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This cellular diversity contributes to treatment failure, residual disease, and early relapse by enabling tumor adaptation and therapeutic resistance. Although increasingly recognized as a critical feature of breast cancer biology, it remains under-investigated and has not yet been integrated into routine clinical care. This review synthesizes current evidence on the role of ITH in chemotherapy resistance in primary breast cancer. Following PRISMA guidelines, we searched MEDLINE via PubMed, Web of Science, and Scopus through June 2026. Twelve studies met the inclusion criteria. Data were extracted on tumor subtypes, study design, ITH assessment modality (genomic, transcriptomic, radiomic, or immunologic), sampling method, treatment type, and outcomes. Among the 12 included studies, covering triple-negative, HER2-positive, and mixed breast cancer cohorts, high or increasing ITH, assessed using molecular or imaging-based methods, was associated with reduced sensitivity to chemotherapy. Proposed mechanisms underlying resistance included clonal selection, transcriptional plasticity, immune exclusion, and phenotypic drift. Radiomic and MRI-derived features may provide additional predictive value beyond molecular classifiers, and integrated radiomic-genomic models outperformed either modality alone in identifying patients with poor treatment response. In conclusion, current evidence suggests that ITH may be associated with chemotherapy resistance in primary breast cancer through several biological mechanisms. Integrating radiomic and imaging-based assessments with molecular profiling has the potential to improve the prediction of treatment response and facilitate monitoring of changes in tumor heterogeneity during therapy, although further prospective validation is needed before routine clinical implementation.<\/jats:p>\n                  <jats:p>Protocol Registration Number at PROSPERO: CRD42024533885<\/jats:p>","DOI":"10.1007\/s12032-026-03426-z","type":"journal-article","created":{"date-parts":[[2026,10,3]],"date-time":"2026-10-03T06:10:32Z","timestamp":1791007832000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The impact of intratumor heterogeneity on outcome and resistance to therapy in primary breast cancer: a systematic review"],"prefix":"10.1007","volume":"43","author":[{"given":"Aria","family":"Dianati","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Andre","family":"Dekker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anke","family":"Wesselius","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leonard","family":"Wee","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,10,3]]},"reference":[{"issue":"6","key":"3426_CR1","first-page":"477","volume":"74","author":"AN Giaquinto","year":"2024","unstructured":"Giaquinto AN, Sung H, Newman LA, Freedman RA, Smith RA, Star J, Jemal A, Siegel RL. 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