In patients with early-stage HER2+ breast cancer with HER2 heterogeneity, HER2-targeted therapies are doomed to fail: a phase II study recently published in Cancer Discovery showed that the pathologic complete response rate is 55% in patients without HER2 heterogeneity but falls to 0% in heterogeneity subgroups.
The trial enrolled 164 patients with early-stage HER2+ breast cancer treated with trastuzumab emtansine (T-DM1) and pertuzumab as neoadjuvant therapy; since one potential mechanisms of therapeutic resistance is heterogeneous expression of the therapeutic target within the tumor, the authors assessed HER2 heterogeneity on pretreatment biopsies from two locations of each tumor to understand if this affected the pathologic complete response rate. The results show that in the subset of heterogeneous tumors all cases had residual disease at the time of surgery, while the pathologic complete response rate rate was 55% in the subset without heterogeneity. The analysis at the single-cell level confirmed the presence of a direct relationship between HER2 heterogeneity and response to targeted anti-HER2 therapies. These therapies are very effective in some subsets of patients, where chemotherapy could be avoided.
«Cancer, almost by definition, implies the presence of intra-tumor heterogeneity, as tumors arise from accumulating genetic and epigenetic alterations», authors say. «As treatments have evolved to targeted therapies, studying how heterogeneity of the drug target affects responses to therapies becomes increasingly important. The results of this study suggest that efforts to reduce the amount of conventional chemotherapy and rely more on HER2-targeted therapies for patients diagnosed with HER2-positive early-stage disease may not be successful if intratumor heterogeneity is not taken into consideration: if these results are validated in additional studies, assessment of HER2 heterogeneity may facilitate optimal selection of therapy for patients with early-stage HER2+ cancers».
