Long-term cause of death patterns and mode of breast cancer detection in The Netherlands, 2004-2019.

OBJECTIVE: Early detection through mammographic screening and various treatment modalities of cancer may have changed life expectancy and cause-specific mortality of breast cancer patients. We aimed to determine the long-term cause of death patterns in screening-detected patients and clinically diagnosed patients in the Netherlands compared with the general population. METHODS: Using data from the Netherlands Cancer Registry and Statistics Netherlands of around 26,000 women, aged 50-75 at diagnosis and surgically treated for invasive breast cancer in 2004-2008, we compared patients with screening-detected and clinically diagnosed cancer for major causes of death until 2020. The expected number of all-cause and cause-specific deaths was calculated using rates of the general population. RESULTS: During the follow-up period, 4310 women died. The age-standardised all-cause mortality ratio for the screening-detected cancer group was 1.41 (95% confidence interval (95% CI), 1.37-1.46). A higher mortality ratio was observed for patients with clinically detected cancer: 2.27 (95% CI, 2.19-2.34). The observed versus expected breast cancer mortality ratio in the screening-detected patient group was 8.92 (95% CI, 8.45-9.40) and 20.23 (19.38-21.09) in the clinical group. Excess mortality was found for lung cancer in both patient groups, and small elevations for circulatory and respiratory disease in the clinically detected group. CONCLUSION: Our results indicate that for the screening group no other causes of death but breast and lung cancer were prominent compared with the general population. The clinical group showed excess mortality for some other causes of death as well, suggesting a less healthy group compared with the general population.

Trends in three major histological subtypes of cutaneous melanoma in the Netherlands between 1989 and 2016.

BACKGROUND: Time trend analysis of cutaneous melanoma (CM) mortality in fair skin populations shows both a gradual decrease and/or an increase. To explain these differences, we analyzed long-term time trends in the incidence of the most common histological subtypes of CM: superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM), and nodular melanoma (NM). METHODS: Using data from the Netherlands Cancer Registry and Statistics Netherlands, the number and rates of cases diagnosed with SSM, LLM, and NM from 1989 to 2016 were analyzed by age, calendar period, and birth cohort of people born in successive periods from 1925 to 1973. RESULTS: Primary CM was diagnosed in 52,000 men and 66,588 women in the study period. The annual age-standardized incidence rate increased three-fold from 14 to 42 per 100,000 person-years. The most common subtype was SSM (50%), followed by LMM (23%) and NM (14%). Age-specific subtype rates showed an upward trend over time for both men and women. Younger birth cohorts had higher rates of SSM and LMM diagnosis than older birth cohorts. This birth cohort pattern was not observed for NM. CONCLUSIONS: We observed a strong increase in the melanoma epidemic curves in the light-skinned Dutch population over the last three decades. This increase is explained by younger generations having higher rates of SSM and LMM than older generations.

Value of routine follow-up in oropharyngeal squamous cell cancer patients treated with curative intent.

BACKGROUND: The major goal of routine follow-up in oropharyngeal squamous cell carcinoma (OPSCC) patients is the asymptomatic detection of new disease in order to improve survival. This study evaluated the effect of routine follow-up on overall survival (OS). METHODS: A retrospective cohort of 307 consecutive OPSCC patients treated with curative intent between 2006 and 2012 was analyzed. The effectiveness of routine follow-up was studied by comparing treatment-intent and OS in patients with asymptomatically versus symptomatically detected new disease. RESULTS: Three- and five-year risks of new disease were 29% (95% CI: 24-34) and 33% (95% CI: 27-39). Of the 81 patients with locoregional recurrence or second primary head and neck cancer, 8 (10%) were detected asymptomatically with no difference in OS with those detected with symptoms. CONCLUSIONS: Asymptomatic detection of new disease during routine visits was not associated with improved OS. The focus of follow-up should be on providing psychosocial care and rehabilitation.

Quantifying the duration of the preclinical detectable phase in cancer screening: a systematic review.

OBJECTIVES: The aim of this study was to provide an overview of published mathematical estimation approaches to quantify the duration of the preclinical detectable phase (PCDP) using data from cancer screening programs. METHODS: A systematic search of PubMed and Embase was conducted for original studies presenting mathematical approaches using screening data. The studies were categorized by mathematical approach, data source, and assumptions made. Furthermore, estimates of the duration of the PCDP of breast and colorectal cancer were reported per study population. RESULTS: From 689 publications, 34 estimation methods were included. Five distinct types of mathematical estimation approaches were identified: prevalence-to-incidence ratio (n=8), maximum likelihood estimation (n=16), expectation-maximization algorithm (n=1), regression of observed on expected (n=6) and Bayesian Markov-chain Monte Carlo estimation (n=5). Fourteen studies used data from both screened and unscreened populations, whereas 19 studies included only information from a screened population. Estimates of the duration of the PCDP varied between 2 years and 7 years for breast cancer in the Health Insurance Plan study (annual mammography and clinical breast examinations in women aged 40-64 years) and 2 years and 5 years for colorectal cancer in the Calvados study (a guaiac fecal occult blood test in men and women aged 45-74 years). CONCLUSIONS: Different types of mathematical approaches lead to different estimates of the PCDP duration. We advise researchers to use the method that matches the data available, and to use multiple methods for estimation when possible, since no method is perfect.

Trends and projections in the incidence of oesophageal cancer in the Netherlands: An age-period-cohort analysis from 1989 to 2041.

In Western populations, the incidence of oesophageal squamous cell carcinoma (OSCC) has been declining, whereas the incidence of oesophageal adenocarcinoma (OAC) has been increasing. Our study examines temporal trends in the incidence of oesophageal cancer in the Netherlands between 1989 and 2016, in addition to predicting future trends through 2041. Data from the Netherlands Cancer Registry and Statistics Netherlands were collected to obtain incidence trends of OSCC and OAC for the period 1989 to 2016. Age-period-cohort (APC) modelling was used to estimate the contribution of age, calendar period and birth cohort on the observed incidence trends. To predict the future numbers of new cases of both OSCC and OAC from 2017 to 2041, log-linear APC models were fitted to the trends of 1989 to 2016. The age-standardised incidence rates of OSCC have decreased slightly for men and increased slightly for women. In contrast, a marked increase in the incidence of OAC was observed, ranging from 2.8 per 100 000 persons in 1989 to 10.1 in 2016. This increase in OAC incidence was more prominent in men, and it will result in an increased risk of OAC for successive generations. Future projections indicate that the incidence of OAC will further increase to 13.1 per 100 000 persons in 2037 to 2041, meaning that there will be 13 259 cases of OAC in 2037 to 2041, as compared to 9386 diagnoses in 2017 to 2021. The changing epidemiologic trends in oesophageal cancer in the Netherlands should be reflected in the development of prevention, early detection and treatment strategies.

Second primary tumours after squamous cell carcinoma of the oral cavity.

INTRODUCTION: The aim of this study was to determine the incidence, location and timing of second primary tumours (SPT) after diagnosis of oral squamous cell carcinoma (OSCC) and relate the risk of SPT to that after head and neck squamous cell carcinoma (HNSCC) and the risks of those tumours in the general population in order to assess the need for a separate follow-up programme for OSCC patients and to aid development of an evidence-based and individualized follow-up programme for OSCC patients. MATERIALS AND METHODS: All patients diagnosed with OSCC or HNSCC in the Netherlands in 1991-2015 were selected from the Netherlands Cancer Registry. Cumulative incidence rates and Standardized Incidence Ratios (SIR) were calculated. Analyses were stratified by incidence period and age at primary diagnosis of the index tumour, follow-up time, and site of the SPT. RESULTS: We included 11263 patients with OSCC from a population of 34244 patients with HNSCC, of which the median follow-up time was 4.0 years. OSCC SPT develop in different patterns and at different locations than after HNSCC. The 5-year risk of SPT and SIR (95% confidence intervals) were respectively 0.13 (0.13-0.14) and 3.0 (2.9-3.1) for OSCC. The risk of a SPT was continuous over follow-up time and calendar period but decreased with an increasing age at diagnosis of the index tumour up to the age of 75 and there were differences in sites of SPT. CONCLUSION: A specific follow-up protocol for OSCC is needed, which can be individualized on the basis of, among others, age.

Trends and projections in cutaneous melanoma death in the Netherlands from 1950 to 2045.

ABSTRACT: Child sun protection has recently been linked to the future disappearance of fatal melanoma in adults in successive generations. In the Netherlands, however, mortality rates from melanoma have increased gradually from the 1950s, with some indication of stabilisation since 2010, which may be compatible with a birth cohort effect by sun-protective measures and screening. To study the trajectories ahead a trend analysis was applied. Numbers of people with cutaneous melanoma as underlying cause of death from 1950 to 2018 and population data were derived from Statistics Netherlands. A graphical approach was used to explore trends in mortality by age, calendar period, and cohorts born in the successive periods of 1889 to 1979. Age-period-cohort modelling outcomes and population forecasts provided projections of mortality until 2045. Based on 24,151 cases of melanoma death (13,256 men, 10,895 women), age-standardised mortality rates were similar from 1950 to 1989 for both genders, and increased thereafter more in men. The age-curve patterns changed gradually towards higher death rates at older age, implying the existence of a birth cohort effect. The age-period-cohort models showed an increase in melanoma mortality rates in successive generations. For women, the birth cohort effect plateaued for generations born since the mid-1980s. The projected total mortality number was predicted to rise in the next 3 decades.It is concluded that a small future decline of mortality in younger generations can be expected in the Netherlands, but mortality is still rising for the total population.

Correlates of Total and domain-specific Sedentary behavior: a cross-sectional study in Dutch adults.

BACKGROUND: Sedentary behavior (SB) is associated with increased risks of detrimental health outcomes. Few studies have explored correlates of SB in physically active individuals. Furthermore, SB correlates may depend on settings of SB, such as occupation, transportation and leisure time sitting. This study aims to identify subject-, lifestyle- and health-related correlates for total SB and different SB domains: transportation, occupation, and leisure time. METHODS: Dutch participants were recruited between June, 2015 and December, 2016. Participant characteristics (i.e. age, sex, weight, height, marital status, education level, employment), lifestyle (sleep, smoking, alcohol consumption, physical activity) and medical history were collected via an online questionnaire. SB was assessed using the Sedentary Behavior Questionnaire and estimated for 9 different activities during weekdays and weekend days. Logistic regression was used to calculate odds ratios and 95% confidence intervals for the association between correlates and SB. Total SB was dichotomized at > 8 h/day and > 10 h/day, and being sedentary during transportation, occupation and leisure time at the 75th percentile (60 min/day, 275 min/day and 410 min/day, respectively). RESULTS: In total, 8471 participants (median age 55, 55% men) were included of whom 86% met the physical activity guidelines. Median SB was 9.1 h/day (Q25 6.3-Q75 12.0) during weekdays and 7.4 h/day (Q25 5.5-Q75 9.5) during weekend days. SB was most prevalent during leisure time (5.3 h/day; Q25 3.9-Q75 6.8), followed by occupation (2 h/day; Q25 0.1-Q75 4.6) and transportation (0.5 h/day; Q25 0.2-Q75 1.0). Younger age, male sex, being unmarried, higher education, employment and higher BMI were significantly related to higher levels of total SB. Younger age, male sex, employment, and higher BMI increased the odds for high SB volumes during occupation and transportation. Higher education, being unmarried and smoking status were positively associated with high volumes of occupational SB only, whereas older age, being unmarried, unemployment, higher BMI and poor health were positively linked to leisure time SB. CONCLUSIONS: SB is highly prevalent in physically active individuals, with SB during leisure time as the most important contributor. Correlates for high volumes of SB vary substantially across SB domains, emphasizing the difficulty to target this unhealthy lifestyle.

Time patterns of recurrence and second primary tumors in a large cohort of patients treated for oral cavity cancer.

INTRODUCTION: Routine follow-up after curative treatment of patients with oral squamous cell carcinoma (OSCC) is common practice considering the high risk of second primaries and recurrences (ie second events). Current guidelines advocate a follow-up period of at least 5 years. The recommendations are not evidence-based and benefits are unclear. This is even more so for follow-up after a second event. To facilitate the development of an evidence- and personalized follow-up program for OSCC, we investigated the course of time until the second and subsequent events and studied the risk factors related to these events. MATERIALS AND METHODS: We retrospectively studied 594 OSCC patients treated with curative intent at the Head and Neck Cancer Unit of the Radboud University Medical Centre from 2000 to 2012. Risk of recurrence was calculated addressing death from intercurrent diseases as competing event. RESULTS: The 1-, 5- and 10-year cumulative risks of a second event were 17% (95% CI:14%;20%), 30% (95% CI:26%;33%), and 37% (95% CI:32%;41%). Almost all locoregional recurrences occurred in the first 2 years after treatment. The incidence of second primary tumors was relatively stable over the years. The time pattern of presentation of third events was similar. DISCUSSION: Our findings support a follow-up time of 2 years after curative treatment for OSCC. Based on the risk of recurrence there is no indication for a different follow-up protocol after first and second events. After 2 years, follow-up should be tailored to the individual needs of patients for supportive care, and monitoring of late side-effects of treatment.

Breast density and breast cancer-specific survival by detection mode.

BACKGROUND: Breast density is known to affect breast cancer risk and screening sensitivity, but it may also be associated with breast cancer survival. The interpretation of results from previous studies on breast density and survival is complicated by the association between detection mode and survival. Here, we studied the effect of breast density on breast cancer-specific survival for different detection modes (screen-detected, interval ≤ 24 or > 24 months, non-participant). METHODS: Data from the Nijmegen (Dutch) breast cancer screening programme were used. Women diagnosed with invasive breast cancer between 1975 and 2011 were included. Breast density was assessed visually, based on a dichotomized Wolfe scale: 'fatty breasts' (≤25%) and 'dense breasts' (> 25%). Cox proportional hazard regression was used to obtain hazard ratios (HR). RESULTS: We identified 2742 eligible women, with a breast pattern available for 2233 women. A diagnosis of interval cancer (HR 2.06, 95% CI 1.62-2.61) led to a significantly increased risk of breast cancer death compared with screen-detected cancer. No significant cause-specific survival difference between women with dense and fatty breasts was observed (HR 0.94, 95% CI 0.77-1.15). The hazard was only higher for women with dense breasts among interval cancers ≤24 m (HR 1.07, 95% CI 0.74-1.56). The hazard appeared to be lower for women with dense breasts than for women with fatty breasts among screen-detected (HR 0.77, 95% CI 0.53-1.11) and interval cancers > 24 m (HR 0.80, 95% CI 0.53-1.20). None of the effects were statistically significant. CONCLUSIONS: Detection mode is strongly associated with breast cancer death. No clear association is apparent between breast density and breast cancer death, regardless of detection mode.

Detection and interval cancer rates during the transition from screen-film to digital mammography in population-based screening.

BACKGROUND: Between 2003 and 2010 digital mammography (DM) gradually replaced screen-film mammography (SFM) in the Dutch breast cancer screening programme (BCSP). Previous studies showed increases in detection rate (DR) after the transition to DM. However, national interval cancer rates (ICR) have not yet been reported. METHODS: We assessed programme sensitivity and specificity during the transition period to DM, analysing nationwide data on screen-detected and interval cancers. Data of 7.3 million screens in women aged 49-74, between 2004 and 2011, were linked to the Netherlands Cancer Registry to obtain data on interval cancers. Age-adjusted DRs, ICRs and recall rates (RR) per 1000 screens and programme sensitivity and specificity were calculated by year, age and screening modality. RESULTS: 41,662 screen-detected and 16,160 interval cancers were analysed. The DR significantly increased from 5.13 (95% confidence interval (CI):5.00-5.30) in 2004 to 6.34 (95% CI:6.15-6.47) in 2011, for both in situ (2004:0.73;2011:1.24) and invasive cancers (2004:4.42;2011:5.07), whereas the ICR remained stable (2004: 2.16 (95% CI2.06-2.25);2011: 2.13 (95% CI:2.04-2.22)). The RR changed significantly from 14.0 to 21.4. Programme sensitivity significantly increased, mainly between ages 49-59, from 70.0% (95% CI:68.9-71.2) to 74.4% (95% CI:73.5-75.4) whereas specificity slightly declined (2004:99.1% (95% CI:99.09-99.13);2011:98.5% (95% CI:98.45-98.50)). The overall DR was significantly higher for DM than for SFM (6.24;5.36) as was programme sensitivity (73.6%;70.1%), the ICR was similar (2.19;2.20) and specificity was significantly lower for DM (98.5%;98.9%). CONCLUSIONS: During the transition from SFM to DM, there was a significant rise in DR and a stable ICR, leading to increased programme sensitivity. Although the recall rate increased, programme specificity remained high compared to other countries. These findings indicate that the performance of DM in a nationwide screening programme is not inferior to, and may be even better, than that of SFM.

Substantial clinical benefit for Neck Disability Index revisited: establishing the goal for treatment?

PURPOSE: It is difficult for clinicians to inform patients about the success rate of a treatment as a cervical anterior discectomy procedure. Ideally, a proportion of good outcome as rated by patients is known. Patient-reported outcome measurements are helpful. The purpose is to relate the difference in Neck Disability Index (NDI) after a cervical anterior discectomy procedure for single level cervical degenerative disc disease with the patients' rating of their actual clinical situation after long-term follow-up to define the substantial clinical benefit (SCB). METHODS: After completion of the NDI, patients who were surgically treated for cervical single level degenerative disease were asked to complete a five-item Likert scale to rate their clinical situation. After dichotomisation of the outcome in good versus less than good, a cut-off value was defined by determining the value of the difference of NDI with the highest specificity and sensitivity. Funding was not obtained. RESULTS: SCB for NDI after surgery for cervical single level degenerative disease should be set at ten with area under the curve (AUC) of 0.71 for sensitivity as well specificity. CONCLUSIONS: The goal for each treatment is a good outcome. While comparing treatments for cervical degenerative disc disease only those with an SCB of ten will be relevant for the patient, as patients who achieved this difference in NDI rated their actual situation at long-term follow-up as good.

The impact of histological subtype in developing both ovarian and endometrial cancer: A longstanding nationwide incidence study.

OBJECTIVES: To estimate the incidence of ovarian cancer (OC) and endometrial cancer (EC) separately, as well as double cancers diagnosed in the same calendar year, and to relate the occurrences to histological subtype. STUDY DESIGN: All cases of epithelial OC and EC diagnosed in the Netherlands in 1989-2009 were related to population data. Histologically specific associations were made using the ratio of observed and expected incidence numbers, calculated with age-specific incidence rates. RESULTS: 25,489 OC and 32,729 EC were analyzed, and 649 OC/EC. Life-time risks for OC and EC were 1.8% and 2.4%. Among OC, adenocarcinoma (18%) and serous cancers (33%) were the most prevalent subtypes. In EC, adenocarcinoma (39%) and endometrioid cancer (37%) were highest, with hardly any serous cancers. The observed incidence of OC/EC was 50-fold higher than expected (95% CI, 46-54). For patients aged <55years, the O/E ratio was 274, for the elderly 32, both findings are significant. Of the 2345 OC endometrioid subtype, 294 had EC (12.5%), whereas 1.1 was expected. In EC patients, no particular histological subtype was distinguished with a highly elevated occurrence of OC. The 680 serous EC patients had 11 double cancers (1.6%), of which 8 with the ovarian serous subtype. CONCLUSION: Strong relationships exist between malignancies in the ovary and a second primary malignancy in the endometrium, especially for the endometrioid subtype of ovarian cancer. Viewed from the endometrial site, no special subtype was noted, and the influence of endometrial serous adenocarcinoma in developing serous OC is not plausible.

Quantifying Overdiagnosis in Cancer Screening: A Systematic Review to Evaluate the Methodology.

Background: Overdiagnosis is the main harm of cancer screening programs but is difficult to quantify. This review aims to evaluate existing approaches to estimate the magnitude of overdiagnosis in cancer screening in order to gain insight into the strengths and limitations of these approaches and to provide researchers with guidance to obtain reliable estimates of overdiagnosis in cancer screening. Methods: A systematic review was done of primary research studies in PubMed that were published before January 1, 2016, and quantified overdiagnosis in breast cancer screening. The studies meeting inclusion criteria were then categorized by their methods to adjust for lead time and to obtain an unscreened reference population. For each approach, we provide an overview of the data required, assumptions made, limitations, and strengths. Results: A total of 442 studies were identified in the initial search. Forty studies met the inclusion criteria for the qualitative review. We grouped the approaches to adjust for lead time in two main categories: the lead time approach and the excess incidence approach. The lead time approach was further subdivided into the mean lead time approach, lead time distribution approach, and natural history modeling. The excess incidence approach was subdivided into the cumulative incidence approach and early vs late-stage cancer approach. The approaches used to obtain an unscreened reference population were grouped into the following categories: control group of a randomized controlled trial, nonattenders, control region, extrapolation of a prescreening trend, uninvited groups, adjustment for the effect of screening, and natural history modeling. Conclusions: Each approach to adjust for lead time and obtain an unscreened reference population has its own strengths and limitations, which should be taken into consideration when estimating overdiagnosis.

What's the best surgical treatment for patients with cervical radiculopathy due to single-level degenerative disease? A randomized controlled trial.

BACKGROUND: To investigate the efficacy of adding supplemental fusion or arthroplasty after cervical anterior discectomy for symptomatic mono-level cervical degenerative disease (radiculopathy), which has not been substantiated in controlled trials until now. METHODS: A randomized controlled trial is reported with 9 years follow up comparing anterior cervical anterior discectomy without fusion, with fusion by cage standalone, or with disc prosthesis. Patients suffering from symptomatic cervical disk degeneration at one level referred to spinal sections of department of neurosurgery or orthopedic surgery of a large general hospital with educational facilities were eligible. Neck Disability Index (NDI), McGill Pain Questionnaire Dutch language version (MPQ-DLV), physical-component summary (PCS), and mental-component summary (MCS) of the 36-item Short-Form Health Survey (SF-36), and re operation rate were evaluated. FINDINGS: 142 patients between 18 and 55 years were allocated. The median follow-up was 8.9±1.9 years (5.6 to 12.2 years). The response rate at last follow-up was 98.5%. NDI at the last follow-up did not differ between the three treatment groups, nor did the secondary outcomes as MPQ-DLV and PCS or MCS from SF-36. The major improvement occurred within the first 6 weeks after surgery. Afterward, it remained stable. Eleven patients underwent surgery for recurrent symptoms and signs due to nerve root compression at the index or adjacent level. CONCLUSIONS: This randomized trial could not detect a difference between three surgical modalities for treating a single-level degenerative disk disease. Anterior cervical discectomy without implant seems to be similar to anterior cervical discectomy with fusion by cage stand-alone or with disk prosthesis. Due to the small study sample size, this statement should be considered as inconclusive so far. TRIAL REGISTRATION: ISRCTN41681847.

Early Assessment of Thiopurine Metabolites Identifies Patients at Risk of Thiopurine-induced Leukopenia in Inflammatory Bowel Disease.

BACKGROUND AND AIMS: Only a quarter of thiopurine-induced myelotoxicity in inflammatory bowel disease [IBD] patients is related to thiopurine S-methyltransferase deficiency. We determined the predictive value of 6-thioguanine nucleotide [6-TGN] and 6-methylmercaptopurine ribonucleotide [6-MMPR] concentrations 1 week after initiation [T1] for development of leukopenia during the first 8 weeks of thiopurine treatment. METHODS: The study was performed in IBD patients starting thiopurine therapy as part of the Dutch randomized controlled TOPIC trial [ClinicalTrials.gov NCT00521950]. Blood samples for metabolite measurement were collected at T1. Leukopenia was defined by leukocyte counts of <3.0 × 109/L. For comparison, patients without leukopenia who completed the 8 weeks on the stable dose were selected from the first 272 patients of the TOPIC trial. RESULTS: Thirty-two patients with, and 162 patients without leukopenia were analysed. T1 threshold 6-TGN concentrations of 213 pmol/8 × 108 erythrocytes and 3525 pmol/8 × 108 erythrocytes for 6-MMPR were defined: patients exceeding these values were at increased leukopenia risk (odds ratio [OR] 6.2 [95% CI: 2.8-13.8] and 5.9 [95% CI: 2.7-13.3], respectively). Leukopenia rates were higher in patients treated with mercaptopurine, compared with azathioprine (OR 7.3 [95% CI: 3.1-17.0]), and concurrent anti-TNF therapy (OR 5.1 [95% CI: 1.6-16.4]). Logistic regression analysis of thiopurine type, threshold concentrations, and concurrent anti-tumour necrosis factor [TNF] therapy revealed that elevations of both T1 6-TGN and 6-MMPR resulted in the highest risk for leukopenia, followed by exceeding only the T1 6-MMPR or 6-TGN threshold concentration (area under the curve 0.84 [95% CI: 0.76-0.92]). CONCLUSIONS: In ~80% of patients, leukopenia could be explained by T1 6-TGN and/or 6-MMPR elevations. Validation of the predictive model is needed before implementing in clinical practice.

Breast cancer screening effect across breast density strata: A case-control study.

Breast cancer screening is known to reduce breast cancer mortality. A high breast density may affect this reduction. We assessed the effect of screening on breast cancer mortality in women with dense and fatty breasts separately. Analyses were performed within the Nijmegen (Dutch) screening programme (1975-2008), which invites women (aged 50-74 years) biennially. Performance measures were determined. Furthermore, a case-control study was performed for women having dense and women having fatty breasts. Breast density was assessed visually with a dichotomized Wolfe scale. Breast density data were available for cases. The prevalence of dense breasts among controls was estimated with age-specific rates from the general population. Sensitivity analyses were performed on these estimates. Screening performance was better in the fatty than in the dense group (sensitivity 75.7% vs 57.8%). The mortality reduction appeared to be smaller for women with dense breasts, with an odds ratio (OR) of 0.87 (95% CI 0.52-1.45) in the dense and 0.59 (95% CI 0.44-0.79) in the fatty group. We can conclude that high density results in lower screening performance and appears to be associated with a smaller mortality reduction. Breast density is thus a likely candidate for risk-stratified screening. More research is needed on the association between density and screening harms.

The relative effect of mammographic screening on breast cancer mortality by socioeconomic status.

Breast cancer incidence and mortality are higher in women with a high socioeconomic status (SES). The potential to prevent death from breast cancer is therefore greater in the high SES group. This does, however, require that the effectiveness of screening in the high SES group is equal to or greater than the effectiveness in the low SES group. The aim of this study is to assess the relative effectiveness of mammographic screening on breast cancer mortality by SES.In Nijmegen, the Netherlands, women are invited to participate in biennial mammographic screening since 1975. Postal code is collected at each round and is used to calculate the SES of each woman based on the SES indicator of the Netherlands Institute for Social Research. The Dutch average was used to classify the SES score of each woman as either high or low. We designed a case-control study to investigate the effect of mammographic screening in women aged 50 to 75, 40 to 75, and 50 to 69 years, and calculated the odds ratios (ORs) and 95% confidence intervals (CIs).Among the women invited to the mammographic screening program in Nijmegen, 10% had a high SES. In women aged 50 to 75 years, the breast cancer death rate was 38% lower in screened women than in unscreened women. The ORs for women with high SES (OR 0.82, 95% CI 0.31-2.19) and low SES did not differ significantly (OR 0.61, 95% CI 0.47-0.78).Mammographic screening reduces breast cancer mortality, but we did not observe a significant difference in the relative effectiveness of screening by SES. If the effectiveness of mammographic screening is indeed not dependent on SES status, the absolute number of breast cancer deaths prevented by mammographic screening will be greater in the high SES than low SES group, because women with a high SES have a greater risk of breast cancer death.

Towards personalized screening: Cumulative risk of breast cancer screening outcomes in women with and without a first-degree relative with a history of breast cancer.

Several reviews have estimated the balance of benefits and harms of mammographic screening in the general population. The balance may, however, differ between individuals with and without family history. Therefore, our aim is to assess the cumulative risk of screening outcomes; screen-detected breast cancer, interval cancer, and false-positive results, in women screenees aged 50-75 and 40-75, with and without a first-degree relative with a history of breast cancer at the start of screening. Data on screening attendance, recall and breast cancer detection were collected for each woman living in Nijmegen (The Netherlands) since 1975. We used a discrete time survival model to calculate the cumulative probability of each major screening outcome over 19 screening rounds. Women with a family history of breast cancer had a higher risk of all screening outcomes. For women screened from age 50-75, the cumulative risk of screen-detected breast cancer, interval cancer and false-positive results were 9.0, 4.4 and 11.1% for women with a family history and 6.3, 2.7 and 7.3% for women without a family history, respectively. The results for women 40-75 followed the same pattern for women screened 50-75 for cancer outcomes, but were almost doubled for false-positive results. To conclude, women with a first-degree relative with a history of breast cancer are more likely to experience benefits and harms of screening than women without a family history. To complete the balance and provide risk-based screening recommendations, the breast cancer mortality reduction and overdiagnosis should be estimated for family history subgroups.

Comparing Visually Assessed BI-RADS Breast Density and Automated Volumetric Breast Density Software: A Cross-Sectional Study in a Breast Cancer Screening Setting.

INTRODUCTION: The objective of this study is to compare different methods for measuring breast density, both visual assessments and automated volumetric density, in a breast cancer screening setting. These measures could potentially be implemented in future screening programmes, in the context of personalised screening or screening evaluation. MATERIALS AND METHODS: Digital mammographic exams (N = 992) of women participating in the Dutch breast cancer screening programme (age 50-75y) in 2013 were included. Breast density was measured in three different ways: BI-RADS density (5th edition) and with two commercially available automated software programs (Quantra and Volpara volumetric density). BI-RADS density (ordinal scale) was assessed by three radiologists. Quantra (v1.3) and Volpara (v1.5.0) provide continuous estimates. Different comparison methods were used, including Bland-Altman plots and correlation coefficients (e.g., intraclass correlation coefficient [ICC]). RESULTS: Based on the BI-RADS classification, 40.8% of the women had 'heterogeneously or extremely dense' breasts. The median volumetric percent density was 12.1% (IQR: 9.6-16.5) for Quantra, which was higher than the Volpara estimate (median 6.6%, IQR: 4.4-10.9). The mean difference between Quantra and Volpara was 5.19% (95% CI: 5.04-5.34) (ICC: 0.64). There was a clear increase in volumetric percent dense volume as BI-RADS density increased. The highest accuracy for predicting the presence of BI-RADS c+d (heterogeneously or extremely dense) was observed with a cut-off value of 8.0% for Volpara and 13.8% for Quantra. CONCLUSION: Although there was no perfect agreement, there appeared to be a strong association between all three measures. Both volumetric density measures seem to be usable in breast cancer screening programmes, provided that the required data flow can be realized.