Integrating Immunotherapy Into the Treatment Landscape for Patients With Triple-Negative Breast Cancer

Dixon-Douglas, Julia; Loibl, Sibylle; Denkert, Carsten; Telli, Melinda L.; Loi, Sherene

doi:10.1200/edbk_351186

Cited by 13 publications

(7 citation statements)

References 78 publications

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“…Indeed, pembrolizumab (anti-PD-1 antibody) has recently been FDA-approved for TNBC 78 , 79 , and atezolizumab (anti-PD-L1 antibody), though more recently withdrawn from further regulatory considerations in the US, initially generated favorable clinical responses 80 . Despite this enthusiasm, the clinical response for currently adopted forms of immunotherapies has not been satisfactory (e.g., the median overall survival among patients with advanced TNBC highly positive for PD-L1 was 23.0 months when treated with pembrolizumab plus chemotherapy, and 16.1 months for placebo plus chemotherapy) 78 , 81 . Thus, there is considerable interest in identifying resistance mechanisms for and superior predictive biomarkers of response to ICIs in TNBC.…”

Section: Discussionmentioning

confidence: 99%

S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models

Begg,

Orriols,

Zannikou

et al. 2024

Commun Med

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Background Understanding why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well remains a challenge. This study aims to understand the potential underlying mechanisms distinguishing early-stage TNBC tumors that respond to clinical intervention from non-responders, as well as to identify clinically viable therapeutic strategies, specifically for TNBC patients who may not benefit from existing therapies. Methods We conducted retrospective bioinformatics analysis of historical gene expression datasets to identify a group of genes whose expression levels in early-stage tumors predict poor clinical outcomes in TNBC. In vitro small-molecule screening, genetic manipulation, and drug treatment in syngeneic mouse models of TNBC were utilized to investigate potential therapeutic strategies and elucidate mechanisms of drug action. Results Our bioinformatics analysis reveals a robust association between increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors and subsequent disease progression in TNBC. A targeted small-molecule screen identifies PIM kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Combining PIM inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Notably, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC. Conclusions Our data propose S100A8/A9 as a potential predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting PIM and immune checkpoints in TNBC. This work encourages the development of S100A8/A9-based liquid biopsy tests for treatment guidance.

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Section: Discussionmentioning

confidence: 99%

S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models

Begg,

Orriols,

Zannikou

et al. 2024

Commun Med

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show abstract

“…Indeed, pembrolizumab (anti-PD-1 antibody) has recently been FDA-approved for TNBC 68,69 , and atezolizumab (anti-PD-L1 antibody), though more recently withdrawn from further regulatory considerations in the US, initially generated favorable clinical responses 70 . Despite this enthusiasm, the clinical response for currently adopted forms of immunotherapies has not been satisfactory (e.g., the median overall survival among patients with advanced TNBC highly positive for PD-L1 was 23.0 months when treated with pembrolizumab plus chemotherapy, and 16.1 months for placebo plus chemotherapy) 68,71 . Thus, there is considerable interest in identifying resistance mechanisms for and superior predictive biomarkers of response to ICIs in TNBC.…”

Section: Discussionmentioning

confidence: 99%

S100A8/A9 predicts triple-negative breast cancer response to PIM kinase and PD-1/PD-L1 inhibition

Begg,

Orriols,

Zannikou

et al. 2023

Preprint

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It remains elusive why some triple-negative breast cancer (TNBC) patients respond poorly to existing therapies while others respond well. Our retrospective analysis of historical gene expression datasets reveals that increased expression of immunosuppressive cytokine S100A8/A9 in early-stage tumors is robustly associated with subsequent disease progression in TNBC. Although it has recently gained recognition as a potential anticancer target, S100A8/A9 has not been integrated into clinical study designs evaluating molecularly targeted therapies. Our small molecule screen has identified PIM kinase inhibitors as capable of decreasing S100A8/A9 expression in multiple cell types, including TNBC and immunosuppressive myeloid cells. Furthermore, combining PIM inhibition and immune checkpoint blockade induces significant antitumor responses, especially in otherwise resistant S100A8/A9-high PD-1/PD-L1-positive tumors. Importantly, serum S100A8/A9 levels mirror those of tumor S100A8/A9 in a syngeneic mouse model of TNBC. Thus, our data suggest that S100A8/A9 could be a predictive and pharmacodynamic biomarker in clinical trials evaluating combination therapy targeting PIM and immune checkpoints in TNBC and encourage the development of S100A8/A9-based liquid biopsy tests.

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“…At present, neoadjuvant chemotherapy is the current standard of care for patients with early TNBC. Three phase III randomized controlled trials are now available to guide the use of immune checkpoint inhibitors combined with neoadjuvant chemotherapy for early‐stage TNBC: KEYNOTE‐522, IMpassion031, and NeoTRIPaPDL1 38 . KEYNOTE‐522 trial showed neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab after surgery, resulted in significantly longer event‐free survival than neoadjuvant chemotherapy alone in stage II‐III TNBC patients 21 …”

Section: Discussionmentioning

confidence: 99%

Comparison of the tumor immune microenvironment phenotypes in different breast cancers after neoadjuvant therapy

Han

et al. 2022

Cancer Medicine

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Neoadjuvant therapy (NAT) treats early‐stage breast cancers, especially triple‐negative breast cancers (TNBCs). NAT improves pathological complete response (pCR) rates for different breast cancer patients. Recently, immune checkpoint inhibitors that target programmed death 1 (PD‐1) or programmed death ligand 1 (PD‐L1) in combination with NAT have shown antitumor activity in patients with early breast cancer. However, the tumor immune microenvironment (TME) in different subtypes of breast cancers, like TNBC, hormone receptor‐positive (HR+), and human epidermal growth factor receptor 2 amplified (HER2+) and its changes by NAT remain to be fully characterized. We analyzed pre‐NAT tumor biopsies from TNBC (n = 27), HR+ (n = 24), and HER2+ (n = 30) breast cancer patients who received NAT, followed by surgery. The different immune makers (PD‐1, PD‐L1, CD3, and CD8) of tumor‐infiltrating lymphocytes (TILs) were identified with immunofluorescence‐based microenvironment analysis. TILs within cancer parenchyma (iTILs) and in cancer stroma (sTILs) were counted separately. We found that PD‐L1+ cells in tumor and stroma were significantly higher in TNBC patients than in others. PD‐L1+ sTILs were significantly higher in pCR than in non‐pCR patients of all the subtypes. The infiltration scores of B‐cell memory, T‐cell CD4+ memory activated, T‐cell follicular helper, and Macrophage M0 and M1 were relatively higher in TNBC patients, indicating immunoreactive TME in TNBC. Analysis of TCGA‐BRCA RNA‐seq indicated that PD‐L1 was highly expressed in TNBC patients compared with HR+ and HER2+ patients. Higher PD‐L1 expression in TNBC patients was associated with significantly longer overall survival (OS). Our results demonstrated that PD‐L1 expression level of iTILs and sTILs is highest in TNBC among breast cancers. TNBC patients had significantly different immunoreactive TME compared with HR+ and HER2+ patients, suggesting potentially favorable outcomes for immunotherapy in these patients. Also, PD‐L1+ could be a powerful predictor of pCR in TNBC patients after NAT.

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Integrating Immunotherapy Into the Treatment Landscape for Patients With Triple-Negative Breast Cancer

Cited by 13 publications

References 78 publications

S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models

S100A8/A9 predicts response to PIM kinase and PD-1/PD-L1 inhibition in triple-negative breast cancer mouse models

S100A8/A9 predicts triple-negative breast cancer response to PIM kinase and PD-1/PD-L1 inhibition

Comparison of the tumor immune microenvironment phenotypes in different breast cancers after neoadjuvant therapy

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