Evolving Evidence for the Optimization of Neoadjuvant Therapy in Triple-Negative Breast Cancer.
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ABSTRACT:
SUBMITTER: Silva D
PROVIDER: S-EPMC9243491 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Systemic treatment for triple negative breast cancer (tnbcnegative for the expression of estrogen receptor and progesterone receptor and HER2 amplification) has been limited to chemotherapy options. Neoadjuvant chemotherapy induces tumor shrinkage and improves the surgical outcomes of patients with locally advanced disease and also identifies those at high risk of disease relapse despite today's standard of care. By using pathologic complete response as a surrogate endpoint, novel treatment strategies can be efficiently assessed. Tissue analysis in the neoadjuvant setting is also an important research tool for the identification of chemotherapy resistance mechanisms and new therapeutic targets. In this paper, we review data on completed and ongoing neoadjuvant clinical trials in patients with TNBC and discuss treatment controversies that face clinicians and researchers when neoadjuvant chemotherapy is employed.
| S-EPMC3747378 | biostudies-literature
Project description:PurposeIncreasing tumor-infiltrating lymphocytes (TIL) is associated with higher rates of pathologic complete response (pCR) to neoadjuvant therapy (NAT) in patients with triple-negative breast cancer (TNBC). However, the presence of TILs does not consistently predict pCR, therefore, the current study was undertaken to more fully characterize the immune cell response and its association with pCR.Experimental designWe obtained pretreatment core-needle biopsies from 105 patients with stage I-III TNBC enrolled in ARTEMIS (NCT02276443) who received NAT from Oct 22, 2015 through July 24, 2018. The tumor-immune microenvironment was comprehensively profiled by performing T-cell receptor (TCR) sequencing, programmed death-ligand 1 (PD-L1) IHC, multiplex immunofluorescence, and RNA sequencing on pretreatment tumor samples. The primary endpoint was pathologic response to NAT.ResultsThe pCR rate was 40% (42/105). Higher TCR clonality (median = 0.2 vs. 0.1, P = 0.03), PD-L1 positivity (OR: 2.91, P = 0.020), higher CD3+:CD68+ ratio (median = 14.70 vs. 8.20, P = 0.0128), and closer spatial proximity of T cells to tumor cells (median = 19.26 vs. 21.94 μm, P = 0.0169) were associated with pCR. In a multivariable model, closer spatial proximity of T cells to tumor cells and PD-L1 expression enhanced prediction of pCR when considered in conjunction with clinical stage.ConclusionsIn patients receiving NAT for TNBC, deep immune profiling through detailed phenotypic characterization and spatial analysis can improve prediction of pCR in patients receiving NAT for TNBC when considered with traditional clinical parameters.
| S-EPMC8752638 | biostudies-literature
Project description:PurposeTo investigate the value of performing mid-treatment axillary ultrasound (AUS) in triple-negative breast cancer (TNBC) patients who are undergoing neoadjuvant systemic therapy (NAST) by determining the optimal cutoff number of abnormal nodes associated with residual nodal disease on surgical pathology.Materials and methodsThis sub-study, an interim analysis of an ongoing single-institution clinical trial enrolling patients with stage I-III TNBC, included 106 patients. Number of abnormal nodes at mid-treatment was assessed and recorded by experienced breast radiologists, who empirically categorized lymph nodes using a binary approach of sonographically-normal versus abnormal. Pathologic lymph node positivity was defined as presence of macrometastasis or micrometastasis in ≥1 axillary node from sentinel lymph node biopsy and/or axillary lymph node dissection.ResultsOf 106 patients, 26 (25 %) had residual nodal disease and 80 (75 %) had no nodal disease at surgery. Median number of abnormal nodes at mid-treatment was 5 (standard deviation [SD], 5) for patients with residual nodal disease and 0 (SD, 2) for patients with no nodal disease at surgery (p < 0.0001). TNBC patients with >4 abnormal nodes at mid-treatment had a significantly higher chance of being node-positive at surgery (AUC = 0.908, p < 0.0001; PPV = 90 %).ConclusionOur data suggest that a cutoff of >4 abnormal nodes on mid-treatment AUS is associated with residual disease post-NAST. If our findings are substantiated by subsequent analyses, then mid-treatment AUS could be used to identify patients unlikely to achieve nodal pathologic complete response and who should be offered alternative therapy.
| S-EPMC7534548 | biostudies-literature
Project description:The optimal neoadjuvant chemotherapy (NACT) regimen in triple-negative breast cancer (TNBC) has not been clearly defined. Achieving a pathologic complete response (pCR) provides important prognostic information, and, especially in TNBC, is considered a surrogate endpoint for event-free survival. Thus, many neoadjuvant studies in TNBC focus on this as a primary endpoint, and such information may be used for accelerated US Food and Drug Administration approval. Current controversies in the field include: (1) the role of platinum-based compounds; (2) the optimal chemotherapy backbone; and (3) the benefits of additional therapy after surgery. Conflicting results of 2 major studies adding carboplatin to NACT have highlighted the need to balance potential benefits to disease outcomes against increased toxicity. While the PROGECT study suggests efficacy of a nonanthracycline-containing regimen, this is observational data, and evidence in the form of a clinical trial remains to be seen. Data surrounding optimal taxane use support the use of nab-paclitaxel in place of paclitaxel in limited clinical situations. Although bevacizumab may increase pCR rates, this has not translated into survival benefit. Capecitabine shows promise in patients who have not achieved pCR after NACT. The neoadjuvant setting remains an important model for drug development. This review will focus on the most important and most current neoadjuvant trials in women with TNBC.
| S-EPMC5865448 | biostudies-literature
Project description:PURPOSE Cisplatin is a chemotherapeutic agent not used routinely for breast cancer treatment. As a DNA cross-linking agent, cisplatin may be effective treatment for hereditary BRCA1-mutated breast cancers. Because sporadic triple-negative breast cancer (TNBC) and BRCA1-associated breast cancer share features suggesting common pathogenesis, we conducted a neoadjuvant trial of cisplatin in TNBC and explored specific biomarkers to identify predictors of response. PATIENTS AND METHODS Twenty-eight women with stage II or III breast cancers lacking estrogen and progesterone receptors and HER2/Neu (TNBC) were enrolled and treated with four cycles of cisplatin at 75 mg/m(2) every 21 days. After definitive surgery, patients received standard adjuvant chemotherapy and radiation therapy per their treating physicians. Clinical and pathologic treatment response were assessed, and pretreatment tumor samples were evaluated for selected biomarkers. Results Six (22%) of 28 patients achieved pathologic complete responses, including both patients with BRCA1 germline mutations;18 (64%) patients had a clinical complete or partial response. Fourteen (50%) patients showed good pathologic responses (Miller-Payne score of 3, 4, or 5), 10 had minor responses (Miller-Payne score of 1 or 2), and four (14%) progressed. All TNBCs clustered with reference basal-like tumors by hierarchical clustering. Factors associated with good cisplatin response include young age (P = .001), low BRCA1 mRNA expression (P = .03), BRCA1 promoter methylation (P = .04), p53 nonsense or frameshift mutations (P = .01), and a gene expression signature of E2F3 activation (P = .03). CONCLUSION Single-agent cisplatin induced response in a subset of patients with TNBC. Decreased BRCA1 expression may identify subsets of TNBCs that are cisplatin sensitive. Other biomarkers show promise in predicting cisplatin response.
| S-EPMC2834466 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) is known to have a poor prognosis and limited treatment options, namely chemotherapy. Different molecular studies have recently classified TNBC into different subtypes opening the door to potential new-targeted treatment options. In this review, we discuss the current standard of care in the treatment of TNBC in the neoadjuvant, adjuvant and metastatic settings. In addition, we summarize the ongoing phase III clinical trials evaluating different associations between the 3 pillars of anticancer treatment: chemotherapy, targeted therapy and immunotherapy.
| S-EPMC6682754 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC) is an aggressive malignancy with a poor prognosis despite the high rates of response to chemotherapy. This scenario highlights the need to develop novel therapies and/or treatment strategies to reduce the mortality associated with TNBC. The neoadjuvant setting provides a model for rapid assessment of treatment efficacy with smaller patient accruals and over shorter periods of time compared to the traditional adjuvant setting. In addition, a clear surrogate endpoint of improved survival, known as pathologic complete response, already exists in this setting. Here, we review current data from completed and ongoing neoadjuvant clinical trials for TNBC.
| S-EPMC3270519 | biostudies-literature
Project description:Patients with the triple negative subtype of breast cancer have an overall poor outcome, with earlier relapses, distinct patterns of metastases, and lack of specific targets for treatment selection. Classification of these tumors has begun to be modified by inclusion of immunohistochemistry for various markers, and gene profiling. Further characterization of this subtype of breast cancer may aid in the identification of new targeted therapies. Anthracyclines and taxanes remain the standard of care in the adjuvant setting. However, novel anti-angiogenesis, anti-tubulin, and DNA repair agents are already under evaluation in (neo) adjuvant trials. Molecular characterization is being included in trials to identify optimal adjuvant strategies. The aim of this manuscript is to review data concerning the molecular characterization of triple negative breast cancers as well as the clinical outcomes of treating patients with existing adjuvant treatments, and to highlight newer adjuvant research strategies in development.
| S-EPMC3918886 | biostudies-literature
Project description:Pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) can predict better survival outcomes in patients with early triple negative breast cancer (TNBC). Tumor infiltrating lymphocytes (TILs), Programmed Death-Ligand 1 (PD-L1), and Cluster of Differentiation 73 (CD73) are immune-related biomarkers that can be evaluated in the tumor microenvironment. We investigated if the contemporary expression of these biomarkers combined in a tissue immune profile (TIP) can predict pCR better than single biomarkers in TNBC. Tumor infiltrating lymphocytes (TILs), CD73 expression by cancer cells (CC), and PD-L1 expression by immune cells (IC) were evaluated on pre-NACT biopsies. We defined TIP positive (TIP+) as the simultaneous presence of TILS ? 50%, PD-L1 ? 1%, and CD73 ? 40%. To consider the effects of all significant variables on the pCR, multivariate analysis was performed. Akaike information criterion (AIC) and Bayesian information criterion (BIC) were used for model selection. We retrospectively analyzed 60 biopsies from patients with TNBC who received standard NACT. Pathological complete response was achieved in 23 patients (38.0%). Twelve (20.0%) cases resulted to be TIP+. The pCR rate was significantly different between TIP+ (91.7%) and TIP- (25.0%) (p < 0.0001). Using a multivariate analysis, TIP was confirmed as an independent predictive factor of pCR (OR 49.7 (6.30-392.4), p < 0.0001). Finally, we compared the efficacy of TIP versus each single biomarker in predicting pCR by AIC and BIC. The combined immune profile is more accurate in predicting pCR (AIC 68.3; BIC 74.5) as compared to single biomarkers. The association between TIP+ and pCR can be proposed as a novel link between immune background and response to chemotherapy in TNBC, highlighting the need to consider an immunological patients' profile rather than single biomarkers.
| S-EPMC7565153 | biostudies-literature
Project description:Triple-negative breast cancer (TNBC), as a collective group of heterogenous tumours, displays the highest rate of distant recurrence and lowest survival from metastatic disease across breast cancer subtypes. However, a subset of TNBC display impressive primary tumour response to neoadjuvant chemotherapy, translating to reduction in future relapse and increased overall survival. Maximizing early treatment response is crucial to improving the outlook in this subtype. Numerous systemic therapy strategies are being assessed in the neoadjuvant setting and the current paradigm of generic chemotherapy components in regimens for high-risk breast cancers, regardless of biological subtype, is changing. Therapeutic approaches with evidence of benefit include platinum drugs, polyadenosine diphosphate ribose polymerase (PARP) inhibitors, immunotherapy and second adjuvant therapy for those not achieving pathological complete response. Importantly, molecular testing can identify subgroups within TNBC, such as deoxyribonucleic acid (DNA) homologous recombination repair deficiency, lymphocyte-predominant tumours, and TNBC type 4 molecular subtypes. Clinical trials that address the interaction between these biomarkers and treatment approaches are a priority, to identify subgroups benefiting from additional therapy.
| S-EPMC6826917 | biostudies-literature