Dataset Information

XIST and TSIX: Novel Cancer Immune Biomarkers in PD-L1-Overexpressing Breast Cancer Patients.

ABSTRACT: Escaping antitumor immunity is a hallmark in cancer progression. Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor responsible for the maintenance of immune tolerance; PD-1 ligand (PD-L1) is overexpressed in tumor cells, simplifying their escape from the immune system through T-cell function suppression. Notwithstanding that cancer antigen (CA)125, carcinoembryonic antigen (CEA), CA15-3, and alpha-fetoprotein (AFP) are among conventional breast cancer diagnostic biomarkers, their lack of sensitivity and specificity resides among their major limitations. Furthermore, human epidermal growth factor receptor (HER)2 and interleukin (IL)-6-demonstrated as breast cancer immune biomarkers-still possess limitations, for instance, technical detection problems and stability problems, which necessitate the discovery of novel, stable non-invasive cancer immune biomarkers. XIST and TSIX are two long non-coding (lnc)RNAs possessing a role in X chromosome inactivation (XCI) as well as in breast cancer (BC). In the present study, they were investigated as stable non-invasive breast cancer immune biomarkers. The study demonstrated that PD-L1 was overexpressed in the different molecular subtypes of breast cancer patients as well as in MDA-MB-231 cells. Furthermore, lncRNAs XIST and TSIX were markedly increased in the tissues, lymph nodes, and different body fluids of breast cancer patients compared to controls. In addition, XIST and TSIX were differentially expressed in subtypes of BC patients, and their levels were correlated to PD-L1 expression level. In conclusion, this correlative study has shed light on the role of both lncRNAs XIST and TSIX as potential non-invasive BC immune biomarkers reflecting the evaded immune system of the patient and overcoming the instability problem of common BC biomarkers.

SUBMITTER: Salama EA

PROVIDER: S-EPMC6966712 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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XIST and TSIX: Novel Cancer Immune Biomarkers in PD-L1-Overexpressing Breast Cancer Patients.

Salama Esraa A EA Adbeltawab Reda E RE El Tayebi Hend M HM

Frontiers in oncology 20200110

Escaping antitumor immunity is a hallmark in cancer progression. Programmed cell death protein 1 (PD-1) is an immune checkpoint receptor responsible for the maintenance of immune tolerance; PD-1 ligand (PD-L1) is overexpressed in tumor cells, simplifying their escape from the immune system through T-cell function suppression. Notwithstanding that cancer antigen (CA)125, carcinoembryonic antigen (CEA), CA15-3, and alpha-fetoprotein (AFP) are among conventional breast cancer diagnostic biomarkers, ...[more]

PMID: 31998636

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Project description:BackgroundThe activity of PD-1/PD-L1 inhibitors in the treatment of advanced bladder cancer (BC) is promising for many patients. However, a subset of patients do not benefit from treatment, thus leading to an effort to better identify predictive molecular biomarkers of response.ObjectiveTo conduct a systematic review of the literature on predictive molecular biomarkers associated with response to PD-1 and PD-L1 inhibitors in advanced bladder cancer, defined as locally-advanced, unresectable, or metastatic (mBC) disease.MethodsA search of the literature was performed using Embase (1947 - January 2019), Medline (1946 - January 2019), and EBM Reviews for Cochrane Central Register of Controlled Trials (as of December 2018). Studies examining the association of molecular biomarkers with clinical outcome in BC treated with PD-1 or PD-L1 monotherapy were included. Outcomes of interest were overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), duration of response, and objective response rate (ORR).ResultsUsing the study search criteria, 899 unique abstract citations were found, of which 834 did not meet the eligibility criteria. Full text of the remaining 65 citations were screened, and 50 studies excluded, including 18 review articles. Eight additional studies from the bibliography of the review papers were included, making a total of 23 studies. Five PD-1 / PD-L1 antibodies have been tested in BC immunohistochemistry (IHC). These studies used different expression scoring criteria and generally had poor ability to discriminate likelihood for response. Overall, the data suggests CD8+ T cell infiltration is necessary to mediate an antitumor immune response, but other immune cell populations, such as neutrophils may suppress T cell-mediated immunity and efficacy of PD-1/PD-L1 blockade. An IFNγ signature is a promising predictor, but there needs to be consensus on the optimal gene panel composition, and prospective validation. Tumor mutation burden (TMB) is a promising predictor in six studies reporting on 1200 patients, but there is not a consensus on the optimal definition of "high TMB". Detection of T cell receptor (TCR) clonal expansion has only been conducted in small studies and so its predictive value remains inconclusive. Epithelial-mesenchymal transformation (EMT) and transforming growth factor β (TGFβ) are associated with poor prognosis and possibly intrinsic resistance to PD-1/PD-L1 checkpoint blockade, but more work needs to be done to build upon and confirm the initial findings.ConclusionsCurrently no molecular biomarker is sufficiently mature for routine clinical use, while some candidates, or a combination show great promise and need further study.

Project description:BackgroundWe examined the current biomarker landscape in breast cancer when programmed death-ligand 1 (PD-L1) testing is integrated with comprehensive genomic profiling (CGP).Material and methodsWe analyzed data from samples of 312 consecutive patients with breast carcinoma tested with both CGP and PD-L1 (SP142) immunohistochemistry (IHC) during routine clinical care. These samples were stratified into hormone receptor positive (HR+)/human epidermal growth factor receptor negative (HER2-; n = 159), HER2-positive (n = 32), and triple-negative breast cancer (TNBC) cohorts (n = 121).ResultsWe found that in the TNBC cohort, 43% (52/121) were immunocyte PD-L1-positive, and in the HR+/HER2- cohort, 30% (48/159) had PIK3CA companion diagnostics mutations, and hence were potentially eligible for atezolizumab plus nab-paclitaxel or alpelisib plus fulvestrant, respectively. Of the remaining 212 patients, 10.4% (22/212) had a BRCA1/2 mutation, which, if confirmed by germline testing, would allow olaparib plus talazoparib therapy. Of the remaining 190 patients, 169 (88.9%) were positive for another therapy-associated marker or a marker that would potentially qualify the patient for a clinical trial. In addition, we examined the relationship between immunocyte PD-L1 positivity and different tumor mutation burden (TMB) cutoffs and found that when a TMB cutoff of ≥9 mutations per Mb was applied (cutoff determined based on prior publication), 11.6% (14/121) patients were TMB ≥9 mutations/Mb and of these, TMB ≥9 mutations per Mb, 71.4% (10/14) were also positive for PD-L1 IHC.ConclusionOur integrated PD-L1 and CGP methodology identified 32% of the tested patients as potentially eligible for at least one of the two new Food and Drug Administration approved therapies, atezolizumab or alpelisib, and an additional 61.2% (191/312) had other biomarker-guided potential therapeutic options.Implications for practiceThis integrated programmed death-ligand 1 immunohistochemistry and comprehensive genomic profiling methodology identified 32% of the tested patients as eligible for at least one of the two new Food and Drug Administration-approved therapies, atezolizumab or alpelisib, and an additional 61.2% (191/312) had other biomarker-guided potential therapeutic options. These findings suggest new research opportunities to evaluate the predictive utility of other commonly seen PIK3CA mutations in hormone receptor-positive breast cancers and to standardize tumor mutation burden cutoffs to evaluate its potentially predictive role in triple-negative breast cancer.

Dataset Information

XIST and TSIX: Novel Cancer Immune Biomarkers in PD-L1-Overexpressing Breast Cancer Patients.

Publications

XIST and TSIX: Novel Cancer Immune Biomarkers in PD-L1-Overexpressing Breast Cancer Patients.

Similar Datasets

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