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BACKGROUND: The 21-gene recurrence score (RS) assay (Oncotype DX) is used to guide adjuvant chemotherapy use for patients with hormone receptor-positive, HER2 (human epidermal growth factor receptor 2)-negative, axillary node-negative breast cancer. Its role, however, in providing prognostic information for late distant recurrence when added to clinicopathologic prognostic factors is unknown. METHODS: A patient-specific meta-analysis including 10,004 women enrolled in three trials was updated using extended follow-up data from TAILORx, integrating the RS with histologic grade, tumor size, and age at surgery for the RSClin tool. Cox models integrating clinicopathologic factors and the RS were compared by using likelihood ratio (LR) tests. External validation of prognosis for distant recurrence in years 0 to 10 and 5 to 10 was performed in an independent cohort of 1098 women in a real-world registry. RESULTS: RSClin provided significantly more prognostic information than either the clinicopathologic factors (ΔLR chi-square, 86.2; P<0.001) or RS alone (ΔLR chi-square, 131.0; P<0.001). The model was prognostic in an independent cohort for distant recurrence by 10 years after diagnosis (standardized hazard ratio, 1.56; 95% confidence interval, 1.25 to 1.94), was associated with late distant recurrence risk between 5 and 10 years after diagnosis (standardized hazard ratio, 1.78; 95% confidence interval, 1.25 to 2.55), and approximated the observed 10-year distant recurrence risk (Lin concordance, 0.87) and 5- to 10-year distant recurrence risk (Lin concordance, 0.92). CONCLUSIONS: The 21-gene RS is prognostic for distant recurrence and overall survival in early breast cancer. A model integrating the 21-gene RS and clinicopathologic factors improved estimates of distant recurrence risk compared with either used individually and stratified late distant recurrence risk. (Funded by the National Cancer Institute, National Institutes of Health [U10CA180820, U10CA180794, UG1CA189859, U10CA180868, and U10CA180822] and others.).
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Neoplasias da Mama , Recidiva Local de Neoplasia , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Neoplasias da Mama/mortalidade , Neoplasias da Mama/terapia , Feminino , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Prognóstico , Pessoa de Meia-Idade , Idoso , Adulto , Fatores de RiscoRESUMO
BACKGROUND: The density of tumour-infiltrating lymphocytes (TILs) could be prognostic in ductal carcinoma in situ (DCIS). However, manual TIL quantification is time-consuming and suffers from interobserver and intraobserver variability. In this study, we developed a TIL-based computational pathology biomarker and evaluated its association with the risk of recurrence and benefit of adjuvant treatment in a clinical trial cohort. METHODS: In this retrospective cohort study, a computational pathology pipeline was developed to generate a TIL-based biomarker (CPath TIL categories). Subsequently, the signature underwent a masked independent validation on H&E-stained whole-section images of 755 patients with DCIS from the UK/ANZ DCIS randomised controlled trial. Specifically, continuous biomarker CPath TIL score was calculated as the average TIL density in the DCIS microenvironment and dichotomised into binary biomarker CPath TIL categories (CPath TIL-high vs CPath TIL-low) using the median value as a cutoff. The primary outcome was ipsilateral breast event (IBE; either recurrence of DCIS [DCIS-IBE] or invasive progression [I-IBE]). The Cox proportional hazards model was used to estimate the hazard ratio (HR). FINDINGS: CPath TIL-score was evaluable in 718 (95%) of 755 patients (151 IBEs). Patients with CPath TIL-high DCIS had a greater risk of IBE than those with CPath TIL-low DCIS (HR 2·10 [95% CI 1·39-3·18]; p=0·0004). The risk of I-IBE was greater in patients with CPath TIL-high DCIS than those with CPath TIL-low DCIS (3·09 [1·56-6·14]; p=0·0013), and the risk of DCIS-IBE was non-significantly higher in those with CPath TIL-high DCIS (1·61 [0·95-2·72]; p=0·077). A significant interaction (pinteraction=0·025) between CPath TIL categories and radiotherapy was observed with a greater magnitude of radiotherapy benefit in preventing IBE in CPath TIL-high DCIS (0·32 [0·19-0·54]) than CPath TIL-low DCIS (0·40 [0·20-0·81]). INTERPRETATION: High TIL density is associated with higher recurrence risk-particularly of invasive recurrence-and greater radiotherapy benefit in patients with DCIS. Our TIL-based computational pathology signature has a prognostic and predictive role in DCIS. FUNDING: National Cancer Institute under award number U01CA269181, Cancer Research UK (C569/A12061; C569/A16891), and the Breast Cancer Research Foundation, New York (NY, USA).
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Neoplasias da Mama , Carcinoma Intraductal não Infiltrante , Linfócitos do Interstício Tumoral , Humanos , Feminino , Carcinoma Intraductal não Infiltrante/patologia , Neoplasias da Mama/patologia , Estudos Retrospectivos , Prognóstico , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Biomarcadores Tumorais , Reino Unido , Idoso , AdultoRESUMO
Importance: The absolute benefit of chemotherapy for all patients with stage I triple-negative breast cancer (TNBC) is unclear, and biomarkers are not currently available for selecting patients with an excellent outcome for whom neoadjuvant or adjuvant chemotherapy may have negligible benefit. High levels of stromal tumor-infiltrating lymphocytes (sTILs) are associated with favorable survival in TNBC, but data solely in stage I TNBC are lacking. Objective: To examine the outcomes of patients of all ages with stage I TNBC solely and who received neither neoadjuvant nor adjuvant chemotherapy, according to centrally reviewed sTIL levels at prespecified cutoffs. Design, Setting, and Participants: This cohort study used the Netherlands Cancer Registry to identify patients diagnosed with stage I TNBC between January 1, 2005, and December 31, 2015, who were not treated with chemotherapy. Only patients who did not receive neoadjuvant and/or adjuvant chemotherapy were selected. The clinical data were matched with their corresponding pathology data provided by the Dutch Pathology Registry. Data analysis was performed between February and October 2023. Main Outcomes and Measures: The primary end point was breast cancer-specific survival (BCSS) at 5, 10, and 15 years for the prespecified sTIL level cutoffs of 30%, 50%, and 75%. Hematoxylin and eosin-stained slides were used for central review of histologic subtype, grade, and lymphovascular invasion. The International Immuno-Oncology Biomarker Working Group guidelines were used to score the sTIL levels; these levels were determined for 1041 patients. Results: Of a total of 4511 females with stage I TNBC, patients who were not treated with chemotherapy were selected and tissue blocks requested; sTILs were scored in 1041 patients (mean [SD] age at diagnosis, 64.4 [11.1] years, median follow-up 11.4 [95% CI, 10.9-11.9] years) who were included in the analyses.. Most tumors (952 [91.5%]) were invasive carcinomas of nonspecial histologic subtype. Most patients (548 [52.6%]) had pT1cN0 tumors. Median (range) sTIL level was 5% (1%-99%). A total of 775 patients (74.4%) had sTIL levels below 30%, 266 (25.6%) had 30% or greater, 203 (19.5%) had 50% or greater, and 141 (13.5%) had 75% or greater. Patients with pT1abN0 tumors had a more favorable outcome vs patients with pT1cN0 tumors, with a 10-year BCSS of 92% (95% CI, 89%-94%) vs 86% (95% CI, 82%-89%). In the overall cohort, sTIL levels of at least 30% were associated with better BCSS compared with sTIL levels less than 30% (96% and 87%, respectively; hazard ratio [HR], 0.45; 95% CI, 0.26-0.77). High sTIL levels of 50% or greater were associated with a better outcome than low sTIL levels of less than 50% (HR, 0.27; 95% CI, 0.10-0.74) in patients with pT1C tumors, with a 10-year BCSS of 95% increasing to 98% with sTIL levels of 75% or greater. Conclusions and Relevance: Results of this study showed that patients with stage I TNBC and high level of sTILs who did not receive neoadjuvant or adjuvant chemotherapy had excellent 10-year BCSS. The findings further support the role of sTILs as integral biomarkers in prospective clinical trials of therapy optimization for this patient population.
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Linfócitos do Interstício Tumoral , Estadiamento de Neoplasias , Neoplasias de Mama Triplo Negativas , Humanos , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/patologia , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/mortalidade , Linfócitos do Interstício Tumoral/imunologia , Feminino , Pessoa de Meia-Idade , Idoso , Adulto , Países Baixos , Terapia Neoadjuvante , Quimioterapia Adjuvante , Estudos de CoortesRESUMO
Triple negative breast cancer is defined on the basis of what it is not. It has served as a useful umbrella entity for management of patients with breast cancer for the last couple of decades. However, during this period a number of novel therapies have become available. These therapies have been documented to be useful in subsets of TNBCs that can be identified on the basis of distinct biologic alterations. Herein we revisit the categorization and usage of the TNBC as an entity to assess its utility in view of the currently available therapies.
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Neoplasias da Mama , Neoplasias de Mama Triplo Negativas , Humanos , Feminino , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/terapia , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/terapiaRESUMO
PURPOSE: Although axillary dissection is no longer indicated for many breast cancer patients with 1-2 positive axillary sentinel lymph nodes (ASLN), intraoperative ASLN assessment is still performed in many institutions for patients undergoing mastectomy or neoadjuvant therapy. With recent advancements in digital pathology, pathologists increasingly evaluate ASLN via remote telepathology. We aimed to compare the performance characteristics of remote telepathology and conventional on-site intraoperative ASLN assessment. METHODS: Data from ASLN evaluation for breast cancer patients performed at two sites between April 2021 and October 2022 was collated. Remote telepathology consultation was conducted via the Aperio eSlideManager system. RESULTS: A total of 385 patients were identified during the study period (83 telepathology, 302 on-site evaluations). Although not statistically significant (P = 0.20), the overall discrepancy rate between intraoperative and final diagnoses was slightly higher at 9.6% (8/83) for telepathology compared with 5.3% (16/302) for on-site assessment. Further comparison of performance characteristics of ASLN assessment between telepathology and conventional on-site evaluation revealed no statistically significant differences between deferral rates, discrepancy rates, interpretive or sampling errors, major or minor disagreements, false negative or false positive results as well as clinical impact and turn-around time (P ≥ 0.12). CONCLUSION: ASLN assessment via telepathology is not significantly different from conventional on-site evaluation, although it shows a slightly higher overall discrepancy rate between intraoperative and final diagnoses (9.6% vs. 5.3%). Further studies are warranted to ensure accuracy of ASLN assessment via telepathology.
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INTRODUCTION: Cancer development and progression is a complex process influenced by co-evolution of the cancer cells and their microenvironment. However, traditional anti-cancer therapy is mostly targeted toward cancer cells. To improve the efficacy of cancer drugs, the complex interactions between the tumor (T) and the tumor microenvironment (TME) should be considered while developing therapeutics. AREAS COVERED: The present review article will discuss the components of T-TME as well as the potential to co-target these two distinct elements. We document that these approaches have resulted in success in preventing tumor progression and metastasis, albeit in animal models in some cases. Lastly, it is important to consider the tissue context and tumor type as these could significantly modify the role of these molecules/pathways and hence the overall likelihood of response. Furthermore, we discuss the potential strategies to target the components of tumor microenvironment in anti-cancer therapy. PubMed and ClinicalTrials.gov was searched through May 2023. EXPERT OPINION: The tumor-tumor microenvironment cross talk and heterogeneity are major mechanisms conferring resistance to standard of care. Better understanding of the tissue specific T-TME interactions and dual targeting has the promise of improving cancer control and clinical outcomes.
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Antineoplásicos , Neoplasias , Animais , Microambiente Tumoral , Neoplasias/patologia , Antineoplásicos/farmacologiaRESUMO
Standard clinicopathological parameters (age, growth pattern, tumor size, margin status, and grade) have been shown to have limited value in predicting recurrence in ductal carcinoma in situ (DCIS) patients. Early and accurate recurrence prediction would facilitate a more aggressive treatment policy for high-risk patients (mastectomy or adjuvant radiation therapy), and simultaneously reduce over-treatment of low-risk patients. Generative adversarial networks (GAN) are a class of DL models in which two adversarial neural networks, generator and discriminator, compete with each other to generate high quality images. In this work, we have developed a deep learning (DL) classification network that predicts breast cancer events (BCEs) in DCIS patients using hematoxylin and eosin (H & E) images. The DL classification model was trained on 67 patients using image patches from the actual DCIS cores and GAN generated image patches to predict breast cancer events (BCEs). The hold-out validation dataset (n = 66) had an AUC of 0.82. Bayesian analysis further confirmed the independence of the model from classical clinicopathological parameters. DL models of H & E images may be used as a risk stratification strategy for DCIS patients to personalize therapy.
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Reliable, reproducible methods to interpret programmed death ligand-1 (PD-L1) expression on tumor cells (TC) and immune cells (IC) are needed for pathologists to inform decisions associated with checkpoint inhibitor therapies. Our international study compared interpathologist agreement of PD-L1 expression using the combined positive score (CPS) under standardized conditions on samples from patients with gastric/gastroesophageal junction/esophageal adenocarcinoma. Tissue sections from 100 adenocarcinoma pretreatment biopsies were stained in a single laboratory using the PD-L1 immunohistochemistry 28-8 and 22C3 (Agilent) pharmDx immunohistochemical assays. PD-L1 CPS was evaluated by 12 pathologists on scanned whole slide images of these biopsies before and after a 2-hour CPS training session by Agilent. Additionally, pathologists determined PD-L1-positive TC, IC, and total viable TC on a single tissue fragment from 35 of 100 biopsy samples. Scoring agreement among pathologists was assessed using the intraclass correlation coefficient (ICC). Interobserver variability for CPS for 100 biopsies was high, with only fair agreement among pathologists both pre- (range, 0.45-0.55) and posttraining (range, 0.56-0.57) for both assays. For the 35 single biopsy samples, poor/fair agreement was also observed for the total number of viable TC (ICC, 0.09), number of PD-L1-positive IC (ICC, 0.19), number of PD-L1-positive TC (ICC, 0.54), and calculated CPS (ICC, 0.14), whereas calculated TC score (positive TC/total TC) showed excellent agreement (ICC, 0.82). Retrospective histologic review of samples with the poorest interpathologist agreement revealed the following as possible confounding factors: (1) ambiguous identification of positively staining stromal cells, (2) faint or variable intensity of staining, (3) difficulty in distinguishing membranous from cytoplasmic tumor staining, and (4) cautery and crush artifacts. These results emphasize the need for objective techniques to standardize the interpretation of PD-L1 expression when using the CPS methodology on gastric/gastroesophageal junction cancer biopsies to accurately identify patients most likely to benefit from immune checkpoint inhibitor therapy.
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Adenocarcinoma , Neoplasias Gástricas , Humanos , Antígeno B7-H1/metabolismo , Estudos Retrospectivos , Variações Dependentes do Observador , Patologistas , Biomarcadores Tumorais , Adenocarcinoma/patologia , Junção Esofagogástrica/metabolismo , Junção Esofagogástrica/patologia , Neoplasias Gástricas/patologiaRESUMO
Resistance to hormone therapy leads to a recurrence of estrogen receptor-positive breast cancer. We have demonstrated that the epithelial splicing regulatory protein 1 (ESRP1) significantly affects cell/tumor growth and metabolism and is associated with a poor prognosis in this breast cancer subtype. In this study, we aimed to investigate the ESRP1 protein-messenger RNA (mRNA) interaction in hormone therapy-resistant breast cancer. RNA-binding protein immunoprecipitation (RIP) followed by Clariom D (Applied Biosystems/Thermo Fisher Scientific) transcriptomics microarray (RIP-Chip) was performed to identify mRNA-binding partners of ESRP1. The integration of RIP-Chip and immunoprecipitation-mass spectrometry analyses identified phosphoglycerate dehydrogenase (PHGDH), a key metabolic enzyme, as a binding partner of ESRP1 in hormone-resistant breast cancer. Bioinformatic analysis showed ESRP1 binding to the 5' untranslated region of PHGDH. RNA electrophoresis mobility shift assay and RIP-quantitative reverse transcription-polymerase chain reaction further validated the ESRP1-PHGDH binding. In addition, knockdown of ESRP1 decreased PHGDH mRNA stability significantly, suggesting the posttranscriptional regulation of PHGDH by ESRP1. The presence or absence of ESRP1 levels significantly affected the stability in tamoxifen-resistant LCC2 and fulvestrant-resistant LCC9 cells. PHGDH knockdown in tamoxifen-resistant cells further reduced the oxygen consumption rate (ranging from P = .005 and P = .02), mimicking the effects of ESRP1 knockdown. Glycolytic parameters were also altered (ranging P = .001 and P = .005). ESRP1 levels did not affect the stability of PHGDH in T-47D cells, although knockdown of PHGDH affected the growth of these cells. In conclusion, to our knowledge, this study, for the first time, reports that ESRP1 binds to the 5' untranslated region of PHGDH, increasing its mRNA stability in hormone therapy-resistant estrogen receptor-positive breast cancer. These findings provide evidence for a novel mechanism of action of RNA-binding proteins such as ESRP1. These new insights could assist in developing novel strategies for the treatment of hormone therapy-resistant breast cancer.
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Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/patologia , Receptores de Estrogênio/genética , Receptores de Estrogênio/metabolismo , Fosfoglicerato Desidrogenase/genética , Fosfoglicerato Desidrogenase/metabolismo , Regiões 5' não Traduzidas , Tamoxifeno/farmacologia , Fatores de Transcrição/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Hormônios , Linhagem Celular TumoralRESUMO
The Immunoscore is a method to quantify the immune cell infiltration within cancers to predict the disease prognosis. Previous immune profiling approaches relied on limited immune markers to establish patients' tumor immunity. However, immune cells exhibit a higher-level complexity that is typically not obtained by the conventional immunohistochemistry methods. Herein, we present a spatially variant immune infiltration score, termed as SpatialVizScore, to quantify immune cells infiltration within lung tumor samples using multiplex protein imaging data. Imaging mass cytometry (IMC) was used to target 26 markers in tumors to identify stromal, immune, and cancer cell states within 26 human tissues from lung cancer patients. Unsupervised clustering methods dissected the spatial infiltration of cells in tissue using the high-dimensional analysis of 16 immune markers and other cancer and stroma enriched labels to profile alterations in the tumors' immune infiltration patterns. Spatially resolved maps of distinct tumors determined the spatial proximity and neighborhoods of immune-cancer cell pairs. These SpatialVizScore maps provided a ranking of patients' tumors consisting of immune inflamed, immune suppressed, and immune cold states, demonstrating the tumor's immune continuum assigned to three distinct infiltration score ranges. Several inflammatory and suppressive immune markers were used to establish the cell-based scoring schemes at the single-cell and pixel-level, depicting the cellular spectra in diverse lung tissues. Thus, SpatialVizScore is an emerging quantitative method to deeply study tumor immunology in cancer tissues.
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Tumor-infiltrating lymphocytes (TILs) are prognostic in invasive breast cancer. However, their prognostic significance in ductal carcinoma in situ (DCIS) has been controversial. To investigate the prognostic role of TILs in DCIS outcome, we used different scoring methods for TILs in multi-national cohorts from Asian and European women. Self-described race was genetically confirmed using QC Infinium array combined with radmixture software. Stromal TILs, touching TILs, circumferential TILs, and hotspots were quantified on H&E-stained slides and correlated with the development of second breast cancer events (BCE) and other clinico-pathological variables. In univariate survival analysis, age older than 50 years, hormone receptor positivity and the presence of circumferential TILs were weakly associated with the absence of BCE at the 5-year follow-up in all cohorts (p < 0.03; p < 0.02; and p < 0.02, respectively, adjusted p = 0.11). In the multivariable analysis, circumferential TILs were an independent predictor of a better outcome (Wald test p = 0.01), whereas younger age was associated with BCE. Asian patients were younger with larger, higher grade, HR negative DCIS lesions, and higher TIL variables. The spatial arrangement of TILs may serve as a better prognostic indicator in DCIS cases than stromal TILs alone and may be added in guidelines for TILs evaluation in DCIS.
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The objective of this study was to measure concordance of results obtained from the US Food and Drug Administration-approved Ki-67 immunohistochemistry MIB-1 pharmDx assay performed on the Dako Omnis automated staining instrument (Omnis) versus results produced from the assay reagents applied using an optimized protocol on the more widely available Autostainer Link 48 (ASL48) platform. Tissue sections obtained from 40 formalin-fixed paraffin-embedded breast carcinoma samples, with available Oncotype DX Breast Recurrence Score (RS) results, were stained. Three certified pathologists scored slides at 3 timepoints, totaling 360 observations for each instrument (N=720 total) using the approved scoring approach. Using the ≥20% cutoff, agreement was calculated with corresponding 2-sided 95% percentile bootstrap confidence intervals (CIs). Pairwise comparisons (N=360) from the interinstrument evaluation, performed with all observers, resulted in 325 (90.3%) concordant outcomes (244 negative and 81 positive) and 35 (9.7%) discordant outcomes. The overall agreement was 90.3% (95% confidence interval, 85.6% to 94.4%). No significant systematic differences were observed between instruments. Specimens scored from the Omnis were on average <1% higher than ASL48, with high correlation and little bias between the continuous Ki-67 scores (concordance correlation coefficient=0.916). Most specimens with a Ki-67 score ≥20% had a RS >25. This study demonstrated that good concordance can be achieved with the reagents run on the ASL48 instrument when using an optimized protocol and standardized scoring.
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Neoplasias da Mama , Neoplasias da Mama/diagnóstico , Feminino , Humanos , Imuno-Histoquímica , Indicadores e Reagentes , Antígeno Ki-67 , Estados Unidos , United States Food and Drug AdministrationRESUMO
Ki67 has potential clinical importance in breast cancer but has yet to see broad acceptance due to inter-laboratory variability. Here we tested an open source and calibrated automated digital image analysis (DIA) platform to: (i) investigate the comparability of Ki67 measurement across corresponding core biopsy and resection specimen cases, and (ii) assess section to section differences in Ki67 scoring. Two sets of 60 previously stained slides containing 30 core-cut biopsy and 30 corresponding resection specimens from 30 estrogen receptor-positive breast cancer patients were sent to 17 participating labs for automated assessment of average Ki67 expression. The blocks were centrally cut and immunohistochemically (IHC) stained for Ki67 (MIB-1 antibody). The QuPath platform was used to evaluate tumoral Ki67 expression. Calibration of the DIA method was performed as in published studies. A guideline for building an automated Ki67 scoring algorithm was sent to participating labs. Very high correlation and no systematic error (p = 0.08) was found between consecutive Ki67 IHC sections. Ki67 scores were higher for core biopsy slides compared to paired whole sections from resections (p ≤ 0.001; median difference: 5.31%). The systematic discrepancy between core biopsy and corresponding whole sections was likely due to pre-analytical factors (tissue handling, fixation). Therefore, Ki67 IHC should be tested on core biopsy samples to best reflect the biological status of the tumor.
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Neoplasias da Mama , Biomarcadores Tumorais/análise , Biópsia , Neoplasias da Mama/patologia , Feminino , Humanos , Processamento de Imagem Assistida por Computador/métodos , Imuno-Histoquímica , Antígeno Ki-67/análise , Receptores de EstrogênioRESUMO
The increasing use of neoadjuvant therapy has resulted in therapeutic decisions being made on the basis of diagnostic needle core biopsy. For many patients, this method might yield the only fragment of tumor available for biomarker analysis, necessitating judicious use. Many multiplex protein analytic methods have been developed that employ fluorescence or other tags to overcome the limitations of immunohistochemistry while still retaining the spatial annotation. Interpretation of the data can be difficult because of the limitations of the human eye. Computational deconvolution of the signals may be necessary for some of these methods to enable identification of cell-specific localization and coexpression of biomarkers. Herein, we present the different methods that are coming of age and their application in cancer research, with a focus on breast cancer. We also discuss the limitations, which include high costs and long turnaround times. The methods are also based on the premise that preanalytical factors will have identical impact on all proteins analyzed. There is a need to establish standards to normalize the data and enable cross-sample comparisons. In spite of these limitations, the multiplex technologies are extremely valuable discovery tools and can provide novel insights into the biology of cancer and mechanisms of drug resistance.
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Neoplasias da Mama , Biomarcadores Tumorais/uso terapêutico , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Feminino , Humanos , Terapia NeoadjuvanteRESUMO
Nonsurgical management of ductal carcinoma in situ is controversial and little is known about the long-term consequences of this approach. In this study, we aimed to determine the risk of (a) upstaging to invasive carcinoma at excision and (b) ipsilateral breast cancer events in patients who might have been eligible for nonsurgical management of DCIS trials. Data from women aged 20 years or older with a biopsy diagnosis of DCIS between January 1, 2010 to December 31, 2014 were collated. The women underwent biopsy and surgical resection (lumpectomy or mastectomy) and were treated with radiation or endocrine therapy as per treating physicians' choice. The development of ipsilateral breast cancer events (IBEs) was analyzed in patients with at least 5 years of follow-up after standard of care therapy for DCIS. Subset-analysis was undertaken to identify the incidence of IBEs in patients eligible for nonsurgical management trials. The study population consisted of 378 patients with matched cases of biopsy and surgical excision. The overall upstaging rate to IBC was 14.3 and 12.9% for COMET, 8.8% for LORIS, and 10.7% for LORD trial "eligible" patients. At 5 years of follow-up, ~11.5% of overall and trial eligible patients developed IBEs of which approximately half were invasive IBEs. In conclusion, women with DCIS who would have been eligible for nonsurgical management trials have a significantly high risk of developing ipsilateral breast events within 5 years of diagnosis. Better selection criteria are needed to identify DCIS patients who are at very low risk for the development of IBC.
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Breast implant augmentation is a low-risk procedure with few life-threatening complications. Capsular contracture and rupture/leakage of the implant are the most common complications encountered. Malignant breast implant augmentation-associated lesions are rare, with anaplastic large cell lymphoma being the most common. Squamous cell carcinomas associated with breast implant augmentation are exceedingly rare, with only eight patients reported. Breast implant capsule-associated squamous cell carcinoma occurs in patients with long standing breast implant augmentations (>11 years). We report two additional patients with breast implant capsule-associated squamous cell carcinoma. Review of the literature reveals that invasion beyond the breast implant capsule into the adjacent tissue by the squamous cell carcinoma appears to have negative prognostic implications, and possibly warrants close clinical follow-up.
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Implante Mamário , Implantes de Mama , Neoplasias da Mama , Carcinoma de Células Escamosas , Linfoma Anaplásico de Células Grandes , Mamoplastia , Humanos , Feminino , Implantes de Mama/efeitos adversos , Implante Mamário/efeitos adversos , Mamoplastia/efeitos adversos , Linfoma Anaplásico de Células Grandes/etiologia , Neoplasias da Mama/patologia , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/cirurgiaRESUMO
Triple-negative breast cancer (TNBC) accounts for approximately 12% to 17% of all breast cancers and has an aggressive clinical behavior. Increased tumor-infiltrating lymphocyte counts are prognostic for survival in TNBC, making this disease a potential target for cancer immunotherapy. Research on immunophenotyping of tumor-infiltrating lymphocytes is revealing molecular and structural organization in the tumor microenvironment that may predict patient prognosis. The anti-programmed death-ligand 1 (PD-L1) antibody atezolizumab plus nab-paclitaxel was the first cancer immunotherapy combination to demonstrate progression-free survival benefit and clinically meaningful overall survival benefit in the first-line treatment of metastatic TNBC (mTNBC) in patients with PD-L1-expressing tumor-infiltrating immune cells in 1% or more of the tumor area. This led to its United States and European Union approval for mTNBC and US approval of the VENTANA PD-L1 (SP142) assay as a companion diagnostic immunohistochemistry assay. Subsequently, the anti-programmed death-1 (PD-1 ) antibody pembrolizumab plus chemotherapy was approved by the US Food and Drug Administration for mTNBC based on progression-free survival benefit in patients with a combined positive score of at least 10 by its concurrently approved 22C3 companion diagnostic assay. Treatment guidelines now recommend PD-L1 testing for patients with mTNBC, and the testing landscape will likely become increasingly complex as new anti-PD-L1 and anti-PD-1 agents and diagnostics are approved for TNBC. Integrating PD-L1 testing into current diagnostic workflows for mTNBC may provide more treatment options for these patients. Therefore, it is critical for medical oncologists and pathologists to understand the available assays and their relevance to therapeutic options to develop an appropriate workflow for immunohistochemistry testing.