Patient characteristics
409,796 BC patients diagnosed between 2010–2018 were selected in this study, with a median follow-up period for 44 months. HER2 + BC (N = 64,740) accounted for 15.80% of all patients, 3.54% of which (N = 2293) were reported to develop SPMs, while HER2- BC (N = 345,056) had a higher SPM incidence of 4.63% (N = 15990). Table 1 outlines the clinicopathologic characteristics and occurrence of SPM, grouped by HER2 status at first primary BC diagnosis. All factors were statistically significantly associated with HER2 status (p < 0.001) based on Pearson’s chi-square test. For HER2 + BC patients, 11592 (17.91%) women were diagnosed aged < 45 and 26282 (40.60%) aged between 45–59, accounting for significantly higher proportions than those with HER2- BC.
Table 1 Patients Characteristics
Characteristics
|
HER2 Positive
|
HER2 Negative
|
p-value
|
|
64,740 (100.00)
|
345,056 (100.00)
|
|
Age (years), n (%)
|
|
|
< 0.001
|
< 45
|
11592 (17.91)
|
38307 (11.10)
|
|
45–59
|
26282 (40.60)
|
117291 (33.99)
|
|
60–74
|
19906 (30.75)
|
133339 (38.64)
|
|
≥ 75
|
6960 (10.75)
|
56119 (16.26)
|
|
Grade, n (%)
|
|
|
< 0.001
|
Well differentiated
|
3030 (4.68)
|
88356 (25.61)
|
|
Moderately differentiated
|
22762 (35.16)
|
152963 (44.33)
|
|
Poorly differentiated/Undifferentiated
|
35310 (54.54)
|
91326 (26.47)
|
|
Unknown
|
3638 (5.62)
|
12411 (3.60)
|
|
Stage, n (%)
|
|
|
< 0.001
|
0/I
|
24020 (37.10)
|
181579 (52.62)
|
|
II
|
23874 (36.88)
|
107334 (31.11)
|
|
III
|
9788 (15.12)
|
34492 (10.00)
|
|
IV
|
4997 (7.72)
|
13937 (4.04)
|
|
Unknown
|
2061 (3.18)
|
7714 (2.24)
|
|
HR status, n (%)
|
|
|
< 0.001
|
Negative
|
19162 (29.6)
|
45841 (13.29)
|
|
Positive
|
45578 (70.4)
|
299215 (86.71)
|
|
With SPM, n (%)
|
|
|
< 0.001
|
Yes
|
2293 (3.54)
|
15990 (4.63)
|
|
No
|
62447 (96.46)
|
329066 (95.37)
|
|
Abbreviations: HR hormone receptor, HER2 human epidermal growth factor receptor 2 |
Besides, HER2 + BC were more likely to have advanced grade and stage, and negative HR status. However, SPMs were remarkably less common in HER2 + BC patients, despite their clinicopathologic characteristics reflect more aggressive clinical courses.
Profile of SPM incidence
18,283 patients were diagnosed with at least one SPM after 2 months of first BC diagnosis, with 19,297 SPMs overall, which was significantly more than the 17,346.64 expected cases based on the rates in the general population (SIR = 1.11; 95% CI 1.10–1.13). As listed in Table 2, compared with the general population, SPM incidence was
Table 2 Standardized incidence ratios (SIRs) of second primary malignancy (SPM) only significantly elevated following HER2- BCs, of which SIR was 1.13 (95% CI 1.11-1.14; p<0.05). Based on the Poisson regression, the RR of SPMs following HER2+ versus HER2- BCs was 0.92 (95% CI 0.88-0.96; p<0.001). The results were consistent in both HR status subgroups. Regarding HR status, the SPM risk for HR- versus HR+ BC patients was significantly increased, with an RR of 1.14 (95% CI1.11-
|
HER2+
|
HER2-
|
HER2+ versus HER2-
|
|
|
SIR
|
95% CI
|
SIR
|
95% CI
|
RR (95%CI)
|
p-value
|
RR (95%CI)
|
All patients
|
1.03
|
0.99-1.07
|
1.13*
|
1.11-1.14
|
0.92 (0.88-0.96)
|
<0.001
|
|
HR status
|
|
|
|
|
|
|
|
Positive
|
1.02
|
0.98-1.07
|
1.10*
|
1.09-1.12
|
0.94 (0.88-1.00)
|
<0.001
|
Reference
|
Negative
|
1.04
|
0.97-1.12
|
1.30*
|
1.24-1.35
|
0.80 (0.74-0.88)
|
<0.001
|
1.14 (1.11-1.16)
|
Age(years)
|
|
|
|
|
|
|
|
<45
|
1.99*
|
1.75-2.44
|
2.12*
|
1.99-2.25
|
0.94 (0.82-1.07)
|
0.347
|
Reference
|
45-59
|
1.13*
|
1.06-1.21
|
1.28*
|
1.25-1.32
|
0.88 (0.82-0.95)
|
<0.001
|
0.60 (0.58-0.62)
|
60-74
|
0.87*
|
0.81-0.93
|
1.01
|
0.99-1.04
|
0.86 (0.80-0.92)
|
<0.001
|
0.47 (0.46-0.49)
|
≥75
|
0.94
|
0.85-1.04
|
1.07*
|
1.04-1.1
|
0.88 (0.79-0.98)
|
0.02
|
0.50 (0.49-0.52)
|
1.16;p<0.001). Among BC molecular subtypes, the uppermost SIR of 1.30 (95% CI 1.24-1.35) belongs to the triple negative BC. In different age subgroups, the significantly lower SPM incidence after HER2+ BCs was only consistent in patients older than 44 years. The SPM risk also decreased as patients age. It is noteworthy that HER2+ BC patients aged 60-74 had a significantly SPM incidence reduction than the general population (SIR, 0.87; 95% CI 0.81-0.93).
The impact of HER2 status on SPM risk may differ by specific SPM types, thus SPM occurrence in different sites was then profiling. The most frequent SPM sites were female breast (N=5,499 [28.50%]), followed by lung and bronchus (N=2,388 [12.38%]),
colon (N=1129 [5.85%]), corpus uteri (N=1090 [5.65%]) and thyroid (N=968 [5.02%]). Number of patients developing SPM and the SIRs of different SPM types following HER2+ vs. HER2- BC are exhibited in Fig. 1. For HER2+ BC patients, SIRs significantly greater than 1 were only observed with second thyroid cancer, renal carcinoma, leukemia and gastric cancer (site-specific SIRs were 2.38, 1.58, 1.69 and 1.51, respectively; all p <0.05). Except gastric cancer, incidence of the other three SPMs in HER2- BC survivors also significantly exceed the general population. For most SPM sites, including female breast, lung and bronchus, colon, melanoma, pancreas, SPMs with higher occurrence rates than the general population were only observed among HER2- BC patients. Poisson regression was used again to estimate different second malignancy risks according to different HER2 status. Fig. 2 demonstrated the forest plots visualizing the relative risks of HER2 positive status for SPM occurrence. Notably, only for second primary malignancies in female breast (RR, 0.89; 95% CI, 0.82-0.96;
p=0.003) and lung and bronchus (RR, 0.84; 95% CI, 0.74-0.95; p=0.007), the risks were significantly reduced after HER2+ BC in comparison to HER2- BC patients. The risk was marginally reduced for second corpus uteri cancer (RR, 0.83; 95% CI, 0.69-0.99; p=0.041). In addition, HER2 positive status was revealed to be a risk factor for second thyroid malignancy occurrence (RR, 1.22; 95% CI, 1.04-1.42; p=0.015).
Competing risk analysis
When estimating the SPM incidence, occurrence of death can compete and should be taken into account by competing risk analysis. Fig. 3 depicted the cumulative incidence of SPMs and deaths via CIF. The 5-year cumulative incidence of SPMs following first
HER2- and HER2+ BC were 5.16% and 4.09%, respectively. HER2- BC patients had a markedly higher cumulative SPM incidence than HER2+ BC patients (p<0.001), and on the contrary, lower significantly death incidence (p<0.001). To understand whether the difference of SPM cumulative incidence is solely due to the HER2 status, subdistribution hazard function was performed, as shown in Table 3. Univariate regression analysis indicated that not only HER2 status, but also age, grade, stage and HR status were correlated with SPM risk. Multivariate regression analysis further screenedHER2 status and diagnosis age as independent risk factor for SPM. HER2 positive status significantly reduced the total SPM risk (sdHR, 0.86; 95% CI, 0.82-0.90; p<0.001), in accordance with aforementioned results. However, the inconsistence was that SPM risk increased as patients diagnosed at older age (p<0.001), and HR status did not differ statistically in SPM risk (p=0.28).
In addition, multivariate proportional subdistribution hazards regression was
Table 3 Univariate and multivariate proportional subdistribution hazard regression of second primary malignancy (SPM) in breast cancer patients.
Characteristics
|
Univariate
|
Multivariate
|
sdHR (95% CIs)
|
p-value
|
sdHR (95% CIs)
|
p-value
|
Age (years)
|
|
|
|
|
<45
|
Reference
|
|
Reference
|
|
45-59
|
1.42 (1.33, 1.51)
|
<0.001
|
1.40 (1.31, 1.49)
|
<0.001
|
60-74
|
2.15 (2.02, 2.28)
|
<0.001
|
2.09 (1.96, 2.22)
|
<0.001
|
≥75
|
2.56 (2.39, 2.74)
|
<0.001
|
2.49 (2.32, 2.67)
|
<0.001
|
Grade
|
|
|
|
|
Well differentiated
|
Reference
|
|
Reference
|
|
Moderately differentiated
|
0.93 (0.90, 0.97)
|
<0.001
|
0.98 (0.94, 1.02)
|
0.29
|
Poorly differentiated/Undifferentiated
|
0.81 (0.77, 0.84)
|
<0.001
|
0.94 (0.89, 0.98)
|
0.0043
|
Unknown
|
0.80 (0.74, 0.87)
|
<0.001
|
0.91 (0.84, 0.99)
|
0.024
|
Stage
|
|
|
|
|
0/I
|
Reference
|
|
Reference
|
|
II
|
0.91 (0.88, 0.94)
|
<0.001
|
0.98 (0.95, 1.02)
|
0.31
|
III
|
0.91 (0.87, 0.96)
|
<0.001
|
1.03 (0.97, 1.08)
|
0.36
|
IV
|
0.67 (0.61, 0.74)
|
<0.001
|
0.73 (0.66, 0.80)
|
<0.001
|
Unknown
|
0.83 (0.74, 0.93)
|
0.0016
|
0.85 (0.76, 0.95)
|
0.005
|
HR status
|
|
|
|
|
Negative
|
Reference
|
|
Reference
|
|
Positive
|
1.11 (1.06, 1.15)
|
<0.001
|
0.98 (0.93, 1.02)
|
0.28
|
HER2 status
|
|
|
|
|
Negative
|
Reference
|
|
Reference
|
|
Positive
|
0.77 (0.74, 0.80)
|
<0.001
|
0.86 (0.82, 0.90)
|
<0.001
|
Abbreviations:sdHR subdistribution hazard ratios,HRhormonereceptor, HER2 human epidermal growth factor receptor 2 |
performed according to different SPM sites. For second primary BC, as well as lung and bronchus cancer, SPM risk decreased significantly after first HER2+ BC, with sdHR of 0.82 (95% CI, 0.75-0.89; p<0.001) and 0.78 (95% CI 0.68-0.90; p<0.001)respectively. Whereas, little variance on second corpus uteri cancer risk were shown between different HER2 status BC patients (sdHR, 0.79; 95% CI, 0.66-0.95; p=0.014), and no difference on second thyroid cancer risk (sdHR, 1.18; 95% CI, 1.00-1.39; p=0.053).
Kaplan-Meier survival analysis
Finally, the impact of SPM and HER2 status on OS and BCSS was analyzed (Fig. 4). Among the 18,283 BC patients with SPMs, 1828 (10.00%) died of BC, whereas 3645 (19.94%) patients died of other causes. In line with previous studies, SPM was associated with prominently worse OS (HR, 2.00; 95% CI, 1.93-2.08;p<0.0001), but sightly worsen BCSS (HR, 1.09; 95% CI, 1.03-1.14;p=0.0012). The 5-year OS probability was 74.4% (p=0.004) and 85.5% (p<0.001) for BC patients with/without SPMs. We also found a substantial difference in BCSS between HER2- and HER2+ BC patients (HR, 0.79; 95% CI, 0.77-0.82;p<0.0001) but a minor disparity in OS (HR, 0.97; 95% CI, 0.95-1.00;p=0.0221). Better survival outcomes favored negative HER2 status. For BC patients followed by SPMs, reversely, positive HER2 status was associated with superior OS (5-year OS, 76.2% vs74.2%; p=0.0011). However, no variance was shown regrading BCSS, indicating the survival difference may be attributed to other causes of death concerning SPM.