High expression of progesterone receptor may be an adverse prognostic factor in oestrogen receptor-negative/progesterone receptor-positive breast cancer: results of comprehensive re-evaluation of multi-institutional case series

Oestrogen receptor (ER)-negative (–) progesterone receptor (PgR)-positive (+) is the least common combination of steroid receptor expression observed in breast cancer. There are many controversies regarding the actual existence of ER–/PgR+ phenotype. In the current study, we aimed to perform comprehensive immunohistochemical re-evaluation of ER–/PgR+ breast cancers from multiple institutions. A total of 135 cases of ER–/PgR+ breast cancer were collected from 11 institutions from the period 2006–2020 and subsequently stained with three clinically validated anti-ER antibody clones: SP1 (Roche), 1D5 (Dako), and EP1 (Dako), and two anti-PgR antibody clones: 636 (Dako), and 1E2 (Roche). Clinicopathological characteristics of confirmed and re-categorised cases were analysed. Seventy-six cases retained the original ER–/PgR+ phenotype, including 21 HER2+ and 55 HER2– tumours. Forty-seven cases were ER+ with at least one anti-ER antibody, and 12 cases were re-categorised as double-negatives across all anti-ER and anti-PgR antibodies. No significant differences in survival were observed between groups in the HER2+ category. In the HER2– cohort, confirmed ER–/PgR+, ER+ tumours with discrepant ER staining, and triple negatives had inferior overall survival compared to concordant ER+ cases. Progesterone receptor expression in >20% of cells was identified as an adverse prognostic factor in ER–/PgR+/HER2– breast cancer in a multivariable model adjusted by stage (HR 5.0, 95% CI 1.3–19.2, p=0.019). We performed one of the largest validation studies so far on ER–/PgR+ breast cancer and confirmed the existence of this subgroup. Moreover, we identified high PgR expression as an adverse prognostic factor.