In patients with advanced disease in a small phase I trial of the 9-cis-RA/tamoxifen combination, the dose-limiting toxicities were headache, hypercalcemia and noncardiogenic pulmonary edema; and of nine assessable patients, there was one partial response and one complete response, both in patients who had ER-positive tumors and previous tamoxifen therapy [75]. Here, ESR1 is linked to hypercalcemia disease.