Clinical and genomic assessment of PD-L1 SP142 expression in triple-negative breast cancer

Ahn, Sung Gwe; Kim, Seon‐Kyu; Shepherd, Jonathan H.; Jin, Yoon; Bae, Soong June; Kim, Chungyeul; Lee, Jeong Eon; Perou, Charles M.

doi:10.1007/s10549-021-06193-9

Cited by 22 publications

(20 citation statements)

References 66 publications

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“…7-11 13 14 The efficacy of ICIs is affected by the subtypes of tumor microenvironments (TMEs). [35][36][37] It has been reported that the TMEs can be clustered into three groups: immune-desert type that lacks lymphocyte Open access infiltration, innate immune-inactivated type that infiltrated with inactivated innate immune cells and immuneinflamed type that infiltrated with high numbers of innate and adaptive immune cells. 38 Only the immune-inflamed type TME is predicted to benefit from ICI therapies, 38 which limits the efficacy of ICIs for TNBC patients.…”

Section: Discussionmentioning

confidence: 99%

Bispecific antibody targeting TROP2xCD3 suppresses tumor growth of triple negative breast cancer

Liu

Bai

Huang

et al. 2021

J Immunother Cancer

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BackgroundTriple negative breast cancer (TNBC) is a subtype of breast cancers with poor prognosis and targeted drug therapies are limited. To develop novel and efficacious therapies for TNBC, we developed a bispecific antibody F7AK3 that recognizes both trophoblast cell surface antigen 2 (TROP2) and CD3 and evaluated its antitumor activities both in vitro and in vivo.MethodsThe binding affinities of F7AK3 to the two targets, TROP2 and CD3, were evaluated by surface plasmon resonance. Binding of F7AK3 to TNBC cells and T cells were evaluated by flow cytometry. Immunofluorescent staining was performed to demonstrate the interactions between T cells with TNBC cells. The cytotoxicity of T cells against TNBC cell lines and primary tumor cells mediated by F7AK3 were determined in vitro. In vivo antitumor activity of F7AK3 was investigated in a xenograft TNBC tumor model, using immunodeficient mice that were reconstituted with human peripheral blood mononuclear cells.ResultsWe demonstrated that F7AK3 binds specifically to human TROP2 and CD3 antigens, as well as TNBC cell lines and primary tumor cells. Human T cells can only be activated by F7AK3 in the presence of target tumor cells. F7AK3 recruits T cells to TROP2+ tumor cells in vitro and into tumor tissues in vivo. Antitumor growth activity of F7AK3 is observed in a xenograft TNBC tumor model.ConclusionThis study showed the antitumor potential of an anti-TROP2xCD3 bispecific antibody F7AK3 to TNBC tumor cells both in vitro and in vivo. These data demonstrate that F7AK3 has the potential to treat TNBC patients, which warrants further preclinical and clinical evaluation of the F7AK3 in advanced or metastatic TNBC patients.

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Section: Discussionmentioning

confidence: 99%

Bispecific antibody targeting TROP2xCD3 suppresses tumor growth of triple negative breast cancer

Liu

Bai

Huang

et al. 2021

J Immunother Cancer

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“…Furthermore, the frequency of PD-L1 expression was higher in ICs in patients with node-negative status. In triple-negative BC, PD-L1 positive tumors have more immunogenic characteristics, including elevated tumor infiltrating lymphocyte (TIL) and CD8 counts, enrichment of the immunogenic genomic subtype, and elevated immunogenic gene signatures at the gene expression level [ 47 ]. However, it is not clear whether these characteristics could determine the occurrence of tumors at older ages or early stages.…”

Section: Discussionmentioning

confidence: 99%

“…However, it is not clear whether these characteristics could determine the occurrence of tumors at older ages or early stages. It should be noted that the SP142 assay detects more ICs and fewer TCs compared to the other assays, which can generate conflicting results depending on the PD-L1 assay utilized [ 47 ]. Furthermore, the interobserver agreement for PD-L1 expression in ICs is inferior to TCs in various types of tumors regardless of the type of assay used, which could also contribute to the divergence of prognostic factors [ 3 , 44 ].…”

Section: Discussionmentioning

confidence: 99%

Prognostic Role of PD-L1 Expression in Invasive Breast Cancer: A Systematic Review and Meta-Analysis

Cirqueira

Mendonça

Soares

et al. 2021

Cancers

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Programmed death ligand 1 (PD-L1) has been investigated in various types of cancer; however, the role of PD-L1 expression in breast cancer remains controversial. We performed a systematic review and meta-analysis to assess the association of PD-L1 expression with clinicopathological variables, overall survival (OS), and disease-free survival (DFS) in invasive breast cancer. A total of 965 articles were included from CINAHL, Embase, PubMed, and Scopus databases. Of these, 22 studies encompassing 6468 cases of invasive breast cancer were included in the systematic review, and 15 articles were included in the meta-analysis. PD-L1 expression was associated with age ≥ 50 years, lymph node status-negative, progesterone receptor-negative, Ki67 ≥ 20%, and human epidermal growth factor receptor 2 (HER2)-negative. PD-L1 positivity was associated with worse OS (hazard ratio, HR, 2.39; 95% confidence interval, CI, 1.26–3.52; p =< 0.000); however, there was no significant improvement in DFS (HR 0.17; 95% CI −0.12–0.46; p =< 0.252). PD-L1 positivity was significantly associated with the clinicopathological characteristics of favorable and unfavorable prognoses. However, the final clinical outcome was associated with lower OS and had no significant association with DFS.

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“…As TNBCs with high TILs are more likely to contain ≥1% PD-L1-positive immune cells [ 45 ], a combined evaluation of TILs and PD-L1 expression in locally advanced and metastatic TNBC has been proposed by the International Immuno-Oncology Biomarker Working Group to reduce the risk of suboptimal patient selection for immunotherapy [ 19 ]. Suboptimal patient selection might result from inter-pathologist variability in the PD-L1/SP142 assessment.…”

Section: Discussionmentioning

confidence: 99%

Interobserver Agreement of PD-L1/SP142 Immunohistochemistry and Tumor-Infiltrating Lymphocytes (TILs) in Distant Metastases of Triple-Negative Breast Cancer: A Proof-of-Concept Study. A Report on Behalf of the International Immuno-Oncology Biomarker Working Group

Bockstal

Cooks

Nederlof

et al. 2021

Cancers

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Patients with advanced triple-negative breast cancer (TNBC) benefit from treatment with atezolizumab, provided that the tumor contains ≥1% of PD-L1/SP142-positive immune cells. Numbers of tumor-infiltrating lymphocytes (TILs) vary strongly according to the anatomic localization of TNBC metastases. We investigated inter-pathologist agreement in the assessment of PD-L1/SP142 immunohistochemistry and TILs. Ten pathologists evaluated PD-L1/SP142 expression in a proficiency test comprising 28 primary TNBCs, as well as PD-L1/SP142 expression and levels of TILs in 49 distant TNBC metastases with various localizations. Interobserver agreement for PD-L1 status (positive vs. negative) was high in the proficiency test: the corresponding scores as percentages showed good agreement with the consensus diagnosis. In TNBC metastases, there was substantial variability in PD-L1 status at the individual patient level. For one in five patients, the chance of treatment was essentially random, with half of the pathologists designating them as positive and half negative. Assessment of PD-L1/SP142 and TILs as percentages in TNBC metastases showed poor and moderate agreement, respectively. Additional training for metastatic TNBC is required to enhance interobserver agreement. Such training, focusing on metastatic specimens, seems worthwhile, since the same pathologists obtained high percentages of concordance (ranging from 93% to 100%) on the PD-L1 status of primary TNBCs.

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Clinical and genomic assessment of PD-L1 SP142 expression in triple-negative breast cancer

Cited by 22 publications

References 66 publications

Bispecific antibody targeting TROP2xCD3 suppresses tumor growth of triple negative breast cancer

Bispecific antibody targeting TROP2xCD3 suppresses tumor growth of triple negative breast cancer

Prognostic Role of PD-L1 Expression in Invasive Breast Cancer: A Systematic Review and Meta-Analysis

Interobserver Agreement of PD-L1/SP142 Immunohistochemistry and Tumor-Infiltrating Lymphocytes (TILs) in Distant Metastases of Triple-Negative Breast Cancer: A Proof-of-Concept Study. A Report on Behalf of the International Immuno-Oncology Biomarker Working Group

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