Genomic Evolution of Breast Cancer Metastasis and Relapse

Yates, Lucy R.; Knappskog, Stian; Wedge, David C.; Farmery, James H.R.; González, Santiago; Martincorena, Iñigo; Alexandrov, Ludmil B.; Loo, Peter Van; Haugland, Hans Kristian; Lilleng, Peer Kåre; Gundem, Gunes; Gerstung, Moritz; Pappaemmanuil, Elli; Gazinska, Patrycja; Bhosle, Shriram G.; Jones, David R.; Raine, Keiran; Mudie, Laura; Latimer, Calli; Sawyer, Elinor J.; Desmedt, Christine; Sotiriou, Christos; Stratton, Michael R.; Sieuwerts, Anieta M.; Lynch, Andy G.; Martens, John W.M.; Richardson, Andrea L.; Tutt, Andrew; Lønning, Per Eystein; Campbell, Peter J.

doi:10.1016/j.ccell.2017.07.005

Cited by 546 publications

(577 citation statements)

References 58 publications

(84 reference statements)

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“…We found that cfDNA alterations (SNVs and small, activating indels) in TP53, EGFR, KRAS, PIK3CA, BRAF strongly correlated with TCGA tissue alterations (r=0.90-0.99, Figure 2A and B), and that correlations for amplification frequency ranks in breast cancer and locations of intronic fusion breakpoints in NSCLC were similarly high (Figure 2C and D). The high sensitivity of the cfDNA assay combined with the more evolved advanced cancers tested at progression, which have greater numbers of mutations than earlier-stage, treatment-naïve cancers, may contribute to differences in estimated tumor mutation burden versus TCGA (10,27). Importantly, we show that accurate estimation of tumor mutation burden from plasma cfDNA will require taking ctDNA level into account, as the two factors are correlated ( Figure 1D).…”

Section: Discussionmentioning

confidence: 87%

“…However, the desire to increase treatment efficacy in advanced cancers that likely have evolved considerably from baseline has led to a recent shift to "real world" cancer genomics studies focused on the realities of the clinic, yet grounded in lessons from earlier-stage cancers (26,27). It is becoming increasingly clear that obtaining comprehensive genomic assessments, across heterogeneous tumor subclones, will be necessary for tailoring effective therapies for advanced cancer patients (9,10).…”

Section: Discussionmentioning

confidence: 99%

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The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

Zill

Banks

Fairclough

et al. 2018

Clinical Cancer Research

290

249

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Running title: Somatic genomic landscape of circulating tumor DNA Keywords: circulating tumor DNA, tumor heterogeneity, resistance, genomic landscape, cfDNA clonality Financial support: The study was funded by and conducted at Guardant Health, Inc. No additional grant support or administrative support was provided for the study. *Corresponding author:Stephen R. Fairclough Translational relevanceThis study describes genomic alterations from the largest cell-free circulating tumor DNA cohort to date, as derived from regular clinical practice. The high prevalence of resistance alterations found in advanced, treated cancer patients necessitated accurate methods for determining mutation clonality and driver/resistance status from plasma. We provide such methods, thereby extending the utility of cell-free DNA sequencing analysis. Our finding of an association between estimated circulating tumor DNA (ctDNA) levels and tumor mutational burden ascertained from plasma suggests that ctDNA level is likely an important variable to consider for immunotherapy applications of ctDNA analysis. Although cell-free DNA can provide a summary of tumor heterogeneity across multiple metastatic sites in a patient, our findings of high variability in ctDNA levels across patients, and its impact on variant detection, highlight the need for an improved understanding of factors influencing ctDNA levels and safe methods for maximizing them at the time of ctDNA testing. AbstractPurpose: Cell-free DNA (cfDNA) sequencing provides a non-invasive method for obtaining actionable genomic information to guide personalized cancer treatment, but the presence of multiple alterations in circulation related to treatment and tumor heterogeneity complicate the interpretation of the observed variants.Experimental Design: We describe the somatic mutation landscape of 70 cancer genes from cfDNA deep-sequencing analysis of 21,807 patients with treated, late-stage cancers across >50 cancer types. To facilitate interpretation of the genomic complexity of circulating tumor DNA in advanced, treated cancer patients, we developed methods to identify cfDNA copy-number driver alterations and cfDNA clonality.Results: Patterns and prevalence of cfDNA alterations in major driver genes for non-small cell lung, breast, and colorectal cancer largely recapitulated those from tumor tissue sequencing compendia (TCGA and COSMIC;, with the principle differences in alteration prevalence being due to patient treatment. This highly sensitive cfDNA sequencing assay revealed numerous subclonal tumor-derived alterations, expected as a result of clonal evolution, but leading to an apparent departure from mutual exclusivity in treatment-naïve tumors. Upon applying novel cfDNA clonality and copy-number driver identification methods, robust mutual exclusivity was observed among predicted truncal driver cfDNA alterations (FDR=5x10 -7 for EGFR and ERBB2), in effect distinguishing tumor-initiating alterations from secondary alterations. Treatment-associated resistance, including both novel ...

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Section: Discussionmentioning

confidence: 87%

Section: Discussionmentioning

confidence: 99%

The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

Zill

Banks

Fairclough

et al. 2018

Clinical Cancer Research

290

249

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“…A shift in mutational rates of cancer genes in metastasis has been observed, but only TP53 showed a significantly increased mutational rate when analyzing pair samples of multiple cancer types, including breast cancer (11). Yates et al recently reported that most distant metastases acquired additional mutations in a wider repertoire of cancer genes, while only a few additional mutated driver genes were found in lymph node metastasis of breast cancers (12). Moreover, other studies have shown that metastasis-related aberrations originate from the primary tumor or certain subclones thereof (13)(14)(15), suggesting that metastasisrelated genes are altered in both primary tumors and metastasis, thus hindering identification by genomic comparison of paired primary tumor and metastasis.…”

Section: Introductionmentioning

confidence: 99%

Coexisting genomic aberrations associated with lymph node metastasis in breast cancer

Bao¹,

Qian²,

Lyng³

et al. 2018

Journal of Clinical Investigation

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“…Genomic characterization of metastatic disease when matched to the primary breast cancer has been shown to provide valuable information about clonality, acquired mutations, and metastatic potential [10,11,12]. Monoclonal and polyclonal seeding from the primary breast cancer to distant metastases has been observed in luminal subtype, polyclonal seeding in triple-negative basal and human epidermal growth factor receptor 2(HER2)-enriched cancers.…”

Section: Tumor Clonality - Intratumoral Heterogeneitymentioning

confidence: 99%

“…Yates et al [12] found that lymph node metastases from breast cancer had only a few mutated driver genes, but additional acquired mutations were found in distant metastases. Their findings support previous investigations showing that the number of mutations in synchronous axillary node metastases are very similar to the mutations of the primary lesion, indicating a chronologic probability of mutational accrual in comparison to distant metastasis with additional acquired mutations.…”

Section: Concordance Of Tumor Biology In the Primary Tumor Versus Nodmentioning

confidence: 99%

Lymph Nodes in Breast Cancer - What Can We Learn from Translational Research

Peintinger¹,

Reitsamer²,

Smidt³

et al. 2018

Breast Care

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Clinical observations about lack of survival benefit after extensive axillary surgery and biological discordance between primary breast tumors and axillary lymph nodes raise the question of the actual metastatic potential of axillary nodal disease. The exploration of intratumoral heterogeneity and detection of genomic differences between the primary and lymph nodes indicate some similarity between the number of mutations in synchronous axillary node metastases and those in the primary lesion, suggesting a favorable prognosis. The hematogenous route of metastasis needs to be considered in findings of different subclones between nodal and distant metastases. Modern tools such as whole-genome sequencing applied in multiple tumor areas may guide more precisely the extent of axillary surgery.

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Genomic Evolution of Breast Cancer Metastasis and Relapse

Cited by 546 publications

References 58 publications

The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

The Landscape of Actionable Genomic Alterations in Cell-Free Circulating Tumor DNA from 21,807 Advanced Cancer Patients

Coexisting genomic aberrations associated with lymph node metastasis in breast cancer

Lymph Nodes in Breast Cancer - What Can We Learn from Translational Research

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