Elsevier

The Breast

Volume 29, October 2016, Pages 241-250
The Breast

Original article
The genomic landscape of breast cancer and its interaction with host immunity

https://doi.org/10.1016/j.breast.2016.07.015Get rights and content

Abstract

Molecular profiling of thousands of primary breast cancers has uncovered remarkable genomic diversity between breast cancer subtypes, and even within subtypes. Only a few driver genes are recurrently altered at high frequency highlighting great challenges for precision medicine. Considerable evidence also confirms the role of host immunosurveillance in influencing response to therapy and prognosis in HER2+ and triple negative breast cancer. The role of immunosurveillance in ER + disease remains unclear. Advances in both these fields have lead to intensified interest in the interaction between genomic landscapes and host anti-tumour immune responses in breast cancer. In this review, we discuss the potential genomic determinants of host anti-tumour immunity – mutational load, driver alterations, mutational processes and neoantigens – and their relationship with immunity in breast cancer. Significant differences exist in both the genomic and immune characteristics amongst breast cancer subtypes. While ER + disease appears to be less immunogenic than HER2+ and triple negative breast cancer, it displays the greatest degree of heterogeneity. Mutational and neoantigen load appears to incompletely explains immune responses in breast cancer. Driver alterations do not appear to increase immunogenicity. Instead, they could contribute to immune-evasion or an immunosuppressive microenvironment, and therefore represent potential therapeutic targets. Finally, we also discuss the tailoring of immunotherapeutic strategies by genomic alterations, with possible multimodal combination approaches to maximise clinical benefits.

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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