Dataset for reporting of the invasive carcinoma of the breast: recommendations from the International Collaboration on Cancer Reporting (ICCR)

BACKGROUND AND OBJECTIVES: Current national or regional guidelines for the pathology reporting on invasive breast cancer differ in certain aspects, resulting in divergent reporting practice and a lack of comparability of data. Here we report on a new international dataset for the pathology reporting of resection specimens with invasive cancer of the breast. The dataset was produced under the auspices of the International Collaboration on Cancer Reporting (ICCR), a global alliance of major (inter-)national pathology and cancer organizations. METHODS AND RESULTS: The established ICCR process for dataset development was followed. An international expert panel consisting of breast pathologists, a surgeon, and an oncologist prepared a draft set of core and noncore data items based on a critical review and discussion of current evidence. Commentary was provided for each data item to explain the rationale for selecting it as a core or noncore element, its clinical relevance, and to highlight potential areas of disagreement or lack of evidence, in which case a consensus position was formulated. Following international public consultation, the document was finalized and ratified, and the dataset, which includes a synoptic reporting guide, was published on the ICCR website. CONCLUSIONS: This first international dataset for invasive cancer of the breast is intended to promote high-quality, standardized pathology reporting. Its widespread adoption will improve consistency of reporting, facilitate multidisciplinary communication, and enhance comparability of data, all of which will help to improve the management of invasive breast cancer patients

Cohort profile of the Sloane Project: methodology for a prospective UK cohort study of >15 000 women with screen-detected non-invasive breast neoplasia.

PURPOSE: The introduction of breast screening in the UK led to an increase in the detection of non-invasive breast neoplasia, predominantly ductal carcinoma in situ (DCIS), a non-obligatory precursor of invasive breast cancer. The Sloane Project, a UK prospective cohort study of screen-detected non-invasive breast neoplasia, commenced in 2003 to evaluate the radiological assessment, surgical management, pathology, adjuvant therapy and outcomes for non-invasive breast neoplasia. Long-term follow-up and accurate data collection are essential to examine the clinical impact. Here, we describe the establishment, development and analytical processes for this large UK cohort study. PARTICIPANTS: Women diagnosed with non-invasive breast neoplasia via the UK National Health Service Breast Screening Programme (NHSBSP) from 01 April 2003 are eligible, with a minimum age of 46 years. Diagnostic, therapeutic and follow-up data collected via proformas, complement date and cause of death from national data sources. Accrual for patients with DCIS ceased in 2012 but is ongoing for patients with epithelial atypia/in situ neoplasia, while follow-up for all continues long term. FINDINGS TO DATE: To date, patients within the Sloane cohort comprise one-third of those diagnosed with DCIS within the NHSBSP and are representative of UK practice. DCIS has a variable outcome and confirms the need for longer-term follow-up for screen-detected DCIS. However, the radiology and pathology features of DCIS can be used to inform patient management. We demonstrate validation of follow-up information collected from national datasets against traditional, manual methods. FUTURE PLANS: Conclusions derived from the Sloane Project are generalisable to women in the UK with screen-detected DCIS. The follow-up methodology may be extended to other UK cohort studies and routine clinical follow-up. Data from English patients entered into the Sloane Project are available on request to researchers under data sharing agreement. Annual follow-up data collection will continue for a minimum of 20 years.https://bmjopen.bmj.com/content/12/12/e06158

Menstrual cycle associated changes in hormone-related gene expression in oestrogen receptor positive breast cancer.

The major changes in hormone levels that occur through the menstrual cycle have been postulated to affect the expression of hormone-regulated and proliferation-associated genes (PAGs) in premenopausal ER+ breast cancer. Whilst previous studies have demonstrated differences in gene expression, here, we investigated if there are within patient changes in the expression of oestrogen- and progesterone-regulated genes (ERGs and PRGs) and PAGs in ER+ breast cancer during the menstrual cycle. Samples from 96 patients in two independent prospective studies of the effect of menstrual cycle on ER+ breast cancer were used. Plasma hormone measurements were used to assign tumours to one of three pre-defined menstrual cycle windows: W1 (days 27-35 and 1-6; low oestradiol and low progesterone), W2 (days 7-16; high oestradiol and low progesterone) and W3 (days 17-26; intermediate oestradiol and high progesterone). RNA expression of 50 genes, including 27 ERGs, 11 putative PRGs and seven PAGs was measured. The AvERG (geomean of PGR, GREB1, TFF1 and PDZK1) was used as a composite measure of ERG expression and showed significant changes between the three windows of the menstrual cycle increasing over 2.2-fold between W1 and W2 and decreasing between W2 and W3 and between W3 and W1. Proliferation gene expression also varied significantly, following the same pattern of changes as ERG expression, but the changes were of lower magnitude (1.4-fold increase between W1 and W2). Significant changes in the expression of eight individual ERGs, including GREB1, PGR and TFF1, and two PAGs were observed between W1 and either W2 or W3 with all genes showing higher levels in W2 or W3 (1.3-2.4-fold; FDR 0.016-0.05). The AvProg, a composite measure of PRG expression, increased significantly (1.5-fold) in W3 compared to W1 or W2 but no significant changes were observed for individual PRGs. In conclusion, we observed significant changes in ERG, PRG and PAG expression in ER+ breast tumours during the menstrual cycle that may affect the assessment and interpretation of prominent biomarkers (e.g. PgR) and commonly used multigene prognostic signatures in premenopausal ER+ breast cancer

Risk factors for the development of invasive cancer in unresected ductal carcinoma in situ

Background: The natural history of ductal carcinoma in situ (DCIS) remains uncertain. The risk factors for the development of invasive cancer in unresected DCIS are unclear.Methods: Women diagnosed with DCIS on needle biopsy after 1997 who did not undergo surgical resection for ≥1 year after diagnosis were identified by breast centres and the cancer registry and outcomes were reviewed.Results: Eighty-nine women with DCIS diagnosed 1998-2010 were identified. The median age at diagnosis was 75 (range 44-94) years with median follow-up (diagnosis to death, invasive disease or last review) of 59 (12-180) months. Twenty-nine women (33%) developed invasive breast cancer after a median interval of 45 (12-144) months. 14/29 (48%) with high grade, 10/31 (32%) with intermediate grade and 3/17 (18%) with low grade DCIS developed invasive cancer after median intervals of 38, 60 and 51 months. The cumulative incidence of invasion was significantly higher in high grade DCIS than other grades (p = .0016, log-rank test). Invasion was more frequent in lesions with calcification as the predominant feature (23/50 v. 5/25; p = .042) and in younger women (p = .0002). Endocrine therapy was associated with a lower rate of invasive breast cancer (p = .048).Conclusions: High cytonuclear grade, mammographic microcalcification, young age and lack of endocrine therapy were risk factors for DCIS progression to invasive cancer. Surgical excision of high grade DCIS remains the treatment of choice. Given the uncertain long-term natural history of non-high grade DCIS, the option of active surveillance of women with this condition should be offered within a clinical trial.</p

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 &lt; 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 &lt; 0.001]) and a 1.9% absolute reduction for ipsilateral invasive breast recurrence (no RT: 3.8% versus RT: 1.9% [p &lt; 0.001]), independent of the excision margin width or size of DCIS. Women without RT after BCS had more ipsilateral breast recurrences (p &lt; 0.001) when the radial excision margin was &lt;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 &lt; 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

HER2-enriched subtype and novel molecular subgroups drive aromatase inhibitor resistance and an increased risk of relapse in early ER+/HER2+ breast cancer

BACKGROUND: Oestrogen receptor positive/ human epidermal growth factor receptor positive (ER+/HER2+) breast cancers (BCs) are less responsive to endocrine therapy than ER+/HER2- tumours. Mechanisms underpinning the differential behaviour of ER+HER2+ tumours are poorly characterised. Our aim was to identify biomarkers of response to 2 weeks’ presurgical AI treatment in ER+/HER2+ BCs. METHODS: All available ER+/HER2+ BC baseline tumours (n=342) in the POETIC trial were gene expression profiled using BC360™ (NanoString) covering intrinsic subtypes and 46 key biological signatures. Early response to AI was assessed by changes in Ki67 expression and residual Ki67 at 2 weeks (Ki672wk). Time-To-Recurrence (TTR) was estimated using Kaplan-Meier methods and Cox models adjusted for standard clinicopathological variables. New molecular subgroups (MS) were identified using consensus clustering. FINDINGS: HER2-enriched (HER2-E) subtype BCs (44.7% of the total) showed poorer Ki67 response and higher Ki672wk (p<0.0001) than non-HER2-E BCs. High expression of ERBB2 expression, homologous recombination deficiency (HRD) and TP53 mutational score were associated with poor response and immune-related signatures with High Ki672wk. Five new MS that were associated with differential response to AI were identified. HER2-E had significantly poorer TTR compared to Luminal BCs (HR 2.55, 95% CI 1.14–5.69; p=0.0222). The new MS were independent predictors of TTR, adding significant value beyond intrinsic subtypes. INTERPRETATION: Our results show HER2-E as a standardised biomarker associated with poor response to AI and worse outcome in ER+/HER2+. HRD, TP53 mutational score and immune-tumour tolerance are predictive biomarkers for poor response to AI. Lastly, novel MS identify additional non-HER2-E tumours not responding to AI with an increased risk of relapse

A randomized trial to assess the biological activity of short-term (pre-surgical) fulvestrant 500 mg plus anastrozole versus fulvestrant 500 mg alone or anastrozole alone on primary breast cancer

Introduction: Fulvestrant shows dose-dependent biological activity. Greater estrogen-receptor (ER) blockade may feasibly be achieved by combining fulvestrant with anastrozole. This pre-surgical study compared fulvestrant plus anastrozole versus either agent alone in patients with ER-positive breast cancer. Methods: In this double-blind, multicenter trial, 121 patients received: fulvestrant 500 mg on day 1 plus anastrozole 1 mg/day for 14-21 days (F+A); fulvestrant plus anastrozole placebo (F); or fulvestrant placebo plus anastrozole (A), 2-3 weeks before surgery. ER, progesterone-receptor (PgR), and Ki67 expression were determined from tumor biopsies before treatment and at surgery. Results: 103 paired samples were available (F, n = 35; F+A, n = 31; A, n = 37). All treatments significantly reduced mean ER expression from baseline (F: 41%, P = 0.0001; F+A: 39%, P = 0.0001; A: 13%, P = 0.0034). F and F+A led to greater reductions in ER versus A (both P = 0.0001); F+A did not lead to additional reductions versus F. PgR and Ki67 expression were significantly reduced with all treatments (means were 34% to 45%, and 75% to 85%, respectively; all P = 0.0001), with no differences between groups. Conclusions: In this short-term study, all treatments reduced ER expression, although F and F+A showed greater reductions than A. No significant differences were detected between the treatment groups in terms of PgR and Ki67 expression. No additional reduction in tumor biomarkers with combination treatment was observed, suggesting that F+A is unlikely to have further clinical benefit over F alone. Trial registration: Clinicaltrials.gov NCT00259090

Breast cancer management pathways during the COVID-19 pandemic: outcomes from the UK ‘Alert Level 4’ phase of the B-MaP-C study

Abstract: Background: The B-MaP-C study aimed to determine alterations to breast cancer (BC) management during the peak transmission period of the UK COVID-19 pandemic and the potential impact of these treatment decisions. Methods: This was a national cohort study of patients with early BC undergoing multidisciplinary team (MDT)-guided treatment recommendations during the pandemic, designated ‘standard’ or ‘COVID-altered’, in the preoperative, operative and post-operative setting. Findings: Of 3776 patients (from 64 UK units) in the study, 2246 (59%) had ‘COVID-altered’ management. ‘Bridging’ endocrine therapy was used (n = 951) where theatre capacity was reduced. There was increasing access to COVID-19 low-risk theatres during the study period (59%). In line with national guidance, immediate breast reconstruction was avoided (n = 299). Where adjuvant chemotherapy was omitted (n = 81), the median benefit was only 3% (IQR 2–9%) using ‘NHS Predict’. There was the rapid adoption of new evidence-based hypofractionated radiotherapy (n = 781, from 46 units). Only 14 patients (1%) tested positive for SARS-CoV-2 during their treatment journey. Conclusions: The majority of ‘COVID-altered’ management decisions were largely in line with pre-COVID evidence-based guidelines, implying that breast cancer survival outcomes are unlikely to be negatively impacted by the pandemic. However, in this study, the potential impact of delays to BC presentation or diagnosis remains unknown

Bridging pre-surgical endocrine therapy for breast cancer during the COVID-19 pandemic: outcomes from the B-MaP-C study

Purpose: The B-MaP-C study investigated changes to breast cancer care that were necessitated by the COVID-19 pandemic. Here we present a follow-up analysis of those patients commenced on bridging endocrine therapy (BrET), whilst they were awaiting surgery due to reprioritisation of resources. Methods: This multicentre, multinational cohort study recruited 6045 patients from the UK, Spain and Portugal during the peak pandemic period (Feb–July 2020). Patients on BrET were followed up to investigate the duration of, and response to, BrET. This included changes in tumour size to reflect downstaging potential, and changes in cellular proliferation (Ki67), as a marker of prognosis. Results: 1094 patients were prescribed BrET, over a median period of 53 days (IQR 32–81 days). The majority of patients (95.6%) had strong ER expression (Allred score 7–8/8). Very few patients required expedited surgery, due to lack of response (1.2%) or due to lack of tolerance/compliance (0.8%). There were small reductions in median tumour size after 3 months’ treatment duration; median of 4 mm [IQR − 20, 4]. In a small subset of patients ( n = 47), a drop in cellular proliferation (Ki67) occurred in 26 patients (55%), from high (Ki67 ≥ 10%) to low (&lt; 10%), with at least one month’s duration of BrET. Discussion: This study describes real-world usage of pre-operative endocrine therapy as necessitated by the pandemic. BrET was found to be tolerable and safe. The data support short-term (≤ 3 months) usage of pre-operative endocrine therapy. Longer-term use should be investigated in future trials