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BACKGROUND: The characterization and comparison of gene expression and intrinsic subtype (IS) changes induced by neoadjuvant chemotherapy (NACT) and endocrine therapy in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2 (HER2)-low versus HR+/HER2-0 breast cancer (BC) has not been conducted so far. Most evidence on the association of HER2 status with pathologic responses and prognosis in HR+/HER2-negative BC is controversial and restricted to NACT-treated disease. Similarly, a temporal heterogeneity in HER2 status has been described only with NACT. METHODS: We retrospectively recruited a consecutive cohort of 186 patients with stage I-IIIB HR+/HER2-negative BC treated with neoadjuvant therapy (NAT). Available diagnostic biopsies and surgical samples were characterized for main pathological features, PAM50 IS and ROR-P score, and gene expression. Associations with pathologic complete response, residual cancer burden-0/I, event-free survival (EFS) and overall survival (OS) based on HER2 status were assessed. Pre/post pathologic/molecular changes were analyzed in matched samples. RESULTS: The HER2-low (62.9%) and HER2-0 (37.1%) cohorts did not differ significantly in main baseline features, treatments administered, breast-conserving surgery, pathologic complete response and residual cancer burden-0/I rates, EFS, and OS. NAT induced, regardless of HER2 status, a significant reduction of estrogen receptor/progesterone receptor and Ki67 levels, a down-regulation of PAM50 proliferation- and luminal-related genes/signatures, an up-regulation of selected immune genes, and a shift towards less aggressive IS and lower ROR-P. Moreover, 25% of HER2-0 changed to HER2-low and 34% HER2-low became HER2-0. HER2 shifts were significant after NACT (P < 0.001), not neoadjuvant endocrine therapy (P = 0.063), with consistent ERBB2 mRNA level dynamics. HER2 changes were not associated with EFS/OS. CONCLUSIONS: HER2-low and HER2-0 status change after NAT in â¼30% of cases, mostly after NACT. Targeted adjuvant strategies should be investigated accordingly. Molecular downstaging with current chemo/endocrine agents and immunotherapy should not rely on HER2 immunohistochemical levels in HR+/HER2-negative BC. Instead, HER2-low-targeted approaches should be explored to pursue more effective and/or less toxic dimensional downstaging.
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Neoplasias da Mama , Terapia Neoadjuvante , Receptor ErbB-2 , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Feminino , Terapia Neoadjuvante/métodos , Receptor ErbB-2/metabolismo , Pessoa de Meia-Idade , Estudos Retrospectivos , Adulto , Idoso , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Prognóstico , Biomarcadores Tumorais/metabolismo , Antineoplásicos Hormonais/uso terapêutico , Antineoplásicos Hormonais/farmacologiaRESUMO
BACKGROUND: HER2DX, a multianalyte genomic test, has been clinically validated to predict breast cancer recurrence risk (relapse risk score), the probability of achieving pathological complete response post-neoadjuvant therapy (pCR likelihood score), and individual ERBB2 messenger RNA (mRNA) expression levels in patients with early-stage human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This study delves into the comprehensive analysis of HER2DX's analytical performance. MATERIALS AND METHODS: Precision and reproducibility of HER2DX risk, pCR, and ERBB2 mRNA scores were assessed within and between laboratories using formalin-fixed paraffin-embedded (FFPE) tumor tissues and purified RNA. Robustness was appraised by analyzing the impact of tumor cell content and protocol variations including different instruments, reagent lots, and different RNA extraction kits. Variability was evaluated across intratumor biopsies and genomic platforms [RNA sequencing (RNAseq) versus nCounter], and according to protocol variations. RESULTS: Precision analysis of 10 FFPE tumor samples yielded a maximal standard error of 0.94 across HER2DX scores (1-99 scale). High reproducibility of HER2DX scores across 29 FFPE tumors and 20 RNAs between laboratories was evident (correlation coefficients >0.98). The probability of identifying score differences >5 units was ≤5.2%. No significant variability emerged based on platform instruments, reagent lots, RNA extraction kits, or TagSet thaw/freeze cycles. Moreover, HER2DX displayed robustness at low tumor cell content (10%). Intratumor variability across 212 biopsies (106 tumors) was <4.0%. Concordance between HER2DX scores from 30 RNAs on RNAseq and nCounter platforms exceeded 90.0% (Cohen's κ coefficients >0.80). CONCLUSIONS: The HER2DX assay is highly reproducible and robust for the quantification of recurrence risk, pCR likelihood, and ERBB2 mRNA expression in early-stage HER2-positive breast cancer.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Reprodutibilidade dos Testes , Recidiva Local de Neoplasia/genética , RNA/análise , RNA Mensageiro/genéticaRESUMO
BACKGROUND: The HER2DX risk-score has undergone rigorous validation in prior investigations involving patients with early-stage human epidermal growth factor receptor 2 (HER2)-positive (HER2+) breast cancer. In this study, we present the outcomes of the HER2DX risk-score within the most recent release of the Sweden Cancerome Analysis Network-Breast (SCAN-B) HER2+ cohort. This updated examination benefits from a larger patient sample, an extended follow-up duration, and detailed treatment information. MATERIALS AND METHODS: Clinical and RNAseq data from the SCAN-B dataset were retrieved from Gene Expression Omnibus (GSE81538). Among the 6600 patients, 819 had HER2+ breast cancer, with 757 individuals with research-based HER2DX risk-scores and corresponding survival outcomes. The HER2DX risk-score was evaluated (i) as a continuous variable and (ii) using predefined cut-offs. The primary endpoint for this study was overall survival (OS). The Kaplan-Meier method and Cox models were used to estimate OS and a multistate model with four states was fitted to better characterize patients' follow-up. RESULTS: The median follow-up time was 7.5 years (n = 757). The most common systemic therapy was chemotherapy with trastuzumab (82.0%) and most tumors were classified as T1-T2 (97.1%). The HER2DX risk-score as a continuous variable was significantly associated with OS after adjustment for clinical variables and treatment regimen [hazard ratios (HR) per 10-unit increment = 1.31, 95% confidence interval (CI) 1.13-1.51, P < 0.001] as well as within predefined risk groups (high versus low; HR = 2.57, 95% CI 1.36-4.85, P < 0.001). Patients classified as HER2DX high-risk also had higher risk of (i) breast cancer recurrence and (ii) death without previous recurrence. Within the subgroup of HER2+ T1N0 tumors (n = 297), those classified as high-risk demonstrated inferior OS compared to low-risk tumors (7-year OS 77.8% versus 96.8%, P < 0.001). The HER2DX mRNA ERBB2 score was associated with clinical HER2 status (area under the receiver operating characteristic curve = 0.91). CONCLUSIONS: In patients with early-stage HER2+ breast cancer, HER2DX risk-score provides prognostic information beyond clinicopathological variables, including treatment regimen with or without trastuzumab.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Prognóstico , Suécia/epidemiologia , Recidiva Local de Neoplasia/tratamento farmacológico , Trastuzumab/farmacologia , Trastuzumab/uso terapêuticoRESUMO
BACKGROUND: HER2 mutations are targetable alterations in patients with hormone receptor-positive (HR+) metastatic breast cancer (MBC). In the SUMMIT basket study, patients with HER2-mutant MBC received neratinib monotherapy, neratinib + fulvestrant, or neratinib + fulvestrant + trastuzumab (N + F + T). We report results from 71 patients with HR+, HER2-mutant MBC, including 21 (seven in each arm) from a randomized substudy of fulvestrant versus fulvestrant + trastuzumab (F + T) versus N + F + T. PATIENTS AND METHODS: Patients with HR+ HER2-negative MBC with activating HER2 mutation(s) and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) therapy received N + F + T (oral neratinib 240 mg/day with loperamide prophylaxis, intramuscular fulvestrant 500 mg on days 1, 15, and 29 of cycle 1 then q4w, intravenous trastuzumab 8 mg/kg then 6 mg/kg q3w) or F + T or fulvestrant alone. Those whose disease progressed on F + T or fulvestrant could cross-over to N + F + T. Efficacy endpoints included investigator-assessed objective response rate (ORR), clinical benefit rate (RECIST v1.1), duration of response, and progression-free survival (PFS). Plasma and/or formalin-fixed paraffin-embedded tissue samples were collected at baseline; plasma was collected during and at end of treatment. Extracted DNA was analyzed by next-generation sequencing. RESULTS: ORR for 57 N + F + T-treated patients was 39% [95% confidence interval (CI) 26% to 52%); median PFS was 8.3 months (95% CI 6.0-15.1 months). No responses occurred in fulvestrant- or F + T-treated patients; responses in patients crossing over to N + F + T supported the requirement for neratinib in the triplet. Responses were observed in patients with ductal and lobular histology, 1 or ≥1 HER2 mutations, and co-occurring HER3 mutations. Longitudinal circulating tumor DNA sequencing revealed acquisition of additional HER2 alterations, and mutations in genes including PIK3CA, enabling further precision targeting and possible re-response. CONCLUSIONS: The benefit of N + F + T for HR+ HER2-mutant MBC after progression on CDK4/6is is clinically meaningful and, based on this study, N + F + T has been included in the National Comprehensive Cancer Network treatment guidelines. SUMMIT has improved our understanding of the translational implications of targeting HER2 mutations with neratinib-based therapy.
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Neoplasias da Mama , Feminino , Humanos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Fulvestranto , Receptor ErbB-2 , TrastuzumabRESUMO
Aims: To assess the impact of the molecular subtype (MS) on the total number of CK19 mRNA copies in all positive SLN (TTL) threshold, to predict non-SLN affectation, and to compare 5 years progression-free survival (PFS) according to the risk of recurrence (ROR) group by PAM50. Methods: Cohort with infiltrating breast cancer with intra-operative metastatic SLN detected by one-step nucleic acid amplification (OSNA) assay who underwent subsequent ALND. Logistic regression was used to assess a possible interaction between TTL and MS(Triple Negative, Her-2-Enriched, Luminal A, or Luminal B), or hormone receptors (HR: positive or negative) by immunohistochemistry (IMH). Cox regression was used to compare PFS and OS in the 3 ROR groups (high, medium, or low). Results: TTL was predictive of non-SLN affectation in both univariate (OR [95% CI]: 1.72 [1.43, 2.05], P < .001) and multivariate (1.55 [95% CI: 1.04, 2.32], P = .030) models, but MS-IMH or HR-IMH, and their interactions with TTL were not (best multivariate model: HR + main effect OR 1.16 [95% CI: 0.18, 7.64], P = .874; interaction OR: 1.04 [0.7, 1.55], P = .835; univariate model: HR + main effect OR: 1.44 [95% CI: 0.85, 2.44], P = .180). PFS was lower in the high-risk ROR group (81.1%) than in the low-risk group (93.9%) (HR: 3.68 [95 CI: 1.70, 7.94], P < .001). Conclusions: our results do not provide evidence to support the utilization of subtype-specific thresholds for TTL values to make therapeutic decisions on the axilla. The ROR group was predictive of 5 years-PFS.
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BACKGROUND: Human epidermal growth factor receptor 2 (HER2)-low expression in breast cancer has been recently identified as a new therapeutic target. However, it is unclear if HER2-low status has an independent impact on prognosis. MATERIALS AND METHODS: A systematic literature research was carried out to identify studies comparing survival outcomes of patients affected by HER2-low versus HER2-zero breast cancer. Using random-effects models, pooled hazard ratios (HRs) and odds ratios (ORs) with 95% confidence intervals (CIs) were calculated for progression-free survival (PFS) and overall survival (OS) in the metastatic setting as well as disease-free survival (DFS), OS and pathological complete response (pCR) in the early setting. Subgroup analyses by hormone receptor (HoR) status were carried out. The study protocol is registered on PROSPERO (n.CRD42023390777). RESULTS: Among 1916 identified records, 42 studies including 1 797 175 patients were eligible. In the early setting, HER2-low status was associated with significant improved DFS (HR 0.86, 95% CI 0.79-0.92, P < 0.001) and OS (HR 0.90, 95% CI 0.85-0.95, P < 0.001) when compared to HER2-zero status. Improved OS was observed for both HoR-positive and HoR-negative HER2-low populations, while DFS improvement was observed only in the HoR-positive subgroup. HER2-low status was significantly associated with a lower rate of pCR as compared to HER2-zero status both in the overall population (OR 0.74, 95% CI 0.62-0.88, P = 0.001) and in the HoR-positive subgroup (OR 0.77, 95% CI 0.65-0.90, P = 0.001). In the metastatic setting, patients with HER2-low breast cancers showed better OS when compared with those with HER2-zero tumours in the overall population (HR 0.94, 95% CI 0.89-0.98, P = 0.008), regardless of HoR status. No significant PFS differences were found. CONCLUSIONS: Compared with HER2-zero status, HER2-low status appears to be associated with a slightly increased OS both in the advanced and early settings, regardless of HoR expression. In the early setting, HER2-low tumours seem to be associated to lower pCR rates, especially if HoR-positive.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Prognóstico , Intervalo Livre de Doença , Intervalo Livre de Progressão , Modelos de Riscos ProporcionaisRESUMO
BACKGROUND: The HER2DX genomic test predicts pathological complete response (pCR) and survival outcome in early-stage HER2-positive (HER2+) breast cancer. Here, we evaluated the association of HER2DX scores with (i) pCR according to hormone receptor status and various treatment regimens, and (ii) survival outcome according to pCR status. MATERIALS AND METHODS: Seven neoadjuvant cohorts with HER2DX and clinical individual patient data were evaluated (DAPHNe, GOM-HGUGM-2018-05, CALGB-40601, ISPY-2, BiOnHER, NEOHER and PAMELA). All patients were treated with neoadjuvant trastuzumab (n = 765) in combination with pertuzumab (n = 328), lapatinib (n = 187) or without a second anti-HER2 drug (n = 250). Event-free survival (EFS) and overall survival (OS) outcomes were available in a combined series of 268 patients (i.e. NEOHER and PAMELA) with a pCR (n = 118) and without a pCR (n = 150). Cox models were adjusted to evaluate whether HER2DX can identify patients with low or high risk beyond pCR status. RESULTS: HER2DX pCR score was significantly associated with pCR in all patients [odds ratio (OR) per 10-unit increase = 1.59, 95% confidence interval 1.43-1.77; area under the ROC curve = 0.75], with or without dual HER2 blockade. A statistically significant increase in pCR rate due to dual HER2 blockade over trastuzumab-only was observed in HER2DX pCR-high tumors treated with chemotherapy (OR = 2.36 (1.09-5.42). A statistically significant increase in pCR rate due to multi-agent chemotherapy over a single taxane was observed in HER2DX pCR-medium tumors treated with dual HER2 blockade (OR = 3.11, 1.54-6.49). The pCR rates in HER2DX pCR-low tumors were ≤30.0% regardless of treatment administered. After adjusting by pCR status, patients identified as HER2DX low-risk had better EFS (P < 0.001) and OS (P = 0.006) compared with patients with HER2DX high-risk. CONCLUSIONS: HER2DX pCR score and risk score might help identify ideal candidates to receive neoadjuvant dual HER2 blockade in combination with a single taxane in early-stage HER2+ breast cancer.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor ErbB-2/genética , Resultado do Tratamento , Trastuzumab , Taxoides , Terapia Neoadjuvante/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversosRESUMO
BACKGROUND: Patritumab deruxtecan (HER3-DXd) is a human epidermal growth factor receptor 3 (HER3)-directed antibody-drug conjugate composed of a fully human anti-HER3 monoclonal antibody (patritumab) covalently linked to a topoisomerase I inhibitor payload via a stable, tumor-selective, tetrapeptide-based cleavable linker. TOT-HER3 is a window-of-opportunity study designed to assess the biological activity, measured by CelTIL score [= -0.8 × tumor cellularity (in %) + 1.3 × tumor-infiltrating lymphocytes (TILs) (in %)], and clinical activity of HER3-DXd during short-term (21 days) pre-operative treatment in patients with primary operable HER2-negative early breast cancer. PATIENTS AND METHODS: Patients with previously untreated hormone receptor-positive/HER2-negative tumors were allocated to one of four cohorts according to baseline ERBB3 messenger RNA expression. All patients received one dose of HER3-DXd 6.4 mg/kg. The primary objective was to evaluate change from baseline in CelTIL score. RESULTS: Seventy-seven patients were evaluated for efficacy. A significant change in CelTIL score was observed, with a median increase from baseline of 3.5 (interquartile range, -3.8 to 12.7; P = 0.003). Among patients assessable for clinical response (n = 62), an overall response rate of 45% was observed (tumor measurement by caliper), with a trend toward an increase in CelTIL score among responders compared with non-responders (mean difference, +11.9 versus +1.9). Change in CelTIL score was independent of baseline ERBB3 messenger RNA and HER3 protein levels. Genomic changes occurred, including switching toward a less proliferative tumor phenotype based on PAM50 subtypes, suppression of cell proliferation genes, and induction of genes associated with immunity. Treatment-emergent adverse events were observed in 96% of patients (14% grade ≥3); most common were nausea, fatigue, alopecia, diarrhea, vomiting, abdominal pain, and neutrophil count decrease. CONCLUSIONS: A single dose of HER3-DXd was associated with clinical response, increased immune infiltration, suppression of proliferation in hormone receptor-positive/HER2-negative early breast cancer, and a tolerable safety profile consistent with previously reported results. These findings support further study of HER3-DXd in early breast cancer.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Receptor ErbB-2/metabolismo , Camptotecina/uso terapêutico , Trastuzumab/uso terapêuticoRESUMO
BACKGROUND: In hormone receptor-positive (HoR+) breast cancer (BC), gene expression analysis identifies luminal A (LumA), luminal B (LumB), human epidermal growth factor receptor 2 (HER2)-enriched (HER2-E), basal-like (BL) intrinsic subtypes and a normal-like group. This classification has an established prognostic value in early-stage HoR+ BC. Here, we carried out a trial-level meta-analysis to determine the prognostic ability of subtypes in metastatic BC (MBC). MATERIALS AND METHODS: We systematically reviewed all the available prospective phase II/III trials in HoR+ MBC where subtype was assessed. The primary endpoint was progression-free survival (PFS)/time to progression (TTP) of the LumA subtype compared to non-LumA. Secondary endpoints were PFS/TTP of each individual subtype, according to treatment, menopausal and HER2 status and overall survival (OS). The random-effect model was applied, and heterogeneity assessed through Cochran's Q and I2. Threshold for significance was set at P < 0.05. The study was registered in PROSPERO (ID: CRD42021255769). RESULTS: Seven studies were included (2536 patients). Non-LumA represented 55.2% and was associated with worse PFS/TTP than LumA [hazard ratio (HR) 1.77, P < 0.001, I2 = 61%], independently of clinical HER2 status [Psubgroup difference (Psub) = 0.16], systemic treatment (Psub = 0.96) and menopausal status (Psub = 0.12). Non-LumA tumors also showed worse OS (HR 2.00, P < 0.001, I2 = 65%), with significantly different outcomes for LumB (PFS/TTP HR 1.46; OS HR 1.41), HER2-E (PFS/TTP HR 2.39; OS HR 2.08) and BL (PFS/TTP HR 2.67; OS HR 3.26), separately (PFS/TTP Psub = 0.01; OS Psub = 0.005). Sensitivity analyses supported the main result. No publication bias was observed. CONCLUSIONS: In HoR+ MBC, non-LumA disease is associated with poorer PFS/TTP and OS than LumA, independently of HER2, treatment and menopausal status. Future trials in HoR+ MBC should consider this clinically relevant biological classification.
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Antineoplásicos , Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Prognóstico , Estudos Prospectivos , Antineoplásicos/uso terapêutico , Modelos de Riscos ProporcionaisRESUMO
Diffraction instruments using filtering by one or several analyser crystals exist since the 1980s and 1990s at synchrotron radiation sources, but, due to its low efficiency, this filtering is little used on laboratory sources. In order to overcome this limitation, the efficiency of a small diffraction filtering multi-analyzer block (MAD block) realized with a `single-crystal-comb' curved on a rigid support is demonstrated here. The geometry of this curved surface is logarithmic spiral and is optimized to allow multi-filtering over a relatively important diffraction angular range and to be also applicable over an X-ray spectral range. The efficiency of such a small rigid-compact MAD block consisting of this single-crystal-comb generating 20-50 Si(111) single-crystal blades, associated with a block of Soller collimators, is demonstrated. The angle between each crystal is 0.1°, so the measurement range of the comb is 2-5°. The geometry of this system has been optimized for operation with a synchrotron X-ray source over an energy range of 22â keV to 46â keV and could be used with laboratory X-ray sources (Agâ Kα1, 22.1â keV). This MAD block complements and exploits the qualities of the `photon-counting' detectors which have very low intrinsic noise. Their joint efficacy is supported by powder pattern measurements of a LaB6 reference sample and of several heterogeneous samples of cultural heritage materials, carried out at 22â keV on the D2AM beamline at the ESRF. Their signal-to-noise ratio is excellent (1000/1) and allows the detection thresholds of the measurements (from 3-1% to 0.1%) to detect minor phases in the studies of `real' heterogeneous materials to be drastically improved.
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Diffraction and spectroscopy instruments using a filtering process with several analyser crystals have existed for about 30 years at synchrotron radiation sources, but they are difficult to use on laboratory sources. Several diffraction multi-filtering systems for powder diffraction experiments have been studied and optimized, in order to show the relevance, simplicity and efficiency of their implementation. Optical filter systems containing one or many diffracting elements, precisely positioned in a rigid manner on a logarithmic spiral surface and having a stability that allows high resolution and high sensitivity to powder diffraction experiments, have been developed. After having tested prototypes with various geometries, we present in particular the realization of a small rigid-compact multi-analyser comb that allows 20-50 measurements on synchrotron radiation sources to be filtered in parallel, but also and especially that can be adapted on laboratory X-ray sources (Agâ Kα1) to increase by an order of magnitude the intensities and resolutions of the measurements. Such a rigid-compact multi-analyser block can advantageously be associated with `photon-counting' 1D and 2D detectors in order to drastically improve the detection thresholds of powder diffraction measurements to better than 0.1%, which allows the detection/quantification/analysis of minor phases in studies of `real' complex materials.
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BACKGROUND: Two promising therapeutic strategies in oncology are chimeric antigen receptor-T cell (CAR-T) therapies and antibody-drug conjugates (ADCs). To be effective and safe, these immunotherapies require surface antigens to be sufficiently expressed in tumors and less or not expressed in normal tissues. To identify new targets for ADCs and CAR-T specifically targeting breast cancer (BC) molecular and pathology-based subtypes, we propose a novel in silico strategy based on multiple publicly available datasets and provide a comprehensive explanation of the workflow for a further implementation. METHODS: We carried out differential gene expression analyses on The Cancer Genome Atlas BC RNA-sequencing data to identify BC subtype-specific upregulated genes. To fully explain the proposed target-discovering methodology, as proof of concept, we selected the 200 most upregulated genes for each subtype and undertook a comprehensive analysis of their protein expression in BC and normal tissues through several publicly available databases to identify the potentially safest and viable targets. RESULTS: We identified 36 potentially suitable and subtype-specific tumor surface antigens (TSAs), including fibroblast growth factor receptor-4 (FGFR4), carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6), GDNF family receptor alpha 1 (GFRA1), integrin beta-6 (ITGB6) and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1). We also identified 63 potential TSA pairs that might be appropriate for co-targeting strategies. Finally, we validated subtype specificity in a cohort of our patients, multiple BC cell lines and the METABRIC database. CONCLUSIONS: Overall, our in silico analysis provides a framework to identify novel and specific TSAs for the development of new CAR-T and antibody-based therapies in BC.
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Neoplasias da Mama , Imunoconjugados , Receptores de Antígenos Quiméricos , Antígenos CD , Neoplasias da Mama/tratamento farmacológico , Moléculas de Adesão Celular , Feminino , Proteínas Ligadas por GPI , Humanos , Imunoterapia Adotiva , Linfócitos TRESUMO
Despite their recognised role in HER2-positive (HER2+) breast cancer (BC), the composition, localisation and functional orientation of immune cells within tumour microenvironment, as well as its dynamics during anti-HER2 treatment, is largely unknown. We here investigate changes in tumour-immune contexture, as assessed by stromal tumour-infiltrating lymphocytes (sTILs) and by multiplexed spatial cellular phenotyping, during treatment with lapatinib-trastuzumab in HER2+ BC patients (PAMELA trial). Moreover, we evaluate the relationship of tumour-immune contexture with hormone receptor status, intrinsic subtype and immune-related gene expression. sTIL levels increase after 2 weeks of HER2 blockade in HR-negative disease and HER2-enriched subtype. This is linked to a concomitant increase in cell density of all four immune subpopulations (CD3+, CD4+, CD8+, Foxp3+). Moreover, immune contexture analysis showed that immune cells spatially interacting with tumour cells have the strongest association with response to anti-HER2 treatment. Subsequently, sTILs consistently decrease at the surgery in patients achieving pathologic complete response, whereas most residual tumours at surgery remain inflamed, possibly reflecting a progressive loss of function of T cells. Understanding the features of the resulting tumour immunosuppressive microenvironment has crucial implications for the design of new strategies to de-escalate or escalate systemic therapy in early-stage HER2+ BC.
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OBJECTIVES: A centralised approach to health technology assessment (HTA) may facilitate optimal use of HTA resources. A regional approach may increase the chances of local implementation of recommendations. This study aimed to compare assessment procedures in England (centralised HTA approach) with Spain (regional HTA approach) discussing key challenges and opportunities from both approaches. METHODS: We compared technology assessments of anticancer medicines in the two jurisdictions from 2008 to 2015. To assess the implementation of HTA recommendations, we assessed trends in medicine usage using regression methods. We used IQVIA data, from 2011 to 2016, for a sample of 11 medicines. We used CatSalut data from Catalonia to assess the implementation of local recommendations. RESULTS: In England, 66 assessments were undertaken by the National Institute for Health and Care Excellence (NICE), using a standardised methodology. In Spain, there were 79 reports undertaken by a range of bodies using a shared process and coordinated through the GENESIS collaboration; the assessment methods used varied substantially. Overall, the recommendations in the two jurisdictions were similar. Regression analyses indicate that where there is a positive recommendation by HTA bodies, the usage of the medicine responds most strongly (p < 0.001) in Catalonia (4.892), followed by England (3.120) and Spain (1.693). CONCLUSIONS: This study suggests that medicine utilisation does respond to the positive recommendations of HTA bodies. However, if HTA capacity is organised primarily regionally, considerable effort may be required in coordination, to ensure consistent and rigorous assessments and adequate implementation of HTA findings.
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Recursos em Saúde/estatística & dados numéricos , Medicamentos sob Prescrição/economia , Medicina Estatal/organização & administração , Avaliação da Tecnologia Biomédica/organização & administração , Análise Custo-Benefício , Inglaterra , Humanos , EspanhaRESUMO
OBJECTIVES: To validate the performance of multiparametric magnetic resonance (MR) imaging to assess pathologic response to neoadjuvant systemic therapy (NST) in various breast cancer subtypes considering two definitions of pCR: absence of any residual invasive cancer or DCIS (ypT0) and absence of invasive tumour cells (ypT0/is). METHODS: Institutional review board-approved retrospective study, with waiver of the need to obtain informed consent. From January 2015 to June 2017, 81 women with 82 breast cancers undergoing NST were included. Eighteen lesions (22%) were immunohistochemically HER2-positive, 12 (15%) triple negative (TN), 42 (51%) luminal B-like and 10 (12%) luminal B-like/HER2-positive. Breast MR imaging was performed before and after NST. A comparative analysis considering pCR as ypT0 and ypT0/is was carried out. Performance of univariate and multivariate models to potentially predict pathologic response were evaluated. RESULTS: ypT0 was attained in 23% (19/82) of cases and ypT0/is in 33% (27/82) of cases. In both scenarios, HER2-positive subtype achieved the best response, 53% and 48%, respectively. A significant relationship was found between late enhancement and pathologic response (pâ¯<â¯0.001) regardless of pCR definition. In the ypT0 scenario, mean ADC ratio in the pCR subgroup was significantly higher than that in the non-pCR subgroup (pâ¯=â¯0.021) but no significant relationship was noted in ypT0/is. A multivariate model including MR late enhancement, ADC ratio and tumor subtype identified pathologic response with 86% and 84% accuracy when ypT0 and ypT0/is were considered, respectively. CONCLUSION: MR imaging late enhancement and ADC ratio along with breast cancer IHC subtype identify pathologic response following NST with high accuracy, achieving the highest NPV in TN and HER2-positive tumors and the highest PPV in luminal B-like subtypes, regardless of the definition of pCR as ypT0 or ypT0/is. In light of these findings and given that residual DCIS does not have an impact on survival rates, ypT0/is seems to be the preferable definition of pCR.
Assuntos
Neoplasias da Mama/patologia , Imageamento por Ressonância Magnética , Terapia Neoadjuvante/métodos , Neoplasia Residual/patologia , Adulto , Antineoplásicos , Neoplasias da Mama/diagnóstico por imagem , Feminino , Humanos , Neoplasia Residual/diagnóstico por imagem , Estudos RetrospectivosRESUMO
BACKGROUND: HER2-positive (+) breast cancers, defined by HER2 overexpression and/or amplification, are often addicted to HER2 to maintain their malignant phenotype. Yet, some HER2+ tumors do not benefit from anti-HER2 therapy. We hypothesize that HER2 amplification levels and PI3K pathway activation are key determinants of response to HER2-targeted treatments without chemotherapy. PATIENTS AND METHODS: Baseline HER2+ tumors from patients treated with neoadjuvant lapatinib plus trastuzumab [with endocrine therapy for estrogen receptor (ER)+ tumors] in TBCRC006 (NCT00548184) were evaluated in a central laboratory for HER2 amplification by fluorescence in situ hybridization (FISH) (n = 56). HER2 copy number (CN) and FISH ratios, and PI3K pathway status, defined by PIK3CA mutations or PTEN levels by immunohistochemistry were available for 41 tumors. Results were correlated with pathologic complete response (pCR; no residual invasive tumor in breast). RESULTS: Thirteen of the 56 patients (23%) achieved pCR. None of the 11 patients with HER2 ratio <4 and/or CN <10 achieved pCR, whereas 13/45 patients (29%) with HER2 ratio ≥4 and/or CN ≥10 attained pCR (P = 0.0513). Of the 18 patients with tumors expressing high PTEN or wild-type (WT) PIK3CA (intact PI3K pathway), 7 (39%) achieved pCR, compared with 1/23 (4%) with PI3K pathway alterations (P = 0.0133). Seven of the 16 patients (44%) with HER2 ratio ≥4 and intact PI3K pathway achieved pCR, whereas only 1/25 (4%) patients not meeting these criteria achieved pCR (P = 0.0031). CONCLUSIONS: Our findings suggest that there is a clinical subtype in breast cancer with high HER2 amplification and intact PI3K pathway that is especially sensitive to HER2-targeted therapies without chemotherapy. A combination of HER2 FISH ratio and PI3K pathway status warrants validation to identify patients who may be treated with HER2-targeted therapy without chemotherapy.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Receptor ErbB-2/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Classe I de Fosfatidilinositol 3-Quinases/genética , Classe I de Fosfatidilinositol 3-Quinases/metabolismo , Feminino , Seguimentos , Amplificação de Genes , Humanos , Hibridização in Situ Fluorescente , Lapatinib/administração & dosagem , Terapia Neoadjuvante , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Prognóstico , Receptor ErbB-2/antagonistas & inibidores , Receptor ErbB-2/genética , Indução de Remissão , Trastuzumab/administração & dosagemRESUMO
BACKGROUND: In human epidermal growth factor receptor 2 (HER2+) breast cancers, neoadjuvant trials of chemotherapy plus anti-HER2 treatment consistently showed lower pathologic complete response (pCR) rates in hormone receptor (HR) positive versus negative tumors. The PerELISA study was aimed to evaluate the efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HR+/HER2+ breast cancer patients selected on the basis of Ki67 inhibition after 2-week letrozole. PATIENTS AND METHODS: PerELISA is a phase II, multicentric study for postmenopausal patients with HR+/HER2+ operable breast cancer. Patients received 2-week letrozole, and then underwent re-biopsy for Ki67 evaluation. Patients classified as molecular responders (Ki67 relative reduction >20% from baseline) continued letrozole and started trastuzumab-pertuzumab for five cycles. Patients classified as molecular non-responders started weekly paclitaxel for 13 weeks combined with trastuzumab-pertuzumab. Primary aim was breast and axillary pCR. According to a two-stage Simon's design, to reject the null hypothesis, at least 8/43 pCR had to be documented. RESULTS: Sixty-four patients were enrolled, 44 were classified as molecular responders. All these patients completed the assigned treatment with letrozole-trastuzumab-pertuzumab and underwent surgery. A pCR was observed in 9/44 cases (20.5%, 95% confidence interval 11.1% to 34.5%). Among molecular non-responders, 16/17 completed treatment and underwent surgery, with pCR observed in 81.3% of the cases. PAM50 intrinsic subtype was significantly associated with Ki67 response and pCR. Among molecular responders, the pCR rate was significantly higher in HER2-enriched than in other subtypes (45.5% versus 13.8%, P = 0.042). CONCLUSIONS: The primary end point of the study was met, by reaching the pre-specified pCRs. In patients selected using Ki67 reduction after short-term letrozole exposure, a meaningful pCR rate can be achieved without chemotherapy. PAM50 intrinsic subtyping further refines our ability to identify a subset of patients for whom chemotherapy might be spared. EUDRACT NUMBER: 2013-002662-40. CLINICALTRIALS.GOV IDENTIFIER: NCT02411344.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Antígeno Ki-67/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patologia , Carcinoma Ductal de Mama/cirurgia , Carcinoma Lobular/tratamento farmacológico , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patologia , Carcinoma Lobular/cirurgia , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Letrozol/administração & dosagem , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica , Prognóstico , Indução de Remissão , Trastuzumab/administração & dosagemRESUMO
Breast cancer is the most common cancer in women in our country and it is usually diagnosed in the early and potentially curable stages. Nevertheless, around 20-30% of patients will relapse despite appropriate locoregional and systemic therapies. A better knowledge of this disease is improving our ability to select the most appropriate therapy for each patient with a recent diagnosis of an early stage breast cancer, minimizing unnecessary toxicities and improving long-term efficacy.