Differences of demographic and clinicopathological features among IDC, ASC and SCC
After omitting censored data, an original of 557,203 female breast cancer patients were enrolled in our study. In total patients, 173 patients (3.10‱) were diagnosed as adenosquamous carcinoma of breast (ASC group) and 372 patients (6.68‱) were identified as squamous cell carcinoma (SCC group). Mean age was significantly different among the three groups, with a greater age among SCC participants; mean age were not significantly different between ASC and IDC groups. (F= 32.03, P=0.001, ANOVA, IDC vs ASC P =0.06; ASC vs SCC P =0.05; Bonferroni). More patients of other race and higher proportion of married in IDC group did not constitute a meaningful result. Compared with IDC, ASC had similar tumor size but low histological grade and less lymph node metastasis, while SCC was just the opposite. More distant metastasis of SCC leads its advanced AJCC stage at the time of diagnosis. The molecular markers of ASC were close to SCC, such as less positive rate of hormone receptors (estrogen receptor (ER): ASC 27.74% and SCC 21.53%, progesterone receptor (PR): ASC 18.06% and SCC 12.85%), barely expression of HER2 (ASC 4.44% and SCC 7.53%), which were totally different to IDC (all P < 0.05). In terms of molecular subtype of breast cancer, triple-negative and Luminal A were more common in ASC due to the absence of HER2. ASC patients underwent the same treatment as IDC (chemotherapy 36.99% vs. 41.86%, BCS 50.58% vs 52.83%, P >0.05), only with less radiotherapy (39.88% vs. 48.34%, P<0.05). The comparisons of features among the three groups were shown in Table 1.
Survival analysis among IDC, ASC and SCC patients
All breast cancer patients enrolled in our study were followed-up for a median of 78 months (range of 1 to 155 months). By the end of the follow-up period, 108397 IDC patients had died, 54543 patients died of breast cancer, with the corresponding, 48 and 170 patients in ASC and SCC group had died, of which 26 and 103 patients due to recurrence and metastasis of breast cancer. In the total sample, the OS and BCSM of three histological group had noticeable difference from those of each other (OS: IDC vs ASC P=0.001; ASC vs SCC P=0.001, BCSM: IDC vs ASC P=0.008; ASC vs SCC P=0.001, log-rank test) (Fig.1A1B).
Survival analysis between IDC and ASC patients in PS matched groups
The propensity score matching method (Match Ratio 1:1; Logit model; the nearest neighbor matching approach) was employed to eliminate the bias of demographic and clinicopathological features between ASC and IDC groups. Because almost no expression of HER2 in ASC, we assumed the missing HER2 in ASC records before 2010 as negative to retain as many matched cases as possible. After matching, the hypothesis test showed that except for race, there was no statistical difference in the mean standard deviation of each variable between the two groups (Table 2). The kernel density functions showed that the general features between ASC group and IDC group (143 patients from the original ASC and IDC group respectively) were similar (Fig.1C1D). After PSM, 22 of 143 patients in IDC group had died, 13 of whom owing to breast cancer. Accordingly, 19 patients died from breast cancer in 34 death cases of ASC. The OS and BCSM curve of ASC and IDC groups interwove with each other (P=0.645 for OS and P=0.596 for BCSM, log-rank test) (Fig.1E1F). The prognosis of ASC seemed not inferior to that of IDC.
Clinical outcomes of IDC, ASC and SCC in different breast cancer subtype groups
Molecular subtypes of breast cancer play an essential role in guiding clinical treatment and predicting prognosis. In ASC group, the absence of HER2 expression led us to divide ASC into triple negative and luminal A only through hormone receptor expression. In HR-negative subgroup, we found that the OS and BCSM of ASC patients were close to that of IDC (P=0.736 for OS and P=0.226 for BCSM, log-rank test) (Fig.2A2C). The prognosis of IDC and ASC with negative HR receptor was better than that of SCC with the same immunophenotype (all P < 0.05 for OS and BCSM between groups, log-rank test). On the contrary, in HR-positive subgroup, the prognosis of ASC was poor, which was similar to that of SCC (OS: IDC vs ASC P=0.001; ASC vs SCC P=0.193, BCSM: IDC vs ASC P=0.001; ASC vs SCC P=0.470, log-rank test) (Fig.2B2D). The five-year survival rate of ASC with HR-positive was only about 60%, which was far less than that in the HR-negative subgroup (Fig.2C2D).
Cox proportional hazards models for OS and BCSM
To further investigate the effect of baseline characteristics on prognosis of breast cancer, the multivariate Cox proportional hazards model was utilized to fitted for OS and BCSM. As shown in Table 3, as the consensus that had been achieved, demographic factors such as older age, black race and unmarried were the poor prognostic factors for breast cancer, clinicopathological features such as higher histological grade, larger tumor size, more lymph node metastasis and negative expression of HR/HER2 related to poor prognosis of breast cancer. Standard mastectomy/breast conserving surgery and adjuvant radiotherapy/chemotherapy brought survival benefits to the patients (all P<0.05 for HR). However, after adjusting other prognostic factors, histology type of ASC was no longer an independent prognostic factor in multivariate analysis (HR=0.93 for BCSM, 95% CI 0.35-2.47, P=0.880; HR=1.06 for OS, 95% CI 0.53-2.12, P=0.866) (Table 3). We also analyzed the variables potentially influencing OS and BCSM of ASC by Cox proportional hazards model and Table 4 showed that older age (age≥60) and advanced AJCC stage (III and IV) were independent factors of poor prognosis in ASC (all P<0.05 for HR). BCS had the same therapeutic effect as mastectomy for OBC patients (HR =1.45 for BCSM P=0.530, HR =0.93 for OS P=0.857). Chemotherapy and radiotherapy also failed to bring significant survival benefits to ASC patients (all P>0.05 for HR).