Original articleThe genomic landscape of breast cancer and its interaction with host immunity
Introduction
Genomic instability provides the diversity required for dysregulation of essential cellular processes of proliferation, differentiation and death – these form the hallmarks of cancer [1]. Stepwise advances in sequencing technology have lead to a stepwise accumulation of genomic data. The Human Genome Project ambitiously sequenced the entire human genome. This was of unprecedented scale, took 13 years to complete [2], and has paved the way for subsequent successes. Next Generation Sequencing has lead to contrastingly rapid accumulation of genomic data in a short period of time. Thousands of primary breast cancers have now been sequenced, determining the landscape of somatic mutations in this cancer [3], [4], [5], [6]. Many recurrent cancer gene alterations have been identified, with no breast tumour 100% identical to another and most tumours containing multiple alterations. However detailed understanding of the biology and specific drivers is often lacking, underlying one of the major challenges for precision medicine.
Observations and associations of lymphocytic infiltrates in breast cancer, and success of immune checkpoint blockade in other tumour types, have provided renewed excitement in the role of immunosurveillance in the progression of cancers [7], [8]. Immune avoidance is recognised as a further hallmark of cancer [9]. As the burgeoning field of immunotherapeutics becomes increasingly relevant, important concepts regarding the interface between genomic alteration landscapes and host anti-tumour immunity are being explored. This review article aims to summarise the genomic and driver landscape of breast cancer, and explore its associations with host immunity.
Section snippets
The genomic landscape of primary breast cancer
Genomic instability leads to the accumulation of somatic alterations. Driver alterations provide a selective advantage, through gain-of-function in oncogenes, or loss-of-function in tumour suppressor genes. The remainder of somatic alterations provide no selective advantage and are termed passenger alterations. Studies suggest as few as three driver alterations are required for oncogenesis [10], [11].
Distinguishing true driver alterations from genomic data alone remains a major challenge, with
The immunogenicity of breast cancer
In a cancer cell-autonomous disease model, the accumulation of driver alterations confer a selective advantage toward increased replicative capacity and survival of a cancer clone [1]. Clonal hierarchy of tumours is evidence of these Darwininan principles. However, clonal selection is also vulnerable to host immunosurveillance whereby the host immune system recognises malignant cells and attempts to eliminate them. This sculpts the genomic and clonal structure of a malignant population of cells
The genomic determinants of immunogenicity
To mount effective anti-tumour responses, host immunosurveillance must recognise tumour-specific epitopes, defining a tumour's antigenicity [50]. Mutant cancer peptides arise as end products of the expression of somatic cancer mutations, and are termed neoantigens [51], [52]. These peptides are presented in association with major histocompatibility complex (MHC) proteins to effector cells of the immune system.
Genomic tailoring of immunotherapies
Anti-PD1 checkpoint inhibition has demonstrated activity as monotherapy in early phase trials in ER + and TNBC but response rates are low [70], [71]. This is likely to be due, at least in part, to mechanisms of immune-evasion and suppression. ER + disease in particular, has low TIL levels suggesting mechanisms of immune-suppression may be more established. Mechanisms of immune-escape, broadly speaking, fall into two categories – tumour cell-intrinsic alterations; and adjustments in the tumour
Conclusions
Sequencing studies have provided comprehensive genomic blueprints of primary breast cancer. Many recurrent driver alterations have been identified, however with the exception of HER2-amplification, few have suitable therapies with proven clinical responses, implying major challenges to overcome on the road to precision medicine [25]. The field continues to evolve but therapeutic success such as those seen in EGFR mutated lung adenocarcinoma [111] and BRAF mutated melanoma [112] remain elusive.
Conflict of interest
None declared.
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