Loss of ataxia-telangiectasia-mutated protein expression correlates with poor prognosis but benefits from anthracycline-containing adjuvant chemotherapy in breast cancer

Abstract

We investigated the correlation of ataxia-telangiectasia-mutated (ATM) protein expression with clinicopathological features and prognosis in patients with breast cancer. ATM expression was determined by immunohistochemistry in 420 surgically resected breast tumors. ATM loss was observed in 126/407 evaluable cases (31.0 %), and was significantly associated with larger tumor size, lymph node metastasis, higher tumor grade, and ER- and/or PR-negative status. ATM loss was also associated with significantly lower disease-free survival rates than those in patients with intact ATM (5-year disease-free survival rate 81.2 vs. 90.7 %, p = 0.015). In multivariate analysis, ATM loss combined with abnormal p53 expression was an independent predictor of shorter disease-free survival [hazard ratio (HR) 3.48; 95 % confidence interval (CI), 1.48-8.17, p = 0.004]. A tendency towards a poorer prognosis was observed for tumoral ATM loss alone, although statistical significance was not reached (HR 1.74; 95 % CI 0.95-3.20; p = 0.075). In subgroup analysis, ATM loss was associated with shorter disease-free survival in patients who did not receive adjuvant anthracycline chemotherapy (5-year disease-free survival rate 92.7 % in intact ATM group vs. 68.1 % in ATM loss group, p = 0.002), but this poor prognosis was overcome in patients who did (5-year disease-free survival rate 89.8 vs. 84.4 %, p = 0.243), suggesting more benefit from anthracycline-based chemotherapy. Tumors with loss of ATM expression have a poor prognosis and their prognoses are dependent on the use of adjuvant anthracycline. ATM loss might be a practical tool for predicting benefits from anthracycline-based adjuvant therapy.

Loss of tumour-specific ATM protein expression is an independent prognostic factor in early resected NSCLC

“…[19]. Similarly, quantitative IHC of ATM in breast cancer identified a smaller subgroup of ATM-deficient patients [26] than does standard histopathology [27], however in both of these studies ATM-loss was associated with poor DFS.…”

Immune recurrence score using 7 immunoregulatory protein expressions can predict recurrence in stage I–III breast cancer patients

“…Immunohistochemical staining was performed with formalin-fixed, paraffin-embedded tissue using Benchmark automatic immunostaining device (Ventana, Arizona, USA) as previously described. 12 The primary antibodies were diluted as follows: oestrogen receptor (ER) (1D5; Novocastra Laboratories, Newcastle, UK), 1:100; progesterone receptors (PR) (PgR636; DAKO, Hamburg, Germany), 1:200; human epidermal growth factor receptor 2 (HER2) (Ventana, Arizona, USA), 1:1; PD-1 (Cell Marque, California, USA), 1:20; PD-L1 (B7-H1) (Cell Signaling, Massachusetts, USA), 1:100; PD-L2 (B7-DC) (Sigma-Aldrich, Missouri, USA), 1:500; IDO (Millipore-Sigma, Massachusetts, USA), 1:30; TIM-3 (Abbexa Ltd, Cambridge, UK), 1:550; OX40 (Novus Biologicals, Colorado, USA), 1:125; OX40L (Millipore-Sigma, Massachusetts, USA), 1:30; B7-H2 (Novus Biologicals, Colorado, USA), 1:300; B7-H3 (Cell Signaling, Massachusetts, USA), 1:50; B7-H4 (Cell Signaling, Massachusetts, USA), 1:50. Nuclear expression of tumour cells was interpreted as positive for ER and PR, while membrane staining of tumour cells was considered positive for HER2.…”

Reduced expression of phosphorylated ataxia-telangiectasia mutated gene is related to poor prognosis and gemcitabine chemoresistance in pancreatic cancer

“…Previously, it was reported that the loss of ATM and normal TP53 expression is associated with poor prognosis in PC patients [ 31 ]. Likewise, ATM expression can be used as a prognostic marker in breast, gastric, and gall bladder cancers [ 20 , 32 , 33 ]. Although we did not obtain any evidence that ATM loss has an impact on PC patient prognosis, we are the first to report that low phospho-ATM expression is significantly important for OS and DFS in PC patients.…”