RESUMEN
BACKGROUND: Previous studies have suggested that patients with HER2-low breast cancers do not benefit from trastuzumab treatment although the reasons remain unclear. METHODS: We investigated the effect of trastuzumab monotherapy and its combination with different HER2 targeting treatments in a panel of breast cancer cell lines and patient-derived organoids (PDOs) using biochemical methods and cell viability assays. RESULTS: Compared to sensitive HER2 over-expressing (IHC3 + ) breast cancer cells, increasing doses of trastuzumab could not achieve IC50 in MDA-MB-361 (IHC 2 + FISH + ) and MDA-MB-453 (IHC 2 + FISH-) cells which showed an intermediate response to trastuzumab. Trastuzumab treatment induced upregulation of HER ligand release, resulting in the activation of HER receptors in these cells, which could account for their trastuzumab insensitivity. Adding a dual ADAM10/17 inhibitor to inhibit the shedding of HER ligands in combination with trastuzumab only showed a modest decrease in the cell viability of HER2-low breast cancer cells and PDOs. However, the panHER inhibitor neratinib was an effective monotherapy in HER2-low breast cancer cells and PDOs, and showed additive effects when combined with trastuzumab. CONCLUSION: This study demonstrates that neratinib in combination with trastuzumab may be effective in a subset of HER2-low breast cancers although further validation is required in a larger panel of PDOs and in future clinical studies.
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Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Organoides , Quinolinas , Receptor ErbB-2 , Trastuzumab , Humanos , Trastuzumab/farmacología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Receptor ErbB-2/metabolismo , Femenino , Organoides/efectos de los fármacos , Quinolinas/farmacología , Quinolinas/administración & dosificación , Línea Celular Tumoral , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Supervivencia Celular/efectos de los fármacosRESUMEN
BACKGROUND: There are limited data on the role of multigene tests and their correlation with immunohistochemistry (IHC), especially on core biopsy. MammaTyper is a quantitative conformite Europeeanne (CE) marked, National Institute for Health and Care excellence (NICE) approved, in in vitro diagnostic quantitative real-time polymerase chain reaction (RT-qPCR) test for assessment of mRNA expression of four biomarkers (ESR1, PGR, ERBB2, MKI67). METHODS: We evaluated the concordance of MammaTyper with oestrogen receptor (ER), progesterone receptor (PR), HER2, and Ki67 by IHC on 133 core needle biopsies of breast cancer. HER2 was positive if IHC 3+ or 2+ and fluorescence in situ hybridization (FISH)-amplified. Global and hotspot Ki67 expression was analysed using a cutoff of ≥20% assessed manually and by digital image analysis. Agreements were expressed as overall percent agreement (OPA), positive percent agreement (PPA), negative percent agreement (NPA), and Cohen's kappa. RESULTS: RT-qPCR results of ESR1 were highly concordant with IHC with OPA of 94.7% using 1% cutoff and 91.7% when the low ER-positive category was included. The PPA and NPA between RT-qPCR and IHC for PR was 91.5% and 88.0%, respectively, when using the 1% cutoff. For ERBB2/HER2, the OPA was 95% and the PPA was 84.6%. 40 of 72 HER2 IHC score 0 tumours were classified as ERBB2 low. Best concordance between MKI67 by MammaTyper and Ki67 IHC was achieved using hotspot digital image analysis (OPA: 87.2%, PPA: 90.6%, NPA: 80%). CONCLUSION: RT-qPCR-based assessment of the mRNA expression of ESR1, PGR, ERBB2, and MKI67 showed high concordance with IHC, suggesting that the MammaTyper test on core needle biopsies represents a reliable, efficient, and reproducible alternative for breast cancer classification and refining HER2 low categorisation.
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Biomarcadores de Tumor , Neoplasias de la Mama , Inmunohistoquímica , Antígeno Ki-67 , Reacción en Cadena en Tiempo Real de la Polimerasa , Receptor ErbB-2 , Receptores de Estrógenos , Receptores de Progesterona , Humanos , Neoplasias de la Mama/patología , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/diagnóstico , Femenino , Receptor ErbB-2/metabolismo , Receptor ErbB-2/genética , Antígeno Ki-67/metabolismo , Antígeno Ki-67/análisis , Inmunohistoquímica/métodos , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/genética , Receptores de Progesterona/metabolismo , Receptores de Estrógenos/metabolismo , Biopsia con Aguja Gruesa , Adulto , Persona de Mediana Edad , Hibridación Fluorescente in Situ/métodosRESUMEN
AIMS: Standard neoadjuvant endocrine therapy (NAET) is used for 6-9 months to downstage hormone-receptor-positive breast cancer. Bridging ET was introduced during the COVID-19 pandemic to delay surgical intervention. There are no data in the literature on the effect of short course therapy on tumour response. We aimed to analyse the effect of bridging ET and validate the previously proposed neoadjuvant ET pathological reporting criteria. METHODS AND RESULTS: This was a multicentre cohort of 256 patients who received bridging ET between March and October 2020. Assessment of paired pre- and post-NAET hormone receptors and HER2 and posttherapy Ki67 expression was done. The median duration of NAET was 45 days. In all, 86% of cases achieved partial pathological response and 9% showed minimal residual disease. Histological response to ET was observed from as early as day 6 posttherapy. Central scarring was noted in 32.8% of cases and lymphocytic infiltrate was seen in 43.4% of cases. Significant changes associated with the duration of ET were observed in tumour grade (21%), with downgrading identified in 12% of tumours (P < 0.001), progesterone receptor (PR) expression with switch to PR-negative status in 26% of cases (P < 0.001), and HER2 status with a switch from HER2-low to HER2-negative status in 32% of cases (P < 0.001). The median patient survival was 475 days, with an overall survival rate of 99.6%. CONCLUSIONS: Changes characteristic of tumour regression and significant changes in PR and HER2 occurred following a short course of NAET. The findings support biomarker testing on pretreatment core biopsies and retesting following therapy.
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Antineoplásicos Hormonales , Neoplasias de la Mama , Terapia Neoadyuvante , Receptores de Estrógenos , Humanos , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Persona de Mediana Edad , Receptores de Estrógenos/metabolismo , Anciano , Adulto , Reino Unido , Antineoplásicos Hormonales/uso terapéutico , Receptor ErbB-2/metabolismo , COVID-19 , Receptores de Progesterona/metabolismo , Biomarcadores de Tumor/metabolismo , Biomarcadores de Tumor/análisisRESUMEN
Breast cancer poses a global health challenge, yet the influence of ethnicity on the tumor microenvironment (TME) remains understudied. In this investigation, we examined immune cell infiltration in 230 breast cancer samples, emphasizing diverse ethnic populations. Leveraging tissue microarrays (TMAs) and core samples, we applied multiplex immunofluorescence (mIF) to dissect immune cell subtypes across TME regions. Our analysis revealed distinct immune cell distribution patterns, particularly enriched in aggressive molecular subtypes triple-negative and HER2-positive tumors. We observed significant correlations between immune cell abundance and key clinicopathological parameters, including tumor size, lymph node involvement, and patient overall survival. Notably, immune cell location within different TME regions showed varying correlations with clinicopathologic parameters. Additionally, ethnicities exhibited diverse distributions of cells, with certain ethnicities showing higher abundance compared to others. In TMA samples, patients of Chinese and Caribbean origin displayed significantly lower numbers of B cells, TAMs, and FOXP3-positive cells. These findings highlight the intricate interplay between immune cells and breast cancer progression, with implications for personalized treatment strategies. Moving forward, integrating advanced imaging techniques, and exploring immune cell heterogeneity in diverse ethnic cohorts can uncover novel immune signatures and guide tailored immunotherapeutic interventions, ultimately improving breast cancer management.
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Neoplasias de la Mama , Análisis de Matrices Tisulares , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Femenino , Neoplasias de la Mama/patología , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/etnología , Análisis de Matrices Tisulares/métodos , Persona de Mediana Edad , Técnica del Anticuerpo Fluorescente , Adulto , Anciano , Etnicidad , Biomarcadores de Tumor/metabolismoRESUMEN
Early evidence suggests a strong impact of tumour-infiltrating lymphocytes (TILs) on both the prognosis and clinical behaviour of ovarian cancer. Proven associations, however, have not yet translated to successful immunotherapies and further work in the field is urgently needed. We aimed to analyse the tumour microenvironment of a well-characterised cohort of ovarian cancer samples. Tumour markers were selected owing to their comparative underrepresentation in the current literature. Paraffin-embedded, formalin-fixed tumour tissue blocks of 138 patients representative of the population and including early stage disease were identified, stained for CD3, CD20, CD68 and CD163 and analysed for both the stromal and intertumoral components. Data were statistically analysed in relation to clinical details, histological subtype, borderline vs. malignant status, survival and management received. Mean stromal CD3, total CD3 count, mean stromal CD20 and total CD20 count all correlated negatively with survival. Malignant ovarian tumours consistently demonstrated significantly higher infiltration of all analysed immune cells than borderline tumours. Assessment of the stromal compartment produced a considerably higher proportion of significant results when compared to the intra-tumoural infiltrates. Customary assessment of solely intra-tumoural cells in advanced stage disease patients undergoing primary debulking surgery should be challenged, with recommendations for future scoring systems provided.
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Carcinoma Epitelial de Ovario , Linfocitos Infiltrantes de Tumor , Neoplasias Ováricas , Microambiente Tumoral , Macrófagos Asociados a Tumores , Humanos , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Femenino , Pronóstico , Neoplasias Ováricas/patología , Neoplasias Ováricas/inmunología , Neoplasias Ováricas/mortalidad , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo , Macrófagos Asociados a Tumores/patología , Persona de Mediana Edad , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/inmunología , Microambiente Tumoral/inmunología , Anciano , Adulto , Biomarcadores de Tumor , Antígenos CD/metabolismo , Anciano de 80 o más AñosRESUMEN
Oestrogen receptor (ER)-positive breast cancer (BC) is generally well responsive to endocrine therapy. Neoadjuvant endocrine therapy (NAET) is increasingly being used for downstaging ER-positive tumours. This study aims to analyse the effect of NAET on a well-characterised cohort of ER-positive BC with particular emphasis on receptor expression. This is a retrospective United Kingdom (UK) multicentre study of 391 patients who received NAET between October 2012 and October 2020. Detailed analyses of the paired pre- and post-NAET morphological changes and hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression were performed. The median duration of NAET was 86 days, with median survival and overall survival rates of 380 days and 93.4%, respectively. A total of 90.3% of cases achieved a pathological partial response, with a significantly higher rate of response in the HER2-low cancers. Following NAET, BC displayed some pathological changes involving the tumour stroma including central scarring and an increase in tumour infiltrating lymphocytes (TILs) and tumour cell morphology. Significant changes associated with the duration of NAET were observed in tumour grade (30.6% of cases), with downgrading identified in 19.3% of tumours (p < 0.001). The conversion of ER status from positive to low or negative was insignificant. The conversion of progesterone receptor (PR) and HER2 status to negative status was observed in 31.3% and 38.1% of cases, respectively (p < 0.001). HER2-low breast cancer decreased from 63% to 37% following NAET in the paired samples. Significant morphological and biomarker changes involving PR and HER2 expression occurred following NAET. The findings support biomarker testing on pre-treatment core biopsies and post-treatment residual carcinoma.
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Neoplasias de la Mama , Terapia Neoadyuvante , Receptor ErbB-2 , Receptores de Estrógenos , Humanos , Neoplasias de la Mama/patología , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Femenino , Terapia Neoadyuvante/métodos , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Anciano , Adulto , Receptores de Estrógenos/metabolismo , Estudios Retrospectivos , Antineoplásicos Hormonales/uso terapéutico , Biomarcadores de Tumor/metabolismo , Anciano de 80 o más AñosRESUMEN
In our 2020 consensus paper, we devised ten recommendations for conducting Complex Innovative Design (CID) trials to evaluate cancer drugs. Within weeks of its publication, the UK was hit by the first wave of the SARS-CoV-2 pandemic. Large CID trials were prioritised to compare the efficacy of new and repurposed COVID-19 treatments and inform regulatory decisions. The unusual circumstances of the pandemic meant studies such as RECOVERY were opened almost immediately and recruited record numbers of participants. However, trial teams were required to make concessions and adaptations to these studies to ensure recruitment was rapid and broad. As these are relevant to cancer trials that enrol patients with similar risk factors, we have added three new recommendations to our original ten: employing pragmatism such as using focused information sheets and collection of only the most relevant data; minimising negative environmental impacts with paperless systems; and using direct-to-patient communication methods to improve uptake. These recommendations can be applied to all oncology CID trials to improve their inclusivity, uptake and efficiency. Above all, the success of CID studies during the COVID-19 pandemic underscores their efficacy as tools for rapid treatment evaluation.
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COVID-19 , Humanos , SARS-CoV-2 , Pandemias , Consenso , Oncología MédicaRESUMEN
Neoadjuvant chemotherapy (NACT) has become the standard of care for high-risk breast cancer, including triple-negative (TNBC) and HER2-positive disease. As a result, handling and reporting of breast specimens post-NACT is part of routine practice, and it is important for pathologists to recognise the changes in tumour cells, tumour-associated stroma and background breast tissue induced by NACT. Familiarity with characteristic stromal features enables identification of the pre-treatment tumour site and allows confident diagnosis of pathological complete response (pCR) which is important for decisions concerning adjuvant therapy. Neoadjuvant endocrine therapy (NAET) is used less frequently than NACT; however, the SARS-COVID-19 pandemic has changed practice, with increased use as bridging therapy if surgery is delayed. NAET also induces characteristic changes in the tumour and stroma. Changes in the tumour microenvironment following NACT and NAET are also described. Immunotherapy is approved for use in advanced TNBC, and there are several trials exploring its role in early TNBC in the neoadjuvant setting. The current biomarker to determine eligibility for treatment with immune checkpoint inhibitors is programmed death ligand-1 (PD-L1) immunohistochemistry; however, this is complicated by lack of standardisation with different drugs linked to tests using different antibodies with different scoring systems. The situation in the neoadjuvant setting is further complicated by improved pCR rates for PD-L1-positive tumours in both immune therapy and placebo arms. Alternative biomarkers are urgently needed to identify which patients will derive benefit from immunotherapy and key candidates are discussed.
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Neoplasias de la Mama , COVID-19 , Humanos , Femenino , Terapia Neoadyuvante , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/terapia , Antígeno B7-H1 , Pandemias , Microambiente TumoralRESUMEN
INTRODUCTION: Inflammatory breast cancer (IBC) is an aggressive form of breast cancer with a poorly characterized immune microenvironment. METHODS: We used a five-colour multiplex immunofluorescence panel, including CD68, CD4, CD8, CD20, and FOXP3 for immune microenvironment profiling in 93 treatment-naïve IBC samples. RESULTS: Lower grade tumours were characterized by decreased CD4+ cells but increased accumulation of FOXP3+ cells. Increased CD20+ cells correlated with better response to neoadjuvant chemotherapy and increased CD4+ cells infiltration correlated with better overall survival. Pairwise analysis revealed that both ER+ and triple-negative breast cancer were characterized by co-infiltration of CD20 + cells with CD68+ and CD4+ cells, whereas co-infiltration of CD8+ and CD68+ cells was only observed in HER2+ IBC. Co-infiltration of CD20+, CD8+, CD4+, and FOXP3+ cells, and co-existence of CD68+ with FOXP3+ cells correlated with better therapeutic responses, while resistant tumours were characterized by co-accumulation of CD4+, CD8+, FOXP3+, and CD68+ cells and co-expression of CD68+ and CD20+ cells. In a Cox regression model, response to therapy was the most significant factor associated with improved patient survival. CONCLUSION: Those results reveal a complex unique pattern of distribution of immune cell subtypes in IBC and provide an important basis for detailed characterization of molecular pathways that govern the formation of IBC immune landscape and potential for immunotherapy.
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Neoplasias de la Mama , Neoplasias Inflamatorias de la Mama , Neoplasias de la Mama Triple Negativas , Humanos , Femenino , Neoplasias Inflamatorias de la Mama/metabolismo , Neoplasias Inflamatorias de la Mama/patología , Neoplasias de la Mama/patología , Linfocitos Infiltrantes de Tumor , Técnica del Anticuerpo Fluorescente , Factores de Transcripción Forkhead/genética , Microambiente TumoralRESUMEN
Despite significant improvements in the way breast cancer is managed and treated, it continues to persist as a leading cause of death worldwide. If detected and diagnosed early, when tumours are small and localised, there is a considerably higher chance of survival. However, current methods for detection and diagnosis lack the required sensitivity and specificity for identifying breast cancer at the asymptomatic or very early stages. Thus, there is a need to develop more rapid and reliable methods, capable of detecting disease earlier, for improved disease management and patient outcome. Raman spectroscopy is a non-destructive analytical technique that can rapidly provide highly specific information on the biochemical composition and molecular structure of samples. In cancer, it has the capacity to probe very early biochemical changes that accompany malignant transformation, even prior to the onset of morphological changes, to produce a fingerprint of disease. This review explores the application of Raman spectroscopy in breast cancer, including discussion on its capabilities in analysing both ex-vivo tissue and liquid biopsy samples, and its potential in vivo applications. The review also addresses current challenges and potential future uses of this technology in cancer research and translational clinical application.
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Neoplasias de la Mama , Espectrometría Raman , Biopsia , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/patología , Femenino , Humanos , Sensibilidad y Especificidad , Espectrometría Raman/métodosRESUMEN
BACKGROUND: The diagnosis, management and prognosis of microinvasive breast carcinoma remain controversial. METHODS: We analysed the outcomes of patients with DCIS with and without microinvasion diagnosed between 2003 and 2012 within the Sloane project. RESULTS: Microinvasion was recorded in 521 of 11,285 patients (4.6%), with considerable variation in reported incidence among screening units (0-25%). Microinvasion was associated with high-grade DCIS, larger DCIS size, comedo necrosis and solid, cribriform architecture (all P < 0.001). Microinvasion was more frequent in patients who underwent mastectomy compared with breast-conserving surgery (BCS) (6.9% vs 3.6%, P < 0.001), and in those undergoing axillary nodal surgery (60.4% vs 30.3%, P < 0.001) including the subset undergoing BCS (43.4% vs 8.5%, P < 0.001). Nodal metastasis rate was low and not statistically significant difference from the DCIS only group (P = 0.68). Following median follow-up of 110 months, 3% of patients had recurrent ipsilateral high-grade DCIS, and 4.2% developed invasive carcinoma. The subsequent ipsilateral invasion was of Grade 3 in 71.4% of patients with microinvasion vs 30.4% in DCIS without microinvasion (P = 0.02). Distant metastasis and breast cancer mortality were higher with microinvasion compared with DCIS only (1.2% vs 0.3%, P = 0.01 and 2.1% vs 0.8%; P = 0.005). CONCLUSIONS: The higher breast cancer mortality with microinvasion indicates a more aggressive disease.
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Neoplasias de la Mama , Carcinoma Intraductal no Infiltrante , Humanos , Femenino , Carcinoma Intraductal no Infiltrante/cirugía , Neoplasias de la Mama/cirugía , Mastectomía , Reino UnidoRESUMEN
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.
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Neoplasias de la Mama , Aberraciones Cromosómicas , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Centrómero , Cromosomas Humanos Par 17/genética , Femenino , Amplificación de Genes , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ/métodos , Receptor ErbB-2/análisisRESUMEN
AIMS: To describe a new international dataset for pathology reporting of ductal carcinoma in situ (DCIS), variants of lobular carcinoma in situ (LCIS) and low-grade lesions (encapsulated papillary carcinoma, solid papillary carcinoma in situ, Paget's disease) produced by the International Collaboration on Cancer Reporting (ICCR). METHODS AND RESULTS: The ICCR, a global alliance of pathology bodies, uses a rigorous and efficient process for the development of evidence-based, structured datasets for pathology reporting of common cancers. Their aim is to support quality pathology reporting and engender understanding between the breast surgeon, pathologist, and oncologist for optimal and uniform patient management globally. Here we describe the dataset for DCIS, some variants of LCIS (namely the pleomorphic and the florid variants), and low-grade lesions by a multidisciplinary panel of internationally recognized experts. The agreed dataset comprises 12 core (required) and five noncore (recommended) elements suitable for both developed and low-income jurisdictions, derived from a review of current evidence. Areas of contention were addressed using a pragmatic approach in the absence of evidence. Use of all core elements is the minimum reporting standard for any individual case. Commentary is provided, explaining each element's clinical relevance, definitions to be applied where appropriate for the agreed list of value options and the rationale for considering the element as core or noncore. CONCLUSION: This first internationally agreed dataset for DCIS, variants of LCIS, and low-grade lesions reporting will enable their standardization of pathology reporting and enhance clinicopathological communication leading to improved patient outcomes. Widespread adoption will also facilitate international comparisons, multinational clinical trials, and help to improve the management of breast disease globally.
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Carcinoma de Mama in situ , Neoplasias de la Mama , Carcinoma in Situ , Carcinoma Intraductal no Infiltrante , Carcinoma Lobular , Carcinoma Papilar , Carcinoma de Mama in situ/cirugía , Carcinoma Intraductal no Infiltrante/patología , Carcinoma Lobular/patología , Femenino , Humanos , Hiperplasia , PatólogosRESUMEN
Neoadjuvant chemotherapy (NACT) is now established in routine management of early breast cancer. Alterations in oestrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) following NACT are reported, with wide variation in results across series. In larger series, changes in ER status are identified in 5-23%, whilst changes in PR status are more frequent (14.5-67%). HER2 status changes less frequently with loss being more common than gain, and higher rates of change with immunohistochemistry are observed compared to in situ hybridization and following HER2-targeted therapy compared with chemotherapy alone. Triple negative is the most stable molecular subtype with combined ER, and HER2-positive cancers show the highest rate of change. Neoadjuvant endocrine therapy is used less commonly than NACT, and whilst loss of ER is rare, changes in PR status can occur in up to 40% of cases. There is relatively little published data on the impact of change in receptor status on survival outcomes. In patients whose tumours become ER or HER2 positive post-NACT, endocrine or anti-HER2 therapy can be initiated, although evidence from clinical trials is lacking. Most guidelines do not currently recommend routine retesting; however it should be considered in some circumstances.
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Neoplasias de la Mama , Terapia Neoadyuvante , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Femenino , Humanos , Inmunohistoquímica , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismoRESUMEN
The 2013 SPIRIT (Standard Protocol Items: Recommendations for Interventional Trials) Statement provides evidence-based recommendations for the minimum content to be included in a clinical trial protocol. Assessment of biospecimens is often required for trial eligibility or as part of an outcome evaluation, and precision molecular approaches are increasingly used in trial design. However, cellular and molecular pathology practices within trials have not been codified or formalised. We developed international consensus reporting guidelines for cellular and molecular pathology content in clinical trial protocols (the SPIRIT-Path extension) using an international Delphi process, which assesses candidate items generated from a previous systematic review, followed by an expert consensus meeting. 74 individuals from five continents responded, including clinicians, statisticians, laboratory scientists, patient advocates, funders, industry representatives, journal editors, and regulators. The SPIRIT-Path guidelines recommend 14 additional items (seven extensions to the SPIRIT checklist and seven elaborations) that should be addressed in trial protocols containing pathology content, alongside the SPIRIT 2013 Statement items. SPIRIT-Path recommends that protocols should document the individuals, processes, and standards for all cellular and molecular pathology components of the trial, including all stages of the specimen pathway and any digital pathology methods, with specific consideration of the value of trial data and biological tissues for additional translational studies.
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Protocolos de Ensayos Clínicos como Asunto , Ensayos Clínicos como Asunto/normas , Patología Molecular/normas , Proyectos de Investigación/normas , Lista de Verificación , Consenso , Técnica Delphi , HumanosRESUMEN
BACKGROUND: The Sloane audit compares screen-detected ductal carcinoma in situ (DCIS) pathology with subsequent management and outcomes. METHODS: This was a national, prospective cohort study of DCIS diagnosed during 2003-2012. RESULTS: Among 11,337 patients, 7204 (64%) had high-grade DCIS. Over time, the proportion of high-grade disease increased (from 60 to 65%), low-grade DCIS decreased (from 10 to 6%) and mean size increased (from 21.4 to 24.1 mm). Mastectomy was more common for high-grade (36%) than for low-grade DCIS (15%). Few (6%) patients treated with breast-conserving surgery (BCS) had a surgical margin <1 mm. Of the 9191 women diagnosed in England (median follow-up 9.4 years), 7% developed DCIS or invasive malignancy in the ipsilateral and 5% in the contralateral breast. The commonest ipsilateral event was invasive carcinoma (n = 413), median time 62 months, followed by DCIS (n = 225), at median 37 months. Radiotherapy (RT) was most protective against recurrence for high-grade DCIS (3.2% for high-grade DCIS with RT compared to 6.9% without, compared with 2.3 and 3.0%, respectively, for low/intermediate-grade DCIS). Ipsilateral DCIS events lessened after 5 years, while the risk of ipsilateral invasive cancer remained consistent to beyond 10 years. CONCLUSION: DCIS pathology informs patient management and highlights the need for prolonged follow-up of screen-detected DCIS.
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Neoplasias de la Mama/patología , Carcinoma Ductal de Mama/patología , Carcinoma Intraductal no Infiltrante/patología , Neoplasias de la Mama/epidemiología , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/epidemiología , Carcinoma Ductal de Mama/cirugía , Carcinoma Intraductal no Infiltrante/epidemiología , Carcinoma Intraductal no Infiltrante/cirugía , Femenino , Estudios de Seguimiento , Humanos , Mastectomía , Pronóstico , Estudios Prospectivos , Reino Unido/epidemiologíaRESUMEN
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 <4.0 signals/cell were re-classified as HER2 negative. This study aims to examine the response of Group 2 tumours to neoadjuvant chemotherapy (NACT). METHODS: 749 BC cases were identified from 11 institutions. The association between HER2 groups and pathological complete response (pCR) was assessed. RESULTS: 54% of immunohistochemistry HER2 positive (score 3+) BCs showed pCR, compared to 19% of immunohistochemistry 2+ FISH amplified cases. 27% of Group 2 treated with HER2 targeted therapy achieved pCR, compared to 19 and 11% in the combined Groups 1 + 3 and Groups 4 + 5, respectively. No difference in pCR rates was identified between Group 2 and Group 1 or combined Groups 1 + 3. However, Group 2 response rate was higher than Groups 4 + 5 (p = 0.017). CONCLUSION: No difference in pCR was detected in tumours with a HER2/CEP17 ratio ≥2.0 and a HER2 score 2+ by IHC when stratified by HER2 gene copy number. Our data suggest that ASCO/CAP HER2 Group 2 carcinomas should be evaluated further with respect to eligibility for HER2 targeted therapy.
Asunto(s)
Neoplasias de la Mama , Dosificación de Gen , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/diagnóstico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Estudios de Casos y Controles , Estudios de Cohortes , Femenino , Amplificación de Genes , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Terapia Neoadyuvante , Clasificación del Tumor , Receptor ErbB-2/análisis , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudios RetrospectivosRESUMEN
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.
Asunto(s)
Neoplasias de la Mama/patología , Neoplasias de la Mama/terapia , Receptor ErbB-2/análisis , Receptor ErbB-2/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/metabolismo , Quimioterapia Adyuvante/métodos , Femenino , Humanos , Persona de Mediana Edad , Terapia Neoadyuvante/métodos , Resultado del TratamientoRESUMEN
High stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative breast cancer (TNBC) are associated with pathological complete response (pCR) after neoadjuvant chemotherapy (NAC). Histopathological assessment of sTILs in TNBC biopsies is characterized by substantial interobserver variability, but it is unknown whether this affects its association with pCR. Here, we aimed to investigate the degree of interobserver variability in an international study, and its impact on the relationship between sTILs and pCR. Forty pathologists assessed sTILs as a percentage in digitalized biopsy slides, originating from 41 TNBC patients who were treated with NAC followed by surgery. Pathological response was quantified by the MD Anderson Residual Cancer Burden (RCB) score. Intraclass correlation coefficients (ICCs) were calculated per pathologist duo and Bland-Altman plots were constructed. The relation between sTILs and pCR or RCB class was investigated. The ICCs ranged from -0.376 to 0.947 (mean: 0.659), indicating substantial interobserver variability. Nevertheless, high sTILs scores were significantly associated with pCR for 36 participants (90%), and with RCB class for eight participants (20%). Post hoc sTILs cutoffs at 20% and 40% resulted in variable associations with pCR. The sTILs in TNBC with RCB-II and RCB-III were intermediate to those of RCB-0 and RCB-I, with lowest sTILs observed in RCB-I. However, the limited number of RCB-I cases precludes any definite conclusions due to lack of power, and this observation therefore requires further investigation. In conclusion, sTILs are a robust marker for pCR at the group level. However, if sTILs are to be used to guide the NAC scheme for individual patients, the observed interobserver variability might substantially affect the chance of obtaining a pCR. Future studies should determine the 'ideal' sTILs threshold, and attempt to fine-tune the patient selection for sTILs-based de-escalation of NAC regimens. At present, there is insufficient evidence for robust and reproducible sTILs-guided therapeutic decisions.
Asunto(s)
Linfocitos Infiltrantes de Tumor/patología , Células del Estroma/patología , Neoplasias de la Mama Triple Negativas/patología , Microambiente Tumoral , Adulto , Anciano , Anciano de 80 o más Años , Australia , Quimioterapia Adyuvante , Toma de Decisiones Clínicas , Europa (Continente) , Femenino , Humanos , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Linfocitos Infiltrantes de Tumor/inmunología , Mastectomía , Persona de Mediana Edad , Terapia Neoadyuvante , Invasividad Neoplásica , América del Norte , Variaciones Dependientes del Observador , Valor Predictivo de las Pruebas , Reproducibilidad de los Resultados , Células del Estroma/efectos de los fármacos , Células del Estroma/inmunología , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/terapia , Microambiente Tumoral/inmunologíaRESUMEN
AIMS: Neoadjuvant endocrine therapy (NAET) is used in the management of oestrogen receptor (ER)-positive breast cancer. The optimal method for histological assessment of response and the effect of NAET on the tumour morphology, grade and molecular profile remain unclear. The aim of this study is to investigate the NAET effect on tumour type, grade and molecular profile by analysing a well-characterised cohort of breast cancer samples in a single large UK tertiary referral centre, and to provide guidance on the pathological assessment of those lesions to inform adjuvant management and prognosis. METHODS AND RESULTS: A single large-institution cohort of 132 patients who received NAET over a 13-year period was identified. Comprehensive clinical, histopathological and follow-up data were collected. A detailed histological review of a subset with residual post-treatment carcinoma was undertaken. Two carcinomas (both of the lobular type) achieved complete pathological response. Central scarring was seen in 49.3% of tumours post-treatment. Significant changes in tumour type (41.6%), tumour grade (downgrading in one-third of tumours), and progesterone receptor (PR) expression (22.3%), with a switch to PR-negative status in 17.6% of cases, were observed. The last of these was associated with an absence of tumour-infiltrating lymphocytes (P = 0.005). Ten per cent of cases showed a change in HER2 expression (P = 0.002). The median patient survival was 60 months, and downgrading of tumours was associated with better overall survival (P = 0.05). CONCLUSIONS: We propose a histological method for assessment of residual carcinoma following NAET, and recommend repeat ER/PR/HER2 testing to inform management and prognosis.