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BACKGROUND AND AIMS: Chromosome 17 alterations affect the assessment of HER2 gene amplification in breast cancer (BC), but its clinical significance remains unclear. This study aimed to identify the prevalence of centromere enumeration probe 17 (CEP17) alterations, and its correlation with response to neoadjuvant therapy (NAT) in BC patients with human epidermal growth factor receptor 2 (HER2) immunohistochemistry-equivocal score. METHODS AND RESULTS: A large BC cohort (n = 6049) with HER2 immunohistochemistry score 2+ and florescent in-situ hybridisation (FISH) results was included to assess the prevalence of CEP17 alterations. Another cohort (n = 885) with available clinicopathological data was used to evaluate the effect of CEP17 in the setting of NAT. HER2-amplified tumours with monosomy 17 (CEP17 copy number < 1.5 per nucleus), normal 17 (CEP17 1.5-< 3.0) and polysomy 17 (CEP17 ≥ 3.0) were observed in 16, 59 and 25%, respectively, compared with 3, 74 and 23%, respectively, in HER2-non-amplified tumours. There was no significant relationship between CEP17 alterations and pathological complete response (pCR) rate in both HER2-amplified and HER2-non-amplified tumours. The independent predictors of pCR were oestrogen (ER) negativity in HER2-amplified tumours [ER negative versus positive; odds ratio (OR) = 11.80; 95% confidence interval (CI) = 1.37-102.00; P = 0.02], and histological grade 3 in HER2 non-amplified tumours (3 versus 1, 2; OR = 5.54; 95% CI = 1.61-19.00; P = 0.007). CONCLUSION: The impacts of CEP17 alterations are not as strong as those of HER2/CEP17 ratio and HER2 copy number. The hormonal receptors status and tumour histological grade are more useful to identify BC patients with a HER2 immunohistochemistry-equivocal score who would benefit from NAT.

Lymphovascular invasion (LVI) is a key step in breast cancer (BC) metastasis. Targeting the molecular drivers of LVI can improve BC patients’ management. However, the underlying molecular mechanisms of LVI are complex and interconnected with various carcinogenesis pathways. This study aimed to identify the key regulatory gene associated with LVI and to investigate its mechanisms of action and prognostic significance. Artificial neural network (ANN) was applied to two large transcriptomic datasets of BC with well-characterised LVI status. Cyclin B2 (CCNB2) was identified in the top genes associated with LVI positivity. In vitro functional assays were carried out to assess the role of CCNB2 in tumour cell behaviour and their interactions with endothelial cells using a panel of BC cell lines. Large annotated BC cohorts were used to assess the clinical and prognostic role of CCNB2 at the transcriptomic and protein levels. Knockdown (KD) of CCNB2 mRNA reduced BC cell migration, inhibited proliferation, blocked the G2/M transition during the cell cycle and increased the number of apoptotic cells. Importantly, KD of CCNB2 reduced BC cell lines adherence and transmigration across endothelial cell lines. High CCNB2 protein expression was independently associated with LVI positivity in addition to other features of aggressive behaviour, including larger tumour size, higher histological grade, hormonal receptor-negativity, and HER2-positivity, and with shorter survival. We conclude that CCNB2 plays a crucial role in LVI development in BC, implying that CCNB2 could confer a promising therapeutic target to inhibit LVI and reduce metastatic events.

PurposeThe outcome of the luminal oestrogen receptor-positive (ER +) subtype of breast cancer (BC) is highly variable and patient stratification needs to be refined. We assessed the prognostic significance of oestrogen-regulated solute carrier family 39 member 6 (SLC39A6) in BC, with emphasis on ER + tumours.Materials and methodsSLC39A6 mRNA expression and copy number alterations were assessed using the METABRIC cohort (n = 1980). SLC39A6 protein expression was evaluated in a large (n = 670) and annotated series of early-stage (I–III) operable BC using tissue microarrays and immunohistochemistry. The associations between SLC39A6 expression and clinicopathological parameters, patient outcomes and other ER-related markers were evaluated using Chi-square tests and Kaplan–Meier curves.ResultsHigh SLC39A6 mRNA and protein expression was associated with features characteristic of less aggressive tumours in the entire BC cohort and ER + subgroup. SLC39A6 protein expression was detected in the cytoplasm and nuclei of the tumour cells. High SLC39A6 nuclear expression and mRNA levels were positively associated with ER + tumours and expression of ER-related markers, including the progesterone receptor, forkhead box protein A1 and GATA binding protein 3. In the ER + luminal BC, high SLC39A6 expression was independently associated with longer BC-specific survival (BCSS) (P = 0.015, HR 0.678, 95% CI 0.472‒0.972) even in those who did not receive endocrine therapy (P = 0.001, HR 0.701, 95% CI 0.463‒1.062).ConclusionSLC39A6 may be prognostic for a better outcome in ER + luminal BC. Further functional studies to investigate the role of SLC39A6 in ER + luminal BC are warranted.

Can we predict if an early stage cancer patient is at high risk of developing distant metastasis and what clinicopathological factors are associated with such a risk? In this paper, we propose a ranking based censoring-aware machine learning model for answering such questions. The proposed model is able to generate an interpretable formula for risk stratifi-cation using a minimal number of clinicopathological covariates through L1-regulrization. Using this approach, we analyze the association of time to distant metastasis (TTDM) with various clinical parameters for early stage, luminal (ER+ or HER2-) breast cancer patients who received endocrine therapy but no chemotherapy (n = 728). The TTDM risk stratification formula obtained using the proposed approach is primarily based on mitotic score, histolog-ical tumor type and lymphovascular invasion. These findings corroborate with the known role of these covariates in increased risk for distant metastasis. Our analysis shows that the proposed risk stratification formula can discriminate between cases with high and low risk of distant metastasis (p-value < 0.005) and can also rank cases based on their time to distant metastasis with a concordance-index of 0.73., Comment: Accepted in proc. (Machine Learning for Pharma and Healthcare Applications PharML 2021) European Conference on Machine Learning and Principles and Practice of Knowledge Discovery in Databases, Sep 13-17, 2021

BACKGROUND: The ASCO/CAP guidance on HER2 testing in breast cancer (BC) has recently changed. Group 2 tumours with immunohistochemistry score 2+ and HER2/CEP17 ratio ≥2.0 and HER2 copy number

BackgroundLymphovascular invasion (LVI) is a prognostic factor in early-stage invasive breast cancer (BC). Through bioinformatics, data analyses of multiple BC cohorts revealed the positive association between interferon-stimulated gene 15 (ISG15) LVI status. Thus, we explored the prognostic significance of ISG15 in BC.MethodsThe prognostic significance of ISG15 mRNA was assessed in METABRIC (n = 1980), TCGA (n = 854) and Kaplan–Meier Plotter (n = 3951). ISG15 protein was evaluated using immunohistochemistry (n = 859) in early-stage invasive BC patients with long-term follow-up. The associations between ISG15 expression and clinicopathological features, expression of immune cell markers and patient outcome data were evaluated.ResultsHigh mRNA and protein ISG15 expression were associated with LVI, higher histological grade, larger tumour size, hormonal receptor negativity, HER2 positivity, p53 and Ki67. High ISG15 protein expression was associated with HER2-enriched BC subtypes and immune markers (CD8, FOXP3 and CD68). High ISG15 mRNA and ISG15 expressions were associated with poor patient outcome. Cox proportional multivariate analysis revealed that the elevated ISG15 expression was an independent prognostic factor of shorter BC-specific survival.ConclusionThis study provides evidence for the role of ISG15 in LVI development and BC prognosis. Further functional studies in BC are warranted to evaluate the therapeutic potential of ISG15.

Can we predict if an early stage cancer patient is at high risk of developing distant metastasis and what clinicopathological factors are associated with such a risk? In this paper, we propose a ranking based censoring-aware machine learning model for answering such questions. The proposed model is able to generate an interpretable formula for risk stratifi-cation using a minimal number of clinicopathological covariates through L1-regulrization. Using this approach, we analyze the association of time to distant metastasis (TTDM) with various clinical parameters for early stage, luminal (ER+ or HER2-) breast cancer patients who received endocrine therapy but no chemotherapy (n = 728). The TTDM risk stratification formula obtained using the proposed approach is primarily based on mitotic score, histolog-ical tumor type and lymphovascular invasion. These findings corroborate with the known role of these covariates in increased risk for distant metastasis. Our analysis shows that the proposed risk stratification formula can discriminate between cases with high and low risk of distant metastasis (p-value < 0.005) and can also rank cases based on their time to distant metastasis with a concordance-index of 0.73., Accepted in proc. (Machine Learning for Pharma and Healthcare Applications PharML 2021) European Conference on Machine Learning and Principles and Practice of Knowledge Discovery in Databases, Sep 13-17, 2021

Supplemental material, sj-pdf-1-tam-10.1177_1758835920974201 for XRCC1 deficient triple negative breast cancers are sensitive to ATR, ATM and Wee1 inhibitor either alone or in combination with olaparib by Reem Ali, Adel Alblihy, Michael S. Toss, Mashael Algethami, Rabab Al Sunni, Andrew R. Green, Emad A. Rakha and Srinivasan Madhusudan in Therapeutic Advances in Medical Oncology

Supplemental material, sj-pdf-1-tam-10.1177_1758835920974201 for XRCC1 deficient triple negative breast cancers are sensitive to ATR, ATM and Wee1 inhibitor either alone or in combination with olaparib by Reem Ali, Adel Alblihy, Michael S. Toss, Mashael Algethami, Rabab Al Sunni, Andrew R. Green, Emad A. Rakha and Srinivasan Madhusudan in Therapeutic Advances in Medical Oncology

PurposeEndocrine therapy is the standard treatment for oestrogen receptor positive (ER+) breast cancer. Despite its efficacy, around half of patients will develop resistance to this treatment and eventually relapse. Identification of effective and reliable biomarkers to predict the efficacy of endocrine therapy is of crucial importance in the management of ER+?breast cancer. Emerging evidence has revealed that the cell division regulator CDC20 exhibits an oncogenic function and plays important roles in tumourigenesis and progression of solid tumours. In this study, we investigated the prognostic and predictive role of CDC20 in early ER+?breast cancer patients.MethodsThe biological and clinical impact of CDC20 expression was assessed in large clinical annotated cohort of ER+?breast cancer with long-term follow-up at the mRNA level, using METABRIC and KM-Plotter datasets, and the protein level using immunohistochemistry on patients presenting at Nottingham. CDC20 expression was correlated with clinico-pathological parameters, molecular subtypes, clinical outcome and efficacy of endocrine therapy.ResultsHigh CDC20 mRNA expression was associated with poor clinico-pathological parameters including large tumour size and high tumour grade (P?

Background: Management of breast ductal carcinoma in situ (DCIS) has various approaches with distinct institutional specific practice. Here, we review DCIS management in a single institution with emphasise on re-operation rates and outcome. Methods: DCIS cases diagnosed at the Nottingham Breast Institute between 1987 and 2017 were identified (n=1,249). Clinicopathological data was collected. Cases were histologically reviewed, and different factors associated with primary operation selection, re-excision, presence of residual tumour in the re-excision specimens, use of radiotherapy and ipsilateral recurrences were analysed. Results: 34% of DCIS patients were initially treated by mastectomy and were more frequently symptomatic, of high nuclear tumour grade, size >40mm, and associated with comedo necrosis and Paget’s disease of the nipple. Further surgery was due to involved or narrow surgical margins. Residual tumour tissue was detected in 53% of the re-excision specimens. Re-excision rates of patients treated with breast conserving surgery (BCS) were reduced from approximately 70% to 23% and the final mastectomy rates decreased from 60% to 20%. Changes in surgical practice with acceptance of smaller excision margins and more frequent use of local radiotherapy have led to a significant decrease not only in the re-excision rate but also in the final mastectomy rate together with non-significant reduction in 5- and 10-year local recurrence rates. Conclusion: Although BCS is increasingly the preferred primary surgical option for DCIS management, a proportion of low-risk DCIS patients continue to undergo re-excision surgery or completion mastectomy. Despite acceptance of smaller margins, recurrence rate is decreasing.

Cten is an oncogene promoting EMT in many signaling pathways, namely through Snail. We investigated whether Cten function could be mediated through Src. Cten levels were modulated by forced expression in HCT116 and gene knockdown in SW620 CRC (colorectal cancer) cell lines. In all cell lines, Cten was a positive regulator of Src expression. The functional importance of Src was tested by simultaneous Cten overexpression and Src knockdown. This resulted in abrogation of Cten motility-inducing activity and reduction of colony formation ability together with failure to induce Cten targets. In SW620?Cten reduced Src expression increased following restoration of Cten, also leading to increased cell motility and colony formation, which were lost if Src was concomitantly knocked down. By qRT-PCR we showed modulation of Cten had no effect on Src mRNA. However, a CHX pulse chase assay demonstrated stabilization of Src protein by Cten. Finally, expression of Cten and Src was tested in a series of 84 primary CRCs and there was a significant correlation between them (P?=?0.001). We conclude that Src is a novel and functionally important target of the Cten signaling pathway and that Cten protein causes post-transcriptional stabilization of Src in promoting EMT and possibly metastasis in CRC.

© 2019, United States & Canadian Academy of Pathology. E-cadherin is a tumor suppressor gene in invasive lobular breast cancer. However, a proportion of high-grade ductal carcinoma shows reduced/loss of E-cadherin. In this study, we assessed the underlying mechanisms and molecular implications of E-cadherin loss in invasive ductal carcinoma. This study used large, well-characterized cohorts of early-stage breast cancer-evaluated E-cadherin expression via various platforms including immunohistochemistry, microarray analysis using Illumina HT-12 v3, copy number analysis using Affymetrix SNP 6.0 arrays, and next-generation sequencing for differential gene expression. Our results showed 27% of high-grade invasive ductal carcinoma showed reduced/loss of E-cadherin membranous expression. CDH1 copy number loss was in 21% of invasive ductal carcinoma, which also showed low CDH1 mRNA expression (p = 0.003). CDH1 copy number was associated with copy number loss of TP53, ATM, BRCA1, and BRCA2 (p < 0.001). Seventy-nine percent of invasive ductal carcinoma with reduced CDH1 mRNA expression showed elevated expression of E-cadherin transcription suppressors TWIST2, ZEB2, NFKB1, LLGL2, CTNNB1 (p < 0.01). Reduced/loss E-cadherin expression was associated with differential expression of 2143 genes including those regulating Wnt (FZD2, GNG5, HLTF, WNT2, and CER1) and PIK3-AKT (FGFR2, GNF5, GNGT1, IFNA17, and IGF1) signaling pathways. Interestingly, key genes differentially expressed between invasive lobular carcinoma and invasive ductal tumors did not show association with E-cadherin loss in invasive ductal carcinoma. We conclude that E-cadherin loss in invasive ductal carcinoma is likely a consequence of genomic instability occurring during carcinogenesis. Potential novel regulators controlling E-cadherin expression in invasive ductal carcinoma warrant further investigation.

Collagen11A1 (COL11A1) is a fibrillary type collagen constituting a minor component of the extracellular matrix and plays role in tissue tensile strength. Overexpression of COL11A1 expression is associated with aggressive behavior and poor outcome in several human malignancies. In this study, we evaluated the association between COL11A1 expression and clinicopathological parameters of the breast ductal carcinoma in situ (DCIS) and its prognostic value. COL11A1 protein expression was assessed immunohistochemically in a large well-characterized cohort of DCIS including pure (n = 776) and DCIS associated with invasive carcinoma (DCIS-mixed, n = 239). COL11A1 expression was assessed in tumor cells and surrounding stromal cells, and correlated with clinicopathological parameters, immunoprofile and disease outcome. In pure DCIS, high COL11A1 expression was observed in tumor cells and surrounding stromal cells in 25 and 13% of cases, respectively. Higher COL11A1 expression within the stromal cells was associated with hormone receptor negative, HER2 enriched and triple negative molecular subtypes and showed a positive linear correlation with proliferation index, dense tumor infiltrating lymphocytes and hypoxia-inducible factor 1 alpha. COL11A1 expression in tumor and stromal cells was significantly higher in DCIS associated with invasive carcinoma than in pure DCIS, and within the DCIS-mixed cohort, the invasive component showed higher COL11A1 expression than the DCIS component (all, p [less than] 0.0001). Overexpression of stromal COL11A1 was an independent predictor of shorter local recurrence-free interval for all recurrences (HR = 13.2, 95% CI = 6.9–25.4, p [less than] 0.0001) and for invasive recurrences (HR = 11.2, 95% CI = 4.9–25.8, p [les than] 0.0001). When incorporated with other risk factors, stromal COL11A1 provided better patient risk stratification. DCIS with higher stromal COL11A1 expression showed poor outcome even with adjuvant radiotherapy management. In conclusion, overexpression of stromal COL11A1 is associated with invasive recurrence in DCIS and is a potential marker to predict the response to radiotherapy.

Collagen plays a key role in normal and malignant tissue homeostasis. While the prognostic significance of collagen fibre remodeling in invasive breast cancer has been studied, its role in ductal carcinoma in situ (DCIS) remains poorly defined. Using image analysis, we aimed to evaluate the prognostic significance of the geometric characteristics of collagen surrounding DCIS. A large well-characterized cohort of DCIS comprising pure DCIS (n=610) and DCIS co-existing with invasive carcinoma (n=180) were histochemically stained for collagen using picrosirius red. ImageJ software was used to assess collagen density, degree of collagen fibre dispersion and directionality in relation to DCIS ducts’ boundary. We developed a collagen prognostic index and evaluated its prognostic significance. A poor index was observed in 24% of the pure DCIS and was associated with determinants of high-risk DCIS including higher grade, comedo necrosis, hormonal receptor negativity, HER2 positivity and high proliferation index. High index was associated with overexpression of the collagen remodeling protein prolyl-4-hydroxlase alpha 2 and the hypoxia inducible factor 1α. DCIS co-existing with invasive carcinoma had a higher collagen prognostic index than pure DCIS (p

© 2018, United States & Canadian Academy of Pathology. Legumain is a proteolytic enzyme that plays a role in the regulation of cell proliferation in invasive breast cancer. Studies evaluating its role in ductal carcinoma in situ (DCIS) are lacking. Here, we aimed to characterize legumain protein expression in DCIS and evaluate its prognostic significance. Legumain was assessed immunohistochemically in a tissue microarray of a well-characterized cohort of DCIS (n = 776 pure DCIS and n = 239 DCIS associated with invasive breast cancer (DCIS-mixed)). Legumain immunoreactivity was scored in tumor cells and surrounding stroma and related to clinicopathological parameters and patient outcome. High legumain expression was observed in 23% of pure DCIS and was associated with features of high-risk DCIS including higher nuclear grade, comedo necrosis, hormone receptor negativity, HER2 positivity, and higher proliferation index. Legumain expression was higher in DCIS associated with invasive breast cancer than in pure DCIS (p < 0.0001). In the DCIS-mixed cohort, the invasive component showed higher legumain expression than the DCIS component (p < 0.0001). Legumain was an independent predictor of shorter local recurrencefree interval for all recurrences (p = 0.0003) and for invasive recurrences (p = 0.002). When incorporated with other risk factors, legumain provided better patient risk stratification. High legumain expression is associated with poor prognosis in DCIS and could be a potential marker to predict DCIS progression to invasive disease.

PurposeCD133/ prominin 1 is a cancer stem cell marker associated with cancer progression and patient outcome in a variety of solid tumours, but its role in invasive breast cancer (BC) remains obscure. The current study aims to assess the prognostic value of CD133 expression in early invasive BC.MethodsCD133 mRNA was assessed in the METABRIC cohort and at the proteomic level using immunohistochemistry utilising a large well-characterised BC cohort. Association with clinicopathological characteristics, expression of other stem cell markers and patient outcome were evaluated.ResultsHigh expression of CD133 either in mRNA or protein levels was associated with characteristics of poor prognosis including high tumour grade, larger tumour size, high Nottingham Prognostic Index, HER2 positivity and hormonal receptor negativity (all; p?less than 0.01). Tumours expressing CD133 showed higher expression of other stem cell markers including CD24, CD44, SOX10, ALDHA3 and ITGA6. High expression of CD133 protein was associated with shorter BC-specific survival (p?=?0.026). Multivariate analysis revealed that CD133 protein expression was an independent risk factor for shorter BC-specific survival (p?=?0.038).ConclusionThis study provides evidence for the prognostic value of CD133 in invasive BC. A strong positive association of BC stem cell markers is observed at the protein level. Further studies to assess the value of stem cell markers individually or in combination in BC is warranted.

Background: Cathepsin A (CTSA) is a key regulatory enzyme for galactoside metabolism. Additionally, it has a distinct proteolytic activity and plays a role in tumour progression. CTSA is differentially expressed at the mRNA level between breast ductal carcinoma in situ (DCIS) and invasive breast carcinoma (IBC). In this study, we aimed to characterise CTSA protein expression in DCIS and evaluate its prognostic significance. Methods: A large cohort of DCIS (n=776 for pure DCIS and n=239 for DCIS associated with IBC (DCIS/IBC)) prepared as tissue microarray was immunohistochemically stained for CTSA. Results: High CTSA expression was observed in 48% of pure DCIS. High expression was associated with features of poor DCIS prognosis including younger age at diagnosis (less than 50 years), higher nuclear grade, hormone receptor negativity, HER2 positivity, high proliferative index and high hypoxia inducible factor 1 alpha expression. High CTSA expression was associated with shorter recurrence free interval (RFI) (p=0.0001). In multivariate survival analysis for patients treated with breast conserving surgery, CTSA was an independent predictor of shorter RFI (p=0.015). DCIS associated with IBC showed higher CTSA expression than pure DCIS (p=0.04). In the DCIS/IBC cohort, CTSA expression was higher in the invasive component than DCIS component (p less than 0.0001). Conclusion: CTSA is not only associated with aggressive behaviour and poor outcome in DCIS but also a potential marker to predict co-existing invasion in DCIS.

PURPOSE: Identification of effective and reliable biomarkers that could be used to predict the efficacy of endocrine therapy is of crucial importance to the management of oestrogen receptor positive (ER+) breast cancer (BC). KIF18A, a key regulator of cell cycle, is overexpressed in many human cancers, including BC. In this study, we investigated the role of KIF18A as a biomarker to predict the benefit from endocrine treatment in early ER?+?BC patients.METHODS: KIF18A expression was assessed at the genomic level using the METABRIC dataset to explore its prognostic and predictive value in ER?+?BC patients (n?=?1506). Predictive significance of KIF18A mRNA was validated using KM-Plot datasets (n?=?2061). KIF18A protein expression was assessed using immunohistochemistry in a large annotated series of early-stage ER?+?BC (n?=?1592) with long-term follow-up.RESULTS: High mRNA and protein expression of KIF18A were associated with short recurrence-free survival (RFS), distant-metastasis free survival (DMFS) and BC specific survival (all P? less than 0.05) in ER?+?BC in patients who received no adjuvant treatment or adjuvant endocrine therapy. In multivariate analysis, high KIF18A expression was an independent prognostic biomarker for poor RFS (P?=?0.027) and DMFS (P?=?0.028) in patients treated with adjuvant endocrine therapy.Conclusion: KIF18A appears to be a candidate biomarker of a subgroup of ER?+?BC characterised by poor clinical outcome. High KIF18A expression has prognostic significance to predict poor benefit from endocrine treatment for patients with ER?+?BC. Therefore, measurement of KIF18A on ER?+?BC patients prior to treatment could guide clinician decision on benefit from endocrine therapy.

Current clinicopathological parameters are useful predictors of breast ductal carcinoma in situ behaviour, but they are insufficient to define high risk patients for disease progression precisely. Thioredoxin interacting protein (TXNIP) is a key player of oxidative stress. This study aims to evaluate the role of TXNIP as a predictor of ductal carcinoma in situ progression. Tissue microarrays from 776 pure ductal carcinoma in situ and 239 mixed ductal carcinoma in situ and invasive tumors were constructed. All patients were treated at a single institution with a long-term follow-up and TXNIP expression was assessed using immunohistochemistry. TXNIP expression was investigated in terms of associations with clinicopathological and molecular features and patient outcome. Loss/reduced cytoplasmic expression of TXNIP was associated with features of aggressiveness including high nuclear grade (p=1.6x10-5), presence of comedo necrosis (p=0.001) and oestrogen receptor negative (ER-)/HER2- ductal carcinoma in situ (p=4.6x10-5). Univariate analysis showed an inverse association between TXNIP expression and outcome in terms of shorter local recurrence free survival (p=0.009). Multivariable analyses showed that independent predictors of ductal carcinoma in situ recurrence were low TXNIP expression (p=0.005, HR=0.51 and 95%CI: 0.32-0.81), larger ductal carcinoma in situ size and high nuclear grade. TXNIP functions as a tumor suppressor gene with loss of its expression associated with ductal carcinoma in situ recurrence. TXNIP can be used as a potentially useful marker in prognostic stratification of ductal carcinoma in situ for management decisions.

The response of human epidermal growth factor receptor2 (HER2)- positive breast cancer (BC) patients to anti-HER2 targeted therapy is significant. However, the response is not uniform and a proportion of HER2-positive patients do not respond. This study aims to identify predictors of response in the neoadjuvant treatment and to assess the discordance rate of HER2 status between pre- and post-treatment specimens in HER2-positive BC patients. The study group comprised 500 BC patients treated with neoadjuvant chemotherapy (NACT) and/or neoadjuvant anti-HER2 therapy and surgery who had tumours that were 3+ or 2+ with HER2 immunohistochemistry (IHC). HER2 IHC 2+ tumours were classified into five groups by fluorescence in situ hybridisation (FISH) according to the 2018 ASCO/CAP guidelines of which Groups 1, 2 and 3 were considered HER2 amplified. Pathological complete response (pCR) was more frequent in HER2 IHC 3+ tumours than in HER2 IHC 2+/HER2 amplified tumours, when either in receipt of NACT alone (38% versus 13%; p = 0.22) or neoadjuvant anti-HER2 therapy (52% versus 20%; p < 0.001). Multivariate logistic regression analysis showed that HER2 IHC 3+ and histological grade 3 were independent predictors of pCR following neoadjuvant anti-HER2 therapy. In the HER2 IHC 2+/HER2 amplified tumours or ASCO/CAP FISH Group 1 alone, ER-negativity was an independent predictor of pCR following NACT and/or neoadjuvant anti-HER2 therapy. In the current study, 22% of HER2-positive tumours became HER2-negative by IHC and FISH following neoadjuvant treatment, the majority (74%) HER2 IHC 2+/HER2 amplified tumours. Repeat HER2 testing after neoadjuvant treatment should therefore be considered.

Despite the significant biological, behavioural and management differences between ductal carcinoma in situ (DCIS) and invasive carcinoma of the breast, they share many morphological and molecular similarities. Differentiation of these two different lesions in breast pathological diagnosis is based typically on the presence of an intact barrier between the malignant epithelial cells and stroma; namely, the myoepithelial cell (MEC) layer and surrounding basement membrane (BM). Despite being robust diagnostic criteria, the identification of MECs and BM to differentiate in-situ from invasive carcinoma is not always straightforward. The MEC layer around DCIS may be interrupted and/or show an altered immunoprofile. MECs may be absent in some benign locally infiltrative lesions such as microglandular adenosis and infiltrating epitheliosis, and occasionally in non-infiltrative conditions such as apocrine lesions, and in these contexts this does not denote malignancy or invasive disease with metastatic potential. MECs may also be absent around some malignant lesions such as some forms of papillary carcinoma, yet these behave in an indolent fashion akin to some DCIS. In Paget's disease, malignant mammary epithelial cells extend anteriorly from the ducts to infiltrate the epidermis of the nipple but do not typically infiltrate through the BM into the dermis. Conversely, BM-like material can be seen around invasive carcinoma cells and around metastatic tumour cell deposits. Here, we review the role of MECs and BM in breast pathology and highlight potential clinical implications. We advise caution in interpretation of MEC features in breast pathology and mindfulness of the substantive evidence base in the literature associated with behaviour and clinical outcome of lesions classified as benign on conventional morphological examination before changing classification to an invasive lesion on the sole basis of MEC characteristics.