Alfonso Frigerio

False-positive results in mammographic screening for breast cancer in Europe: a literature review and survey of service screening programmes

Objective To estimate the cumulative risk of a false-positive screening result in European mammographic screening programmes, and examine the rates and procedures of further assessment. Methods A literature review was conducted to identify studies of the cumulative risk of a false-positive result in European screening programmes (390,000 women). We then examined aggregate data, cross-sectional information about further assessment procedures among women with positive results in 20 mammographic screening programmes from 17 countries (1.7 million initial screens, 5.9 million subsequent screens), collected by the European Network for Information on Cancer project (EUNICE). Results The estimated cumulative risk of a false-positive screening result in women aged 50–69 undergoing 10 biennial screening tests varied from 8% to 21% in the three studies examined (pooled estimate 19.7%). The cumulative risk of an invasive procedure with benign outcome ranged from 1.8% to 6.3% (pooled estimate 2.9%). The risk of undergoing surgical intervention with benign outcome was 0.9% (one study only). From the EUNICE project, the proportions of all screening examinations in the programmes resulting in needle biopsy were 2.2% and 1.1% for initial and subsequent screens, respectively, though the rates differed between countries; the corresponding rates of surgical interventions among women without breast cancer were 0.19% and 0.07%. Conclusion The specific investigative procedures following a recall should be considered when examining the cumulative risk of a false-positive screening result. Most women with a positive screening test undergo a non-invasive assessment procedure. Only a small proportion of recalled women undergo needle biopsy, and even fewer undergo surgical intervention.

Mammographically detected in situ lobular carcinomas of the breast.

Abstract We present ten cases of mammographically detected lobular carcinoma in situ (LCIS), involving a single area of variable size (up to a quadrant) in seven cases and the entire gland in three cases. Histologically, calcifications were associated with necrotic central areas within the in situ carcinomatous foci. Multiple foci of LCIS were observed in all five cases in which mastectomy had been performed. Cytologically, the lesions were characterized by a solid proliferation of round noncohesive cells with nuclei of intermediate size. Immunocytochemically, all cases were E-cadherin and p53 negative, and c-ErbB-2, GCDFP-15 and estrogen receptor positive. The proliferation index, evaluated with Ki67, was in the low range. Four cases were associated with foci of infiltrating lobular carcinoma (ILC). These findings contradict the commonly held opinion that LCIS is not mammographically detectable because of its lack of necrosis and calcification. This study documents the existence of a variant of LCIS exhibiting the mammographic features and central necrosis classically associated with ductal carcinoma in situ (DCIS), while retaining the spatial distribution, cytological composition and immunocytochemical features of lobular carcinoma.

A pooled analysis of interval cancer rates in six European countries.

The objective of this study was to assess detection rates and interval breast cancer (IC) rates from eight programmes in the European Breast Cancer Screening Network. A common data collection protocol was used to explore differences in IC rates among programmes and discuss their potential determinants. Pooled analysis was used to describe IC rates by age, compliance in screening, recall rate, screening detection (SD) rate and expected breast cancer incidence. Participation in screening averaged 77.9% (range 42.6–88.7%), recall rate 5.4% (range 3.3–17.7%) in the initial and 3.4% (range 1.8–8.9%) in the subsequent screening rounds, and SD rate was 60.4 (range 41.6–91) per 10 000 women in initial and 38.5 (range 31.3–62.6) in subsequent screens. IC rate during first 12 months after screening was 5.9 (range 2.1–7.3) per 10 000 women screened negative and 12.6 (range 6.3–15) in the second year of the interval. IC comprised 28% of the IC and SD cancers. The ratio between IC rate and expected incidence was 0.29 for the first 12 months and 0.63 for the 13–24 months period. Sensitivity was higher for the ages 60–69 years and for initial tests than subsequent tests. There were distinct differences in the IC rates between programmes. The results of this study reveal large variations in screening sensitivity and performance. Pooled evaluation of some process indicators within the European breast cancer screening programmes proved to be feasible and is likely to be useful for the future, particularly if it is performed regularly and extensively.

The requirements of a specialist Breast Centre.

INTRODUCTION In recognition of the advances and evidence based changes in clinical practice that have occurred in recent years and taking into account the knowledge and experience accumulated through the voluntary breast unit certification programme, Eusoma has produced this up-dated and revised guidelines on the requirements of a Specialist Breast Centre (BC). METHODS The content of these guidelines is based on evidence from the recent relevant peer reviewed literature and the consensus of a multidisciplinary team of European experts. The guidelines define the requirements for each breast service and for the specialists who work in specialist Breast Centres. RESULTS The guidelines identify the minimum requirements needed to set up a BC, these being an integrated Breast Centre, dealing with a sufficient number of cases to allow effective working and continuing expertise, dedicated specialists working with a multidisciplinary approach, providing all services throughout the patients pathway and data collection and audit. It is essential that the BC also guarantees the continuity of care for patients with advanced (metastatic) disease offering treatments according to multidisciplinary competencies and a high quality palliative care service. The BC must ensure that comprehensive support and expertise may be needed, not only through the core BC team, but also ensure that all other medical and paramedical expertise that may be necessary depending on the individual case are freely available, referring the patient to the specific care provider depending on the problem. CONCLUSIONS Applying minimum requirements and quality indicators is essential to improve organisation, performance and outcome in breast care. Efficacy and compliance have to be constantly monitored to evaluate the quality of patient care and to allow appropriate corrective actions leading to improvements in patient care.

Inter-observer and intra-observer variability of mammogram interpretation: a field study

To evaluate the performance of radiologists in mammographic mass screening, seven radiologists read blindly the mammograms of 45 women (two views for each breast). The films included 12 normal, 24 benign disease and 9 cancers. The readings were repeated after 2 years. As expected, variability was higher among radiologists than between the two readings of the same radiologist, but general reproducibility was moderate. Kappa values for a positive/negative classification were 0.45 at the first and 0.44 at the second reading (inter-observer comparisons). For the intra-observer comparisons, Kappa values ranged from 0.35 to 0.67 (mean 0.56). Generally, accuracy was low partly due to the difficulty of the cases. A slight increase in sensitivity was observed at the second reading. The level of agreement is a good indicator of accuracy. Proper training and standardization of criteria are essential before mass breast screening is implemented.

Effect of population-based screening on breast cancer mortality

Although the wider scientifi c community has long embraced the benefi ts of population-based breast screening, there seems to be an active anti-screening campaign orchestrated in part by members of the Nordic Cochrane Centre. These contrary views are based on erroneous interpretation of data from cancer registries and peerreviewed articles. Their specifi c aim seems to be to support a pre-existing opposition to all forms of screening. These individuals, making claims of poor methods, selectively discount overwhelming scientifi c evidence from numerous randomised trials in diff erent countries that organised screening reduces breast cancer mortality. They claim that the signifi cant decrease in breast cancer mortality achieved by screening is due to improvements in treatment alone, discounting the benefi ts of early detection. If true, this would imply that breast cancer is an exception among adenocarcinomas in that early detection does not improve prog nosis—a claim contrary to the evidence. For women with breast cancer, early detection also results in improved quality of life from less extensive surgical treatment. Women with screen-detected breast cancer in the UK have half the mastectomy rate of women with symptomatic cancers— ie, 27% versus 53%. Organised, high-quality breast screening is an important public health initiative by numerous governments worldwide. These policies are based on robust and extensive analysis of individualised patient data from scientifi c trials, with particular attention paid to the balance of potential benefi ts and harms. To imply that such an international action is mass misrepresentation, or that screening is done for the benefi t of self-interested professionals, is as perverse as it is unjustifi ed. Comprehensive guidelines deal with the entire screening process. Organisations responsible for screening programmes regularly review published evidence on the eff ects of mammographic screening, and also contradictory interpretations. We consider the interpretation by Jorgensen, Keen, and Gotzsche, of the balance of benefi ts and harms to be scientifi cally unsound. Women would be better served by focusing eff orts on how best, and not whether, to provide breast screening. The signatories below, charged with provision and implementation of breast screening in many diff erent countries, remain convinced that the scientifi c foundation for populationbased, quality-assured, organised breast screening is one of the major accomplishments of the translation of clinical cancer research into public health practice. Early detection, in combination with appropriate treatment, signifi cantly lowers breast cancer mortality and improves the life quality of patients with the disease.

Variation in detection of ductal carcinoma in situ during screening mammography: a survey within the International Cancer Screening Network

BACKGROUND There is concern about detection of ductal carcinoma in situ (DCIS) in screening mammography. DCIS accounts for a substantial proportion of screen-detected lesions but its effect on breast cancer mortality is debated. The International Cancer Screening Network conducted a comparative analysis to determine variation in DCIS detection. PATIENTS AND METHODS Data were collected during 2004-2008 on number of screening examinations, detected breast cancers, DCIS cases and Globocan 2008 breast cancer incidence rates derived from national or regional cancer registers. We calculated screen-detection rates for breast cancers and DCIS. RESULTS Data were obtained from 15 screening settings in 12 countries; 7,176,050 screening examinations; 29,605 breast cancers and 5324 DCIS cases. The ratio between highest and lowest breast cancer incidence was 2.88 (95% confidence interval (CI) 2.76-3.00); 2.97 (95% CI 2.51-3.51) for detection of breast cancer; and 3.49 (95% CI 2.70-4.51) for detection of DCIS. CONCLUSIONS Considerable international variation was found in DCIS detection. This variation could not be fully explained by variation in incidence nor in breast cancer detection rates. It suggests the potential for wide discrepancies in management of DCIS resulting in overtreatment of indolent DCIS or undertreatment of potentially curable disease. Comprehensive cancer registration is needed to monitor DCIS detection. Efforts to understand discrepancies and standardise management may improve care.

Screen-detected vs clinical breast cancer: the advantage in the relative risk of lymph node metastases decreases with increasing tumour size.

Screen-detected (SD) breast cancers are smaller and biologically more indolent than clinically presenting cancers. An often debated question is: if left undiagnosed during their preclinical phase, would they become more aggressive or would they only increase in size? This study considered a registry-based series (1988–1999) of 3329 unifocal, pT1a-pT3 breast cancer cases aged 50–70 years, of which 994 were SD cases and 2335 clinical cases. The rationale was that (1) the average risk of lymph node involvement (N+) is lower for SD cases, (2) nodal status is the product of biological aggressiveness and chronological age of the disease, (3) for any breast cancer, tumour size is an indicator of chronological age, and (4) for SD cases, tumour size is specifically an indicator of the duration of the preclinical phase, that is, an inverse indicator of lead time. The hypothesis was that the relative protection of SD cases from the risk of N+ and, thus, their relative biological indolence decrease with increasing tumour size. The odds ratio (OR) estimate of the risk of N+ was obtained from a multiple logistic regression model that included terms for detection modality, tumour size category, patient age, histological type, and number of lymph nodes recovered. A term for the detection modality-by-tumour size category interaction was entered, and the OR for the main effect of detection by screening vs clinical diagnosis was calculated. This increased linearly from 0.05 (95% confidence interval: 0.01–0.39) in the 2–7 mm size category to 0.95 (0.64–1.40) in the 18–22 mm category. This trend is compatible with the view that biological aggressiveness of breast cancer increases during the preclinical phase.

Compliance with clinical practice guidelines for breast cancer treatment: a population-based study of quality-of-care indicators in Italy

BackgroundIt has been documented that variations exist in breast cancer treatment despite wide dissemination of clinical practice guidelines. The aim of this population-based study was to evaluate the impact of regional guidelines (Piedmont guidelines, PGL) for breast cancer diagnosis and treatment on quality-of-care indicators in the Northwestern Italian region of Piedmont.MethodsWe included two samples of women aged 50–69 years with incident breast cancer treated in Piedmont before and after the introduction of PGL: 600 in 2002 (pre-PGL) and 621 in 2004 (post-PGL). Patients were randomly selected among all incident breast cancer cases identified through the hospital discharge records database. We extracted clinical data on breast cancer cases from medical charts and ascertained vital status through linkage with town offices. We assessed compliance with 14 quality-of-care indicators from PGL recommendations, before and after their introduction in clinical practice.ResultsAmong patients with invasive lesions, 77.1% (N = 368) and 77.5% (N = 383) in the pre-PGL and post-PGL groups, respectively, received breast conservative surgery (BCS) as a first-line treatment. Following BCS, 87.7% received radiotherapy in 2002, compared to 87.9% in 2004. Of all patients at medium-to-high risk of distant metastasis, 65.5% (N = 268) and 63.6% (N = 252) received chemotherapy in 2002 and in 2004, respectively. Among the 117 patients with invasive lesions and negative estrogen receptor status in 2002, hormonal therapy was prescribed in 23 of them (19.6%). The incorrect prescription of hormonal therapy decreased to 10.8% (N = 10) among the 92 estrogen receptor-negative patients in 2004 (p < 0.01).Compliance with PGL recommendations was already high in the pre-PGL group, although some quality-of-care indicators did not reach the standard. In the pre/post analysis, 8 out of 14 quality-of-care indicators showed an improvement from 2002 to 2004, but only 4 out of 14 reached statistical significance. We did not find any change in the risk of mortality in the post-PGL versus the pre-PGL group (adjusted hazard ratio 0.94, 95%CI 0.56–1.56).ConclusionsThese results highlight the need to continue to improve breast cancer care and to measure adherence to PGL.

Micropapillary ductal carcinoma in situ of the breast: an inter-institutional study.

The clinical significance of micropapillary growth pattern in ductal carcinoma in situ is controversial and the impact of nuclear grading in terms of recurrence of this lesion is yet to be clarified. Our aim was to evaluate, on a series of micropapillary in situ carcinomas, the histological features correlated with recurrence and whether the micropapillary subtype had a different behavior from other non-micropapillary ductal carcinoma in situ. We collected 55 cases of micropapillary in situ carcinomas from four institutions. All cases were reviewed for nuclear grade, extent, necrosis, microinvasion and tested for estrogen and progesterone receptors, Ki67, HER2, EGFR and p53 expression. Clinical data, type of surgery and follow up were obtained for all patients. Our results showed that the nuclear grade is crucial in determining the biology of micropapillary carcinoma in situ, so that the high nuclear grade micropapillary ductal carcinoma in situ more frequently overexpressed HER2, showed higher proliferation index, displayed necrosis and microinvasion and was more extensive than low/intermediate nuclear grade. Logistic regression analysis confirmed the high nuclear grade (Odds ratio: 6.86; CI: 1.40–33.57) as the only parameter associated with elevated risk of local recurrence after breast-conserving surgery. However, the recurrence rate of 19 micropapillary carcinoma in situ, which were part of a cohort of 338 consecutive ductal carcinoma in situ, was significantly higher (log-rank test, P-value=0.019) than that of non-micropapillary, independently of the nuclear grade. In conclusion, although nuclear grade may significantly influence the biological behavior of micropapillary ductal carcinoma in situ, micropapillary growth pattern per se represents a risk factor for local recurrence after breast-conserving surgery.