Mutations affecting p53 or its upstream activator Chk2 are associated with resistance to DNA-damaging chemotherapy in breast cancer. ATM is the key activator of p53 and Chk2 in response to genotoxic stress. Here, we sought to evaluate ATM's potential role in resistance to chemotherapy.

We sequenced ATM and assessed gene expression levels in pre-treatment biopsies from 71 locally advanced breast cancers treated in the neoadjuvant setting with doxorubicin monotherapy or mitomycin combined with 5-fluorouracil. Findings were confirmed in a separate patient cohort treated with epirubicin monotherapy. Each tumor was previously analyzed for CHEK2 and TP53 mutation status.

While ATM mutations were not associated with chemoresistance, low ATM expression levels predicted chemoresistance among patients with tumors wild-type for TP53 and CHK2 (p=0.028). Analyzing the ATM-chk2-p53 cascade, low ATM levels (defined as the lower 5 - 50% percentiles) or mutations inactivating TP53 or CHK2 robustly predicted anthracycline resistance (p-values varying between 0.001 and 0.027 pending on the percentile used to define "low" ATM levels). These results were confirmed in an independent cohort of 109 patients treated with epirubicin monotherapy. In contrast, ATM-levels were not suppressed in resistant tumors harbouring TP53 or CHK2 mutations (p>0.5).

Our data indicate loss of function of the ATM-Chk2-p53 cascade to be strongly associated with resistance to anthracycline / mitomycin-containing chemotherapy in breast cancer.

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