3.1 Clinicopathological characteristics of patients with her-2 negative breast cancer
We identified 97,527 eligible patients with her-2 negative breast cancer from SEER. The endpoint date of the follow-up was November 2014, with a median follow-up of 48 months (range: 1 to 83 months). There were 0.86% women diagnosed with sPR positive in HoR positive resectable breast cancer, and 0.76% in all resectable breast cancer.
Compared with the sER positive, patients with sPR positive were younger at time of diagnosis (median age 55 versus 62 years, P<0.001), less likely had infiltrative lobar carcinoma (1.61% versus 13.38%, P<0.001), had more poor-differentiated (80.27% versus 36.71%, P<0.001) as well as late-stage breast cancer. More patients with sPR positive received chemotherapy (73.56 vs. 45.27%, P<0.001). However, patients with dHR negative and sPR positive tumors had similar clinicopathological characteristics. The detail information was indicated in Table 1.
3.2 Univariate and multivariate analysis of CSS
In total, 3,454 (3.07%) patients died of breast cancer. The 5-year CSS rates of patients with sPR positive breast cancer and dHR negative breast cancer were 89.03 % and 87.69%, respectively. The survival of patients with sER positive and dHR positive were much better, with 5-year CSS rates of 93.57% and 97.81% (P<0.001, Figure 1).
Multivariate analysis revealed that HoR status was an independent prognostic factor. Compared with sPR positive breast cancer, the dHR positive and sER positive breast cancer had favorable survivals (HR=0.29, 95% CI, 0.22-0.36; P<0.001; HR=0.65 ,95% CI, 0.51-0.84; P<0.001, respectively). The detail results were indicated in Table 2.
3.3 The hazard rate of death (HRD) in different phenotypes of breast cancer
The dHR positive phenotype continued to had a low level of the HRD during the disease progression. The HRD of sPR positive phenotype was higher than the other three phenotypes during the initial 1-2 years of follow-up, and then descended rapidly and successively crossed with the other three phenotypes during the 3-5 years of follow-up. However, the HRD of sPR positive phenotype decreased nearly to zero during the later years of follow-up time (Figure 2).
3.4 Analyzing treatment benefits according to HoR status in the PSM cohort
In the initial data, the sample size of patients in the chemotherapy group was fewer than non-chemotherapy group. Also, there were different baseline characteristics between these two groups (Table 1). Therefore, the PSM method was used to balance differences of baseline characteristics. A total of 21,208 patients with chemotherapy were matched with 21,208 patients without chemotherapy (Supplemental figure 2). All covariates included were well balanced between chemotherapy and non-chemotherapy groups in the PSM cohort (Supplemental table 1).
In the PSM cohort, patients with sPR positive and dHR negative phenotypes benefited significantly from chemotherapy both with P<0.001, while patients with sER positive could not benefit from chemotherapy with P=0.052 (Figure 3). Furthermore, we performed an interaction analysis using Cox model between the chemotherapy and HoR status in the PSM cohort (Figure 4). The results showed that the sPR positive phenotype benefited more from chemotherapy than dHR negative phenotype (P for interaction = 0.001). Besides, in the non-chemotherapy group, patients with sPR positive phenotype had worse survival than dHR negative phenotype with P=0.034. In the patients with chemotherapy, patients with sPR positive had similar prognosis to dHR negative with P=0.614 (Supplemental figure 3).
3.5 Systematic review of the intrinsic subtypes with sPR positive phenotype
Intrinsic molecular subtypes of breast cancer have been thoroughly studied and can indicate the existence of sPR positive phenotype [11, 12, 22]. In total, the sPR positive phenotype had a higher likelihood of being the basal-like subtype (46.15%). Normal-like and her-2 positive subtypes comprised a small proportion, accounting for 4.41%, 9.89%, respectively (Table 3).