for 188 cases of DCIS. Immunohistochemistry was performed to examine the expression patterns of oestrogen receptor (ER), progesterone receptor (PR), Her2, EGFR, cytokeratin (CK) 5/6, CK14, CK17, CK18, β4-integrin, β6-integrin, p53, SMA, maspin, Bcl-2, topoisomerase IIα and P-cadherin. Hierarchical clustering analysis was undertaken to identify any natural groupings, and the findings were validated in an independent sample series.Results:Each of the intrinsic molecular subtypes described for invasive breast cancer can be identified in DCIS, though there are differences in the relative frequency of subgroups, in particular, the triple negative and basal-like phenotype is very uncommon in DCIS. Hierarchical cluster analysis identified three main subtypes of DCIS determined largely by ER, PR, Her2 and Bcl-2, and this classification is related to conventional prognostic indicators. These subtypes were confirmed in an analysis on independent series of DCIS cases.Conclusion:This study indicates that DCIS may be classified in a similar manner to invasive breast cancer, and determining the relative frequency of different subtypes in DCIS and invasive disease may shed light on factors determining disease progression. It also demonstrates a role for Bcl-2 in classifying DCIS, which has recently been identified in invasive breast cancer.

Clinical and epidemiological issues in mammographic density

High mammographic density is associated with an increased risk of breast cancer, and of all known breast cancer risk factors has the greatest attributable fraction. Mammographic density is estimated to account for 16% of all breast cancers, but can be altered by endogenous and exogenous hormonal factors, and generally declines with age. Confounding factors such as age, parity, menopausal status and BMI make the interpretation of mammographic density particularly challenging. Furthermore, none of the established means of measuring mammographic density are entirely satisfactory because they are time consuming or subjective. It is hoped that by adding information regarding mammographic density to existing models of breast cancer risk assessment, the accuracy of individual risk assessments can be improved. Although mammographic density has clearly been shown to be a powerful factor for predicting the risk of developing breast cancer, its potential role in assessing hormonal preventive regimens and helping to tailor screening algorithms cannot be fully realized until we have more-precise, simple and reproducible density measures.

All-cause mortality among breast cancer patients in a screening trial: support for breast cancer mortality as an end point

BACKGROUND: It has recently been suggested that all-cause mortality is a more appropriate end point than disease specific mortality in cancer screening trials, and that disease specific mortality is biased in favour of screening. This suggestion is based partly on supposed inconsistencies between all-cause mortality results and disease specific results in cancer screening trials, and alleged increases in deaths from causes other than breast cancer among breast cancer cases diagnosed among women invited to screening. METHODS: We used data from the Swedish Two-County Trial of mammographic screening for breast cancer, in which 77 080 women were randomised to an invitation to screening and 55 985 to no invitation. We estimated relative risks (RRs) (invited v control) of death from breast cancer, death from other causes within the breast cancer cases, and death from all causes within the breast cancer cases. RRs were adjusted for age and took account of the longer follow up of breast cancer cases in the invited group due to lead time. RESULTS: There was a significant 31% reduction in breast cancer mortality in the invited group (RR 0.69, 95% confidence interval (CI) 0.58–0.80; p<0.001). There was no significant increase in deaths from other causes among breast cancer cases in the invited group (RR 1.12, 95% CI 0.96–1.31; p=0.14). A significant 19% reduction in deaths from all causes was observed among breast cancer cases in the group invited to screening (RR 0.81, 95% CI 0.72–0.90; p<0.001). A more conservative estimation gave a significant 13% reduction (RR 0.87, 95% CI 0.78–0.97; p=0.01). These findings are consistent with the magnitude of the reduction in breast cancer mortality. CONCLUSIONS: Invitation to screening was associated with a reduction in deaths from all causes among breast cancer cases, consistent with high participation rates in screening. There is no significant evidence of bias in cause of death classification in the Two-County Trial, and as breast cancer mortality is the targeted clinical outcome in breast cancer screening, it is the appropriate end point in a breast cancer screening trial. All-cause mortality is a poor and inefficient surrogate for breast cancer mortality.