Genomic Drivers in Breast Cancers

European Oncology & Haematology, 2016;12(1):28–9 DOI: http://doi.org/10.17925/EOH.2016.12.01.28

Abstract:

Significant advances in next-generation sequencing technologies have allowed the identification of genomic alterations in breast cancer. These alterations offer the opportunity to conduct studies with targeted drugs. However, there are still several scientific challenges to be addressed before precision medicine is widely used in the clinic. Nonetheless, different solutions are developed to overcome these obstacles such as the improvement of bioinformatics tools and the use of “liquid biopsy” to assess circulating tumour DNA.
Keywords: Breast cancer, precision medicine, personalised medicine, biomarkers, next-generation sequencing, tumour heterogeneity
Disclosure: Luis Teixeira, Françoise Rothé and Christos Sotiriou have nothing to disclose in relation to this article. This article is a short opinion piece and has not been submitted to external peer reviewers. No funding was received in the publication of this article.
Published Online: 24 May 2016
Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit.
Received: April 29, 2016
Correspondence: Christos Sotiriou, Breast Cancer Translational Research Laboratory J-C Heuson, Université Libre de Bruxelles, Institut Jules Bordet, Rue Héger Bordet 1, 1000 Brussels, Belgium. E: christos.sotiriou@bordet.be

Significant advances in next-generation sequencing (NGS) technologies have allowed the identification of alterations in cancer genomes of different tumour types, providing important insight into the genetic complexity of cancers including breast cancer (BC). Notably, we have learned that primary BC genomes harbour mutations in multiple cancer genes but at a low frequency, less than 5% for the vast majority of the mutations, highlighting the substantial genetic heterogeneity between individual tumours, even at this early stage.1

Precision medicine refers to the tailoring of medical treatment to the individual characteristics of each patient. The genomic alteration in BC offers the opportunity to conduct studies with targeted drugs. However, besides endocrine and anti-human epidermal growth factor (HER2) therapies, there is currently no evidence that it can improve patient outcomes.

There are several potential applications of genomics for precision medicine, including the identification of driver aberrations/mutations, the characterisation of resistant clones, the identification of DNA repair defects and the identification of mechanisms of immune suppression.2 However, there are still several scientific challenges to be addressed before genomics is used in the clinic.

Potential applications of genomics for precision medicine
Identification of ‘driver’ mutations

Large-scale genomics studies have allowed the characterisation of the mutational landscape of BC genomes and have provided key insights into BC genomic alterations. First, there is a substantial variation in the number of mutations in cancer genes in primary BC, the maximum number of mutated cancer genes per tumour being six. It is noteworthy that copy number alterations are more frequent than point mutations in BC. Second, 30% of cases only showed a single ‘driver’ mutation. As a result, 73 different combinations of cancer genes with mutations could be identified.1 Third, driver mutations are infrequent (the vast majority of mutations are present in less than 5% of the cases), highlighting the diversity and complexity of the disease.1 Consequently, few driver genes have been identified, namely, ESR1, ERBB2, PIK3CA and AKT1. Nonetheless, emerging targeted agents against BC cells harbouring these genomic alterations are under clinical development.3

Identification of genomic alterations responsible for secondary resistance
Several studies comparing the genomic landscape of early and metastatic BC (mBC) have identified an increased frequency of mutations in already-known but also in new cancer genes in mBC. ESR1 mutations are increasingly recognised as being acquired mutations in mBC leading to secondary resistance to aromatase inhibitors by a ligand-independent activation of the oestrogen receptor (ER).4,5 It has been shown that 20–30% of mBC patients progressing under several lines of aromatase inhibitors harbour mutations in ESR1 gene which are associated with a worse outcome in ER+/HER2- BC subtype. Another example of acquired genomic alteration is the convergent loss of PTEN leading to secondary resistance to BYL719, a PI3Kα inhibitor.6 It is anticipated that, in the near future, the number of acquired alterations identified in patients treated by targeted therapy will increase.

Identification of DNA-repair defects and mutational processes
The use of whole genome sequencing allowed the identification of specific mutation patterns (mutational signatures), which are considered to reflect chronic exposure of exogenous carcinogens such as UV light or tobacco. In BC, five distinct mutational signatures have been reported and have been associated with defective DNA repair progresses such as those found in patients with BRCA1 and BRCA2 germline mutations.7 Tumours from patients harbouring such mutational signatures may be good candidates to be treated with platinum agents or poly(ADP-ribose) polymerase inhibitors.

References:
1. Stephens PJ, Tarpey PS, Davies H, et al., The landscape of cancer genes and mutational processes in breast cancer, Nature, 2012;486:400–4.
2. Arnedos M, Vicier C, Loi S, et al., Precision medicine for metastatic breast cancer-limitations and solutions, Nat Rev Clin Oncol, 2015;12:693–704.
3. Ignatiadis M, Sotiriou C, Luminal breast cancer: from biology to treatment, Nat Rev Clin Oncol, 2013;10:494–506.
4. Toy W, Shen Y, Won H, et al., ESR1 ligand-binding domain mutations in hormone-resistant breast cancer, Nat Genet, 2013;45:1439–45.
5. Robinson DR, Wu YM, Vats P, et al., Activating ESR1 mutations in hormone-resistant metastatic breast cancer, Nat Genet, 2013;45:1446–51.
6. Juric D, Castel P, Griffith M, et al., Convergent loss of PTEN leads to clinical resistance to a PI(3)Kalpha inhibitor, Nature, 2015;518:240–4.
7. Alexandrov LB, Nik-Zainal S, Wedge DC, et al., Signatures of mutational processes in human cancer, Nature, 2013;500:415–21.
8. Hortobagyi GN, Chen D, Piccart M, et al., Correlative Analysis of Genetic Alterations and Everolimus Benefit in Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From BOLERO-2, J Clin Oncol, 2016; 34:419–26.
9. Finn RS, Crown JP, Lang I, et al., The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study, Lancet Oncol, 2015;16:25–35.
10. Zabransky DJ, Yankaskas CL, Cochran RL, et al., HER2 missense mutations have distinct effects on oncogenic signaling and migration, Proc Natl Acad Sci U S A, 2015;112:E6205–14.
11. Kopetz S, Desai J, Chan E, et al., Phase II Pilot Study of Vemurafenib in Patients With Metastatic BRAF-Mutated Colorectal Cancer, J Clin Oncol, 2015;33:4032–8.
12. Fleming GF, Sill MW, Darcy KM, et al., Phase II trial of trastuzumab in women with advanced or recurrent, HER2- positive endometrial carcinoma: a Gynecologic Oncology Group study, Gynecol Oncol, 2010;116:15–20.
13. Yates LR, Gerstung M, Knappskog S, et al., Subclonal diversification of primary breast cancer revealed by multiregion sequencing, Nat Med, 2015;21:751–9.
14. Rothe F, Laes J-F, Lambrechts D, et al., Plasma circulating tumor DNA as an alternative to metastatic biopsies for mutational analysis in breast cancer, Ann Oncol, 2014;25:1959–65.
15. Ignatiadis M, Dawson S, Circulating tumor cells and circulating tumor DNA for precision medicine: dream or reality?, Ann Oncol, 2014;25:2304–13.
Keywords: Breast cancer, precision medicine, personalised medicine, biomarkers, next-generation sequencing, tumour heterogeneity