Breast cancer genomics and immuno-oncological markers to guide immune therapies

Hammerl, Dora; Smid, Marcel; Timmermans, Annemieke M.; Sleijfer, Stefan; Martens, John W.M.; Debets, Reno

doi:10.1016/j.semcancer.2017.11.003

Cited by 121 publications

(124 citation statements)

References 126 publications

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“…However, recent studies have challenged this idea and showed that Foxp3+Tregs were associated with improved outcome in BCs (77,78) or bared no impact on OS (79), either regarding the entire group or the HR+ subgroup (43). The present study showed that in the HR-subgroup, higher levels of FOXP3+ Tregs were associated with favorable BCSS, as previously reported (34,35). This finding suggests a subtype-dependent relationship between Tregs and BC prognosis and two possible explanations are offered.…”

Section: Discussionsupporting

confidence: 68%

A Standardized Evaluation Method for FOXP3+ Tregs and CD8+ T-cells in Breast Carcinoma: Association With Breast Carcinoma Subtypes, Stage and Prognosis

et al. 2019

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Background/Aim: The role of FOXP3+ Tregs and CD8+ T-cells in different stages and subtypes of breast carcinoma (BC) is yet to be fully defined, mainly because of methodological variations between studies. The aim of this study was to assess FOXP3+ and CD8+ intratumoral stromal TILs (sTILs) by a standardized method, in order to discern differences between the histological subtypes and BC stage and evaluate the applicability of the method. Patients and Methods: FOXP3+ and CD8+ sTILs were studied immunohistochemically in 207 BCs and counted on digital images, amounting to a standard stromal area of a 10×10 grid on ×40 magnification. The results were correlated with clinicopathological features and outcomes. Results: Tregs and CD8+ TILs were more abundant in HER2+ BCs (p=0.02, p=0.007, respectively), estrogen receptor (ER)-BCs (p<0.001, for both cell types), and triple-negative BCs (TNBCs) (p=0.01, p=0.006, respectively). Tregs and CD8+ TILs were associated with high grade (p<0.001 and p=0.002, respectively) and high Ki67 index (p<0.001, for both cell types). Lower CD8/FOXP3 ratio was associated with node metastases (p=0.007). Node metastases and advanced stage paralleled with decreased CD8+ sTILs (p=0. 023, p=0.019, respectively). In the entire group and in ER-BCs, CD8+ TILs were associated with favorable distant metastasis-free survival (p=0.021, p<0.001, respectively), disease-free survival (p=0.022, p<0.001, respectively) and breast cancer specific survival (BCSS) (p=0.022, p=0.005). In ER-BCs, Tregs were associated with favorable BCSS (p=0.02). Conclusion: Tregs and CD8+ TILs are higher in early-stage TNBCs and HER2+ BCs and diminish with progression to advanced stages. The findings provide support for immunotherapeutic manipulation of TILs, particularly in early stages of these BC subtypes. The evaluation methodology can be easily implemented for standardization of immunohistochemically-detected TILs.

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Section: Discussionsupporting

confidence: 68%

A Standardized Evaluation Method for FOXP3+ Tregs and CD8+ T-cells in Breast Carcinoma: Association With Breast Carcinoma Subtypes, Stage and Prognosis

et al. 2019

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“…When we performed miR‐141‐3p correlation to all mRNAs within both ER‐positive and ER‐negative patients, we also found a strong and significant link to several immune‐related processes (data not shown). These results may indicate that miR‐141‐3p may play a larger role in the ER‐negative subset of patients, in line with a higher frequency of tumor infiltrating lymphocytes in ER‐negative vs. ER‐positive tumors (Hammerl et al , ). Nevertheless, the significant anticorrelation between miR‐141‐3p and CXCL12 ( SDF‐1 ), as well as the latter being a predicted target for this miRNA, does suggest immunological effects from this miRNA in the ER‐positive subset of patients responding to Bev as well.…”

Section: Discussionmentioning

confidence: 77%

miRNA expression changes during the course of neoadjuvant bevacizumab and chemotherapy treatment in breast cancer

et al. 2019

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One of the hallmarks of cancer is sustained angiogenesis. Favorable results have been reported in some breast cancer (BC) patients receiving antiangiogenic therapy with bevacizumab (Bev) in combination with chemotherapy, and further knowledge on how Bev can be optimally combined with conventional treatment to increase efficacy is strongly needed. In this randomized, neoadjuvant phase II clinical trial, 132 patients with HER2‐negative, nonmetastatic BC were treated with Bev in combination with sequential chemotherapy. Biopsies were sampled before treatment, after 12 weeks with anthracycline and after taxane therapy at week 25. MicroRNA (miRNA) expression profiling was performed on biopsies from each time point. Altogether, 241 biopsies were analyzed with the aim of identifying miRNA‐based biomarkers of response to therapy. Results from the miRNA analyses were reported for the ER‐positive cohort, which were previously demonstrated to benefit from antiangiogenic therapy in this study. For both treatment arms of this cohort, significantly different expression was observed for 217 miRNAs between objective responding and nonresponding patients before treatment initiation. These miRNAs have been linked to regulation of epithelial–mesenchymal transition, metastasis, and tumor growth, among other processes. Bev in combination with chemotherapy resulted in similar miRNA changes to chemotherapy alone. However, the deregulation of miRNA expression occurred earlier in the Bev arm. In both arms, tumor suppressor miRNAs were found upregulated after treatment, while oncogenic miRNAs were downregulated in the Bev arm. Patients responding to Bev showed a strong correlation between deregulated miRNAs and decreased proliferation score during the course of treatment, with downregulation of miR‐4465 as the strongest indicator of reduced proliferation. Integrative analyses at miRNA‐, gene‐, and protein expression further indicated a longitudinal decrease in proliferation. Altogether, the results indicate that proliferation might represent a predictive factor for increased Bev sensitivity, which may aid in the identification of patients who could potentially benefit from Bev.

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“…Moreover, it has been revealed that M2 macrophages play a significant role in tumor development. This advocates for the efficient identification of the ITME to discover potential therapeutic targets that may help in the development of new therapies targeting tumor-associated macrophages (Hammerl et al 2018).…”

Section: Comparing Methods Over Simulated Datamentioning

confidence: 99%

MIXTURE: an improved algorithm for immune tumor microenvironment estimation based on gene expression data

Fernández

Mahmoud

Veigas

et al. 2019

Preprint

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RNA sequencing has proved to be an efficient high-throughput technique to robustly characterize the presence and quantity of RNA in tumor biopsies at a given time. Importantly, it can be used to computationally estimate the composition of the tumor immune infiltrate and to infer the immunological phenotypes of those cells. Given the significant impact of anti-cancer immunotherapies and the role of the associated immune tumor microenvironment (ITME) on its prognosis and therapy response, the estimation of the immune cell-type content in the tumor is crucial for designing effective strategies to understand and treat cancer. Current digital estimation of the ITME cell mixture content can be performed using different analytical tools. However, current methods tend to overestimate the number of cell-types present in the sample, thus under-estimating true proportions, biasing the results. We developed MIXTURE, a noise-constrained recursive feature selection for support vector regression that overcomes such limitations. MIXTURE deconvolutes cell-type proportions of bulk tumor samples for both RNA microarray or RNA-Seq platforms from a leukocyte validated gene signature. We evaluated MIXTURE over simulated and benchmark data sets. It overcomes competitive methods in terms of accuracy on the true number of present cell-types and proportions estimates with increased robustness to estimation bias. It also shows superior robustness to collinearity problems. Finally, we investigated the human immune microenvironment of breast cancer, head and neck squamous cell carcinoma, and melanoma biopsies before and after anti-PD-1 immunotherapy treatment revealing associations to response to therapy which have not seen by previous methods.

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Breast cancer genomics and immuno-oncological markers to guide immune therapies

Cited by 121 publications

References 126 publications

A Standardized Evaluation Method for FOXP3+ Tregs and CD8+ T-cells in Breast Carcinoma: Association With Breast Carcinoma Subtypes, Stage and Prognosis

A Standardized Evaluation Method for FOXP3+ Tregs and CD8+ T-cells in Breast Carcinoma: Association With Breast Carcinoma Subtypes, Stage and Prognosis

miRNA expression changes during the course of neoadjuvant bevacizumab and chemotherapy treatment in breast cancer

MIXTURE: an improved algorithm for immune tumor microenvironment estimation based on gene expression data

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