Exome sequencing of contralateral breast cancer identifies metastatic disease

Klevebring, Daniel; Lindberg, Johan; Rockberg, Julia; Hilliges, Camilla; Hall, Per; Sandberg, Maria; Czene, Kamila

doi:10.1007/s10549-015-3403-6

Cited by 22 publications

(17 citation statements)

References 19 publications

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“…Nonetheless, both cases confirm the clonal relatedness of the contralateral tumour with the initially diagnosed breast cancer. Together with recent reports2223, this calls into question the current practice of considering metachronous contralateral tumours as second primary cancers. Since treatment strategies offered to patients differ widely between early and advanced stage breast cancers, it is imperative to determine in practice whether contralateral tumours represent a metastatic deposit of the primary tumour.…”

Section: Resultsmentioning

confidence: 99%

Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations

et al. 2017

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Several studies using genome-wide molecular techniques have reported various degrees of genetic heterogeneity between primary tumours and their distant metastases. However, it has been difficult to discern patterns of dissemination owing to the limited number of patients and available metastases. Here, we use phylogenetic techniques on data generated using whole-exome sequencing and copy number profiling of primary and multiple-matched metastatic tumours from ten autopsied patients to infer the evolutionary history of breast cancer progression. We observed two modes of disease progression. In some patients, all distant metastases cluster on a branch separate from their primary lesion. Clonal frequency analyses of somatic mutations show that the metastases have a monoclonal origin and descend from a common 'metastatic precursor'. Alternatively, multiple metastatic lesions are seeded from different clones present within the primary tumour. We further show that a metastasis can be horizontally cross-seeded. These findings provide insights into breast cancer dissemination.

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Section: Resultsmentioning

confidence: 99%

Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations

et al. 2017

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“…This suggests that part of CBCs were in fact metastases even though these were considered to be by definition a second primary BC. One study, assessing the relationship between first BC and CBC using exome sequencing, has shown that 12% of CBCs represents metastatic spread from the first BC [43]. We attempted to minimize the contribution of metastases to the contralateral breast beforehand by starting follow-up 3 months after first BC diagnosis, only including patients without distant metastasis at initial diagnosis, and censoring for distant metastases during follow-up.…”

Section: Discussionmentioning

confidence: 99%

The Influence of Adjuvant Systemic Regimens on Contralateral Breast Cancer Risk and Receptor Subtype

Kramer

Schaapveld²,

Oldenburg

et al. 2019

JNCI: Journal of the National Cancer Institute

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Background An increasing number of breast cancer (BC) survivors are at risk of developing contralateral breast cancer (CBC). We aimed to investigate the influence of various adjuvant systemic regimens on, subtype-specific, risk of CBC. Methods This population-based cohort study included female patients diagnosed with first invasive BC between 2003 and 2010; follow-up was complete until 2016. Clinico-pathological data were obtained from the Netherlands Cancer Registry and additional data on receptor status through linkage with PALGA: the Dutch Pathology Registry. Cumulative incidences (death and distant metastases as competing risk) and hazard ratios (HRs) were estimated for all invasive metachronous CBC and CBC subtypes. Results Of 83 144 BC patients, 2816 developed a CBC; the 10-year cumulative incidence was 3.8% (95% confidence interval [CI] = 3.7% to 4.0%). Overall, adjuvant chemotherapy (HR = 0.70, 95% CI = 0.62 to 0.80), endocrine therapy (HR = 0.46, 95% CI = 0.41 to 0.52), and trastuzumab with chemotherapy (HR = 0.57, 95% CI = 0.45 to 0.73) were strongly associated with a reduced CBC risk. Specifically, taxane-containing chemotherapy (HR = 0.48, 95% CI = 0.36 to 0.62) and aromatase inhibitors (HR = 0.32, 95% CI = 0.23 to 0.44) were associated with a large CBC risk reduction. More detailed analyses showed that endocrine therapy statistically significantly decreased the risk of estrogen receptor (ER)-positive CBC (HR = 0.41, 95% CI = 0.36 to 0.47) but not ER-negative CBC (HR = 1.32, 95% CI = 0.90 to 1.93) compared with no endocrine therapy. Patients receiving chemotherapy for ER-negative first BC had a higher risk of ER-negative CBC from 5 years of follow-up (HR = 2.84, 95% CI = 1.62 to 4.99) compared with patients not receiving chemotherapy for ER-negative first BC. Conclusion Endocrine therapy, chemotherapy, as well as trastuzumab with chemotherapy reduce CBC risk. However, each adjuvant therapy regimen had a different impact on the CBC subtype distribution. Taxane-containing chemotherapy and aromatase inhibitors were associated with the largest CBC risk reduction.

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“…In the largest of these studies, Klevebring et al . examined 25 metachronous breast cancers and concluded that 3 (12%) were clonally related …”

Section: Introductionmentioning

confidence: 99%

“…Later studies employed genome-wide copy number arrays permitting, in principle, greater resolution and a more definitive test for clonal relatedness, but were often hampered by the use of deoxyribonucleic acid (DNA) obtained from paraffin-embedded tissues. 21,22 Three recent studies used mutational data derived from whole-exome sequencing for clonality analyses, [23][24][25] and an additional study examined chromosomal rearrangements in 10 cases using low coverage whole genome sequencing. 26 In the largest of these studies, Klevebring et al examined 25 metachronous breast cancers and concluded that 3 (12%) were clonally related.…”

Section: Introductionmentioning

confidence: 99%

“…26 In the largest of these studies, Klevebring et al examined 25 metachronous breast cancers and concluded that 3 (12%) were clonally related. 25 In our study, we used massively parallel sequencing targeting the 254 genes most frequently mutated in breast cancer or related to DNA repair to address the question of clonality in patients with synchronous and metachronous bilateral breast cancer. We also employed a novel statistical approach that has been developed to address the specific computational challenges in this setting.…”

Section: Introductionmentioning

confidence: 99%

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Contralateral breast cancers: Independent cancers or metastases?

Begg

Ostrovnaya

Geyer

et al. 2017

Intl Journal of Cancer

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A cancer in the contralateral breast in a woman with a previous or synchronous breast cancer is typically considered to be an independent primary tumor. Emerging evidence suggests that in a small subset of these cases the second tumor represents a metastasis. We sought to investigate the issue using massively parallel sequencing targeting 254 genes recurrently mutated in breast cancer. We examined the tumor archives at Memorial Sloan Kettering Cancer Center for the period 1995-2006 to identify cases of contralateral breast cancer where surgery for both tumors was performed at the Center. We report results from 49 patients successfully analyzed by a targeted massively parallel sequencing assay. Somatic mutations and copy number alterations were defined by state-of-the-art algorithms. Clonal relatedness was evaluated by statistical tests specifically designed for this purpose. We found evidence that the tumors in contralateral breasts were clonally related in three cases (6%) on the basis of matching mutations at codons where somatic mutations are rare. Clinical data and the presence of similar patterns of gene copy number alterations were consistent with metastasis for all three cases. In three additional cases, there was a solitary matching mutation at a common PIK3CA locus. The results suggest that a subset of contralateral breast cancers represent metastases rather than independent primary tumors. Massively parallel sequencing analysis can provide important evidence to clarify the diagnosis. However, given the inter-tumor mutational heterogeneity in breast cancer, sufficiently large gene panels need to be employed to define clonality convincingly in all cases.

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Exome sequencing of contralateral breast cancer identifies metastatic disease

Cited by 22 publications

References 19 publications

Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations

Phylogenetic analysis of metastatic progression in breast cancer using somatic mutations and copy number aberrations

The Influence of Adjuvant Systemic Regimens on Contralateral Breast Cancer Risk and Receptor Subtype

Contralateral breast cancers: Independent cancers or metastases?

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