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February 2021: Signatures of mutational processes and response to neoadjuvant chemotherapy in breast cancer

28.02.2021

A translational research project investigating genomic patterns of mutational signatures in breast cancer patients from GeparSepto trial has been published in Annals of Oncology.

Different endogenous and exogenous mutational processes act over the evolutionary history of a malignant tumor, driven by abnormal DNA editing, mutagens or age-related DNA alterations, among others, to generate the specific mutational landscape of each individual tumor. The signatures of these mutational processes can be identified in large genomic datasets. This study investigated the hypothesis that signatures of mutational processes that have contributed to the training of the immune system and other anti-neoplastic processes are relevant for response to neoadjuvant chemotherapy and prognosis in breast cancer. To evaluate this hypothesis, whole-exome sequencing was performed in a cohort of 405 pretherapeutic formalin-fix paraffin-embedded (FFPE) core biopsies from HER2-negative patients included in the neoadjuvant GeparSepto trial. The prevalence of the different mutational signatures in different breast cancer subgroups as well as the role of the most predominant signatures for response to neoadjuvant chemotherapy was also investigated. Overall, 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 were analyzed. Different subgroups of breast carcinomas were defined mainly by differences in HRD-related and APOBEC-related mutational signatures and significant differences between hormone-receptor (HR) negative and HR-positive tumors as well as correlations with age, Ki-67 and immunological parameters were observed. Overall, pCR rate of patients with HR-negative tumors was significantly higher than the pCR rate of patients with HR-positive tumors (38.8% vs 12.7%; p<0.001). Differences in pCR rate for different mutational signatures were observed in HR-positive tumors. In univariate analyses for HR-positive tumors, HRD (p<0.001) and APOBEC (p=0.001) signatures significantly correlated with increased pCR rates. The survival analysis focused on the clinically most relevant subgroup of chemotherapy-resistant tumors. In HR-positive tumors without pCR, the HRD (p=0.006) and tobacco (p=0.011) signatures were prognostic for reduced disease-free survival (DFS) in univariate analysis but not in multivariate analysis including the covariables age, cT, cN, Ki-67, and treatment. Regarding HR-negative tumors, there was no mutational signature that significantly predicted pCR. In therapy-resistant HR-negative tumors, the MMR signature showed a trend towards reduced DFS (univariate p=0.071). In addition to the individual signatures, exonic mutation rate (EMR) as a measurement of total mutational burden was also investigated. EMR correlated highly with increased pCR (univariate p=0.002) but did not predict DFS in HR-positive tumors. In HR-negative tumors, EMR was neither significantly associated with pCR nor with DFS. To further investigate the contribution of HRD and APOBEC signatures to the development and progression of luminal tumors, the association with tumor proliferation and tumor immune infiltrate was analyzed. Both signatures were positively correlated with increased Ki-67 and also with increased levels of tumor-infiltrating lymphocytes (TILs), suggesting an involvement in the development of more aggressive subtypes of luminal tumors which also have a higher immunogenicity. These highly proliferating tumors respond better to chemotherapy, but may have a reduced prognosis overall.
In conclusion, these results suggest that the clinical behavior of a tumor, in particular response to neoadjuvant chemotherapy and DFS of therapy-resistant tumors, could be predicted by the composition of mutational signatures as an indicator of the individual genomic history of a tumor. After additional validations, mutational signatures might be used to identify tumors with an increased response rate to neoadjuvant chemotherapy and to define therapy-resistant subgroups for future therapeutic interventions.

Denkert C, Untch M, Benz S, et al. Reconstructing tumor history in breast cancer: signatures of mutational processes and response to neoadjuvant chemotherapy. Ann Oncol. 2021 Jan 5:S0923-7534(20)43224-7.


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