Because the PgR gene is highly regulated by estrogen action through ER [159,160,161], as early as the 1970s, the measurement of breast tumor PgR levels was proposed as a way to improve the PPV of receptor assays for endocrine therapy benefit [162,163]: an ER-positive tumor that was also PgR-positive would indicate that ER was functional and would respond to endocrine therapy, whereas an ER-positive/PgR-negative tumor would not respond, because the ER, somehow, was nonfunctional. This evidence concerns the gene ESR1 and neoplasm.