# DNA Damage Response in Early Breast Cancer: A Phase III Cohort in the Phobos Study

## TL;DR

This study shows that DNA damage response markers, especially ATM and ATR, can predict outcomes in early breast cancer patients, even when traditional treatments don't show survival differences.

## Contribution

The study introduces a DDR risk score based on ATM and ATR expression as an independent prognostic tool for breast cancer.

## Key findings

- A DDR risk score inversely driven by ATM and ATR expression is an independent prognostic factor for DFS and OS.
- Validation in a public cohort confirmed ATM's protective role in breast cancer outcomes.
- No significant DFS or OS differences were found between treatment groups over 234 months.

## Abstract

This study evaluates DDR biomarkers in 222 node-positive early breast cancer patients from a Phase III trial on adjuvant taxanes. Over a 234-month follow-up period, no differences in DFS or OS were observed between treatment groups. However, a DDR risk score, influenced by ATM and ATR expression, proved to be an independent prognostic factor for both DFS and OS. Validation in a public cohort confirmed ATM’s protective role. These findings highlight the importance of DDR pathways in breast cancer prognostication and support, integrating molecular markers with clinical–pathological factors to inform treatment strategies.

We assessed the impact of DNA damage response and repair (DDR) biomarker expressions in 222 node-positive early breast cancer (BC) patients from a previous Phase III GOIM 9902 trial of adjuvant taxanes. At a median follow-up of 64 months, the original study showed no disease-free survival (DFS) or overall survival (OS) differences with the addition of docetaxel (D) to epirubicine-cyclophosphamide (EC). Immunohistochemistry was employed to assess the expression of DDR phosphoproteins (pATM, pATR, pCHK1, γH2AX, pRPA32, and pWEE1) in tumor tissue, and their association with clinical outcomes was evaluated through the Cox elastic net model. Over an extended follow-up of 234 months, we confirmed no significant differences in DFS or OS between patients treated with EC and those receiving D → EC. A DDR risk score, inversely driven by ATM and ATR expression, emerged as an independent prognostic factor for both DFS (HR = 0.41, p < 0.0001) and OS (HR = 0.61, p = 0.046). Further validation in a public adjuvant BC cohort was possible only for ATM, confirming its protective role. Overall, our findings confirm the potential role of the DDR pathway in BC prognostication and in shaping treatment strategies advocating for an integrated approach, combining molecular markers with clinical–pathological factors.