Differential response of HER2-positive breast cancer to anti-HER2 therapy based on HER2 protein expression level.

BACKGROUND: Increasing data indicate that HER2-positive (HER2 + ) breast cancer (BC) subtypes exhibit differential responses to targeted anti-HER2 therapy. This study aims to investigate these differences and the potential underlying molecular mechanisms. METHODS: A large cohort of BC patients (n = 7390) was utilised. The clinicopathological characteristics and differential gene expression (DGE) of HER2+ immunohistochemical (IHC) subtypes, specifically HER2 IHC 3+ and IHC 2 + /Amplified, were assessed and correlated with pathological complete response (pCR) and survival in the neoadjuvant and adjuvant settings, respectively. The role of oestrogen receptor (ER) status was also investigated. RESULTS: Compared to HER2 IHC 3+ tumours, BC patients with IHC 2 + /Amplified showed a significantly lower pCR rate (22% versus 57%, P < 0.001), shorter survival regardless of HER2 gene copy number, were less classified as HER2 enriched, and enriched for trastuzumab resistance and ER signalling pathway genes. ER positivity significantly decreased response to anti-HER2 therapy in IHC 2 + /Amplified, but not in IHC 3 + BC patients. CONCLUSION: In HER2 + BC, overexpression of HER2 protein is the driver of the oncogenic pathway, and it is the main predictor of response to anti-HER2 therapy. ER signalling pathways are more dominant in BC with equivocal HER2 expression. personalised anti-HER2 therapy based on IHC classes should be considered.

Expression of Lamin A/C in early-stage breast cancer and its prognostic value.

PURPOSE: Lamins A/C, a major component of the nuclear lamina, play key roles in maintaining nuclear integrity, regulation of gene expression, cell proliferation and apoptosis. Reduced lamin A/C expression in cancer has been reported to be a sign of poor prognosis. However, its clinical significance in breast cancer remains to be defined. This study aimed to evaluate expression and prognostic significance of lamin A/C in early-stage breast cancer. METHODS: Using immunohistochemical staining of tissue microarrays, expression of lamin A/C was evaluated in a large well-characterised series of early-stage operable breast cancer (n = 938) obtained from Nottingham Primary Breast Carcinoma Series. Association of lamin A/C expression with clinicopathological parameters and outcome was evaluated. RESULTS: Positive expression rate of lamin A/C in breast cancer was 42.2% (n = 398). Reduced/loss of expression of lamin A/C was significantly associated with high histological grade (p < 0.001), larger tumour size (p = 0.004), poor Nottingham Prognostic Index score (p < 0.001), lymphovascular invasion (p = 0.014) and development of distant metastasis (p = 0.027). Survival analysis showed that reduced/loss of expression of lamin A/C was significantly associated with shorter breast cancer-specific survival (p = 0.008). CONCLUSION: This study suggests lamin A/C plays a role in breast cancer and loss of its expression is associated with variables of poor prognosis and shorter outcome.

The mTOR downstream regulator (p-4EBP1) is a novel independent prognostic marker in ovarian cancer.

Ovarian cancer is associated with the highest mortality rate among gynaecologic malignancies. There is a need to refine the classification of ovarian cancer and identify novel targets. The mammalian target of rapamycin (mTOR) pathway has a crucial role in the pathogenesis and progression of ovarian cancer. This study aims to investigate the prognostic role of p-mTOR and its major downstream effectors p-4EBP1 (eukaryotic initiation factor 4E-binding protein 1) and p-P70S6K (ribosomal protein S6 kinase) in ovarian cancer. p-mTOR, p-4EBP1 and p-P70S6K protein expression was assessed on 195 consecutive ovarian epithelial cancers and correlated to clinicopathological features and survival. We found that high cytoplasmic expression of p-4EBP1 and p-P70S6K was associated with a serous type carcinoma (p = .005) and an advanced FIGO stage (p = .012), respectively. Univariate outcome analysis showed an inverse association between a high expression of p-4EBP1 expression and overall ovarian cancer survival (OS; p = .005) and progression-free survival (PFS; p = .005). p-P70S6K showed an inverse association with PFS (p = .001). Multivariate analyses indicated that p-4EBP1 was an independent predictor of both OS and PFS (p = .016 and p = .041, respectively). Therefore, we concluded that p-4EBP1 high protein expression is an independent predictor of outcome in ovarian cancer patients. Therefore, it could be used as a potential biomarker for prognostic stratification and treatment decisions. Impact statement What is already known on this subject? The mammalian target of rapamycin (mTOR) pathway has a crucial role in the pathogenesis and progression of ovarian cancer. To-date, very limited knowledge is known about the importance of mTOR major downstream effectors p-4EBP1 (eukaryotic initiation factor 4E-binding protein 1) and p-P70S6K (ribosomal protein S6 kinase) in ovarian cancer. What do the results of this study add? In this study, we have provided further evidence of the adverse prognostic behaviour associated with the positive expression of p-mTOR and its major downstream effectors. Moreover and by performing multivariate analysis, we for the first time have proved that p-4EBP1 is an independent predictor of clinical outcome in ovarian cancer. What are the implications of these findings for clinical practice and/or further research? p-4EBP1 could be used as a potential biomarker for prognostic stratification and treatment decisions in ovarian cancer management.

The significance of tumour microarchitectural features in breast cancer prognosis: a digital image analysis.

BACKGROUND: As only a minor portion of the information present in histological sections is accessible by eye, recognition and quantification of complex patterns and relationships among constituents relies on digital image analysis. In this study, our working hypothesis was that, with the application of digital image analysis technology, visually unquantifiable breast cancer microarchitectural features can be rigorously assessed and tested as prognostic parameters for invasive breast carcinoma of no special type. METHODS: Digital image analysis was performed using public domain software (ImageJ) on tissue microarrays from a cohort of 696 patients, and validated with a commercial platform (Visiopharm). Quantified features included elements defining tumour microarchitecture, with emphasis on the extent of tumour-stroma interface. The differential prognostic impact of tumour nest microarchitecture in the four immunohistochemical surrogates for molecular classification was analysed. Prognostic parameters included axillary lymph node status, breast cancer-specific survival, and time to distant metastasis. Associations of each feature with prognostic parameters were assessed using logistic regression and Cox proportional models adjusting for age at diagnosis, grade, and tumour size. RESULTS: An arrangement in numerous small nests was associated with axillary lymph node involvement. The association was stronger in luminal tumours (odds ratio (OR) = 1.39, p = 0.003 for a 1-SD increase in nest number, OR = 0.75, p = 0.006 for mean nest area). Nest number was also associated with survival (hazard ratio (HR) = 1.15, p = 0.027), but total nest perimeter was the parameter most significantly associated with survival in luminal tumours (HR = 1.26, p = 0.005). In the relatively small cohort of triple-negative tumours, mean circularity showed association with time to distant metastasis (HR = 1.71, p = 0.027) and survival (HR = 1.8, p = 0.02). CONCLUSIONS: We propose that tumour arrangement in few large nests indicates a decreased metastatic potential. By contrast, organisation in numerous small nests provides the tumour with increased metastatic potential to regional lymph nodes. An outstretched pattern in small nests bestows tumours with a tendency for decreased breast cancer-specific survival. Although further validation studies are required before the argument for routine quantification of microarchitectural features is established, our approach is consistent with the demand for cost-effective methods for triaging breast cancer patients that are more likely to benefit from chemotherapy.

Impact of intratumoural heterogeneity on the assessment of Ki67 expression in breast cancer.

In breast cancer (BC), the prognostic value of Ki67 expression is well-documented. Intratumoural heterogeneity (ITH) of Ki67 expression is amongst the several technical issues behind the lag of its inclusion into BC prognostic work-up. The immunohistochemical (IHC) expression of anti-Ki67 antibody (MIB1 clone) was assessed in four full-face (FF) sections from different primary tumour blocks and their matched axillary nodal (LN) metastases in a series of 55 BC. Assessment was made using the highest expression hot spots (HS), lowest expression (LS), and overall/average expression scores (AS) in each section. Heterogeneity score (Hes), co-efficient of variation, and correlation co-efficient were used to assess the levels of Ki67 ITH. Ki67 HS, LS, and AS scores were highly variable within the same section and between different sections of the primary tumour, with maximal variation observed in the LS (P < 0.001). The least variability between the different slides was observed with HS scoring. Although the associations between Ki67 and clinicopathological and molecular variables were similar when using HS or AS, the best correlation between AS and HS was observed in tumours with high Ki67 expression only. Ki67 expression in LN deposits was less heterogeneous than in the primary tumours and was perfectly correlated with the HS Ki67 expression in the primary tumour sections (r = 0.98, P < 0.001). In conclusion, assessment of Ki67 expression using HS scoring method on a full-face BC tissue section can represent the primary tumour growth fraction that is likely to metastasise. The association between Ki67 expression pattern in the LN metastasis and the HS in the primary tumour may reflect the temporal heterogeneity through clonal expansion.

Nottingham prognostic index plus (NPI+) predicts risk of distant metastases in primary breast cancer.

The Nottingham prognostic index plus (NPI+) is based on the assessment of biological class combined with established clinicopathologic prognostic variables providing improved patient outcome stratification for breast cancer superior to the traditional NPI. This study aimed to determine prognostic capability of the NPI+ in predicting risk of development of distant disease. A well-characterised series of 1073 primary early-stage BC cases treated in Nottingham and 251 cases from Budapest were immunohistochemically assessed for cytokeratin (Ck)5/6, Ck18, EGFR, oestrogen receptor (ER), progesterone receptor, HER2, HER3, HER4, Mucin 1 and p53 expression. NPI+ biological class and prognostic scores were assigned using individual algorithms for each biological class incorporating clinicopathologic parameters and investigated in terms of prediction of distant metastases-free survival (MFS). The NPI+ identified distinct prognostic groups (PG) within each molecular class which were predictive of MFS providing improved patient outcome stratification superior to the traditional NPI. NPI+ PGs, between series, were comparable in predicting patient outcome between series in luminal A, basal p53 altered and HER2+/ER+ (p > 0.01) tumours. The low-risk groups were similarly validated in luminal B, luminal N, basal p53 normal tumours (p > 0.01). Due to small patient numbers the remaining PGs could not be validated. NPI+ was additionally able to predict a higher risk of metastases at certain distant sites. This study may indicate the NPI+ as a useful tool in predicting the risk of metastases. The NPI+ provides accurate risk stratification allowing improved individualised clinical decision making for breast cancer.

Tumour cell membrane laminin expression is associated with basal-like phenotype and poor survival in Nigerian breast cancer.

INTRODUCTION: Laminin is a glycoprotein with diverse functions in carcinogenesis including cell proliferation, invasion, metastases and epithelial-mesenchymal transition (EMT). In breast cancer (BC) laminin expression is speculated to be associated with unfavourable clinicopathological and molecular characteristics. We hypothesize that laminin expression would contributed to the aggressive nature of basal like and triple negative BC phenotype observed in Black women. METHODS: The expression of laminin was determined in a well-characterised Nigerian cohort of 255 BC using tissue microarray and immunohistochemistry. Laminin expression was compared with clinical, pathological and survival characteristics. RESULTS: Laminin was expressed in 146 (57.3%) cases and significantly correlated with younger age at diagnosis (p=0.005), premenopausal status (p=0.003), expression of EGFR (p=0.002), ID4 and MTA1, basal cytokeratin 5/6, p53, and triple negative tumours (all p<0.001). In addition, there was an inverse association of laminin expression with E-cadherin (p=0.03), ER and PgR (all p<0.001) and a trend with BRCA1 (p=0.05). Univariate survival analysis showed tumours positive for laminin had significantly poorer breast cancer specific survival (BCSS, p=0.009) and disease free interval (p=0.03), but not associated in Cox multivariate analysis. CONCLUSION: This study demonstrates that laminin expression may have important roles in the aggressive nature observed in the basal-like and triple negative molecular subtype of Nigerian BC women.

KPNA2 is a nuclear export protein that contributes to aberrant localisation of key proteins and poor prognosis of breast cancer.

BACKGROUND: It is recognised that modulations of the nuclear import of macromolecules have a role in changing cellular phenotypes and carcinogenesis. We and others have noticed that aberrant subcellular localisation of DNA damage response (DDR) proteins in breast cancer (BC) is associated with loss-of-function phenotype. This study aims to investigate the biological and clinical significance of the nucleocytoplasmic transport protein karyopherin α-2 (KPNA2), and its role in controlling DDR proteins subcellular localisation in BC. METHODS: A large (n=1494) and well-characterised series of early-stage invasive BC with a long-term follow-up was assessed for KPNA2 protein by using immunohistochemistry. RESULTS: KPNA2 expression was associated with the subcellular localisation of key DDR proteins that showed cytoplasmic expression including BRCA1, RAD51, SMC6L1, γH2AX, BARD1, UBC9, PIAS1 and CHK1. High level of KPNA2 was associated not only with cytoplasmic localisation of these proteins but also with their low/negative nuclear expression. Positive KPNA2 expression was associated with negative oestrogen receptor and triple-negative phenotype. Survival analysis showed that KPNA2 was associated with poor outcome (P<0.0001), but this effect was not independent of other prognostic variables. CONCLUSIONS: This study provides further evidence for the complexity of DDR mechanism in BC, and that KNPA2 has a role in the aberrant subcellular localisation of DDR proteins with subsequent impaired function.

Prognostic factors in metaplastic carcinoma of the breast: a multi-institutional study.

BACKGROUND: Metaplastic breast carcinoma (MBC) is a rare type of breast cancer that has basal-like characteristics and is perceived to have poorer prognosis when compared with conventional no specific type/ductal carcinomas (ductal/NST). However, current data on MBC are largely derived from small case series or population-based reports. This study aimed to assess the clinicopathological features and outcome of MBC identified through an international multicentre collaboration. METHODS: A large international multicentre series of MBC (no=405) with histological confirmation and follow-up information has been included in this study. The prognostic value of different variables and outcome has been assessed and compared with grade, nodal status and ER/HER2 receptor-matched ductal/NST breast carcinoma. RESULTS: The outcome of MBC diagnosed in Asian countries was more favourable than those in Western countries. The outcome of MBC is not different from matched ductal/NST carcinoma but the performance of the established prognostic variables in MBC is different. Lymph node stage, lymphovascular invasion and histologic subtype are associated with outcome but tumour size and grade are not. Chemotherapy was associated with longer survival, although this effect was limited to early-stage disease. In this study no association between radiotherapy and outcome was identified. Multivariate analysis of MBC shows that histologic subtype is an independent prognostic feature. CONCLUSIONS: This study suggests that MBC is a heterogeneous disease. Although the outcome of MBC is not different to matched conventional ductal/NST breast carcinoma, its behaviour is dependent on the particular subtype with spindle cell carcinoma in particular has an aggressive biological behaviour. Management of patients with MBC should be based on validated prognostic variables.

Checkpoint kinase1 (CHK1) is an important biomarker in breast cancer having a role in chemotherapy response.

BACKGROUND: Checkpoint kinase1 (CHK1), which is a key component of DNA-damage-activated checkpoint signalling response, may have a role in breast cancer (BC) pathogenesis and influence response to chemotherapy. This study investigated the clinicopathological significance of phosphorylated CHK1 (pCHK1) protein in BC. METHOD: pCHK1 protein expression was assessed using immunohistochemistry in a large, well-characterized annotated series of early-stage primary operable invasive BC prepared as tissue microarray (n=1200). RESULT: pCHK1 showed nuclear and/or cytoplasmic expression. Tumours with nuclear expression showed positive associations with favourable prognostic features such as lower grade, lower mitotic activity, expression of hormone receptor and lack of expression of KI67 and PI3K (P<0.001). On the other hand, cytoplasmic expression was associated with features of poor prognosis such as higher grade, triple-negative phenotype and expression of KI67, p53, AKT and PI3K. pCHK1 expression showed an association with DNA damage response (ATM, RAD51, BRCA1, KU70/KU80, DNA-PKCα and BARD1) and sumoylation (UBC9 and PIASγ) biomarkers. Subcellular localisation of pCHK1 was associated with the expression of the nuclear transport protein KPNA2. Positive nuclear expression predicted better survival outcome in patients who did not receive chemotherapy in the whole series and in ER-positive tumours. In ER-negative and triple-negative subgroups, nuclear pCHK1 predicted shorter survival in patients who received cyclophosphamide, methotrexate and 5-florouracil chemotherapy. CONCLUSIONS: Our data suggest that pCHK1 may have prognostic and predictive significance in BC. Subcellular localisation of pCHK1 protein is related to its function.

Markers of progression in early-stage invasive breast cancer: a predictive immunohistochemical panel algorithm for distant recurrence risk stratification.

Accurate distant metastasis (DM) prediction is critical for risk stratification and effective treatment decisions in breast cancer (BC). Many prognostic markers/models based on tissue marker studies are continually emerging using conventional statistical approaches analysing complex/dimensional data association with DM/poor prognosis. However, few of them have fulfilled satisfactory evidences for clinical application. This study aimed at building DM risk assessment algorithm for BC patients. A well-characterised series of early invasive primary operable BC (n = 1902), with immunohistochemical expression of a panel of biomarkers (n = 31) formed the material of this study. Decision tree algorithm was computed using WEKA software, utilising quantitative biomarkers' expression and the absence/presence of distant metastases. Fifteen biomarkers were significantly associated with DM, with six temporal subgroups characterised based on time to development of DM ranging from <1 to >15 years of follow-up. Of these 15 biomarkers, 10 had a significant expression pattern where Ki67LI, HER2, p53, N-cadherin, P-cadherin, PIK3CA and TOMM34 showed significantly higher expressions with earlier development of DM. In contrast, higher expressions of ER, PR and BCL2 were associated with delayed occurrence of DM. DM prediction algorithm was built utilising cases informative for the 15 significant markers. Four risk groups of patients were characterised. Three markers p53, HER2 and BCL2 predicted the probability of DM, based on software-generated cut-offs, with a precision rate of 81.1 % for positive predictive value and 77.3 %, for the negative predictive value. This algorithm reiterates the reported prognostic values of these three markers and underscores their central biological role in BC progression. Further independent validation of this pruned panel of biomarkers is therefore warranted.

Nottingham Prognostic Index Plus (NPI+): a modern clinical decision making tool in breast cancer.

BACKGROUND: Current management of breast cancer (BC) relies on risk stratification based on well-defined clinicopathologic factors. Global gene expression profiling studies have demonstrated that BC comprises distinct molecular classes with clinical relevance. In this study, we hypothesised that molecular features of BC are a key driver of tumour behaviour and when coupled with a novel and bespoke application of established clinicopathologic prognostic variables can predict both clinical outcome and relevant therapeutic options more accurately than existing methods. METHODS: In the current study, a comprehensive panel of biomarkers with relevance to BC was applied to a large and well-characterised series of BC, using immunohistochemistry and different multivariate clustering techniques, to identify the key molecular classes. Subsequently, each class was further stratified using a set of well-defined prognostic clinicopathologic variables. These variables were combined in formulae to prognostically stratify different molecular classes, collectively known as the Nottingham Prognostic Index Plus (NPI+). The NPI+ was then used to predict outcome in the different molecular classes. RESULTS: Seven core molecular classes were identified using a selective panel of 10 biomarkers. Incorporation of clinicopathologic variables in a second-stage analysis resulted in identification of distinct prognostic groups within each molecular class (NPI+). Outcome analysis showed that using the bespoke NPI formulae for each biological BC class provides improved patient outcome stratification superior to the traditional NPI. CONCLUSION: This study provides proof-of-principle evidence for the use of NPI+ in supporting improved individualised clinical decision making.

Association between CD8+ T-cell infiltration and breast cancer survival in 12,439 patients.

BACKGROUND: T-cell infiltration in estrogen receptor (ER)-negative breast tumours has been associated with longer survival. To investigate this association and the potential of tumour T-cell infiltration as a prognostic and predictive marker, we have conducted the largest study of T cells in breast cancer to date. PATIENTS AND METHODS: Four studies totalling 12 439 patients were used for this work. Cytotoxic (CD8+) and regulatory (forkhead box protein 3, FOXP3+) T cells were quantified using immunohistochemistry (IHC). IHC for CD8 was conducted using available material from all four studies (8978 samples) and for FOXP3 from three studies (5239 samples)-multiple imputation was used to resolve missing data from the remaining patients. Cox regression was used to test for associations with breast cancer-specific survival. RESULTS: In ER-negative tumours [triple-negative breast cancer and human epidermal growth factor receptor 2 (human epidermal growth factor receptor 2 (HER2) positive)], presence of CD8+ T cells within the tumour was associated with a 28% [95% confidence interval (CI) 16% to 38%] reduction in the hazard of breast cancer-specific mortality, and CD8+ T cells within the stroma with a 21% (95% CI 7% to 33%) reduction in hazard. In ER-positive HER2-positive tumours, CD8+ T cells within the tumour were associated with a 27% (95% CI 4% to 44%) reduction in hazard. In ER-negative disease, there was evidence for greater benefit from anthracyclines in the National Epirubicin Adjuvant Trial in patients with CD8+ tumours [hazard ratio (HR) = 0.54; 95% CI 0.37-0.79] versus CD8-negative tumours (HR = 0.87; 95% CI 0.55-1.38). The difference in effect between these subgroups was significant when limited to cases with complete data (P heterogeneity = 0.04) and approached significance in imputed data (P heterogeneity = 0.1). CONCLUSIONS: The presence of CD8+ T cells in breast cancer is associated with a significant reduction in the relative risk of death from disease in both the ER-negative [supplementary Figure S1, available at Annals of Oncology online] and the ER-positive HER2-positive subtypes. Tumour lymphocytic infiltration may improve risk stratification in breast cancer patients classified into these subtypes. NEAT ClinicalTrials.gov: NCT00003577.

Identification of key clinical phenotypes of breast cancer using a reduced panel of protein biomarkers.

BACKGROUND: Breast cancer is a heterogeneous disease characterised by complex molecular alterations underlying the varied behaviour and response to therapy. However, translation of cancer genetic profiling for use in routine clinical practice remains elusive or prohibitively expensive. As an alternative, immunohistochemical analysis applied to routinely processed tissue samples could be used to identify distinct biological classes of breast cancer. METHODS: In this study, 1073 archival breast tumours previously assessed for 25 key breast cancer biomarkers using immunohistochemistry and classified using clustering algorithms were further refined using naïve Bayes classification performance. Criteria for class membership were defined using the expression of a reduced panel of 10 proteins able to identify key molecular classes. We examined the association between these breast cancer classes with clinicopathological factors and patient outcome. RESULTS: We confirm patient classification similar to established genotypic biological classes of breast cancer in addition to novel sub-divisions of luminal and basal tumours. Correlations between classes and clinicopathological parameters were in line with expectations and showed highly significant association with patient outcome. Furthermore, our novel biological class stratification provides additional prognostic information to the Nottingham Prognostic Index. CONCLUSION: This study confirms that distinct molecular phenotypes of breast cancer can be identified using robust and routinely available techniques and both the luminal and basal breast cancer phenotypes are heterogeneous and contain distinct subgroups.

A critical review why assessment of steroid hormone receptors in breast cancer should be quantitative.

Steroid receptors have been around in the field of breast cancer for decades now. Still, controversy remains on how best to report steroid receptors. In this review, we will convince the reader why benefits outweigh pitfalls, when reporting steroid receptors in a quantitative rather than qualitative way. Summarizing decades of research in this field, we will explore the evidence why quantitative reporting is superior in all settings (neoadjuvant, adjuvant and metastatic settings). Furthermore, we will also summarize different staining methods, definitions and pitfalls that have shown to be important points of discussion in earlier debates. Although the molecular unraveling of breast cancer in the past decade has revolutionized the way we think about breast cancer, we should not easily abandon the classical pathological variables such as steroid receptors in favor of molecular tools.

Lack of expression of the proteins GMPR2 and PPARα are associated with the basal phenotype and patient outcome in breast cancer.

UNLABELLED: Basal-like tumours (BP) are a poor prognostic class of breast cancer but remain a biologically and clinically heterogeneous group. We have previously identified two novel genes PPARα (positive) and GMPR2 (negative) whose expression was significantly associated with BP at the transcriptome level. In this study, using a large and well-characterised series of operable invasive breast carcinomas (1,043 cases) prepared as TMAs, we assessed these targets at the protein level using immunohistochemistry and investigated associations with clinicopathological variables and patient outcome. RESULTS: Lack of PPARα and GMPR2 protein expression was associated with BP, as defined by the expression of cytokeratin (CK) 5/6 and/or CK14, (p = 0.023, p = 0.001, respectively) or as triple-negative (ER-, PR-, HER2-) phenotype (p < 0.001 for both proteins). Positive expression of both markers was associated ER and PR positive status (p < 0.05) and with the good Nottingham Prognostic Index group (p = 0.012, p < 0.001, respectively). Univariate survival analysis showed an association between lack of expression of PPARα and GMPR2 and poor outcome in terms of shorter disease-free survival and shorter breast cancer-specific survival, respectively. However, multivariate analysis showed that these associations were not independent of other prognostic variables, namely tumour size, grade, and nodal stage. In conclusion, this study demonstrates that loss of expression of GMPR2 and PPARα is associated with BP at the protein level; indicating that they may play a role in carcinogenesis of this molecularly complex and clinically important subtype. Further studies into their relevance in further classification of BP are warranted.

PREDICT Plus: development and validation of a prognostic model for early breast cancer that includes HER2.

BACKGROUND: Predict (www.predict.nhs.uk) is an online, breast cancer prognostication and treatment benefit tool. The aim of this study was to incorporate the prognostic effect of HER2 status in a new version (Predict+), and to compare its performance with the original Predict and Adjuvant!. METHODS: The prognostic effect of HER2 status was based on an analysis of data from 10 179 breast cancer patients from 14 studies in the Breast Cancer Association Consortium. The hazard ratio estimates were incorporated into Predict. The validation study was based on 1653 patients with early-stage invasive breast cancer identified from the British Columbia Breast Cancer Outcomes Unit. Predicted overall survival (OS) and breast cancer-specific survival (BCSS) for Predict+, Predict and Adjuvant! were compared with observed outcomes. RESULTS: All three models performed well for both OS and BCSS. Both Predict models provided better BCSS estimates than Adjuvant!. In the subset of patients with HER2-positive tumours, Predict+ performed substantially better than the other two models for both OS and BCSS. CONCLUSION: Predict+ is the first clinical breast cancer prognostication tool that includes tumour HER2 status. Use of the model might lead to more accurate absolute treatment benefit predictions for individual patients.

Molecular characteristics and prognostic features of breast cancer in Nigerian compared with UK women.

Although breast cancer (BC) incidence is lower in African-American women compared with White-American, in African countries such as Nigeria, BC is a common disease. Nigerian women have a higher risk for early-onset, with a high mortality rate from BC, prompting speculation that risk factors could be genetic and the molecular portrait of these tumours are different to those of western women. In this study, 308 BC samples from Nigerian women with complete clinical history and tumour characteristics were included and compared with a large series of BC from the UK as a control group. Immunoprofile of these tumours was characterised using a panel of 11 biomarkers of known relevance to BC. The immunoprofile and patients' outcome were compared with tumour grade-matched UK control group. Nigerian women presenting with BC were more frequently premenopausal, and their tumours were characterised by large primary tumour size, high tumour grade, advanced lymph node stage, and a higher rate of vascular invasion compared with UK women. In the grade-matched groups, Nigerian BC showed over representation of triple-negative and basal phenotypes and BRCA1 deficiency BC compared with UK women, but no difference was found regarding HER2 expression between the two series. Nigerian women showed significantly poorer outcome after development of BC compared with UK women. This study demonstrates that there are possible genetic and molecular differences between an indigenous Black population and a UK-based series. The basal-like, triple negative and BRCA1 dysfunction groups of tumours identified in this study may have implications in the development of screening programs and therapies for African patients and families that are likely to have a BRCA1 dysfunction, basal like and triple negative.

Which lesions with a radiological or core biopsy diagnosis of fibroadenoma should be excised?

INTRODUCTION: A recent Association of Breast Surgery summary statement on fibroadenoma management recommends excision only for cellular fibroepithelial lesions and rapidly growing lesions with a core biopsy diagnosis of fibroadenoma; persistent pain is a relative indication for excision. METHODS: This retrospective study looked at the impact this approach would have on the diagnosis of phyllodes tumours. RESULTS: From 2014 to 2018, there were 1,058 core biopsy diagnoses of fibroadenoma; 112 lesions were excised, of which 98 were fibroadenomas, 4 were hamartomas and 10 were phyllodes tumours. In this group, an excision diagnosis of phyllodes tumour was associated with size more than 40 mm, age more than 40 years and radiological suspicion of phyllodes tumour or carcinoma. One hundred and sixty-six excised fibroepithelial lesions with no previous core biopsy included eight phyllodes tumours; in this group, rapid growth was associated with phyllodes tumour diagnosis. Twelve of the 26 fibroepithelial lesions classified as B3 (cellular fibroepithelial lesion or phyllodes tumour) were diagnosed as phyllodes tumours on excision. Using a combination of radiological, clinical and pathological features it was possible to create an excision policy that would recommend excision of 22 of the 31 phyllodes tumours in this period. Eight of the nine 'missed' phyllodes tumours were benign. CONCLUSION: The Association of Breast Surgery summary statement will reduce the number of fibroadenomas excised, but may also result in delayed diagnosis of some phyllodes tumours. Appropriate safety netting advice should be provided to identify rapidly growing lesions.