General characteristics
Between 2008 and 2016, a total of 14627 females in FUSCC met the eligibility criteria. The characteristics of all patients are listed in Supplementary Table S1. Of the entire population, 6111 patients (41.787%) were diagnosed between 2008 and 2012, while 8516 patients (58.22%) were diagnosed between 2013 and 2016. The median follow-up time was 98 months between 2008 and 2012 and 58.6 months between 2013 and 2016. The age at diagnosis, menopausal status, type of surgery, neoadjuvant chemotherapy, adjuvant chemotherapy, radiotherapy, histological grade, pathological nodal stage (pN), pathological tumor size (pT) and molecular subtype differed between the two periods. We found that patients were younger and had lower pN and pT stages in 2013-2016 than in 2008-2012 (p<0.0001). Between 2008 and 2012, 15.61% of patients received BCS, whereas 22.58% of patients received BCS between 2013 and 2016 (p<0.0001). More patients received radiotherapy in 2013-2016 than in 2008-2012 (p=0.002). The proportion of patients who received neoadjuvant chemotherapy in 2013-2016 increased from 7.51% to 8.41% (p=0.049); in contrast, the proportion of who received adjuvant chemotherapy decreased from 80.64% to 72.33% compared with that in 2008-2012 (p<0.0001). We defined the period from 2013 to 2016 as the contemporary era and the period from 2008 to 2012 as the past era.
Differences in the baseline characteristics of each molecular subtype are presented in Supplementary Table S2. The characteristics of the breast cancer patients with different molecular subtypes between 2008-2012 and 2013-2016 are shown in Table 1. During 2013-2016, except for luminal B (HER2-) tumors, each type of tumor presented a lower pN stage than during 2008-2012. Compared with patients in 2008-2012, luminal A tumors had a lower histological grade in 2013-2016; in contrast, other subtypes had a higher histological grade in 2013-2016. More cases of BCS were performed across all subtypes of breast cancer in 2013-2016 than in 2008-2012. In hormone receptor (HR)-positive patients, the proportion of patients who received hormone therapy did not change, but the proportion of HER2-positive patients who received anti-HER2 therapy greatly increased in 2013-2016 compared with that in 2008-2012.
Types of recurrence
The site of the first recurrence in all populations is presented in Supplementary Table S3. Among all patients, 1429 patients (9.77%) experienced recurrence, of whom 187 patients (13.09%) had LR, 18 patients had RR (1.26%), 7 patients had (0.49%) CBC, and 866 patients (60.60%) had DM. In addition, 351 patients (25.56%) experienced more than one type of recurrence. Compared with the period from 2008-2012, during the period from 2013-2016, the proportion of patients experiencing LR and distant brain metastasis increased, and the proportion of patients experiencing distant lymph node and multiple site metastasis decreased. The site of first recurrence in patients with different molecular subtypes is presented in Supplementary Table S4. The recurrence rate of triple-negative tumors was the highest (13.16%, 258/1961), followed by that of luminal B (HER2+) tumors (11.73%, 235/2003), HER2+ tumors (11.05%, 191/1729), luminal B (HER2-) tumors (5.91%, 249/4215) and luminal A tumors (5.73%, 253/4419). The first recurrence sites among different breast cancer subtypes in 2013-2016 did not change relative to 2008-2012, except for luminal B (HER2-) tumors, for which the proportion of patients experiencing LR increased from 6.18% to 12.88% (Table 2).
Relapse-free survival analysis
Survival analysis showed that age, menopausal status, type of surgery, neoadjuvant chemotherapy, adjuvant chemotherapy, radiotherapy, year of diagnosis, histological grade, pN status, pT status and molecular subtype were related to RFS. A Cox proportional hazards regression model further proved that age, menopausal status, neoadjuvant chemotherapy, year of diagnosis, histological grade, pN status, pT status and molecular subtypes were significant predictors of recurrence-free survival (RFS) (Table 3). The patients diagnosed in 2013-2016 showed obvious improvement in recurrence-free survival compared with those diagnosed in 2008-2012 (p<0.001) (Figure 1A). In 2013-2018, the recurrence-free survival (RFS) of patients with luminal A (p<0.001), luminal B (HER2+) (p=0.005), HER2+ (p=0.044) and triple-negative tumors (p=0.014) significantly decreased compared with that in 2008-2012 (Figure 1B, 1D, 1E, 1F), except for those with luminal B (HER2-) tumors (Figure 1C) (p=0.397).
Recurrence hazard analysis
The annual recurrence hazard curve for all populations showed a three-peak pattern, with the first and maximum recurrence peak at the first year after surgery and subsequent recurrence peaks at the sixth and ninth years (Supplementary Figure S1). Similar to the entire population, luminal B (HER2-) tumors showed a three-peaked recurrence pattern, with peaks at the second, sixth and tenth years after surgery, reaching its first peak at five years after surgery. Luminal B (HER2+) tumors showed a one-peaked recurrence pattern, with maximum risk at the third year. Among all subtypes, HER2+ and triple-negative tumors demonstrated the earliest and highest risks of recurrence in the first three years after initial treatment, while LuminalA tumors displayed the slowest increase in risk compared with other subtypes. For HER2+ tumors, the recurrence risk increased rapidly and remained at a high level from five to ten years after treatment. Triple-negative tumors showed a double-peaked recurrence pattern, with the second peak occurring at the sixth year, with the recurrence then remaining low. According to the year of diagnosis, the annual recurrence risk of the entire population was obviously reduced in the 2013-2016 period compared with the 2008-2012 period, but the double-peaked pattern of recurrence did not change over the seven years of follow-up after surgery (Figure 2A). To further investigate whether contemporary treatment changed the recurrence pattern of different molecular subtypes of breast cancer, we compared the annual recurrence hazards between 2008-2013 and 2013-2016. The recurrence hazard analysis revealed that luminal A and triple-negative patients experienced a significantly lower recurrence hazard curve in 2013-2016 than in 2008-2012 (Figure 2B, 2F). Luminal A tumors in 2008-2012 presented a triple-peaked recurrence pattern, but those in 2013-2016 showed a one-peaked recurrence pattern, with the recurrence risk being reduced to a very low level after the peak at the second year (Figure 2B). The annual recurrence risk of luminal B (HER2-) and HER2+ tumors was slightly reduced in 2013-2016 compared with 2008-2012 (Figure 2C, 2D). For luminal B (HER2+) in 2013-2016, its recurrence peak was delayed to the fifth year compared with that in 2008-2012, in which it peaked at the third year after surgery (Figure 2D).