AbstractBackgroundER+HER2+ breast cancer requires most types of systemic therapies perioperatively. However, treatment resistance is often experienced. The current study investigated the predictive and prognostic value of intratumoral heterogeneity and conventional clinicopathological factors in patients with ER+HER2+ breast cancer.MethodsThis research included two patient cohorts with ER+HER2+ breast cancer. Cohort A included patients who underwent surgery without neoadjuvant chemotherapy (NAC). Cohort B comprised patients who received NAC followed by surgery. Intratumoral heterogeneity was assessed via ER and HER2 double staining, and the number of cells stained with different patterns of ER and HER2 was counted.ResultsIn total, 11 of 92 tumors in cohort A and four of 45 tumors in cohort B consisted exclusively of double‐positive (ER+ and HER2+) cells (homogeneous). The rest had different combinations of cells (heterogeneous). The pathological complete response (pCR) rates differed based on tumoral cell components but not intratumoral heterogeneity. The pCR rate of tumors with ER−HER2+ cells but without HER2− cells was higher than that of others (45.5% vs 4.3%;p= 0.0013). Low ER and PgR Allred scores indicated better pCR rates than high scores (p= 0.0005 and 0.024, respectively). Multivariate analysis showed that the ER Allred score and cell component of ER−HER2+ cells without HER2− cells were independent predictors of pCR (p= 0.0055 and 0.0081, respectively).In cohort B, posttreatment Ki67, but not pCR, was a prognostic factor of DFS and OS (p= 0.028 and 0.017, respectively). The prognostic value of combined posttreatment Ki67 and pCR was superior to that of either alone. Combined pCR and posttreatment Ki67 had an independent prognostic value for DFS and OS (p= 0.0068 and 0.0101, respectively).ConclusionsIn ER+HER2+ breast cancer, the presence of ER−HER2+ cells without HER2− cells was independently associated with pCR. Combined posttreatment Ki67 and pCR can be more precise in predicting prognosis than pCR alone.