Management and 5-year outcomes in 9938 women with screen-detected ductal carcinoma in situ: the UK Sloane Project.

BACKGROUND: Management of screen-detected ductal carcinoma in situ (DCIS) remains controversial. METHODS: A prospective cohort of patients with DCIS diagnosed through the UK National Health Service Breast Screening Programme (1st April 2003 to 31st March 2012) was linked to national databases and case note review to analyse patterns of care, recurrence and mortality. RESULTS: Screen-detected DCIS in 9938 women, with mean age of 60 years (range 46-87), was treated by mastectomy (2931) or breast conserving surgery (BCS) (7007; 70%). At 64 months median follow-up, 697 (6.8%) had further DCIS or invasive breast cancer after BCS (7.8%) or mastectomy (4.5%) (p < 0.001). Breast radiotherapy (RT) after BCS (4363/7007; 62.3%) was associated with a 3.1% absolute reduction in ipsilateral recurrent DCIS or invasive breast cancer (no RT: 7.2% versus RT: 4.1% [p < 0.001]) and a 1.9% absolute reduction for ipsilateral invasive breast recurrence (no RT: 3.8% versus RT: 1.9% [p < 0.001]), independent of the excision margin width or size of DCIS. Women without RT after BCS had more ipsilateral breast recurrences (p < 0.001) when the radial excision margin was <2 mm. Adjuvant endocrine therapy (1208/9938; 12%) was associated with a reduction in any ipsilateral recurrence, whether RT was received (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.41-0.80) or not (HR 0.68; 95% CI 0.51-0.91) after BCS. Women who developed invasive breast recurrence had a worse survival than those with recurrent DCIS (p < 0.001). Among 321 (3.2%) who died, only 46 deaths were attributed to invasive breast cancer. CONCLUSION: Recurrent DCIS or invasive cancer is uncommon after screen-detected DCIS. Both RT and endocrine therapy were associated with a reduction in further events but not with breast cancer mortality within 5 years of diagnosis. Further research to identify biomarkers of recurrence risk, particularly as invasive disease, is indicated.

Proximity ligation assays for isoform-specific Akt activation in breast cancer identify activated Akt1 as a driver of progression.

The PI3K/Akt signal transduction pathway plays an important role in cancer progression and cell survival. Akt activation is associated with poor outcome in endocrine-treated breast cancer, whereas high levels of cytoplasmic Akt2 are associated with an improved overall survival. Proximity ligation assays (PLAs) were used to determine quantitative expression levels of isoform-specific activation (phosphorylation) of Akt1 and Akt2 in formalin-fixed, paraffin-embedded cell lines and breast cancer tumour tissues in situ. PLAs demonstrated a range of expression in breast cancer samples for total pAkt1 and pAkt2. High levels of pAkt1 were associated with reduced DRFS (HR: 1.45, 95% CI 1.14-1.83, p = 0.002) and OS (HR: 1.42, 95% CI 1.10-1.83, p = 0.007). When PLA results were combined, patients that had high levels of pAkt1 only had a significantly decreased DRFS (HR: 1.92, 95% CI 1.34-2.76, p = 0.005) and OS (HR: 1.94, 95% CI 1.32-2.86, p = 0.008) compared to other patients. Using PLAs to discriminate activation of Akt1 versus Akt2 suggests that Akt1 drives progression in early breast cancers. In cases where both Akt1/Akt2 are activated, Akt2 may act to reverse this effect. Using PLAs, we have measured activation of Akt1 and Akt2 proteins separately in situ in FFPE breast cancer samples.

The p160 ER co-regulators predict outcome in ER negative breast cancer.

The SRC family of ER co-regulators are frequently overexpressed in breast cancer. Overexpression of AIB1 appears to be linked to hormone resistance in HER2 positive breast cancer. However, the role of these co-regulators in ER negative disease is poorly understood. SRC1, SRC2 and AIB1 expression was determined by immunohistochemical analysis of tissue microarrays constructed from tumours within the Edinburgh Breast Conservation Series (BCS). The BCS represents a fully documented consecutive cohort of 1,812 patients treated by breast conservation surgery in a single institution. Our results demonstrate tumours that overexpress both HER2 and AIB1 were associated with markedly reduced relapse free, distant relapse free and overall survival compared to HER2 and AIB1 only overexpressing tumours irrespective of ER status. In ER negative disease both SRC1 and AIB1 were linked to early relapse and death. The SRC family of ER co-regulators is involved in early relapse and resistance in both ER negative and ER positive breast cancer challenging the conventional concept that this effect is mediated solely via the ER.

Changes in chromatin structure during processing of wax-embedded tissue sections.

The use of immunofluorescence (IF) and fluorescence in situ hybridisation (FISH) underpins much of our understanding of how chromatin is organised in the nucleus. However, there has only recently been an appreciation that these types of study need to move away from cells grown in culture and towards an investigation of nuclear organisation in cells in situ in their normal tissue architecture. Such analyses, however, especially of archival clinical samples, often requires use of formalin-fixed paraffin wax-embedded tissue sections which need addition steps of processing prior to IF or FISH. Here we quantify the changes in nuclear and chromatin structure that may be caused by these additional processing steps. Treatments, especially the microwaving to reverse fixation, do significantly alter nuclear architecture and chromatin texture, and these must be considered when inferring the original organisation of the nucleus from data collected from wax-embedded tissue sections.

Histological grading of invasive breast carcinoma--a simplification of existing methods in a large conservation series with long-term follow-up.

AIMS: To assess the validity of grading in the Edinburgh Breast Conservation Series; a consecutive cohort of 1812 early breast cancer patients treated by breast conservation and radiotherapy between 1981 and 1998 in a single specialist centre with > or =9 years' follow-up and full staging data. METHODS AND RESULTS: A single pathologist (J.St.J.T) graded 1650 cases using the Elston and Ellis method (EE) with particular reference to the component data: acinar differentiation, nuclear pleomorphism and mitotic counts. The original method was then compared with binary scoring of the same components and the relationship to prognosis reassessed. EE grades and individual grade components were prognostic (P < 0.0001) with 10-year cause-specific survival of 95.6%, 86.4% and 74.7% for EE grades 1, 2 and 3, respectively. A binary scoring of grade components produces four groups, splitting EE grade 2 tumours into two groups with different outcomes--10-year survival rates for the four revised grades were 96.0%, 89.0%, 79.7% and 75.4%, respectively. CONCLUSIONS: Existing grading methodology is fully applicable in the narrower context of a conservation series but can be simplified. Subdivision of EE grade 2 into a true intermediate prognosis group and a second group with a worse prognosis also adds benefit.