This heterogeneity may be more marked in ESR1-mutant cancer, as ESR1 mutations may co-occur with other mechanisms of genetic resistance, potentially reflecting cancers that are predisposed to acquiring genetic mechanisms of resistance (20, 28) Recently, the acquisition of secondary mutations in cis with hotspot driver mutations in PIK3CA were described (29), leading to increased signaling and tumor growth. Here, ESR1 is linked to cancer.