Rassegna della letteratura – gennaio 2019

Epidemiologia, prevenzione, diagnosi e screening

Lord SJ, Kiely BE, Pearson SA et Al. – Metastatic breast cancer incidence, site and survival in Australia, 2001-2016: a population-based health record linkage study protocol. –  BMJ Open. 2019 Feb 1;9(2):e026414. doi: 10.1136/bmjopen-2018-026414.

Background: Advances in systemic therapy for early and metastatic breast cancer (BC) over the last two decades have improved patients’ survival, but their impact on metastatic disease outcomes at a population level is not well described. The aim of this study is to investigate changes in the incidence, site and survival of metastatic disease for women with a first diagnosis of BC in 2001-2002 vs 2006-2007

Methods: Population-based retrospective cohort study of women with first primary invasive BC registered in the New South Wales (NSW) Cancer Registry in 2001-2002 and 2006-2007. We will use linked records from NSW hospitals, dispensed medicines, outpatient services and death registrations to determine: women’s demographic and tumour characteristics; treatments received; time to first distant metastasis; site of first metastasis and survival. We will use the Kaplan-Meier method to estimate cumulative incidence of distant metastasis, distant recurrence-free interval and postmetastasis survival by extent of disease at initial diagnosis, site of metastasis and treatment-defined tumour receptor type (hormone receptor-positive, human epidermal growth factor receptor-2-positive, triple negative). We will use Cox proportional hazards regression to estimate the relative effects of prognostic factors, and we will compare systemic therapy patterns by area-of-residence and area-level socioeconomic status to examine equity of access to healthcare.

Results: Research ethics committee approval was granted by the Australian Institute of Health and Welfare (#EO2017/2/255), NSW Population and Health Services (#HREC/17/CIPHS/19) and University of Notre Dame Australia (#0 17 144S). We will disseminate research findings to oncology, BC consumer and epidemiology audiences through national and international conference presentations, lay summaries to BC consumer groups and publications in international peer-reviewed oncology and cancer epidemiology journals.



Bick U, Engel C, Krug B et Al. – High-risk breast cancer surveillance with MRI: 10-year experience from the German consortium for hereditary breast and ovarian cancer. – Breast Cancer Res Treat. 2019 Feb 6

Purpose: To report on 10 years of high-risk service screening with annual MRI in the German Consortium for Hereditary Breast and Ovarian Cancer (GC-HBOC).

Methods: A cohort of 4,573 high-risk, previously unaffected women (954 BRCA1 carriers, 598 BRCA2 carriers, 3021 BRCA1/2 non-carriers) participating in the GC-HBOC surveillance program was prospectively followed. Screening outcomes for 14,142 screening rounds with MRI between 2006 and 2015 were analyzed and stratified by risk group, type of screening round, and age.

Results: A total of 221 primary breast cancers (185 invasive, 36 in situ) were diagnosed within 12 months of an annual screening round with MRI. Of all cancers, 84.5% (174/206, 15 unknown) were stage 0 or I. In BRCA1 carriers, 16.9% (10/59, 5 unknown) of all incident cancers (screen-detected and interval cancers combined) and in BRCA2 carriers 12.5% (3/24, 4 unknown) were stage IIA or higher, compared to only 4.8% (2/42, 2 unknown) in high-risk BRCA1/2 non-carriers. Program sensitivity was 89.6% (95% CI 84.9-93.0) with no significant differences in sensitivity between risk groups or by age. Specificity was significantly lower in the first screening round (84.6%, 95% CI 83.6-85.7) than in subsequent screening rounds (91.1%, 95% CI 90.6-91.7), p < 0.001. Cancer detection rates (CDRs) and as a result positive predictive values were strongly dependent on type of screening round, risk group and patient age. CDRs ranged from 43.5‰ (95% CI 29.8-62.9) for the first screening round in BRCA2 carriers to 2.9‰ (95% CI 1.3-6.3) for subsequent screening rounds in high-risk non-carriers in the age group 30 to 39 years.

Conclusions: High-risk screening with MRI was successfully implemented in the GC-HBOC with high sensitivity and specificity. Risk prediction and inclusion criteria in high-risk non-carriers need to be adjusted to improve CDRs and thus screening efficacy in these patients.



Blanks RG, Given-Wilson RM, Cohen SL et Al. – An analysis of 11.3 million screening tests examining the association between recall and cancer detection rates in the English NHS breast cancer screening programme. Eur Radiol. 2019 Feb 4. doi: 10.1007/s00330-018-5957-2

 Objective: To develop methods to model the relationship between cancer detection and recall rates to inform professional standards.

Methods: Annual screening programme information for each of the 80 English NHSBSP units (totalling 11.3 million screening tests) for the seven screening years from 1 April 2009 to 31 March 2016 and some Dutch screening programme information were used to produce linear and non-linear models. The non-linear models estimated the modelled maximum values (MMV) for cancers detected at different grades and estimated how rapidly the MMV was reached (the modelled ‘slope’ (MS)). Main outcomes include the detection rate for combined invasive/micro-invasive and high-grade DCIS (IHG) detection rate and the low/intermediate grade DCIS (LIG) detection rate.

Results: At prevalent screens for IHG cancers, 99% of the MMV was reached at a recall rate of 7.0%. The LIG detection rate had no discernible plateau, increasing linearly at a rate of 0.12 per 1000 for every 1% increase in recall rate. At incident screens, 99% of the MMV for IHG cancer detection was 4.0%. LIG DCIS increased linearly at a rate of 0.18 per 1000 per 1% increase in recall rate.

Conclusion: Our models demonstrate the diminishing returns associated withincreasing recall rates. The screening programme in England could use the models to set recall rate ranges, and other countries could explore similar methodology.



Tina Shih YC, Dong W, Xu Y at Al. – Assessing the Cost-Effectiveness of Updated Breast Cancer Screening Guidelines for Average-Risk Women. – Value Health. 2019 Feb;22(2):185-193. 

Background: Several specialty societies have recently updated their breast cancer screening guidelines in late 2015/early 2016.

Objiectives: To evaluate the cost-effectiveness of US-based mammography screening guidelines.

Methods:  We developed a microsimulation model to generate the natural history of invasive breast cancer and capture how screening and treatment modified the natural course of the disease. We used the model to assess the cost-effectiveness of screening strategies, including annual screening starting at the age of 40 years, biennial screening starting at the age of 50 years, and a hybrid strategy that begins screening at the age of 45 years and transitions to biennial screening at the age of 55 years, combined with three cessation ages: 75 years, 80 years, and no upper age limit. Findings were summarized as incremental cost-effectiveness ratio (cost per quality-adjusted life-year [QALY]) and cost-effectiveness acceptability frontier.

Results: The screening strategy that starts annual mammography at the age of 45 years and switches to biennial screening between the ages of 55 and 75 years was the most cost-effective, yielding an incremental cost-effectiveness ratio of $40,135/QALY. Probabilistic analysis showed that the hybrid strategy had the highest probability of being optimal when the societal willingness to pay was between $44,000/QALY and $103,500/QALY. Within the range of commonly accepted societal willingness to pay, no optimal strategy involved screening with a cessation age of 80 years or older.

Conclusions: The screening strategy built on a hybrid design is the most cost-effective for average-risk women. By considering the balance between benefits and harms in forming its recommendations, this hybrid screening strategy has the potential to optimize the health care system’s investment in the early detection and treatment of breast cancer.



Jordan V, Khan M, Prill D. – Breast Cancer Screening: Why Can’t Everyone Agree? – Prim Care. 2019 Mar;46(1):97-115.

Abstract: Screening mammography and evolving treatments have improved mortality over the last 25 years. However, breast cancer remains the second leading cause of cancer-related mortality for women in the United States. There are several contradictory recommendations regarding breast cancer screening. Familiarity with these recommendations will allow physicians to counsel their patients and ensure well-informed shared decision making.



Horvat JV, Keating DM, Rodrigues-Duarte H et Al. – Calcifications at Digital Breast Tomosynthesis: Imaging Features and Biopsy Techniques. – Radiographics. 2019 Jan 25:180124.

Abstract: Full-field digital mammography (FFDM), the standard of care for breast cancer screening, has some limitations. With the advent of digital breast tomosynthesis (DBT), improvements including decreased recall rates and increased cancer detection rates have been observed. The quasi-three-dimensional capability of DBT reduces breast tissue overlap, a significant limitation of FFDM. However, early studies demonstrate that a few cancers detected at FFDM may not be diagnosed at DBT-only screening, and lesions with calcifications as the dominant feature may look less suspicious at DBT or not be visible at all. These findings support the use of combined FFDM and DBT protocols to optimize screening performance. However, this combination would approximately double the patient’s radiation exposure. The development of computer algorithms that generate two-dimensional synthesized mammography (SM) views from DBT has improved calcification conspicuity and sensitivity. Therefore, SM may substitute for FFDM in screening protocols, reducing radiation exposure. DBT plus SM demonstrates significantly better performance than that of FFDM alone, although there are reports of missed malignant calcifications. Thus, some centers continue to perform FFDM with DBT. Use of DBT in breast imaging has also necessitated the development of DBT-guided biopsy. DBT-guided biopsy may have a higher success rate than that of stereotactic biopsy, with a shorter procedure time. While DBT brings substantial improvements to breast cancer imaging, it is important to be aware of its strengths and limitations regarding detection of calcifications. This article reviews the imaging appearance of breast calcifications at DBT, discusses calcification biopsy techniques, and provides an overview of the current literature. Online DICOM image stacks are available for this article. ©RSNA, 2019.



Fleming MM, Hughes DR, Golding LP et Al.- Digital Breast Tomosynthesis Implementation: Considerations for Emerging Breast Cancer Screening Bundled Payment Models.  – J Am Coll Radiol. 2019 Jan 22. pii: S1546-1440(18)31477-7.

PURPOSE: Bundled payments have been touted as mechanisms to optimize quality and costs. A recent feasibility study evaluating bundled payments for screening mammography episodes predated widespread adoption of digital breast tomosynthesis (DBT). We explore a similar model reflecting emerging acceptance of DBT in breast cancer screening.

METHODS: Using 4-year data for 59,094 screening episodes from two large facilities within a large academic health system, we utilized published methodology to calibrate Medicare national allowable reference prices for women undergoing screening mammography before and after practice-wide implementation of DBT.

RESULTS: Excluding DBT, Medicare-normalized bundled prices for traditional breast imaging 364 days downstream to screening mammography are extremely similar pre- and post-DBT implementation ($182.86 in 2013; $182.68 in 2015). The addition of DBT increased a DBT-inclusive bundled price by $53.16 (an amount lower than the $56.13 Medicare allowable fee for screening DBT) but was associated with significantly reduced recall rates (13.0% versus 9.4%; P < .0001). Without or with DBT, screening episode bundled prices remained sensitive to bundle-included services and varied little by patient age, race, or insurance status.

CONCLUSIONS: Prior non-DBT approaches to bundled payment models for breast cancer screening remain viable as DBT becomes the standard of care, with bundle prices varying little by patient age, race, or insurance status. Higher DBT-inclusive bundled prices, however, highlight the need to explore societal costs more broadly (eg, reduced time away from work from fewer recalls) as bundled payment models evolve.



Phalak KA, Milton DR, Yang WT et AL. – Supplemental ultrasound screening in patients with a history of lobular neoplasia. – Breast J. 2019 Jan 24.

Abstract: To investigate the role of ultrasound (US) screening as an adjunct to annual mammography (M) in breast cancer detection in women with a history of lobular neoplasia (LN) diagnosed following core needle or excisional biopsy. A retrospective review of our database was performed between 11/2006 and 11/2011 to identify patients diagnosed with LN, and underwent annual screening. Patients with a lifetime risk >20% per risk modeling were excluded. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and cancer detection rate (CDR) of each screening test were identified. Cancer type and detection modality were recorded. A total of 100 patients who had M and/or US screening were included. Mean patient age was 54.7 years (range 33-83). All 100 patients underwent a mean of 3.9 rounds of screening M and 93 (93%) received US screening (mean 3.3 rounds). Of 93 patients who received both M and US screening, 12 (13%) were diagnosed with breast cancer. Mammographic CDR was 4%. Incremental US CDR was 6.5%. The sensitivity, specificity, and NPV for M screening alone was 33% (10%, 65%), 77% (67%, 85%), and 89% (80%, 95%), respectively. US and mammography screening had a combined sensitivity: 83% (52%, 98%), Specificity: 72% (62%, 81%), NPV: 97% (89%, 100%). Supplemental US screening resulted in a significant increase in sensitivity, yielding 6.5% incremental CDR in this high-risk patient subgroup that does not fulfill ACS high-risk MRI screening criteria.

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