Assessment of PD-L1 expression across breast cancer molecular subtypes, in relation to mutation rate, <i>BRCA1</i>-like status, tumor-infiltrating immune cells and survival

Sobral-Leite, Marcelo; Vijver, Koen Van de; Michaut, Magali; Linden, Rianne van der; Hooijer, Gerrit K J; Horlings, Hugo M.; Severson, Tesa; Mulligan, Anna Marie; Weerasooriya, Nayana; Sanders, Joyce; Glas, Annuska M.; Wehkamp, Diederik; Mittempergher, Lorenza; Kersten, Kelly; Cimino‐Mathews, Ashley; Peters, Dennis; Hooijberg, Erik; Broeks, Annegien; Vijver, Marc J. van de; Bernards, René; Andrulis, Irene L.; Kok, Marleen; Visser, Karin E. de; Schmidt, Marjanka K.

doi:10.1080/2162402x.2018.1509820

Cited by 95 publications

(103 citation statements)

References 58 publications

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“…We report, to our knowledge for the first time, a significant association between BRCA1 promoter hypermethylation and PD-L1 expression, in both tumor and immune cells. In the study by Sobral-Leite et al, PD-L1 expression showed a modest but significant positive association with the number of silent mutations in TNBC [71]. However, PD-L1 was not associated with BRCA1-like status evaluated using multiplex ligation-dependent probe amplification, an assay unable to identify methylation status.…”

Section: Discussionmentioning

confidence: 94%

BRCA1 Promoter Hypermethylation is Associated with Good Prognosis and Chemosensitivity in Triple-Negative Breast Cancer

Jacot

Lopez-Crapez

Mollévi

et al. 2020

Cancers

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The aberrant hypermethylation of BRCA1 promoter CpG islands induces the decreased expression of BRCA1 (Breast Cancer 1) protein. It can be detected in sporadic breast cancer without BRCA1 pathogenic variants, particularly in triple-negative breast cancers (TNBC). We investigated BRCA1 hypermethylation status (by methylation-specific polymerase chain reaction (MS-PCR) and MassARRAY® assays), and BRCA1 protein expression using immunohistochemistry (IHC), and their clinicopathological significance in 248 chemotherapy-naïve TNBC samples. Fifty-five tumors (22%) exhibited BRCA1 promoter hypermethylation, with a high concordance rate between MS-PCR and MassARRAY® results. Promoter hypermethylation was associated with reduced IHC BRCA1 protein expression (p = 0.005), and expression of Programmed death-ligand 1 protein (PD-L1) by tumor and immune cells (p = 0.03 and 0.011, respectively). A trend was found between promoter hypermethylation and basal marker staining (p = 0.058), and between BRCA1 expression and a basal-like phenotype. In multivariate analysis, relapse-free survival was significantly associated with N stage, adjuvant chemotherapy, and histological subtype. Overall survival was significantly associated with T and N stage, histology, and adjuvant chemotherapy. In addition, patients with tumors harboring BRCA1 promoter hypermethylation derived the most benefit from adjuvant chemotherapy. In conclusion, BRCA1 promoter hypermethylation is associated with TNBC sensitivity to adjuvant chemotherapy, basal-like features and PD-L1 expression. BRCA1 IHC expression is not a good surrogate marker for promoter hypermethylation and is not independently associated with prognosis. Association between promoter hypermethylation and sensitivity to Poly(ADP-ribose) polymerase PARP inhibitors needs to be evaluated in a specific series of patients.

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Section: Discussionmentioning

confidence: 94%

BRCA1 Promoter Hypermethylation is Associated with Good Prognosis and Chemosensitivity in Triple-Negative Breast Cancer

Jacot

Lopez-Crapez

Mollévi

et al. 2020

Cancers

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“…Details on data management and patient selection were described previously . Survival data, estrogen receptor (ER) status, progesterone receptor (PR) status are updated since the previous publication on TSR according to the last publication using the ONCOPOOL study …”

Section: Methodsmentioning

confidence: 99%

“…14,34 Survival data, estrogen receptor (ER) status, progesterone receptor (PR) status are updated since the previous publication on TSR according to the last publication using the ONCOPOOL study. 14,35 All patient data were used in an anonymized manner and data were handled according to national ethical guidelines ("Code for Proper Secondary Use of Human Tissue", Dutch Federation of Medical Scientific Societies"). No additional informed consent was required.…”

Section: Study Populationmentioning

confidence: 99%

The prognostic value of the tumor–stroma ratio is most discriminative in patients with grade III or triple‐negative breast cancer

Vangangelt

Green

Heemskerk

et al. 2020

Intl Journal of Cancer

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The tumor–stroma ratio (TSR) was evaluated as a promising parameter for breast cancer prognostication in clinically relevant subgroups of patients. The TSR was assessed on hematoxylin and eosin‐stained tissue slides of 1,794 breast cancer patients from the Nottingham City Hospital. An independent second cohort of 737 patients from the Netherlands Cancer Institute to Antoni van Leeuwenhoek was used for evaluation. In the Nottingham Breast Cancer series, the TSR was an independent prognostic parameter for recurrence‐free survival (RFS; HR 1.35, 95% CI 1.10–1.66, p = 0.004). The interaction term was statistically significant for grade and triple‐negative status. Multivariate Cox regression analysis showed a more pronounced effect of the TSR for RFS in grade III tumors (HR 1.89, 95% CI 1.43–2.51, p < 0.001) and triple‐negative tumors (HR 1.86, 95% CI 1.10–3.14, p = 0.020). Comparable hazard ratios and confidence intervals were observed for grade and triple‐negative status in the ONCOPOOL study. The prognostic value of TSR was not modified by age, tumor size, histology, estrogen receptor status, progesterone receptor status, human epidermal growth factor receptor 2 status or lymph node status. In conclusion, patients with a stroma‐high tumor had a worse prognosis compared to patients with a stroma‐low tumor. The prognostic value of the TSR is most discriminative in grade III tumors and triple‐negative tumors. The TSR was not modified by other clinically relevant parameters making it a potential factor to be included for improved risk stratification.

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“…First, PD‐L1 IHC expression was evaluated in TMAs (with duplicate cores from each tumor) rather than in whole‐tissue sections. Previous studies in BC showed that TMA protein assessment underestimated PD‐L1 expression due to its spatial heterogeneity as compared to whole‐tissue sections (Sobral‐Leite et al , 2018). Moreover, SP263 clone was used for PD‐L1 IHC, which should be put into the context of low reported analytical concordance among different antibodies in BC (Rugo et al , 2019).…”

Section: Discussionmentioning

confidence: 99%

Programmed death‐ligand 1 gene expression is a prognostic marker in early breast cancer and provides additional prognostic value to 21‐gene and 70‐gene signatures in estrogen receptor‐positive disease

et al. 2020

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Gene and protein expression of programmed death‐ligand 1 (PD‐L1) are prognostic in early breast cancer (BC), but their prognostic information is inconsistent at least in some biological subgroups. The validated prognostic gene signatures (GS) in BC are mainly based on proliferation and estrogen receptor (ER)‐related genes. Here, we aimed to explore the prognostic capacity of PD‐L1 expression at the protein vs mRNA levels and to investigate the prognostic information that PD‐L1 can potentially add to routinely used GS. Gene expression data were derived from two early BC cohorts (cohort 1: 562 patients; cohort 2: 1081 patients). Tissue microarrays from cohort 1 were immunohistochemically (IHC) stained for PD‐L1 using the SP263 clone. GS scores (21‐gene, 70‐gene) were calculated, and likelihood‐ratio (LR) tests and concordance indices were used to evaluate the additional prognostic information for each signature. The immune cell composition was also evaluated using the CIBERSORT in silico tool. PD‐L1 gene and protein expressions were independently associated with better prognosis. In ER+/HER2− patients, PD‐L1 gene expression provided significant additional prognostic information beyond that of both 21‐GS [LR‐Δχ2 = 15.289 and LR‐Δχ2 = 8.812, P < 0.01 for distant metastasis‐free interval (DMFI) in cohorts 1 and 2, respectively] and 70‐GS score alone (LR‐Δχ2 = 18.198 and LR‐Δχ2 = 8.467, P < 0.01 for DMFI in cohorts 1 and 2, respectively). PD‐L1 expression was correlated with IHC‐determined CD3+ cells (r = 0.41, P < 0.001) and with CD8+ (r = 0.62, P < 0.001) and CD4+ memory activated (r = 0.66, P < 0.001) but not with memory resting (r = −0.063, P = 0.14) or regulatory (r = −0.12, P < 0.01) T cells in silico. PD‐L1 gene expression represents a promising favorable prognostic marker and can provide additional prognostic value to 21‐ and 70‐gene scores in ER+/HER2− BC.

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Assessment of PD-L1 expression across breast cancer molecular subtypes, in relation to mutation rate, BRCA1-like status, tumor-infiltrating immune cells and survival

Cited by 95 publications

References 58 publications

BRCA1 Promoter Hypermethylation is Associated with Good Prognosis and Chemosensitivity in Triple-Negative Breast Cancer

BRCA1 Promoter Hypermethylation is Associated with Good Prognosis and Chemosensitivity in Triple-Negative Breast Cancer

The prognostic value of the tumor–stroma ratio is most discriminative in patients with grade III or triple‐negative breast cancer

Programmed death‐ligand 1 gene expression is a prognostic marker in early breast cancer and provides additional prognostic value to 21‐gene and 70‐gene signatures in estrogen receptor‐positive disease

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