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ADCs that contain topoisomerase I inhibitors have been especially important in breast cancer treatment. Despite the substantial progress brought about by these ADCs, there remains a critical need to explore combination treatment strategies to overcome resistance and enhance the efficacy of these agents. Topoisomerase I inhibitors induce DNA damage and thus activate the DNA damage response (DDR). DDR elements have been examined in terms of their role in resistance and response to topoisomerase I inhibitors, and DDR inhibitors may be especially powerful when combined with topoisomerase I inhibitors.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>This review will discuss the topoisomerase I inhibitor ADCs approved for breast cancer treatment, the relevance of select components of the DNA damage response to topoisomerase I inhibitor-containing therapies, and combination strategies with inhibitors of DNA damage response, specifically focusing on inhibitors of poly (ADP-ribose) polymerase (PARP) and the ataxia-telangiectasia mutated and Rad3-related (ATR) inhibitor.\u00a0<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>The introduction of topoisomerase inhibitors as an ADC payload into breast cancer care has redefined a need to better understand the intricacies of their mechanism of action and tumor methods of escape and resistance, hopefully leading to novel synergistic therapeutic strategies.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s10549-026-07964-y","type":"journal-article","created":{"date-parts":[[2026,4,17]],"date-time":"2026-04-17T02:04:19Z","timestamp":1776391459000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Topoisomerase I inhibitor antibody\u2013drug conjugates in breast cancer: the relevance of the DNA damage response to resistance, response, and combination treatment strategies"],"prefix":"10.1007","volume":"217","author":[{"given":"Dayle K.","family":"Wang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia A.","family":"Steele","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Susan R.","family":"Opalenik","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Justin M.","family":"Balko","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,17]]},"reference":[{"key":"7964_CR1","doi-asserted-by":"publisher","first-page":"3","DOI":"10.1158\/1541-7786.MCR-19-0582","volume":"18","author":"P Khongorzul","year":"2020","unstructured":"Khongorzul P, Ling CJ, Khan FU et al (2020) Antibody\u2013drug conjugates: a comprehensive review. 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