Context: The Women's Health Initiative (WHI) randomized controlled trial that compared estrogen plus progestin versus placebo was stopped because of a significantly increased risk of breast cancer in the active treatment group (reason 1), and because a global index supported a finding of overall harm (reason 2). The possibility that the findings could have been accounted for by bias was not considered. Objective: The present analysis was undertaken to determine whether detection bias is a plausible alternative to causality as an explanation for those findings that contributed to the reasons for discontinuing the study. Design, setting and participants: This work took the form of a sensitivity analysis of the published WHI data to determine the magnitude of the detection bias required to account for those findings that contributed to the two reasons for stopping the study. Main outcome measures: These were differences in incidence rates of breast cancer (reason 1), and breast cancer, coronary heart disease...

Risks of estrogen plus progestin therapy: a sensitivity analysis of findings in the Women's Health Initiative randomized controlled trial.

In the light of the breast density legislation in the USA, it is important to know a woman’s breast cancer risk, but particularly her risk of a tumor that is not detected through mammographic screening (interval cancer). Therefore, we examined the associations of automatically measured volumetric breast density with screen-detected and interval cancer risk, separately. Volumetric breast measures were assessed automatically using Volpara version 1.5.0 (Matakina, New Zealand) for the first available digital mammography (DM) examination of 52,814 women (age 50 − 75 years) participating in the Dutch biennial breast cancer screening program between 2003 and 2011. Breast cancer information was obtained from the screening registration system and through linkage with the Netherlands Cancer Registry. We excluded all screen-detected breast cancers diagnosed as a result of the first digital screening examination. During a median follow-up period of 4.2 (IQR 2.0–6.2) years, 523 women were diagnosed with breast cancer of which 299 were screen-detected and 224 were interval breast cancers. The associations between volumetric breast measures and breast cancer risk were determined using Cox proportional hazards analyses. Percentage dense volume was found to be positively associated with both interval and screen-detected breast cancers (hazard ratio (HR) 8.37 (95% CI 4.34–16.17) and HR 1.39 (95% CI 0.82–2.36), respectively, for Volpara density grade category (VDG) 4 compared to VDG1 (p for heterogeneity < 0.001)). Dense volume (DV) was also found to be positively associated with both interval and screen-detected breast cancers (HR 4.92 (95% CI 2.98–8.12) and HR 2.30 (95% CI 1.39–3.80), respectively, for VDG-like category (C)4 compared to C1 (p for heterogeneity = 0.041)). The association between percentage dense volume categories and interval breast cancer risk (HR 8.37) was not significantly stronger than the association between absolute dense volume categories and interval breast cancer risk (HR 4.92). Our results suggest that both absolute dense volume and percentage dense volume are strong markers of breast cancer risk, but that they are even stronger markers for predicting the occurrence of tumors that are not detected during mammography breast cancer screening.

/pdf/the-effect-of-volumetric-breast-density-on-the-risk-of-599hoz3zfh.pdf

The effect of volumetric breast density on the risk of screen-detected and interval breast cancers: a cohort study

Postmenopausal hormone therapy (HT) is associated with increased risk of breast cancer, but in women undergoing breast cancer screening it is not clear whether use of HT is associated with increased risk of breast cancer detected at screening or between screens (interval cancer). Further, it is unclear whether the use of the HTs that have been common in Scandinavia is associated with higher risk of breast cancer than the HTs used in other countries. Our study was based on data from 296,651 women aged 50-69 years, who participated in the Norwegian Breast Cancer Screening Program during 1995-2004. After a mean enrollment time of 3.8 years, 1,512 women were diagnosed with invasive screen detected breast cancer, and 814 with invasive interval breast cancer. Cox regression models were used to estimate hazard ratios (HRs) of breast cancer associated with HT use, after adjusting for confounders. Ever users of HT had a 58% increased risk of breast cancer, compared to never users. The HRs associated with HT use were 1.45 (95% confidence interval (CI) = 1.29-1.63) for screen detected and 1.89 (95% CI = 1.61-2.23) for interval cancer. The difference between screen detected and interval cancer was statistically significant (p = 0.011). The HR of breast cancer increased with duration of HT use, but significantly more so for interval than for screen detected cancer (use of HT for 5 or more years compared to never use; HR = 2.91, 95% CI = 2.10-4.04 and HR = 1.94, 95% CI = 1.51-2.50, respectively; p = 0.002). The population attributable fraction of breast cancer due to HT use was 19.8% overall. Ever users of HT tended to develop a cancer of lower grade. No other differences in histological tumor characteristics were observed between ever and never users of HT among screen detected or interval cancers. The estimated risks of either breast cancer overall with HT use are higher in Norway than reported in similar studies from the U.S. HT-use is a stronger risk factor for interval cancer than for screen detected cancer. The increased risk of interval cancer, which may partly be due to decreased sensitivity of mammograms in HT users, remains a challenge in breast cancer screening programs.

Use of hormone therapy and risk of breast cancer detected at screening and between mammographic screens.

It is well established that high mammographic density (MD), when adjusted for age and body mass index, is one of the strongest known risk factors for breast cancer (BC), and also associates with higher incidence of interval cancers in screening due to the masking of early mammographic abnormalities. Increasing research is being undertaken to determine the underlying histological and biochemical determinants of MD and their consequences for BC pathogenesis, anticipating that improved mechanistic insights may lead to novel preventative or treatment interventions. At the same time, technological advances in digital and contrast mammography are such that the validity of well-established relationships needs to be re-examined in this context. With attention to old versus new technologies, we conducted a literature review to summarise the relationships between clinicopathologic features of BC and the density of the surrounding breast tissue on mammography, including the associations with BC biological features inclusive of subtype, and implications for the clinical disease course encompassing relapse, progression, treatment response and survival. There is reasonable evidence to support positive relationships between high MD (HMD) and tumour size, lymph node positivity and local relapse in the absence of radiotherapy, but not between HMD and LVI, regional relapse or distant metastasis. Conflicting data exist for associations of HMD with tumour location, grade, intrinsic subtype, receptor status, second primary incidence and survival, which need further confirmatory studies. We did not identify any relationships that did not hold up when data involving newer imaging techniques were employed in analysis.

A review of the influence of mammographic density on breast cancer clinical and pathological phenotype

OBJECTIVE: Breast cancers detected between screening examinations can influence the sensitivity of a screening programme. Studies of the prognosis of these so-called interval breast cancers show diverging results. We investigated the course of interval breast cancer over time in the Malmo Mammographic Screening Trial (MMST) 1976-86 and the Malmo Mammographic Service Screening Programme (MMSSP) 1990-99. MATERIAL AND METHODS: Stage distribution and survival of interval cancers in MMSSP were compared with screen-detected and non-attender cancer cases in MMSSP, with interval cancers in MMST and with breast cancer cases in a non-screened population five years before the start of MMSSP (pre-screening cancer cases). RESULTS: In MMSSP 1990-99, the interval cancers did not differ in stage distribution or survival compared with cancer cases in non-attenders, while screen-detected cancer cases had more favourable stage distribution and rate of survival than had the interval cancer cases. The MMST interval cancer cases, 1976-1986, had more favourable stage distribution but higher overall case fatality rate, relative risks (RR) 1.78 (1.00-3.20), and breast cancer case fatality rate, RR 2.05 (1.05-4.00), compared with the more recent MMSSP interval cancer cases. No significant difference in five-year survival was seen in the MMSSP interval cancer cases compared with pre-screening cancer cases not exposed to screening. CONCLUSION: In this urban population invited to mammographic screening, the survival rate for women with interval cancer has improved over a period of 20 years. Further studies are needed to assess what factors might explain changes in the course of interval breast cancer. (Less)

Improved survival rate for women with interval breast cancer - results from the breast cancer screening programme in Malmo, Sweden 1976-1999

An analysis of factors associated with interval as opposed to screen-detected breast cancers, including hormone therapy and mammographic density.

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An analysis of factors associated with interval as opposed to screen-detected breast cancers, including hormone therapy and mammographic density.