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Immunotherapy for HER2-positive breast cancer: Recent advances and combination therapeutic approaches

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Cancer immunotherapy has evolved dramatically with improved understanding of immune microenvironment and immunosurveillance. The immunogenicity of breast cancer is rather heterogeneous. Specific subtypes of breast cancer such as estrogen receptor (ER)-negative, human EGF receptor 2 (HER2)-positive, and triple-negative breast cancer (TNBC) have shown evidence of immunogenicity based on tumor–immune interactions. Several preclinical and clinical studies have explored the potential for immunotherapy to improve the clinical outcomes for different subtypes of breast cancer. This review describes the immune microenvironment of HER2-positive breast cancer and summarizes recent clinical advances of immunotherapeutic treatments in this breast cancer subtype. The review provides rationale and ongoing clinical evidence to the use of immune checkpoint inhibitors, therapeutic vaccines, and adoptive T cell immunotherapy in breast cancer. In addition, the present paper describes the most relevant clinical progress of strategies for the combination of immunotherapy with standard treatment modalities in HER2-positive breast cancer including chemotherapy, targeted therapy, and radiotherapy. Keywords: immunotherapy, breast cancer, HER2, checkpoint inhibitors, vaccines
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... The interaction between cancer cells and immune cells is best described as immunoediting. Immunoediting involves three phases: elimination, equilibrium, and escape 3,4 . In the elimination phase, the immune system detects and eliminates transformed cells through a process known as immunosurveillance 4 . ...
... The equilibrium phase involves the suppression of tumor expansion by residual tumor cells. Ultimately, tumor cells that survive the previous phases progress and grow to form clinically detectable tumors secondary to a deficient immune response 3,4 . Several mechanisms have been identified to explain the ability of cancer cells to escape the immune system. ...
... Several mechanisms have been identified to explain the ability of cancer cells to escape the immune system. Such mechanisms include the downregulation of surface antigens, the stimulation of cancer cell survival pathways, recruitment of suppressive immune cells, and upregulation of immune checkpoints 3,5 . ...
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Objective: Though tumor-infiltrating lymphocytes (TILs) have a predictive impact in cancer patients, their association with presentation and prognosis in breast cancer is less consistent. This study aimed to assess the level of infiltrating cytotoxic T lymphocytes (CTLs) and regulatory T lymphocytes (Tregs) and their association with the clinicopathological features of breast cancer. Patients and methods: Tissue samples from female patients (n=153) diagnosed with primary invasive breast cancer were stained with CD8 (a CTL marker) and Foxp3 (a Treg marker) using immunohistochemistry. Results: CTLs were distributed between tumor bed and stroma whereas Treg cells were mainly located in the stroma. The level of intratumoral CTLs correlated positively with Tregs in both tumor and stroma (rho=0.312, p<0.001 and rho=0.176, p=0.031; respectively). Stromal CTLs correlated positively with stromal Tregs (rho=0.319, p=0.005). Tumor size correlated inversely with the number of Treg cells in the tumor bed (rho= - 0.179, p=0.028). Tregs were associated with lymphovascular invasion status in the tumor bed (p=0.042). The ratio of intratumoral CTLs to Tregs was associated with estrogen receptor positivity and luminal subtype (p=0.029 and p=0.045, respectively). The median number of CTLs was significantly lower in patients using aspirin or antihypertensive medications compared to nonusers (p=0.024 and p=0.03, respectively). Conclusions: TILs were distributed differently in tumor tissues of breast cancer patients. CTLs infiltrates were found in both tumor bed and stroma while Tregs were dominant in the stroma. TILs were also distinctly associated with tumor features. The impact of TILs on prognosis and treatment outcomes in Jordanian breast cancer patients needs further investigation.
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... Neoplastic cells can elude the immune system by modifying immunological surface markers, down-regulating the expression of MHC class I proteins and co-stimulators, and by T cell receptor signaling defects [160]. Other strategies for escaping immune detection comprise activating regulatory pathways, developing immunosuppressant TME by regulatory T cells (Tregs), augmenting myeloid-originated suppressant cells, producing cancer proliferation factors, and interleukin (IL)-10 [158]. ...
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... In this case, the immune system of the patient will produce its own antibodies [7,100]. Vaccination is considered as a middle solution between mAbs and adoptive cell therapy as it produces less cytotoxicity compared to ACT while also being more effective than mAbs-mediated immunotherapy, since it requires fewer administrations, is more cost-effective, and generates immunological memory, which can help the immune system detect antigens and respond to them upon future exposures, protecting against tumor recurrence [109,113,114]. ...
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... Numerous structural alterations and point mutation accumulation occur in the tumor progression process. Tumor antigens are risen by genomic variations, these tumor antigens are recognized as elicit, and non-self cellular immune responses by the immune system [3]. Malignant cells are eradicated or impaired based on their functions and phenotypes by the effective immune responses. ...
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... The use of dendritic cells (DCs) as a vaccine strategy has the advantage of presenting vaccine antigens to other immune system cell types. Furthermore, some preclinical studies have shown the possibility of generating HER2-loaded DCs as well as DCs engineered to express HER2 antigen epitopes [135,136]. ...
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Background: Stromal tumor-infiltrating lymphocytes (TILs) might predict pathologic complete response (pCR) in patients with HER2-positive (HER2+) breast cancer treated with trastuzumab (H). Docetaxel (T), carboplatin (C), H, and pertuzumab (P) have immune-modulating effects. Pre- and post-treatment immune biomarkers in cancers treated with neoadjuvant TCH with or without P are lacking. In this study we quantified baseline and changes in TILs, cluster of differentiation (CD) 4+, CD8+, FoxP3+, and PD-L1+cells using immunohistochemistry (IHC) and quantified productive T-cell receptor β (TCRβ) rearrangements and TCRβ clonality using next-generation sequencing (NGS) in 30 HER2+breast cancer tissues treated with neoadjuvant H with or without P regimens. Materials and methods: Thirty pre- and post-neoadjuvant TCH (n = 4) or TCHP (n = 26) breast cancer tissues were identified. TILs were quantified manually using hematoxylin and eosin. CD4, CD8, FoxP3, and PD-L1 were stained using IHC. TCRβ was evaluated using NGS. Immune infiltrates were compared between pCR and non-pCR groups using the Wilcoxon rank sum test. Results: A pCR occurred in 15 (n = 15; 50%) cancers (TCH n = 2; TCHP, n = 13). Pretreatment TILs, CD4+, CD8+, FoxP3+, and PD-L1+cells were not associated with response (P = .42, P = .55, P = .19, P = .66, P = .87, respectively. Pretreatment productive TCRβ and TCRβ clonality did not predict response, P = .84 and P = .40, respectively). However, post-treatment CD4+and FoxP3+cells (T-regulatory cells) were elevated in the non-pCR cohort (P = .042 and P = .082, respectively). Conclusion: An increase in regulatory T cells in non-pCR tissues suggests the development of an immunosuppressive phenotype. Further investigation in a larger cohort of samples is warranted to validate these findings.
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Radiation therapy (RT) has been successfully used in the treatment of breast cancer (BC) for over a century. While historically thought to be immunosuppressive, new data have shown that RT can work together with the immune system to eliminate cancer. It can cause immunogenic cell death and facilitate tumor neoantigen presentation and cross-priming of tumor-specific T-lymphocytes, turning irradiated tumor into an in-situ vaccine. Unfortunately, due to various immune escape mechanism put in place by the tumor, RT alone rarely results in a systemic response of metastatic disease sites (known as the abscopal effect). Immunotherapy, a series of agents designed to stimulate the immune system in order to generate tumor-specific immune response, is showing promise in treatment of various cancers, including BC, and can be an ideal complement to RT in stimulating a systemic immune response to reject the tumor cells. This review discusses the mechanisms in which RT can trigger an immune response for tumor rejection, and provide emerging preclinical and clinical data of combination immunoradiotherapy, and its potential in treating BC.
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Background: Tumour-infiltrating lymphocytes (TILs) are predictive for response to neoadjuvant chemotherapy in triple-negative breast cancer (TNBC) and HER2-positive breast cancer, but their role in luminal breast cancer and the effect of TILs on prognosis in all subtypes is less clear. Here, we assessed the relevance of TILs for chemotherapy response and prognosis in patients with TNBC, HER2-positive breast cancer, and luminal-HER2-negative breast cancer. Methods: Patients with primary breast cancer who were treated with neoadjuvant combination chemotherapy were included from six randomised trials done by the German Breast Cancer Group. Pretherapeutic core biopsies from 3771 patients included in these studies were assessed for the number of stromal TILs by standardised methods according to the guidelines of the International TIL working group. TILs were analysed both as a continuous parameter and in three predefined groups of low (0-10% immune cells in stromal tissue within the tumour), intermediate (11-59%), and high TILs (≥60%). We used these data in univariable and multivariable statistical models to assess the association between TIL concentration and pathological complete response in all patients, and between the amount of TILs and disease-free survival and overall survival in 2560 patients from five of the six clinical trial cohorts. Findings: In the luminal-HER2-negative breast cancer subtype, a pathological complete response (pCR) was achieved in 45 (6%) of 759 patients with low TILs, 48 (11%) of 435 with intermediate TILs, and 49 (28%) of 172 with high TILs. In the HER2-positive subtype, pCR was observed in 194 (32%) of 605 patients with low TILs, 198 (39%) of 512 with intermediate TILs, and 127 (48%) of 262 with high TILs. Finally, in the TNBC subtype, pCR was achieved in 80 (31%) of 260 patients with low TILs, 117 (31%) of 373 with intermediate TILs, and 136 (50%) of 273 with high TILs (p<0·0001 for each subtype, χ2 test for trend). In the univariable analysis, a 10% increase in TILs was associated with longer disease-free survival in TNBC (hazard ratio [HR] 0·93 [95% CI 0·87-0·98], p=0·011) and HER2-positive breast cancer (0·94 [0·89-0·99], p=0·017), but not in luminal-HER2-negative tumours (1·02 [0·96-1·09], p=0·46). The increase in TILs was also associated with longer overall survival in TNBC (0·92 [0·86-0·99], p=0·032), but had no association in HER2-positive breast cancer (0·94 [0·86-1·02], p=0·11), and was associated with shorter overall survival in luminal-HER2-negative tumours (1·10 [1·02-1·19], p=0·011). Interpretation: Increased TIL concentration predicted response to neoadjuvant chemotherapy in all molecular subtypes assessed, and was also associated with a survival benefit in HER2-positive breast cancer and TNBC. By contrast, increased TILs were an adverse prognostic factor for survival in luminal-HER2-negative breast cancer, suggesting a different biology of the immunological infiltrate in this subtype. Our data support the hypothesis that breast cancer is immunogenic and might be targetable by immune-modulating therapies. In light of the results in luminal breast cancer, further research investigating the interaction of the immune system with different types of endocrine therapy is warranted. Funding: Deutsche Krebshilfe and European Commission.