Neoadjuvant immunotherapy in early-stage triple negative breast cancer.
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ABSTRACT:
SUBMITTER: Laouris P
PROVIDER: S-EPMC10477652 | biostudies-literature | 2023 Aug
REPOSITORIES: biostudies-literature
Publications
Neoadjuvant immunotherapy in early-stage triple negative breast cancer.
Laouris Panayiotis P Rodrigues Mariana Espirito Santo MES Costa Susanne Crocamo Ventilary SCV Rala de Paula Bruno Henrique BH
Annals of translational medicine 20230627 10
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Project description:A substantial fraction of early-stage triple-negative breast cancer (eTNBC) is characterized by high levels of stromal tumor-infiltrating lymphocytes (sTIL) and has a good prognosis even without systemic treatment, highlighting the importance of an endogenous anticancer immune response. Still, a considerable proportion of patients with eTNBC need some "therapeutical push" to kick-start this immune response. Exploiting this immune response with immune-checkpoint inhibition (ICI), in combination with chemotherapy, has made its way into standard of care in eTNBC. Major challenges in the near future include finding those patients with eTNBC who can be treated with ICI alone or with a reduced chemotherapy backbone. Exploring the optimal duration of ICI and finding biomarkers to predict response will be key to enable personalized implementation of ICI in patients with eTNBC. For patients who currently do not respond effectively to ICI plus chemotherapy, challenges lie in finding new immunomodulatory therapies and developing response-guided neoadjuvant approaches.
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Project description:The advent of immunotherapy, especially immune checkpoint inhibitors (ICIs), has revolutionized antitumor therapy. Programmed cell death receptor 1 (PD-1) and programmed cell death ligand 1 (PD-L1) are among the most promising targets for encouraging the immune system to eliminate cancer cells. PD-1/PD-L1 have made clinical remission for numerous solid tumors, including metastatic triple-negative breast cancer (TNBC). In recent years, integrating PD-1/PD-L1 inhibitors into existing treatments in early-stage TNBC has attracted wide attention. Herein, we summarize the clinical benefit of PD-1/PD-L1 inhibitors plus neoadjuvant chemotherapy, adjuvant chemotherapy, and targeted therapy in early-stage TNBC. Possible immunotherapy biomarkers, immune-related adverse events (irAEs), and the key challenges faced in TNBC anti-PD-1/PD-L1 therapy are also concluded. Numerous studies on immunotherapy are ongoing, and PD-1/PD-L1 inhibitors have demonstrated great clinical prospects in early-stage TNBC. To maximize the efficacy of anti-PD-1/PD-L1 therapy, further research into the challenges which still exist is necessary.
| S-EPMC10055616 | biostudies-literature
Project description:Therapy-induced molecular adaptation of triple-negative breast cancer is crucial for immunotherapy response and resistance. We analyze tumor biopsies from three different time points in the randomized neoadjuvant GeparNuevo trial (NCT02685059), evaluating the combination of durvalumab with chemotherapy, for longitudinal alterations of gene expression. Durvalumab induces an activation of immune and stromal gene expression as well as a reduction of proliferation-related gene expression. Immune genes are positive prognostic factors irrespective of treatment, while proliferation genes are positive prognostic factors only in the durvalumab arm. We identify stromal-related gene expression as a contributor to immunotherapy resistance and poor therapy response. The results provide evidence from clinical trial cohorts suggesting a role for stromal reorganization in therapy resistance to immunotherapy and in the generation of an immune-suppressive microenvironment, which might be relevant for future therapy approaches targeting the tumor stroma parallel to immunotherapy, such as combinations of immunotherapy with anti-angiogenic therapy.
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Project description:Triple-negative breast cancer (TNBC) is characterized by the absence of hormone receptor and HER2 expression, and therefore a lack of therapeutic targets. Anthracyclines and taxane-based neoadjuvant chemotherapy have historically been the cornerstone of treatment of early TNBC. However, genomic and transcriptomic analyses have suggested that TNBCs include various subtypes, characterized by peculiar genomic drivers and potential therapeutic targets. Therefore, several efforts have been made to expand the therapeutic landscape of early TNBC, leading to the introduction of platinum and immunomodulatory agents into the neoadjuvant setting. This review provides a comprehensive overview of the currently available evidence regarding platinum agents and immune-checkpoint-inhibitors for the neoadjuvant treatment of TNBC, as well as the novel target therapies that are currently being evaluated in this setting. Taking into account the economic issues and the side effects of the expanding therapeutic options, we focus on the potential efficacy biomarkers of the emerging therapies, in order to select the best therapeutic strategy for each specific patient.
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Project description:BackgroundThe impact of human epidermal growth factor receptor 2 (HER2) expression determined by immunohistochemistry (IHC) on outcomes in early-stage triple-negative breast cancer (eTNBC) is unclear. Using a large, multi-institutional cohort, we evaluated outcomes by HER2 IHC status in patients with eTNBC who received neoadjuvant therapy (NAT).Patients and methodsPatients with stage I-III TNBC who received NAT and underwent surgery from January 2016 to June 2019 were identified from three databases. HER2 expression was defined as low (IHC1+ or 2+/FISH not amplified) or HER2 IHC score 0 by local testing at diagnosis. Pathological complete response (pCR) rates were compared using logistic regression adjusted for multiple factors. Survival outcomes were estimated using Kaplan-Meier and Cox proportional hazards models.ResultsAmong 977 consecutive patients, 388 (39.7%) had HER2-low and 589 (60.3%) had HER2 IHC score 0 tumors. Median age at eTNBC diagnosis was 50.3 years (range 21.0-83.4 years). At baseline, clinical nodal positivity rate was significantly higher in HER2-low (55.0%) versus HER2 IHC score 0 tumors (46.6%) (P = 0.011); pCR rates were similar (32.0% versus 32.6%; adjusted P = 0.924). At a median follow-up of 3.5 years, recurrence-free survival (RFS) did not vary significantly between HER2-low versus HER2 IHC score 0 among patients with pCR (adjusted P = 0.368) or residual disease (RD) after NAT (adjusted P = 0.573). Distant RFS and overall survival (OS) did not differ by HER2 category for patients with pCR [distant RFS (DRFS), adjusted P = 0.509; OS, adjusted P = 0.514] or RD (DRFS, adjusted P = 0.812; OS, P = 0.285). Discordance of tumor HER2 status was seen in 31.1% of HER2 IHC score 0 cases, with HER2 expression observed post-treatment; 34.8% of HER2-low cases showed discordance, with absent HER2 expression in RD.ConclusionsIn this large cohort of patients with eTNBC treated with NAT, HER2-low status was not associated with pCR or survival after adjusting for clinical factors. The discordance in HER2 IHC pre- and post-NAT likely reflects challenges in HER2 quantification and heterogeneity.
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Project description:BackgroundPatients with triple-negative breast cancer (TNBC) are generally younger and more likely to experience disease recurrence and have the shortest survival among all breast cancer patients. Recently, neoadjuvant delivery of the programmed cell death protein-1 inhibitor pembrolizumab plus chemotherapy followed by adjuvant pembrolizumab was approved for patients with high-risk, early-stage TNBC, but this treatment regimen has not been evaluated in head-to-head trials with other neoadjuvant treatment regimens. Therefore, the objective of this study was to estimate the relative efficacy of neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab versus other neoadjuvant treatments for early-stage TNBC through a systematic review and network meta-analysis (NMA).MethodsEMBASE, MEDLINE, Cochrane Central Register of Controlled Trials, conference abstracts, and clinical trial registries were searched for randomized controlled trials evaluating neoadjuvant treatments for early-stage TNBC. NMA was performed to estimate relative treatment effects among evaluated interventions.ResultsFive trials met the inclusion criteria and were included in the NMA. The relative efficacy of neoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab was favorable to paclitaxel followed by anthracycline + cyclophosphamide in terms of pathologic complete response (pCR), event-free survival (EFS), and overall survival; paclitaxel + carboplatin followed by anthracycline + cyclophosphamide in terms of pCR and EFS; paclitaxel + bevacizumab followed by anthracycline + cyclophosphamide + bevacizumab in terms of pCR; and paclitaxel + carboplatin + veliparib followed by anthracycline + cyclophosphamide in terms of EFS.ConclusionsNeoadjuvant pembrolizumab + chemotherapy followed by adjuvant pembrolizumab confers benefits in response and survival outcomes versus alternative neoadjuvant treatments for early-stage TNBC.
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Project description:Triple negative breast cancer is the most aggressive kind of breast cancer with high risk of recurrences and poor outcomes. Systemic chemotherapy has significantly improved long term outcomes in early stage patients; however, metastatic recurrences still develop in a significant number of patients. Anthracycline and taxane based chemotherapy regimens are standard of care for early stage patients. Neoadjuvant treatment is preferred due to the ability to assess pathologic responses providing important prognostic information and guidance in adjuvant therapy decisions. Carboplatin addition to the anthracycline and taxane backbone is associated with a significant improvement in pathologic complete response but is associated with more toxicity. Understanding the immune microenvironment of triple negative disease is an exciting field and immune checkpoint inhibitors have shown great promise in further improving response rates in early stage patients. Patients with residual disease after neoadjuvant chemotherapy have a significantly higher risk of recurrence compared to those with complete responses. Adjuvant capecitabine for these high-risk patients have shown significant improvement in long term outcomes and is routinely used in this setting. Given the heterogeneity within triple negative tumors, molecular subtypes with variable genomic makeup and chemo sensitivities have been identified and will likely aid in further clinical developmental therapeutics.
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Project description:Immune checkpoint inhibition (ICI) with chemotherapy is now the standard of care for stage II-III triple-negative breast cancer; however, it is largely unknown for which patients ICI without chemotherapy could be an option and what the benefit of combination ICI could be. The adaptive BELLINI trial explored whether short combination ICI induces immune activation (primary end point, twofold increase in CD8+ T cells or IFNG), providing a rationale for neoadjuvant ICI without chemotherapy. Here, in window-of-opportunity cohorts A (4 weeks of anti-PD-1) and B (4 weeks of anti-PD-1 + anti-CTLA4), we observed immune activation in 53% (8 of 15) and 60% (9 of 15) of patients, respectively. High levels of tumor-infiltrating lymphocytes correlated with response. Single-cell RNA sequencing revealed that higher pretreatment tumor-reactive CD8+ T cells, follicular helper T cells and shorter distances between tumor and CD8+ T cells correlated with response. Higher levels of regulatory T cells after treatment were associated with nonresponse. Based on these data, we opened cohort C for patients with high levels of tumor-infiltrating lymphocytes (≥50%) who received 6 weeks of neoadjuvant anti-PD-1 + anti-CTLA4 followed by surgery (primary end point, pathological complete response). Overall, 53% (8 of 15) of patients had a major pathological response (<10% viable tumor) at resection, with 33% (5 of 15) having a pathological complete response. All cohorts met Simon's two-stage threshold for expansion to stage II. We observed grade ≥3 adverse events for 17% of patients and a high rate (57%) of immune-mediated endocrinopathies. In conclusion, neoadjuvant immunotherapy without chemotherapy demonstrates potential efficacy and warrants further investigation in patients with early triple-negative breast cancer. ClinicalTrials.gov registration: NCT03815890 .
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Project description:Opinion statementRecently, the addition of PD-1 pathway targeting immune checkpoint inhibitors (ICI) to standard neoadjuvant chemotherapy for early-stage triple-negative breast cancer (TNBC) has been shown to improve rates of pathological complete response (pCR), as well as event-free survival regardless of attainment of pCR. Recurrent TNBC remains a devastating diagnosis and thus novel treatments that improve chance of cure in early-stage TNBC should be promptly integrated into standard of care paradigms. However, approximately 50% of patients with early TNBC will experience pCR with chemotherapy alone, and the addition of ICI carries the risk of sometimes permanent immune-related toxicities. This raises the critical question whether all early-stage TNBC patients should receive ICI in combination with neoadjuvant chemotherapy. As yet, there is no predictive biomarker to select patients most likely to benefit from ICI; however, it would seem that at least all node positive patients should receive an ICI with their neoadjuvant chemotherapy, on the basis of high clinical risk and potential to increase their pCR rate and ultimately the chance of cure. It is plausible that some lower-risk (stage I/II) TNBC demonstrating strong pre-existing immune activation (high tumor-infiltrating lymphocytes (TILs) and/or PD-L1 expression) may be successfully treated with ICI in combination with less cytotoxic chemotherapy, and this requires further evaluation in clinical trials. The contribution of the adjuvant phase of ICI on clinical benefit is unclear even in patients who do not achieve a pCR and long-term data from ongoing studies without adjuvant ICI component may help inform us on an appropriate strategy in the short term. Similarly, the potential benefit of other adjuvant therapies in patients with poor response to neoadjuvant ICI with chemotherapy, including capecitabine and olaparib with or without ICI, is also unknown, but is rational on the basis of administering a non-cross-resistant anti-tumour agent. In conclusion, the addition of neoadjuvant ICI to chemotherapy significantly improves both the quality and quantity of the anti-tumour T cell response, suggesting that improvements in recurrence-free survival occur through better immune protection from cancer. In the future, development of ICI agents that target tumour-specific T cells may favourably alter the toxicity profile, improving the risk-benefit ratio for survivors.
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Project description:Triple-negative breast cancer (TNBC) is characterized by extensive tumor heterogeneity at both the pathologic and molecular levels, particularly accelerated aggressiveness, and terrible metastasis. It is responsible for the increased mortality of breast cancer patients. Due to the negative expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2, the progress of targeted therapy has been hindered. Higher immune response in TNBCs than for other breast cancer types makes immunotherapy suitable for TNBC therapy. At present, promising treatments in immunotherapy of TNBC include immune checkpoints (ICs) blockade therapy, adoptive T-cell immunotherapy, and tumor vaccine immunotherapy. In addition, nanomedicines exhibit great potential in cancer therapy through the enhanced permeability and retention (EPR) effect. Immunotherapy-involved combination therapy may exert synergistic effects by combining with other treatments, such as traditional chemotherapy and new treatments, including photodynamic therapy (PTT), photodynamic therapy (PDT), and sonodynamic therapy (SDT). This review focuses on introducing the principles and latest development as well as progress in using nanocarriers as drug-delivery systems for the immunotherapy of TNBC.
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