The MARECA (national study of management of breast cancer locoregional recurrence and oncological outcomes) study: protocol for a prospective, multicentre cohort study.

Background: Despite a UK 5-year breast cancer survival rate of 86.6%, patients may develop breast cancer recurrence within the same breast after breast conserving surgery, as well as in the remaining skin or chest wall after mastectomy or in the ipsilateral lymph glands. These recurrences, collectively termed locoregional recurrence (LRR), occur in around 8% of patients within 10 years of their original diagnosis. Currently, there is a lack of robust information on the presentation and prevalence of LRR with no UK-specific clinical guidelines available for the optimal management of this patient group. Additionally, there is a need to identify patterns of LRR presentation and their progression, which will enable prognostic factors to be determined. This will subsequently enable the tailoring of treatment and improve patient outcome. Methods: The MARECA study is a prospective, multicentre cohort study recruiting patients diagnosed with breast cancer LRR +/- associated distant metastases. Over 50 UK breast units are participating in the study with the aim of recruiting at least 500 patients over a recruitment period of 24 months. The data collected will detail the tumour pathology, imaging results, surgical treatment, radiotherapy and systemic therapy of the primary and recurrent breast cancer. Study follow-up will be for up to 5 years following LRR diagnosis to determine subsequent oncological outcomes and evaluate potential prognostic factors. Discussion: This study will address the current knowledge gap and identify subgroups of patients who have less successful treatment outcomes. The results will determine the current management of LRR and the prognosis of patients diagnosed with breast cancer LRR +/- distant metastases in the UK, with the aim of establishing best practice and informing future national guidelines. The results will direct future research and inform the design of additional interventional trials and translational studies.

Minimally invasive treatment of early, good prognosis breast cancer-is this feasible?

Breast cancer screening programmes frequently detect early, good prognosis breast cancers with significant treatment burden for patients, and associated health-cost implications. Emerging evidence suggests a role for minimally invasive techniques in the management of these patients enabling many women to avoid surgical intervention. Minimally invasive techniques include vacuum-assisted excision, cryoablation, and radiofrequency ablation. We review published evidence in relation to the risks and benefits of each technique and discuss ongoing trials. Data to date are promising, and we predict a trend towards minimally invasive treatment for early, good-prognosis breast cancer as technical skills, suitability criteria, and follow-up protocols are established.

Digital pathology for reporting histopathology samples, including cancer screening samples - definitive evidence from a multisite study.

AIMS: To conduct a definitive multicentre comparison of digital pathology (DP) with light microscopy (LM) for reporting histopathology slides including breast and bowel cancer screening samples. METHODS: A total of 2024 cases (608 breast, 607 GI, 609 skin, 200 renal) were studied, including 207 breast and 250 bowel cancer screening samples. Cases were examined by four pathologists (16 study pathologists across the four speciality groups), using both LM and DP, with the order randomly assigned and 6 weeks between viewings. Reports were compared for clinical management concordance (CMC), meaning identical diagnoses plus differences which do not affect patient management. Percentage CMCs were computed using logistic regression models with crossed random-effects terms for case and pathologist. The obtained percentage CMCs were referenced to 98.3% calculated from previous studies. RESULTS: For all cases LM versus DP comparisons showed the CMC rates were 99.95% [95% confidence interval (CI) = 99.90-99.97] and 98.96 (95% CI = 98.42-99.32) for cancer screening samples. In speciality groups CMC for LM versus DP showed: breast 99.40% (99.06-99.62) overall and 96.27% (94.63-97.43) for cancer screening samples; [gastrointestinal (GI) = 99.96% (99.89-99.99)] overall and 99.93% (99.68-99.98) for bowel cancer screening samples; skin 99.99% (99.92-100.0); renal 99.99% (99.57-100.0). Analysis of clinically significant differences revealed discrepancies in areas where interobserver variability is known to be high, in reads performed with both modalities and without apparent trends to either. CONCLUSIONS: Comparing LM and DP CMC, overall rates exceed the reference 98.3%, providing compelling evidence that pathologists provide equivalent results for both routine and cancer screening samples irrespective of the modality used.

Cost-Effectiveness Analysis of Digital Breast Tomosynthesis Added to Synthetic Mammography in Breast Cancer Screening in Brazil.

BACKGROUND: Literature meta-analysis results show that digital breast tomosynthesis (DBT) combined with synthesized two-dimensional (s2D) mammograms can reduce recalls and improve breast cancer detection. Uncertainty regarding the screening of patients with breast cancer presents a health economic challenge, both in terms of healthcare resource use and quality of life impact on patients. OBJECTIVE: This study aims to estimate the cost effectiveness of DBT + s2D versus digital mammography (DM) used in a biennial breast cancer screening setting of women aged 40-69 years with scattered areas of fibroglandular breast density and heterogeneous dense breasts in the Brazilian supplementary health system. METHODS: A cost-effectiveness analysis was performed on the basis of clinical data obtained from a systematic review with meta-analysis performed to evaluate the analytical validity and clinical utility of DBT + s2D compared with DM. The search was conducted in the PubMed, Cochrane Library and Embase databases, with the main descriptors of the technology, a comparator, and the clinical condition in question, on 9 June 2022. The hybrid economic model (decision tree plus Markov model) simulated costs and outcomes over a lifetime for women aged 40-69 years with scattered areas of fibroglandular breast density and heterogeneous dense breasts. We analyzed incremental cost-effectiveness ratio (ICER) to measure the incremental cost difference per quality-adjusted life year (QALY) of adding DBT + s2D to breast cancer screening. RESULTS: DBT + s2D incurred a cost saving of € 954.02 per patient, in the time horizon of 30 years, compared with DM, and gained 5.1989 QALYs, which would be considered a dominant intervention. These results were confirmed in sensitivity analyses. CONCLUSION: Switching from DM to biennial DBT + s2D was cost effective. Furthermore, reductions in false-positive recall rates should also be considered in decision making.

Vaginal Estrogen Therapy Use and Survival in Females With Breast Cancer.

Importance: Genitourinary syndrome of menopause can be treated with vaginal estrogen therapy. However, there are concerns about the safety of vaginal estrogen therapy in patients with breast cancer. Objective: To determine whether the risk of breast cancer-specific mortality was higher in females with breast cancer who used vaginal estrogen therapy vs females with breast cancer who did not use hormone replacement therapy (HRT). Design, Setting, and Participants: This cohort study analyzed 2 large cohorts, one each in Scotland and Wales, of females aged 40 to 79 years with newly diagnosed breast cancer. These population-based cohorts were identified from national cancer registry records from 2010 to 2017 in Scotland and from 2000 to 2016 in Wales and were followed up for breast cancer-specific mortality until 2020. Females were excluded if they had a previous cancer diagnosis (except nonmelanoma skin cancer). Data analysis was performed between August 2022 and August 2023. Exposure: Use of vaginal estrogen therapy, including vaginal tablets and creams, was ascertained from pharmacy dispensing records of the Prescribing Information System for the Scotland cohort and from general practice prescription records for the Wales cohort. Main Outcomes and Measures: The primary outcome was time to breast cancer-specific mortality, which was obtained from national mortality records. Time-dependent Cox proportional hazards regression models were used to calculate hazard ratios (HRs) and 95% CIs for breast cancer-specific mortality, comparing vaginal estrogen therapy users with HRT nonusers and adjusting for confounders, including cancer stage and grade. Results: The 2 cohorts comprised 49 237 females with breast cancer (between 40 and 79 years of age) and 5795 breast cancer-specific deaths. Five percent of patients with breast cancer used vaginal estrogen therapy after breast cancer diagnosis. In vaginal estrogen therapy users compared with HRT nonusers, there was no evidence of a higher risk of breast cancer-specific mortality in the pooled fully adjusted model (HR, 0.77; 95% CI, 0.63-0.94). Conclusions and Relevance: Results of this study showed no evidence of increased early breast cancer-specific mortality in patients who used vaginal estrogen therapy compared with patients who did not use HRT. This finding may provide some reassurance to prescribing clinicians and support the guidelines suggesting that vaginal estrogen therapy can be considered in patients with breast cancer and genitourinary symptoms.

Global trends in psycho-oncology research investments 2016-2020: A content analysis.

OBJECTIVE: An estimated one-third of cancer patients experience a clinically significant psychological disorder, however it is unclear to what extent this is reflected in research funding. To address this a systematic analysis the allocation of psycho-oncology research funding globally between 2016 and 2020 was conducted. METHODS: A global dataset of 66,388 cancer research awards, from 2016 to 2020 inclusive and totalling $24.5 billion USD was assembled from public and philanthropic funders. Each award was previously categorised by cancer site type and research theme, including psychosocial research and these awards were further sub-categorised for this analysis. RESULTS: There was $523m of funding awarded for psychological research across 1122 studies: 2.14% of all cancer research funding during this period ($24.5 billion). Median funding per award was $97,473 (IQR $36,864 - $453,051). Within psychological research, mental health received most funding ($174m, 33.5% of psychological funding). Cognitive behavioural therapy (CBT) focused research was the specific psychological support with the highest proportion of funding at $14 million. By country of funder, the USA provided most investment ($375.5 m, 71.8%). CONCLUSIONS: Psycho-oncology research received relatively little funding, for example, when compared with pre-clinical cancer research. There needs to be a shift from pre-clinical science to research that benefits cancer patients in the shorter-term. Low- and middle-income countries, and ethnic minorities in higher-income settings, were underrepresented despite having a large cancer burden, indicating inequities that need to be addressed.

Global funding for cancer research between 2016 and 2020: a content analysis of public and philanthropic investments.

BACKGROUND: Cancer is a leading cause of disease burden globally, with more than 19·3 million cases and 10 million deaths recorded in 2020. Research is crucial to understanding the determinants of cancer and the effects of interventions, and to improving outcomes. We aimed to analyse global patterns of public and philanthropic investment in cancer research. METHODS: In this content analysis, we searched the UberResearch Dimensions database and Cancer Research UK data for human cancer research funding awards from public and philanthropic funders between Jan 1, 2016, and Dec 31, 2020. Included award types were project and programme grants, fellowships, pump priming, and pilot projects. Awards focused on operational delivery of cancer care were excluded. Awards were categorised by cancer type, cross-cutting research theme, and research phase. Funding amount was compared with global burden of specific cancers, measured by disability-adjusted life-years, years lived with disability, and mortality using data from the Global Burden of Disease study. FINDINGS: We identified 66 388 awards with total investment of about US$24·5 billion in 2016-20. Investment decreased year-on-year, with the largest drop observed between 2019 and 2020. Pre-clinical research received 73·5% of the funding across the 5 years ($18 billion), phase 1-4 clinical trials received 7·4% ($1·8 billion), public health research received 9·4% ($2·3 billion), and cross-disciplinary research received 5·0% ($1·2 billion). General cancer research received the largest investment ($7·1 billion, 29·2% of the total funding). The most highly funded cancer types were breast cancer ($2·7 billion [11·2%]), haematological cancer ($2·3 billion [9·4%]), and brain cancer ($1·3 billion [5·5%]). Analysis by cross-cutting theme revealed that 41·2% of investment ($9·6 billion) went to cancer biology research, 19·6% ($4·6 billion) to drug treatment research, and 12·1% ($2·8 billion) to immuno-oncology. 1·4% of the total funding ($0·3 billion) was spent on surgery research, 2·8% ($0·7 billion) was spent on radiotherapy research, and 0·5% ($0·1 billion) was spent on global health studies. INTERPRETATION: Cancer research funding must be aligned with the global burden of cancer with more equitable funding for cancer research in low-income and middle-income countries (which account for 80% of cancer burden), both to support research relevant to these settings, and build research capacity within these countries. There is an urgent need to prioritise investment in surgery and radiotherapy research given their primacy in the treatment of many solid tumours. FUNDING: None.

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 (< 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.

Identifying research priorities in breast cancer surgery: a UK priority setting partnership with the James Lind Alliance.

PURPOSE: A James Lind Alliance priority setting partnership was developed to identify research priorities in breast cancer surgery from individuals with lived experience, at high genetic risk of breast cancer, and healthcare professionals (HCPs). METHODS: 'Uncertainties' were collected using an online survey. Following an evidence check and development of summary questions, an interim survey asked participants to rank their top 10 research priorities from the question list. Top-ranked questions from patient/carer, high-risk and professional groups were carried forward for discussion to a final online prioritisation workshop. RESULTS: 260 participants (101 patients/carers, 156 HCPs) submitted 940 uncertainties via the initial survey. These were analysed thematically into 128 summary questions in six topic areas. Following evidence checking, 59 questions were included in the interim survey which was completed by 572 respondents. Marked differences were seen in questions prioritised by patients/carers, HCPs and women at high-risk. The top eight priorities in patient/carer and professional groups and top two priorities for high-risk women were carried forward to the online workshop at which 22 participants discussed and agreed the final top 10. Key themes included de-escalation of breast and axillary surgery, factors impacting the development/detection of locoregional recurrence and optimal provision of support for informed treatment decision-making. CONCLUSION: The top 10 research priorities in breast cancer surgery have been agreed. However, the observed differences in research priorities identified by patients and professional groups were not anticipated. Top priorities from both groups should inform future UK breast cancer surgical research, to ensure that it addresses questions that are important to breast cancer community as a whole.

The DNA damage induced immune response: Implications for cancer therapy.

Genomic instability is a hallmark of tumourigenesis, influencing tumour development and progression. In particular, defects in the DNA damage response (DDR) have been extensively investigated and are known to shape therapeutic response. Since immune checkpoint blockade (ICB) therapy has been approved for treatment of tumours with defective mismatch repair the interplay between DDR pathway deficiency and the immune system has been of particular interest. The cGAS/STING signalling pathway has recently emerged as a key mediator of inflammation in response to DNA damage.This was identified through transcriptional profiling of BRCA1/2 deficient breast cancers and Fanconi Anaemia (FA) patient bone marrow, revealing a common transcriptional subgroup associated with BRCA1/2 and FA deficiency characterised by upregulation of innate immune signalling genes. Additionally, it is now apparent that the DNA damage arising from a multitude of DNA repair defects and DNA damage induced by some classical chemotherapies/radiation also has the ability to induce an innate immune response mediated by cGAS/STING activation. Here we review the role of intrinsic and extrinsic DNA damage in mediating immune activation and its context within tumourigenesis, as well as the potential therapeutic opportunities it represents for the treatment of cancer, such as combining DNA damaging agents with immunotherapies.

Cancer-specific mortality in breast cancer patients with hypothyroidism: a UK population-based study.

PURPOSE: Epidemiological studies have indicated a higher prevalence of hypothyroidism in breast cancer patients, possibly related to shared risk factors and breast cancer treatments. However, few studies have evaluated how hypothyroidism impacts survival outcomes in breast cancer patients. We aimed to determine the association between hypothyroidism and breast cancer-specific and all-cause mortality. METHODS: We conducted a population-based study using the Scottish Cancer Registry to identify women diagnosed with breast cancer between 2010 and 2017. A matched comparison cohort of breast cancer-free women was also identified. Using hospital diagnoses and dispensed prescriptions for levothyroxine, we identified hypothyroidism diagnosed before and after breast cancer diagnosis and determined associations with breast cancer-specific and all-cause mortality. Cox proportional hazards regression was used to calculate hazard ratios (HR) and 95% confidence intervals (CI) adjusted for potential confounders. RESULTS: A total of 33,500 breast cancer patients were identified, of which 3,802 had hypothyroidism before breast cancer diagnosis and 565 patients went on to develop hypothyroidism after. Breast cancer patients had higher rates of hypothyroidism compared with cancer-free controls (HR 1.14, 95% CI 1.01-1.30). Among breast cancer patients, we found no association between hypothyroidism (diagnosed before or after) and cancer-specific mortality (before: HR 0.99, 95% CI 0.88-1.12, after: HR 0.97, 95% CI 0.63-1.49). Similar associations were seen for all-cause mortality. CONCLUSION: In a large contemporary breast cancer cohort, there was little evidence that hypothyroidism, either at diagnosis or diagnosed after breast cancer, was associated with cancer-specific or all-cause mortality.

The MARECA (national study of management of breast cancer locoregional recurrence and oncological outcomes) study: National practice questionnaire of United Kingdom multi-disciplinary decision making.

INTRODUCTION: Evidence based guidelines for the optimal management of breast cancer locoregional recurrence (LRR) are limited, with potential for variation in clinical practice. This national practice questionnaire (NPQ) was designed to establish the current practice of UK breast multidisciplinary teams (MDTs) regarding LRR management. METHODS: UK breast units were invited to take part in the MARECA study MDT NPQ. Scenario-based questions were used to elicit preference in pre-operative staging investigations, surgical management, and adjuvant therapy. RESULTS: 822 MDT members across 42 breast units (out of 144; 29%) participated in the NPQ (February-August 2021). Most units (95%) routinely performed staging CT scan, but bone scan was selectively performed (31%). For patients previously treated with breast conserving surgery (BCS) and radiotherapy, few units (7%) always/usually offered repeat BCS. However, in the absence of radiotherapy, most units (90%) always/usually offered repeat BCS. For patients presenting with isolated local recurrence following previous BCS and SLNB (sentinel lymph node biopsy), most units (95%) advocated repeat SLNB. Where SLNs could not be identified, 86% proceeded to a four-node axillary sampling procedure. For ER positive, HER2 negative, node negative local recurrence, 10% of units always/usually offered chemotherapy. For ER positive, HER2 negative, node positive local recurrence, this recommendation increased to 64%. For triple negative breast cancer local recurrence, 90% of units always/usually offered chemotherapy. CONCLUSION: This survey has highlighted where consistencies and variations exist in the multidisciplinary management of breast cancer LRR. However, further research is required to determine how these management patterns influence patient outcomes, which will further refine optimal treatment pathways.

Combined Perioperative Lapatinib and Trastuzumab in Early HER2-Positive Breast Cancer Identifies Early Responders: Randomized UK EPHOS-B Trial Long-Term Results.

PURPOSE: EPHOS-B aimed to determine whether perioperative anti-HER2 therapy inhibited proliferation and/or increased apoptosis in HER2-positive breast cancer. PATIENTS AND METHODS: This randomized phase II, two-part, multicenter trial included newly diagnosed women with HER2-positive invasive breast cancer due to undergo surgery. Patients were randomized to: part 1 (1:2:2), no treatment (control), trastuzumab or lapatinib; part 2 (1:1:2) control, trastuzumab, or lapatinib and trastuzumab combination. Treatment was given for 11 days presurgery. Coprimary endpoints were change in Ki67 and apoptosis between baseline and surgery tumor samples (biologic response: ≥30% change). Central pathology review scored residual cancer burden (RCB). Relapse-free survival (RFS) explored long-term effects. RESULTS: Between November 2010 and September 2015, 257 patients were randomized (part 1: control 22, trastuzumab 57, lapatinib 51; part 2: control 29, trastuzumab 32, combination 66). Ki67 response was evaluable for 223 patients: in part 1 Ki67 response occurred in 29/44 (66%) lapatinib versus 18/49 (37%) trastuzumab (P = 0.007) and 1/22 (5%) control (P < 0.0001); in part 2 in 36/49 (74%) combination versus 14/31 (45%) trastuzumab (P = 0.02) and 2/28 (7%) control (P < 0.0001). No significant increase in apoptosis after 11 days was seen in treatment groups. Six patients achieved complete pathologic response (pCR, RCB0) and 13 RCB1, all but two in the combination group. After 6 years median follow-up, 28 (11%) had recurrence and 19 (7%) died. No recurrences or deaths were observed among patients who achieved a pCR. Ki67% falls ≥50% associated with fewer recurrences (P = 0.002). CONCLUSIONS: Early response after short duration anti-HER2 dual therapy identifies cancers dependent on the HER2 pathway providing a strategy for exploring risk-adapted individualized treatment de-escalation.

Activation of a cGAS-STING-mediated immune response predicts response to neoadjuvant chemotherapy in early breast cancer.

BACKGROUND: The DNA-damage immune-response (DDIR) signature is an immune-driven gene expression signature retrospectively validated as predicting response to anthracycline-based therapy. This feasibility study prospectively evaluates the use of this assay to predict neoadjuvant chemotherapy response in early breast cancer. METHODS: This feasibility study assessed the integration of a novel biomarker into clinical workflows. Tumour samples were collected from patients receiving standard of care neoadjuvant chemotherapy (FEC + /-taxane and anti-HER2 therapy as appropriate) at baseline, mid- and post-chemotherapy. Baseline DDIR signature scores were correlated with pathological treatment response. RNA sequencing was used to assess chemotherapy/response-related changes in biologically linked gene signatures. RESULTS: DDIR signature reports were available within 14 days for 97.8% of 46 patients (13 TNBC, 16 HER2 + ve, 27 ER + HER2-ve). Positive scores predicted response to treatment (odds ratio 4.67 for RCB 0-1 disease (95% CI 1.13-15.09, P = 0.032)). DDIR positivity correlated with immune infiltration and upregulated immune-checkpoint gene expression. CONCLUSIONS: This study validates the DDIR signature as predictive of response to neoadjuvant chemotherapy which can be integrated into clinical workflows, potentially identifying a subgroup with high sensitivity to anthracycline chemotherapy. Transcriptomic data suggest induction with anthracycline-containing regimens in immune restricted, "cold" tumours may be effective for immune priming. TRIAL REGISTRATION: Not applicable (non-interventional study). CRUK Internal Database Number 14232.

Improving preparedness prior to reconstructive breast surgery via inclusion of 3D images during pre-operative counselling: a qualitative analysis.

BACKGROUND: A proportion of women undergoing mastectomy for breast cancer choose to undergo breast reconstruction. Evidence suggests that women's preparedness for this surgery is low and that this may contribute to feelings of unmatched expectations and anxiety. There is substantial interest in decision-aids to remedy this. This study explores the incorporation of digitally rendered three-dimensional images into pre-operative counselling sessions as a means of enhancing patient preparedness. METHODS: A database of three-dimensional images was produced showing both optimal and sub-optimal aesthetic outcome, matched to participant on the basis of type of surgical reconstruction, body habitus, and skin tone. Women undergoing mastectomy for breast cancer followed by immediate reconstruction were targeted for inclusion. Participants interacted with image software during pre-operative counselling sessions by viewing, rotating, and zooming in/out to gain a more in-depth appreciation of post-operative aesthetic outcome. Semi-structured face-to-face interviews followed thereafter. Interviews were audio-recorded, transcribed, coded, and themes identified. RESULTS: Eight semi-structured interviews took place. The major emergent theme was 'increased preparedness' with subthemes including 'expectation management', 'software interaction', and 'enhanced realism'. There were no prohibitively negative emotions after interacting with images. Women reported gaining 'more of a perspective' and feeling 'more informed' after viewing images. They also valued the enhanced interactivity and better appreciation of reconstructed breast symmetry that viewing three-dimensional images offered when compared to viewing two-dimensional photographs. Finally, women also commented that three-dimensional images were more realistic. CONCLUSIONS: Results suggest that incorporation of three-dimensional images into pre-operative counselling sessions prior to breast reconstruction, is a fairly simple yet effective method of enhancing patient preparedness prior to surgery. Women particularly valued the ability to use the software to generate a more realistic idea of what to expect after their operation. Future work should focus on better understanding any quantifiable benefit from incorporating three-dimensional images routinely into pre-operative decision-making.