Abstract
Breast cancer is projected to be the most common cancer in women in 2020 in the USA. Despite high remission rates treatment side effects remain an issue, hence the interest in novel approaches such as immunotherapies which aim to utilize patients’ immune systems to target cancer cells. This review summarizes the basics of breast cancer including staging and treatment options, followed by a discussion on immunotherapy, including immune checkpoint blockade. After this, examples of the role of omics-type data and computational biology/bioinformatics in breast cancer are explored. Ultimately, there are several promising areas to investigate such as the prediction of neoantigens and the use of multi-omics data to direct research, with noted appropriate in clinical trial design in terms of end points.
Papers of special note have been highlighted as: • of interest; •• of considerable interest
References
- 1. . Cancer statistics, 2020. CA Cancer J. Clin. 70(1), 7–30 (2020).
- 2. . Antitumor effects of a recombinant baculovirus displaying anti-HER2 scFv expressing Apoptin in HER2 positive SK-BR-3 breast cancer cells. Future Virol. 14(3), 139–152 (2019).
- 3. Selective replication of miR-145-regulated oncolytic adenovirus in MCF-7 breast cancer cells. Future Virol. 11(10), 671–680 (2016).
- 4. The 2019 WHO classification of tumours of the breast. Histopathology
doi:10.1111/his.14091 (2020) (Epub ahead of print). - 5. . Biological subtypes of breast cancer: prognostic and therapeutic implications. World J. Clin. Oncol. 5(3), 412–424 (2014).
- 6. . Various types and management of breast cancer: an overview. J. Adv. Pharm. Technol. Res. 1(2), 109–126 (2010).
- 7. . Cancer, breast. www.ncbi.nlm.nih.gov/books/NBK482286/
- 8. . Breast cancer treatment: a review. JAMA 321(3), 288–300 (2019).
- 9. . Comparisons of p53, KI67 and BRCA1 expressions in patients with different molecular subtypes of breast cancer and their relationships with pathology and prognosis. J. BUON 24(6), 2361–2368 (2019).
- 10. The National Institute for Health and Care Excellence (NICE). Diagnostics assessment programme tumour profiling tests to guide adjuvant chemotherapy decisions in people with breast cancer (update of DG10) Final scope. www.nice.org.uk/guidance/dg34/documents/final-scope
- 11. The prognostic and predictive potential of Ki-67 in triple-negative breast cancer. Sci. Rep. 10(1), 225–225 (2020).
- 12. . Subgrouping breast cancer patients based on immune evasion mechanisms unravels a high involvement of transforming growth factor-beta and decoy receptor 3. PLoS ONE 13(12), e0207799 (2018).
- 13. . TNM Classification of Malignant Tumours. (8th Edition). John Wiley & Sons, Sussex, United Kingdom (2016).
- 14. . Eighth edition of the AJCC cancer staging manual: breast cancer. Ann. Surg. Oncol. 25(7), 1783–1785 (2018).
- 15. . The Pierre Denoix Memorial Lecture: nature and nurture in the control of cancer. Eur. J. Cancer 35(1), 16–23 (1999).
- 16. . A worldwide approach to the TNM staging system: collaborative efforts of the AJCC and UICC. J. Surg. Oncol. 99(5), 269–272 (2009).
- 17. . The new TNM-based staging of breast cancer. Virchows Arch. 472(5), 697–703 (2018).
- 18. The National Institute for Health and Care Excellence (NICE). Early and locally advanced breast cancer: diagnosis and management. www.nice.org.uk/guidance/ng101
- 19. . Impact of biomarkers and genetic profiling on breast cancer prognostication: a comparative analysis of the 8th edition of breast cancer staging system. Breast J. 25(5), 829–837 (2019).
- 20. The NeST (neoadjuvant systemic therapy in breast cancer) study – protocol for a prospective multi-centre cohort study to assess the current utilization and short-term outcomes of neoadjuvant systemic therapies in breast cancer. Int. J. Surg. Protoc. 18, 5–11 (2019).
- 21. Efficacy of neoadjuvant endocrine therapy versus neoadjuvant chemotherapy in ER-positive breast cancer: results from a prospective institutional database. Clin.Breast Cancer 19(6), e683–e689 (2019).
- 22. Long-term outcomes for neoadjuvant versus adjuvant chemotherapy in early breast cancer: meta-analysis of individual patient data from ten randomised trials. Lancet Oncol. 19(1), 27–39 (2018).
- 23. Locoregional recurrence risk after neoadjuvant chemotherapy: a pooled analysis of nine prospective neoadjuvant breast cancer trials. Eur. J. Cancer (Oxford, England: 1990) 130, 92–101 (2020).
- 24. Lack of standardization in the processing and reporting of post-neoadjuvant breast cancer specimens: a survey of Canadian pathologists and pathology assistants. Arch.Pathol. Lab.Med.
doi:10.5858/arpa.2019-0539-OA (.2020) (Epub ahead of print). - 25. . Survival after lumpectomy and mastectomy for early stage invasive breast cancer: the effect of age and hormone receptor status. Cancer 119(7), 1402–1411 (2013).
- 26. The National Institute for Health and Care Excellence (NICE). Advanced breast cancer: diagnosis and treatment. www.nice.org.uk/guidance/cg81
- 27. Single NIR laser-activated multifunctional nanoparticles for cascaded photothermal and oxygen-independent photodynamic therapy. Nano-Micro Lett. 11(1), 68 (2019).
- 28. Recent advances in nanoparticle carriers for photodynamic therapy. Quant. Imaging Med. Surg. 8(4), 433–443 (2018).
- 29. . Photothermal therapy and photoacoustic imaging via nanotheranostics in fighting cancer. Chem. Soc. Rev. 48(7), 2053–2108 (2019).
- 30. Photothermal cancer immunotherapy by erythrocyte membrane-coated black phosphorus formulation. J. Control. Release 296, 150–161 (2019).
- 31. . Reinvigorating exhausted T cells by blockade of the PD-1 pathway. For. immunopathol. Dis. Therap. 6(1–2), 7–17 (2015).
- 32. . Current approaches in development of immunotherapeutic vaccines for breast cancer. J. Breast Cancer 21(4), 343–353 (2018).
- 33. . Cancer immunotherapy comes of age. Nature 480(7378), 480–489 (2011).
- 34. . What's the place of immunotherapy in malignant mesothelioma treatments? Cell Adh. Migr. 4(1), 153–161 (2010).
- 35. . Cancer and the immune system: the history and background of immunotherapy. Semin. Oncol. Nurs. 35(5), 150923–150923 (2019).
- 36. . Primary, adaptive, and acquired resistance to cancer immunotherapy. Cell 168(4), 707–723 (2017).
- 37. New immunotherapy strategies in breast cancer. Int. J. Environ. Res. Public Health 14(1), 68 (2017).
- 38. Strategies to modulate the immune system in breast cancer: checkpoint inhibitors and beyond. Ther. Adv. Med. Oncol. 8(5), 360–374 (2016).
- 39. . Therapeutic cancer vaccines: past, present, and future. Adv. Cancer Res. 119, 421–475 (2013).
- 40. Expression of mucins (MUC1, MUC2, MUC3, MUC4, MUC5AC and MUC6) and their prognostic significance in human breast cancer. Mod. Pathol. 18(10), 1295–1304 (2005).
- 41. . Anti-HER2 vaccines: new prospects for breast cancer therapy. Cancer Immunol. Immunother. 59(9), 1295–1312 (2010).
- 42. . Targeted therapy for HER2 positive breast cancer. J. Hematol. Oncol. 6(1), 38 (2013).
- 43. . Developing anti-HER2 vaccines: breast cancer experience. Int. J. Cancer 143(9), 2126–2132 (2018).
- 44. Concurrent trastuzumab and HER2/neu-specific vaccination in patients with metastatic breast cancer. J. Clin. Oncol. 27(28), 4685–4692 (2009).
- 45. Toxicity, immunogenicity, and induction of E75-specific tumor-lytic CTLs by HER-2 peptide E75 (369–377) combined with granulocyte macrophage colony-stimulating factor in HLA-A2+ patients with metastatic breast and ovarian cancer. Clin. Cancer Res. 8(11), 3407–3418 (2002).
- 46. Final report of the phase I/II clinical trial of the E75 (nelipepimut-S) vaccine with booster inoculations to prevent disease recurrence in high-risk breast cancer patients. Ann. Oncol. 25(9), 1735–1742 (2014).
- 47. Primary analysis of a prospective, randomized, single-blinded phase II trial evaluating the HER2 peptide GP2 vaccine in breast cancer patients to prevent recurrence. Oncotarget 7(40), 66192–66201 (2016).
- 48. Primary analysis of a prospective, randomized, single-blinded phase II trial evaluating the HER2 peptide AE37 vaccine in breast cancer patients to prevent recurrence. Ann. Oncol. 27(7), 1241–1248 (2016).
- 49. . Rationale for the clinical development of STn-KLH (Theratope) and anti-MUC-1 vaccines in breast cancer. Clin. Breast Cancer 3(Suppl. 4), S134–S138 (2003).
- 50. Survival advantage in patients with metastatic breast cancer receiving endocrine therapy plus Sialyl Tn-KLH vaccine: post hoc analysis of a large randomized trial. J. Cancer 4(7), 577–584 (2013).
- 51. A pilot study of MUC-1/CEA/TRICOM poxviral-based vaccine in patients with metastatic breast and ovarian cancer. Clin. Cancer Res. 17(22), 7164–7173 (2011).
- 52. . Treatment with autologous antigen-presenting cells activated with the HER-2 based antigen Lapuleucel-T: results of a phase I study in immunologic and clinical activity in HER-2 overexpressing breast cancer. J. Clin. Oncol. 25(24), 3680–3687 (2007).
- 53. . Induction of cytotoxic T-lymphocyte responses in vivo after vaccinations with peptide-pulsed dendritic cells. Blood 96(9), 3102–3108 (2000).
- 54. Targeting HER-2/neu in early breast cancer development using dendritic cells with staged interleukin-12 burst secretion. Cancer Res. 67(4), 1842–1852 (2007).
- 55. . Breast cancer vaccines: heeding the lessons of the past to guide a path forward. Cancer Treat. Rev. 84, 101947–101947 (2019).
- 56. . Colorectal cancer vaccines: tumor-associated antigens vs neoantigens. World J. Gastroenterol. 24(48), 5418–5432 (2018).
- 57. Tremelimumab in combination with exemestane in patients with advanced breast cancer and treatment-associated modulation of inducible costimulator expression on patient T cells. Clin. Cancer Res. 16(13), 3485–3494 (2010).
- 58. A pilot study of preoperative (Pre-op), single-dose ipilimumab (Ipi) and/or cryoablation (Cryo) in women (pts) with early-stage/resectable breast cancer (ESBC). J. Clin. Oncol. 32(Suppl. 15), 1098–1098 (2014).
- 59. First-line chemoimmunotherapy in metastatic breast carcinoma: combination of paclitaxel and IMP321 (LAG-3Ig) enhances immune responses and antitumor activity. J. Transl. Med. 8, 71–71 (2010).
- 60. Pembrolizumab in patients with advanced triple-negative breast cancer: Phase Ib KEYNOTE-012 study. J. Clin. Oncol. 34(21), 2460–2467 (2016).
- 61. Abstract P2-11-06: safety and clinical activity of atezolizumab (anti-PDL1) in combination with nab-paclitaxel in patients with metastatic triple-negative breast cancer. Cancer Res. 76(Suppl. 4), P2-11-06 (2016).
- 62. . Differences in treatment effect size between overall survival and progression-free survival in immunotherapy trials: a meta-epidemiologic study of trials with results posted at ClinicalTrials.gov. J. Clin. Oncol. 35(15), 1686–1694 (2017). •• Highlights the importance of robust clinical trial end points, particularly as it applies to immunotherapy.
- 63. Evaluation of tumor response, disease control, progression-free survival, and time to progression as potential surrogate end points in metastatic breast cancer. J. Clin. Oncol. 26(12), 1987–1992 (2008).
- 64. Progression-free survival as surrogate end point for overall survival in clinical trials of HER2-targeted agents in HER2-positive metastatic breast cancer. Ann. Oncol. 27(6), 1029–1034 (2016).
- 65. Immune microenvironment in mesothelioma: Looking beyond PD-L1. J. Clin. Oncol. 35(Suppl. 15), 8515–8515 (2017).
- 66. . Dynamics of DNA damage induced pathways to cancer. PLoS ONE 8(9), e72303–e72303 (2013).
- 67. . Insight into glucocorticoid receptor signalling through interactome model analysis. PLOS Comput. Biol. 13(11), e1005825 (2017).
- 68. p53 modeling as a route to mesothelioma patients stratification and novel therapeutic identification. J. Transl. Med. 16(1), 282 (2018).
- 69. Comprehensive genomic analysis of malignant pleural mesothelioma identifies recurrent mutations, gene fusions and splicing alterations. Nat. Genet. 48(4), 407–416 (2016).
- 70. . Onco-multi-OMICS approach: a new frontier in cancer research. Biomed. Res. Int. 2018, 9836256–9836256 (2018).
- 71. . Proteomic maps of breast cancer subtypes. Nat. Commun. 7, 10259–10259 (2016).
- 72. Proteogenomics connects somatic mutations to signalling in breast cancer. Nature 534(7605), 55–62 (2016).
- 73. MYC-driven accumulation of 2-hydroxyglutarate is associated with breast cancer prognosis. J. Clin. Invest. 124(1), 398–412 (2014).
- 74. A joint analysis of transcriptomic and metabolomic data uncovers enhanced enzyme-metabolite coupling in breast cancer. Sci. Rep. 6, 29662–29662 (2016).
- 75. . Multiple omics analysis of the protective effects of SFN on estrogen-dependent breast cancer cells. Mol. Biol. Rep. 47(5), 3331–3346 (2020).
- 76. B-cell lymphoma 2 family genes show a molecular pattern of spatiotemporal heterogeneity in gynaecologic and breast cancer. Cell Prolif. 53(6), e12826 (.2020).
- 77. A multi-omics analysis of bone morphogenetic protein 5 (BMP5) mRNA expression and clinical prognostic outcomes in different cancers using bioinformatics approaches. Biomedicines 8(2), 19 (2020).
- 78. ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia 6(1), 1–6 (2004).
- 79. . GENT: gene expression database of normal and tumor tissues. Cancer Inform. 10, 149–157 (2011).
- 80. UALCAN: a portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia 19(8), 649–658 (2017).
- 81. . PrognoScan: a new database for meta-analysis of the prognostic value of genes. BMC Med. Genomics 2, 18–18 (2009).
- 82. The cBio cancer genomics portal: an open platform for exploring multidimensional cancer genomics data. Cancer Discov. 2(5), 401–404 (2012).
- 83. Integrative analysis of complex cancer genomics and clinical profiles using the cBioPortal. Sci. Signal. 6(269), pl1 (2013).
- 84. Inferences of individual drug response-related long non-coding RNAs based on integrating multi-omics data in breast cancer. Mol. Ther. Nucleic Acids 20, 128–139 (2020).
- 85. . Multi-omics profiling of the tumor microenvironment: paving the way to precision immuno-oncology. 8(430), (2018).
- 86. . Role of the tumor microenvironment in breast cancer. Pathobiology 82(3–4), 142–152 (2015).
- 87. Multi-omics profiling reveals distinct microenvironment characterization and suggests immune escape mechanisms of triple-negative breast cancer. Clin. Cancer Res. 25(16), 5002 (2019). • Highly relevant paper covering the tumor microenvironment and multi-omics data.
- 88. Multi-omics analysis reveals neoantigen-independent immune cell infiltration in copy-number driven cancers. Nat. Commun. 9(1), 1317–1317 (2018).
- 89. Multi-omics profiling of younger Asian breast cancers reveals distinctive molecular signatures. Nat. Commun. 9(1), 1725–1725 (2018).
- 90. Tumor-infiltrating lymphocyte composition, organization and PD-1/PD-L1 expression are linked in breast cancer. Oncoimmunology 6(1), e1257452 (2017).
- 91. Prevalence and mutational determinants of high tumor mutation burden in breast cancer. Ann. Oncol. 31(3), 387–394 (2020). •• A very recent original research article on nearly 4000 breast cancer patients covering tumor mutational burden.
- 92. Integrative genomic analyses of APOBEC-mutational signature, expression and germline deletion of APOBEC3 genes, and immunogenicity in multiple cancer types. BMC Med. Genomics 12(1), 131 (2019).
- 93. APOBEC3B is an enzymatic source of mutation in breast cancer. Nature 494(7437), 366–370 (2013).
- 94. . Best practices for bioinformatic characterization of neoantigens for clinical utility. Genome Med. 11(1), 56 (2019). • A key paper detailing neoantigen prediction and characterization from bioinformatics to the clinic.
- 95. Cancer immunology. Mutational landscape determines sensitivity to PD-1 blockade in non-small cell lung cancer. Science 348(6230), 124–128 (2015).
- 96. Genomic correlates of response to CTLA-4 blockade in metastatic melanoma. Science 350(6257), 207–211 (2015).
- 97. Neoantigen vaccine: an emerging tumor immunotherapy. Mol. Cancer 18(1), 128 (2019).
- 98. DriverDBv3: a multi-omics database for cancer driver gene research. Nucleic Acids Res. 48(D1), D863–D870 (2019).
- 99. . MOBCdb: a comprehensive database integrating multi-omics data on breast cancer for precision medicine. Breast Cancer Res. Treat. 169(3), 625–632 (2018).
- 100. ClinOmicsTrailbc: a visual analytics tool for breast cancer treatment stratification. Bioinformatics 35(24), 5171–5181 (2019).
- 101. . Multi-omics Data Integration, Interpretation, and Its Application. Bioinform. Biol. Insights 14, 1177932219899051–1177932219899051 (2020). •• Comprehensive paper covering different ways to analyze multi-omics data.