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Tumour Signatures Defined by Next Generation Sequencing Are Linked to Clinical Response in Breast Cancer

Endogenous and exogenous mutational processes driven by abnormal DNA editing, mutagens or age-related DNA alterations over the history of a malignant tumour provide an individual tumour signature
02 Mar 2021
Breast cancer;  Translational research

Mutational signatures were identified that serve as an indicator of the individual genomic history of a tumour in hormone receptor (HR)-negative and HR-positive tumours, which also were prognostic of the clinical behavior of the breast cancer following chemotherapy. These findings were detailed by lead author Carsten Denkert of the Institute of Pathology, Philipps-University Marburg and University Hospital Marburg in Marburg, Germany in an article published in the Annals of Oncology.

Professor Denkert and colleagues investigated the hypothesis that genomic patterns of mutational signatures are associated with the clinical behavior of breast cancer, including the response to chemotherapy response and survival.

The investigators conducted this exploratory retrospective analysis in a cohort from the prospective neoadjuvant multicentre GeparSepto clinical study and began by performing whole exome sequencing in 405 pre-therapeutic samples from these patients. The sequences were analysed for the presence of 11 mutational signatures including biological processes such as APOBEC-mutagenesis, homologous recombination deficiency (HRD), mismatch repair deficiency (MMR) and also age-related or tobacco-induced alterations.

The primary objective was to investigate mutational signatures and mutational load in the tumour to predict response and resistance to neoadjuvant therapy and the secondary objectives were to correlate these mutational signatures with clinicopathological parametres.

The analysis had the predefined endpoints of pathological complete response (pCR; defined as the absence of invasive cancer and in situ cancer in breast and axillary nodes [ypT0ypN0]) and disease-free survival (DFS). The predefined co-variables for multivariate regression models included age (continuous), tumour stage (T1-2 versus T3-4), nodal stage (N0 versus Nþ), Ki-67 (continuous), HR status (negative versus positive), and treatment (nab-paclitaxel versus paclitaxel).

Signatures defined breast cancer subgroups

The investigators determined that subgroups of breast cancers were defined mainly by differences in HRD-related and APOBEC-related mutational signatures, significant differences between HR-negative and HR-positive tumours, as well as by correlations with age, Ki-67 and immunological parametres.

The investigators evaluated the number of mutations in each signature and the exonic mutation rate (EMR; per mb) in HR-positive and HR-negative tumours. Significant differences represented by higher numbers of mutations in HR-negative tumours were observed for S3 (HRD; p < 0.001), S13 (APOBEC; p < 0.001), S6 (MMR); p =  0.015), S21 (MMR; p = 0.015), S4 (tobacco; p < 0.001) and in total (EMR; p < 0.001).

Significantly higher mutation numbers in HR-positive tumours were observed for S16 (unknown process; p < 0.001) and S28 (unknown process; p = 0.002). 

Mutational processes were linked to increased pathological complete response rates after neoadjuvant chemotherapy

As expected, the overall pCR rate of patients with HR-negative (triple-negative breast cancer) tumours was 38%, which was significantly higher than the 12.7% pCR rate of patients with HR-positive tumours (p < 0.001). In HR-positive tumours, differences in the pCR rate were observed for different mutational signatures; the two main mutational signatures were S3 (HRD, p < 0.001) and S13 (APOBEC, p = 0.001) which, in univariable analysis, were significantly associated with an increased pCR rate following neoadjuvant chemotherapy, as was the exonic mutation rate (EMR; p = 0.002).

Negative indicators included the signatures S3 (HRD; p = 0.006) and S4 (tobacco, p = 0.011), which were prognostic for reduced DFS in patients with chemotherapy-resistant tumours.

Conclusions

The main result of this study was that defined signatures could predict the clinical behavior of HR-positive tumours, specifically the response to neoadjuvant chemotherapy and DFS of therapy-resistant tumours.    

The investigators concluded that they identified mutational signatures S3 (HRD) and S13 (APOBEC) that were significantly linked to increased pCR rates with neoadjuvant chemotherapy in the HR-positive subcohort. The signatures S3 (HRD) and S4 (tobacco) were also associated with a reduced DFS in therapy-resistant (non-pCR) HR-positive tumours.

In addition, the authors recommended that, following additional validations, mutational signatures may be used to identify tumours with an increased response rate to neoadjuvant chemotherapy and to define therapy-resistant subgroups for future therapeutic interventions.

This work was supported by the Translational Oncology Programme of the German Cancer Aid (Deutsche Krebshilfe), project TransLuminal B and Integrate –TN. The sequencing analysis was carried out and funded by NantOmics.

Reference

Denkert C, Untch M, Benz S, et al. Reconstructing tumor history in breast cancer: signatures of mutational processes and response to neoadjuvant chemotherapy. Annals of Oncology; Published online 5 January 2021. doi: 10.1016/j.annonc.2020.12.016.

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