Prognostic and predictive value of PDL1 expression in breast cancer

Abstract

Expression of programmed cell death receptor ligand 1 (PDL1) has been scarcely studied in breast cancer. Recently PD1/PDL1-inhibitors have shown promising results in different carcinomas with correlation between PDL1 tumor expression and responses. We retrospectively analyzed PDL1 mRNA expression in 45 breast cancer cell lines and 5,454 breast cancers profiled using DNA microarrays. Compared to normal breast samples, PDL1 expression was upregulated in 20% of clinical samples and 38% of basal tumors. High expression was associated with poor-prognosis features (large tumor size, high grade, ER-negative, PR-negative, ERBB2-positive status, high proliferation, basal and ERBB2-enriched subtypes). PDL1 upregulation was associated with biological signs of strong cytotoxic local immune response. PDL1 upregulation was not associated with survival in the whole population, but was associated with better metastasis-free and overall specific survivals in basal tumors, independently of clinicopathological features. Pathological complete response after neoadjuvant chemotherapy was higher in case of PDL1 upregulation (50% versus 21%). In conclusion, PDL1 upregulation, more frequent in basal breast cancers, was associated with increased T-cell cytotoxic immune response. In this aggressive subtype, upregulation was associated with better survival and response to chemotherapy. Reactivation of dormant tumor-infiltrating lymphocytes by PDL1-inhibitors could represent promising strategy in PDL1-upregulated basal breast cancer.

PDL1 expression is a poor-prognosis factor in soft-tissue sarcomas

“…In breast cancer and in GISTs, we had previously shown a favorable prognostic value of PDL1 expression, 59,68 also associated with a sustained activation of antitumor T-cells, with few transcriptional stigmata of T-cell exhaustion. In these cases, PDL1 was upregulated likely because of a negative feedback loop that follows cytotoxic cells activation, notably through the production of IFNg, a known regulator of PDL1 expression.…”

“…Here, we defined a cut-off optimized for separating two patients' classes with different MFS in learning set, and importantly, validated its robustness in a completely independent large validation set. We did not use normal samples, as we did in our breast cancer study, 59 because defining the "optimal" normal tissue for STS is more complicated. However, the same cut-off (upregulation defined by Tumor/Normal ratio 2 by using the expression of 28 normal connective tissues) identified two STS patients' classes with 93% concordance with our present classification and correlation with MFS (p D 0.05, log-rank test, data not shown).…”

“…This has already been reported in several cancers, 15,58,[62][63][64][65][66] although a favorable prognostic value has been reported in other cancers. 50,55,59,[67][68][69] For comparison and to our knowledge, only four studies-three publications 8,15,42 and one meeting presentation 70 -have described PDL1 expression and clinicopathological correlations in STS. All were based on IHC on standard slides or tissue microarrays.…”

Biological network-driven gene selection identifies a stromal immune module as a key determinant of triple-negative breast carcinoma prognosis

“…The PD1 and CTLA-4 metagenes were constructed from the genes most strongly correlated with the PD1 and CTLA-4 genes, respectively (Pearson correlation score >0.8). The PDL1 metagene was defined by Sabatier et al 30 The Immunity2 metagene was highly correlated with the PD1, PDL1 and CTLA-4 metagenes (Pearson correlation: 0.90, 0.96, 0.91, respectively). The coefficient of correlation between the Immunity2 metagene and the TILs signature was up to 0.90 (Fig.…”

Strategies to modulate the immune system in breast cancer: checkpoint inhibitors and beyond

“…TNBC has a greater expression of the PD-L1 gene compared with the non-TNBC subtype (expressed in 20% of TNBC) [Mittendorf et al 2014b]. In basal-like tumor, PD-L1 was also associated with survival, better response to chemotherapy and increased immune-response [Sabatier et al 2015]. Available data in immune checkpoint show responses among PD-1/PD-L1-negative tumors too and the real prognostic and predictive significance of these markers is still a matter of debate.…”