Progesterone receptor (PR) is a downstream gene target of estrogen receptor (ER) and the loss of PR often indicates a poor prognosis in breast cancer[7, 10, 11]. Previous studies have shown that ER+/PR- phenotype accounts for 10.5–15% of ER-positive breast cancer[6, 7, 10, 12]. However, it’s worth noting that 25.5% of the patients were ER+/PR- IBC in our study and this proportion is much higher than that of the whole breast cancer population, which may partly explain the worse outcome of IBC. Keeping with previous study[3], 87.8% of the patients already had lymph node involved and 39.3% of the patients were distant metastasis at the initial diagnosis of breast cancer, which demonstrated the aggressive biological behavior of IBC. On accounting of higher proportion of patients with ER+/PR- phenotype and more aggressive biological characteristics, it is very necessary to figure out the effect of PR status on IBC.
As previous studies[6, 7, 13], the loss of PR also predicted unfavorable biological characteristics in IBC. In our study, the patients with ER+/PR- phenotype were prone to be poor histological grade (Ⅲ-Ⅳ), which often predicts worse survival[14, 15]. In addition, the tendency of distant metastasis for ER+/PR- phenotype differed from ER+/PR + phenotype. Consistent with our previous study[13], more liver metastasis happened to patients with ER+/PR- phenotype than patients with ER+/PR + phenotype in IBC, which indicates greater propensity of visceral metastasis for ER+/PR- phenotype. However, more bone metastasis occurred to patients with ER+/PR + phenotype than patients with ER+/PR- phenotype, which demonstrated a pattern of bone metastatic spread typically attributed to hormone receptor-positive breast cancer[16].
Although the prognosis of breast cancer has been greatly improved with the advent of various systemic treatments, the survival of IBC was still far from satisfaction. Consistent with previous studies[17, 18], the survival for IBC was very poor in our research (5-year BCSS and OS rate, 47.3% and 42.5%, respectively). On account of the poor prognosis for IBC, previous researches tried to find the risk factors and demonstrated many independent predicted factors, such as race, lymph node ratio, AJCC stage, histological grade, ER status, PR status, HER2 status, surgery status, and radiotherapy status[14, 17]. Although those researches have demonstrated PR-negative status contributing to worse outcome for IBC, the difference of prognosis between ER+/PR + phenotype and ER+/PR- phenotype is still unknown and needed to be further verified because worse outcome of PR-negative cohort mainly resulted from patients with triple-negative IBC in their study. Therefore, we excluded triple-negative IBC and compared the prognosis between ER+/PR + phenotype and ER+/PR- phenotype by those two cohorts. As shown in our study, the patients with ER+/PR- phenotype exhibited significant worse survival than patients with ER+/PR + phenotype, especially in the patients with younger age, lower histological grade, lymph node involved and distant metastasis. Due to the worse clinicopathologic features and prognosis for patients with ER+/PR- phenotype, the loss of PR has aroused wide attention from scholars. The main researches focused on genomics changes, such as PR promoter hypermethylation or loss of heterozygosity at the PR gene locus[19, 20]. A recent study illuminated that almost 20% of the patients with ER+/PR- and HER2-negative were non-luminal-like and didn’t benefit from sufficient endocrine therapy[10], which partly explains the worse outcome for IBC with ER+/PR- phenotype. As mentioned above, higher percentage of patients presented PR loss in IBC and worse survival were seen in those patients. Therefore, the patients with ER+/PR- phenotype belonging to non-luminal-like IBC should also be identified and more effective treatments should be performed on them, such as cyclin-dependent kinase 4/6 inhibitors. In addition to PR status, older age and black race were also prognostic risk factors for patients with ER + and HER2-negative IBC. Poor histological grade and visceral metastasis were recognized as poor prognostic factors for IBC[14, 17], which was also demonstrated by our study. As mentioned above, the patients with ER+/PR- IBC presented poor histological grade and more visceral metastasis, which may also explain the worse outcomes for patients with ER+/PR- phenotype in our study. Chemotherapy, surgery and radiation are the indispensable approaches of trimodality treatment[21], and all of these could significantly improve the survival for IBC in our study.
The limitations of this study must be clarified. Firstly, some bias can’t be avoided for the nature of retrospective study. Thus, multivariable Cox proportional hazards model and subgroup analysis were performed to adjust for confounding effects as much as possible. Then, the information about endocrine therapy can’t be acquired from the database, which impeded the further analysis about the effectiveness of endocrine therapy. Nevertheless, most of the patients should have received enough endocrine therapy for the widespread of standard treatment in the United States. However, our study is the first one that used the relatively large cohort to estimate the influence of PR status on patients with IBC. It illuminated the significant discordance of clinicopathological features and prognosis between ER+/PR + phenotype and ER+/PR- phenotype in IBC, which indicated the necessity that stronger treatments should be applied to patients with ER+/PR- IBC.