Deciphering the Clinical Behaviour of Invasive Lobular Carcinoma of the Breast Defines an Aggressive Subtype

Background: Invasive lobular carcinoma (ILC), the most common special type of breast cancer (BC), has unique clinical behaviour and is different from invasive ductal carcinoma of no special type (IDC-NST). However, ILC further comprises a diverse group of tumours with distinct features. This study aims to examine the clinicopathological and prognostic features of different variants of ILC, with a particular focus on characterising aggressive subtypes. Methods: A large (n = 7140) well-characterised and histologically reviewed BC cohort with treatment and long-term follow-up data was investigated. The cohort was classified based on the WHO classification of tumours into main histological subtypes, including ILC and IDC-NST. ILCs were further classified into variants. Clinicopathological parameters and patient outcomes in terms of BC-specific survival (BCSS) and disease-free survival (DFS) were evaluated. Results: ILC constituted 11% of the cohort. The most common non-classic ILC variants were pleomorphic (pILC) and solid (sILC), constituting 19% of ILC. Compared to classic and related variants (alveolar, trabecular, papillary, and tubulolobular; cILC), pILC and sILC variants were associated with aggressive tumour characteristics. The histologic grade of ILC was an important prognostic variable. The survival patterns identified an aggressive ILC subtype encompassing pILC and high-grade sILC. These tumours, which comprised 14% of the cases, were associated with clinicopathological characteristics of poor prognosis and had high BC-specific death and recurrence rates compared not only to cILC (p < 0.001) but also to IDC-NST (p = 0.02) patients. Contrasting this, cILC patients had significantly longer BCSS and DFS than IDC-NST patients in the first 10 to 15 years of follow-up. Adjuvant chemotherapy did not improve the outcome of patients with aggressive ILC subtypes. Conclusions: pILC and high-grade sILC variants comprise an aggressive ILC subtype associated with poor prognostic characteristics and a poor response to chemotherapy. These results warrant confirmation in randomised clinical trials

Quantitative expression of oestrogen receptor in breast cancer: Clinical and molecular significance

BackgroundOestrogen receptor (ER) positive breast cancer (BC) patients are eligible for endocrine therapy (ET), regardless of ER immunohistochemical expression level. There is a wide spectrum of ER expression and the response to ET is not uniform. This study aimed to assess the clinical and molecular consequences of ER heterogeneity with respect to ET-response.MethodsER expression, categorised by percentage and staining intensity in a large BC cohort (n = 7559) was correlated with clinicopathological parameters and patient ET response. The Cancer Genome Atlas Data BC cohort (n = 1047) was stratified by ER expression and transcriptomic analysis completed to better understand the molecular basis of ER heterogeneity.ResultsThe quantitative proportional increase in ER expression was positively associated with favourable prognostic parameters. Tumours with 1–9% ER expression were characteristically similar to ER-negative (<1%) tumours. Maximum ET-response was observed in tumours with 100% ER expression, with responses significantly different to tumours exhibiting ER at < 100% and significantly decreased survival rates were observed in tumours with 50% and 10% of ER expression. The Histochemical-score (H-score), which considers both staining intensity and percentage, added significant prognostic value over ER percentage alone with significant outcome differences observed at H-scores of 30, 100 and 200. There was a positive correlation between ER expression and ESR1 mRNA expression and expression of ER-regulated genes. Pathway analysis identified differential expression in key cancer-related pathways in different ER-positive groups.ConclusionET-response is statistically proportionally related to ER expression with significant differences observed at 10%, 50% and 100%. The H-score adds prognostic and predictive information

AI‐based intra‐tumor heterogeneity score of Ki67 expression as a prognostic marker for early‐stage ER+/HER2− breast cancer

arly-stage estrogen receptor positive and human epidermal growth factor receptor negative (ER+/HER2−) luminal breast cancer (BC) is quite heterogeneous and accounts for about 70% of all BCs. Ki67 is a proliferation marker that has a significant prognostic value in luminal BC despite the challenges in its assessment. There is increasing evidence that spatial colocalization, which measures the evenness of different types of cells, is clinically important in several types of cancer. However, reproducible quantification of intra-tumor spatial heterogeneity remains largely unexplored. We propose an automated pipeline for prognostication of luminal BC based on the analysis of spatial distribution of Ki67 expression in tumor cells using a large well-characterized cohort (n = 2,081). The proposed Ki67 colocalization (Ki67CL) score can stratify ER+/HER2− BC patients with high significance in terms of BC-specific survival (p < 0.00001) and distant metastasis-free survival (p = 0.0048). Ki67CL score is shown to be highly significant compared with the standard Ki67 index. In addition, we show that the proposed Ki67CL score can help identify luminal BC patients who can potentially benefit from adjuvant chemotherapy

AI-enabled routine H&E image based prognostic marker for early-stage luminal breast cancer

Breast cancer (BC) grade is a well-established subjective prognostic indicator of tumour aggressiveness. Tumour heterogeneity and subjective assessment result in high degree of variability among observers in BC grading. Here we propose an objective Haematoxylin & Eosin (H&E) image-based prognostic marker for early-stage luminal/Her2-negative BReAst CancEr that we term as the BRACE marker. The proposed BRACE marker is derived from AI based assessment of heterogeneity in BC at a detailed level using the power of deep learning. The prognostic ability of the marker is validated in two well-annotated cohorts (Cohort-A/Nottingham: n = 2122 and Cohort-B/Coventry: n = 311) on early-stage luminal/HER2-negative BC patients treated with endocrine therapy and with long-term follow-up. The BRACE marker is able to stratify patients for both distant metastasis free survival (p = 0.001, C-index: 0.73) and BC specific survival (p < 0.0001, C-index: 0.84) showing comparable prediction accuracy to Nottingham Prognostic Index and Magee scores, which are both derived from manual histopathological assessment, to identify luminal BC patients that may be likely to benefit from adjuvant chemotherapy

Combined proliferation and apoptosis index provides better risk stratification in breast cancer

IntroductionBreast cancer (BC) risk stratification is critical for predicting behaviour and guiding management decision-making. Despite the well-established prognostic value of cellular proliferation in BC, the interplay between proliferation and apoptosis remains to be defined. In this study, we hypothesised that the combined proliferation and apoptosis indices can provide a more accurate in vivo growth rate measure and a precise prognostic predictor.Methods and ResultsApoptotic and mitotic figures were counted in whole slide images (WSI) generated from haematoxylin and eosin-stained sections of 1545 BC cases derived from two well-defined BC cohorts. Counts were carried out visually within defined areas. There was a significant correlation between mitosis and apoptosis scores. High apoptotic counts were associated with features of aggressive behaviour including high grade, high pleomorphism score, and hormonal receptor negativity. Although the mitotic index (MI) and apoptotic index (AI) were independent prognostic indicators, the prognostic value was synergistically higher when combined. BC patients with a high combined AI and MI had the shortest survival. Replacing the mitosis score with the mitosis-apoptosis index, in the Nottingham grading system, revealed that the modified grade with the new score had a higher significant association with BC-specific survival with a higher hazard ratio.ConclusionApoptotic figures count provides additional prognostic value in BC when combined with MI, such a combination can be implemented to assess the behaviour of BC and provides an accurate prognostic indicator. This can be considered when using artificial intelligence algorithms to assess proliferation in BC

Potential quality pitfalls of digitalized whole slide image of breast pathology in routine practice

Using digitalized whole slide images (WSI) in routine histopathology practice is a revolutionary technology. This study aims to assess the clinical impacts of WSI quality and representation of the corresponding glass slides. 40,160 breast WSIs were examined and compared with their corresponding glass slides. The presence, frequency, location, tissue type, and the clinical impacts of missing tissue were assessed. Scanning time, type of the specimens, time to WSIs implementation, and quality control (QC) measures were also considered. The frequency of missing tissue ranged from 2% to 19%. The area size of the missed tissue ranged from 1–70%. In most cases (>75%), the missing tissue area size was <10% and peripherally located. In all cases the missed tissue was fat with or without small entrapped normal breast parenchyma. No missing tissue was identified in WSIs of the core biopsy specimens. QC measures improved images quality and reduced WSI failure rates by seven-fold. A negative linear correlation between the frequency of missing tissue and both the scanning time and the image file size was observed (p < 0.05). None of the WSI with missing tissues resulted in a change in the final diagnosis. Missing tissue on breast WSI is observed but with variable frequency and little diagnostic consequence. Balancing between WSI quality and scanning time/image file size should be considered and pathology laboratories should undertake their own assessments of risk and provide the relevant mitigations with the appropriate level of caution

Refining the definition of HER2 low class in invasive breast cancer

BackgroundEmerging evidence indicates that breast cancer (BC) patients whose tumours express HER2 protein without HER2 gene amplification (HER2-low), can benefit from antibody-drug conjugates (ADC). However, the current definition of HER2-low BC remains incomplete with low rates of concordance. This study aims to refine HER2-low definition with emphasis on distinguishing HER2 score 0 from score 1+ to identify patients who are eligible for ADC.MethodsBC cohort (n=363) with HER2 IHC scores 0, 1+ and 2+ (without HER2 gene amplification) and available HER2 mRNA was included. HER2 staining intensity, pattern, and subcellular localisation were reassessed. Artificial neural network analysis was applied to cluster the cohort and to distinguish HER2 score 0 from 1+. Reproducibility and reliability of the refined criteria were tested.ResultsHER2 IHC score 1+ was refined as membranous staining in invasive cells as either: 1) faint intensity in ≥20% of cells regardless the circumferential completeness, 2) weak complete staining in ≤10%, 3) weak incomplete staining in >10%, 4) moderate incomplete staining in ≤10%. Based on this, 63% of the HER2 negative cases were reclassified as positive (HER2-low). The refined score showed perfect observer agreement compared to the moderate agreement in the original clinical scores. Similar results were generated when the refined score was applied on the independent BC cohorts. A proposal to refine the definition of other HER2 classes is presented.ConclusionThis study refined the definition of HER2-low BC based on correlation with HER2 mRNA and distinguished between HER2 IHC score 1+ and score 0 tumours

Concordance of HER2-low scoring in breast carcinoma among expert pathologists in the United Kingdom and the republic of Ireland –on behalf of the UK national coordinating committee for breast pathology

Background: Recent clinical evidence showed that breast cancer with low HER2 expression levels responded to trastuzumab deruxtecan therapy. The HER2-low cancers comprise immunohistochemistry (IHC) score 1+ and 2+ ISH non-amplified tumours, currently classified as HER2 negative. Little data exists on the reproducibility of pathologists reporting of HER2-low cancer. Patient and methods: Sixteen expert pathologists of the UK National Coordinating Committee for Breast Pathology scored 50 digitally scanned HER2 IHC slides. The overall level of agreement, Fleiss multiple-rater kappa statistics and Cohen's Kappa were calculated. Cases with low concordance were re-scored by the same pathologists after a washout period. Results: Absolute agreement was achieved in 6% of cases, all of which scored 3+. Poor agreement was found in 5/50 (10%) of cases. This was due to heterogeneous HER2 expression, cytoplasmic staining and low expression spanning the 10% cut-off value. Highest concordance (86%) was achieved when scores were clustered as 0 versus others. Improvement in kappa of overall agreement was achieved when scores 1+ and 2+ were combined. Inter-observer agreement was moderate to substantial in the whole cohort but fair to moderate in the HER2-low group. Similarly, consensus-observer agreement was substantial to almost perfect in the whole cohort and moderate to substantial in the HER2-low group. Conclusion: HER2-low breast cancer suffers from lower concordance among expert pathologists. While most cases can reproducibly be classified, a small proportion (10%) remained challenging. Refining the criteria for reporting and consensus scoring will help select appropriate patients for targeted therapy

Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries

© 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 licenseBackground: 80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality. Methods: This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494. Findings: Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70–8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39–8·80) and upper-middle-income countries (2·06, 1·11–3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26–11·59) and upper-middle-income countries (3·89, 2·08–7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications. Interpretation: Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications. Funding: National Institute for Health Research Global Health Research Unit

Effects of hospital facilities on patient outcomes after cancer surgery: an international, prospective, observational study

© 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 licenseBackground: Early death after cancer surgery is higher in low-income and middle-income countries (LMICs) compared with in high-income countries, yet the impact of facility characteristics on early postoperative outcomes is unknown. The aim of this study was to examine the association between hospital infrastructure, resource availability, and processes on early outcomes after cancer surgery worldwide. Methods: A multimethods analysis was performed as part of the GlobalSurg 3 study—a multicentre, international, prospective cohort study of patients who had surgery for breast, colorectal, or gastric cancer. The primary outcomes were 30-day mortality and 30-day major complication rates. Potentially beneficial hospital facilities were identified by variable selection to select those associated with 30-day mortality. Adjusted outcomes were determined using generalised estimating equations to account for patient characteristics and country-income group, with population stratification by hospital. Findings: Between April 1, 2018, and April 23, 2019, facility-level data were collected for 9685 patients across 238 hospitals in 66 countries (91 hospitals in 20 high-income countries; 57 hospitals in 19 upper-middle-income countries; and 90 hospitals in 27 low-income to lower-middle-income countries). The availability of five hospital facilities was inversely associated with mortality: ultrasound, CT scanner, critical care unit, opioid analgesia, and oncologist. After adjustment for case-mix and country income group, hospitals with three or fewer of these facilities (62 hospitals, 1294 patients) had higher mortality compared with those with four or five (adjusted odds ratio [OR] 3·85 [95% CI 2·58–5·75]; p<0·0001), with excess mortality predominantly explained by a limited capacity to rescue following the development of major complications (63·0% vs 82·7%; OR 0·35 [0·23–0·53]; p<0·0001). Across LMICs, improvements in hospital facilities would prevent one to three deaths for every 100 patients undergoing surgery for cancer. Interpretation: Hospitals with higher levels of infrastructure and resources have better outcomes after cancer surgery, independent of country income. Without urgent strengthening of hospital infrastructure and resources, the reductions in cancer-associated mortality associated with improved access will not be realised. Funding: National Institute for Health and Care Research