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Published online: 2022-10-10
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Tumor-infiltrating lymphocytes and levels of PD-L1 and BRCA protein expression may identify patients with breast cancer with a higher rate of BRCA1 mutations

Polina Dimitrova1, Savelina Popovska1, Angel Danchev Yordanov2
DOI: 10.5603/NJO.a2022.0049
Affiliations
  1. Department of Pathology, Medical University – Pleven, Pleven, Bulgaria
  2. Department of Gynaecologic Oncology, Medical University Pleven, Bulgaria

open access

Ahead of print
Original article
Published online: 2022-10-10

Abstract

Background & objectives Breast cancer (BC) is a heterogeneous disease, treated as per the predictive role of immunohistochemistry (IHC) identifiers as estrogen / progesterone and HER2 receptor proteins. Deeper molecular classification (MC) identifies molecular subtypes according to the gene-expression profiles with different molecular genetic alterations and biological features, present in the different subtype. Overlap between IHC and MC exists, though incomplete. We aimed to identify overlap between IHC and MC and identify patients with basal-like subtype of BC. We hypothesized that the rates of the tumor expression of breast cancer 1 (BRCA1) protein, the type of tumor-infiltrating lymphocytes and the expression of programmed death ligand 1 (PD-L1) by immune cells may be incorporated in a prognostic algorithm to predict morphological screening, identifying patients with potentially altered BRCA1 gene activity. Methods Parafin-embedded samples from 100 patients with primary invasive BC were analyzed and expression levels estrogen and progesterone receptors, HER2 status and Ki-67 were assessed via IHC, defining four groups - Luminal A-like, Luminal B-like, HER2 positive non-luminal and triple negative (TN). The primary endpoint of our study was to identify via IHC with CK 5/6 and 17 basal-like subtype of BC amongst others and to describe specific clinicopathological features together with protein expression of BRCA1 and PD-L1 and tumor-infiltrating lymphocytes, using CD20, CD3, CD4, CD8 and FoxP3. Results Basal-like BC were predominantly characterized as triple negative by IHC (p < 0.05) and were more frequently seen among special BC ductal subtypes as compared to no special type (NST) with (p=0.036). Their immune response was represented mostly by high concentration of intratumoral cytotoxic CD8+ T-lymphocytes (p < 0.05) and stromal PD-L1 positive immune cells (p=0.008). In these tumors, absence of expression of BRCA1 protein was more frequent (p < 0.001). Basal-like subtype of BC with absent expression of BRCA1 is associated with worse < 5-year survival (p=0.001 and p=0.017, respectively). Conclusion The established dependencies can be, allowing better selection of patients with BC for subsequent genetic analysis of BRCA1 gene and for application of appropriate therapy.

Abstract

Background & objectives Breast cancer (BC) is a heterogeneous disease, treated as per the predictive role of immunohistochemistry (IHC) identifiers as estrogen / progesterone and HER2 receptor proteins. Deeper molecular classification (MC) identifies molecular subtypes according to the gene-expression profiles with different molecular genetic alterations and biological features, present in the different subtype. Overlap between IHC and MC exists, though incomplete. We aimed to identify overlap between IHC and MC and identify patients with basal-like subtype of BC. We hypothesized that the rates of the tumor expression of breast cancer 1 (BRCA1) protein, the type of tumor-infiltrating lymphocytes and the expression of programmed death ligand 1 (PD-L1) by immune cells may be incorporated in a prognostic algorithm to predict morphological screening, identifying patients with potentially altered BRCA1 gene activity. Methods Parafin-embedded samples from 100 patients with primary invasive BC were analyzed and expression levels estrogen and progesterone receptors, HER2 status and Ki-67 were assessed via IHC, defining four groups - Luminal A-like, Luminal B-like, HER2 positive non-luminal and triple negative (TN). The primary endpoint of our study was to identify via IHC with CK 5/6 and 17 basal-like subtype of BC amongst others and to describe specific clinicopathological features together with protein expression of BRCA1 and PD-L1 and tumor-infiltrating lymphocytes, using CD20, CD3, CD4, CD8 and FoxP3. Results Basal-like BC were predominantly characterized as triple negative by IHC (p < 0.05) and were more frequently seen among special BC ductal subtypes as compared to no special type (NST) with (p=0.036). Their immune response was represented mostly by high concentration of intratumoral cytotoxic CD8+ T-lymphocytes (p < 0.05) and stromal PD-L1 positive immune cells (p=0.008). In these tumors, absence of expression of BRCA1 protein was more frequent (p < 0.001). Basal-like subtype of BC with absent expression of BRCA1 is associated with worse < 5-year survival (p=0.001 and p=0.017, respectively). Conclusion The established dependencies can be, allowing better selection of patients with BC for subsequent genetic analysis of BRCA1 gene and for application of appropriate therapy.

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Keywords

Breast cancer; PD-L1; BRCA1; tumor-infiltrating lymphocytes

About this article
Title

Tumor-infiltrating lymphocytes and levels of PD-L1 and BRCA protein expression may identify patients with breast cancer with a higher rate of BRCA1 mutations

Journal

Nowotwory. Journal of Oncology

Issue

Ahead of print

Article type

Research paper (original)

Published online

2022-10-10

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56

Article views/downloads

41

DOI

10.5603/NJO.a2022.0049

Keywords

Breast cancer
PD-L1
BRCA1
tumor-infiltrating lymphocytes

Authors

Polina Dimitrova
Savelina Popovska
Angel Danchev Yordanov

References (36)
  1. Xie Y, Gou Q, Wang Q, et al. The role of BRCA status on prognosis in patients with triple-negative breast cancer. Oncotarget. 2017; 8(50): 87151–87162.
  2. Konsoulova A. Principles of Cancer Immunobiology and Immunotherapy of Solid Tumors. Immunopathology and Immunomodulation. 2015.
  3. Godoy-Ortiz A, Sanchez-Muñoz A, Chica Parrado MR, et al. Deciphering HER2 Breast Cancer Disease: Biological and Clinical Implications. Front Oncol. 2019; 9: 1124.
  4. Kim H, Park K, Kim Y, et al. Discordance of the PAM50 Intrinsic Subtypes Compared with Immunohistochemistry-Based Surrogate in Breast Cancer Patients: Potential Implication of Genomic Alterations of Discordance. Cancer Research and Treatment. 2019; 51(2): 737–747.
  5. Russnes HG, Navin N, Hicks J, et al. Insight into the heterogeneity of breast cancer through next-generation sequencing. J Clin Invest. 2011; 121(10): 3810–3818.
  6. Volovat SR, Volovat C, Hordila I, et al. MiRNA and LncRNA as Potential Biomarkers in Triple-Negative Breast Cancer: A Review. Front Oncol. 2020; 10: 526850.
  7. Sønderstrup IMH, Jensen MB, Ejlertsen B, et al. Evaluation of tumor-infiltrating lymphocytes and association with prognosis in BRCA-mutated breast cancer. Acta Oncol. 2019; 58(3): 363–370.
  8. Honrado E, Benítez J, Palacios J. The molecular pathology of hereditary breast cancer: genetic testing and therapeutic implications. Mod Pathol. 2005; 18(10): 1305–1320.
  9. Tapia T, Smalley SV, Kohen P, et al. Promoter hypermethylation of BRCA1 correlates with absence of expression in hereditary breast cancer tumors. Epigenetics. 2008; 3(3): 157–163.
  10. Lakhani SR, Ellis IO, Schnitt SJ, et al. WHO Classification of Tumours of the Breast, 4th ed. IARC Press, Lyon 2012.
  11. Elston CW, Ellis IO, Elston CW, et al. Pathological prognostic factors in breast cancer. I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology. 1991; 19(5): 403–410.
  12. Edge SB, Byrd DR, Compton CC, et al. AJCC Cancer Staging Manual. 7th ed. Springer, New York 2010.
  13. Goldhirsch A, Winer EP, Coates AS, et al. Panel members. Personalizing the treatment of women with early breast cancer: highlights of the St Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2013. Ann Oncol. 2013; 24(9): 2206–2223.
  14. Hammond MEH, Hayes DF, Dowsett M, et al. American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations for Immunohistochemical Testing of Estrogen and Progesterone Receptors in Breast Cancer. J Clin Oncol. 2010; 28(16): 2784–2795.
  15. Wolff AC, Hammond MEH, Hicks DG, et al. Recommendations for Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer: American Society of Clinical Oncology/College of American Pathologists Clinical Practice Guideline Update. J Clin Oncol. 2013; 31(31): 3997–4013.
  16. Nielsen TO, Leung SCY, Rimm DL, et al. International Ki-67 in Breast Cancer Working Group. Assessment of Ki67 in breast cancer: recommendations from the International Ki67 in Breast Cancer working group. J Natl Cancer Inst. 2011; 103(22): 1656–1664.
  17. Garrido-Castro AC, Lin NU, Polyak K. Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment. Cancer Discov. 2019; 9(2): 176–198.
  18. Mylavarapu S, Das A, Roy M. Role of BRCA Mutations in the Modulation of Response to Platinum Therapy. Front Oncol. 2018; 8: 16.
  19. Mahmoud AM, Macias V, Al-Alem U, et al. BRCA1 protein expression and subcellular localization in primary breast cancer: Automated digital microscopy analysis of tissue microarrays. PLoS One. 2017; 12(9): e0184385.
  20. Hedau S, Batra M, Singh UR, et al. Expression of BRCA1 and BRCA2 proteins and their correlation with clinical staging in breast cancer. J Can Res Ther. 2015; 11(1): 158–163.
  21. Verma D, Agarwal K, Tudu SK. Expression of breast cancer type 1 and its relation with expression of estrogen receptors, progesterone receptors, and human epidermal growth factor receptor 2/neu in breast carcinoma on trucut biopsy specimens. Indian J Pathol Microbiol. 2018; 61(1): 31–38.
  22. Osman MA, Eltom FM, Abdallah ME, et al. The Role of HER2/Neu and BRCA1 Genes in the Diagnosis of Breast Cancer among Sudanese Women . Journal of Cancer Therapy. 2020; 11(8): 491–496.
  23. Jeibouei S, Akbari ME, Kalbasi A, et al. Personalized medicine in breast cancer: pharmacogenomics approaches. Pharmgenomics Pers Med. 2019; 12: 59–73.
  24. Ha SuM, Chae EY, Cha JH, et al. Association of BRCA Mutation Types, Imaging Features, and Pathologic Findings in Patients With Breast Cancer With BRCA1 and BRCA2 Mutations. AJR Am J Roentgenol. 2017; 209(4): 920–928.
  25. Comănescu M, Popescu CF. BRCA1 expression in invasive breast carcinomas and clinicopathological correlations. Rom J Morphol Embryol. 2009; 50(3): 419–424.
  26. Lee KL, Kuo YC, Ho YS, et al. Triple-Negative Breast Cancer: Current Understanding and Future Therapeutic Breakthrough Targeting Cancer Stemness. Cancers (Basel). 2019; 11(9).
  27. Ribeiro-Silva A, Garcia SB, Chahud F, et al. Prognostic impact of BRCA1 immunohistochemistry expression in sporadic breast carcinomas. J Bras Patol Med Lab. 2005; 41(3): 197–203.
  28. Yersal O, Barutca S. Biological subtypes of breast cancer: Prognostic and therapeutic implications. World J Clin Oncol. 2014; 5(3): 412–424.
  29. Lehmann BD, Jovanović B, Chen Xi, et al. Refinement of Triple-Negative Breast Cancer Molecular Subtypes: Implications for Neoadjuvant Chemotherapy Selection. PLoS One. 2016; 11(6): e0157368.
  30. Foulkes WD, Brunet JS, Stefansson IM, et al. The prognostic implication of the basal-like (cyclin E high/p27 low/p53+/glomeruloid-microvascular-proliferation+) phenotype of BRCA1-related breast cancer. Cancer Res. 2004; 64(3): 830–835.
  31. Sobral-Leite M, Van de Vijver K, Michaut M, et al. Assessment of PD-L1 expression across breast cancer molecular subtypes, in relation to mutation rate, -like status, tumor-infiltrating immune cells and survival. Oncoimmunology. 2018; 7(12): e1509820.
  32. Pujol P, Barberis M, Beer P, et al. Clinical practice guidelines for BRCA1 and BRCA2 genetic testing. Eur J Cancer. 2021; 146: 30–47.
  33. Daly MB, Pal T, Berry MP, et al. CGC, CGC, LCGC, CGC, CGC. Genetic/Familial High-Risk Assessment: Breast, Ovarian, and Pancreatic, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2021; 19(1): 77–102.
  34. Burstein HJ, Curigliano G, Thürlimann B, et al. Panelists of the St Gallen Consensus Conference. Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021. Ann Oncol. 2021; 32(10): 1216–1235.
  35. Russo A, Incorvaia L, Capoluongo E, et al. Italian Scientific Societies. Implementation of preventive and predictive BRCA testing in patients with breast, ovarian, pancreatic, and prostate cancer: a position paper of Italian Scientific Societies. ESMO Open. 2022; 7(3): 100459.
  36. Soenderstrup IMH, Laenkholm AV, Jensen MB, et al. Clinical and molecular characterization of BRCA-associated breast cancer: results from the DBCG. Acta Oncol. 2018; 57(1): 95–101.

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