Differential Second Primary Malignancy Occurrence After Breast Cancer According to HER2 Status: A Population-Based Study

Figures & data

Table 1 Baseline Characteristics of Invasive Breast Cancer Samples in 18 SEER Registries (Excluding AK), 2010–2018

Characteristics	HER2-Positive	HER2-Negative	p-value
	64,740 (100.00)	345,056 (100.00)
Age (years)			<0.001*
<45	11,592 (17.91)	38,307 (11.10)
45–59	26,282 (40.60)	117,291 (33.99)
60–74	19,906 (30.75)	133,339 (38.64)
≥75	6960 (10.75)	56,119 (16.26)
Grade			<0.001*
Well differentiated	3030 (4.68)	88,356 (25.61)
Moderately differentiated	22,762 (35.16)	152,963 (44.33)
Poorly differentiated/undifferentiated	35,310 (54.54)	91,326 (26.47)
Unknown	3638 (5.62)	12,411 (3.60)
Stage			<0.001*
0/I	24020 (37.10)	181,579 (52.62)
II	23874 (36.88)	107,334 (31.11)
III	9788 (15.12)	34,492 (10.00)
IV	4997 (7.72)	13,937 (4.04)
Unknown	2061 (3.18)	7714 (2.24)
HR status			<0.001*
Negative	19,162 (29.6)	45,841 (13.29)
Positive	45,578 (70.4)	299,215 (86.71)
With SPM			<0.001*
Yes	2293 (3.54)	15,990 (4.63)
No	62,447 (96.46)	329,066 (95.37)

Notes: *p-value<0.05 was statistically significant using Pearson’s chi-square test.

Abbreviations: HR, hormone receptor; HER2, human epidermal growth factor receptor 2.

Table 2 Standardized Incidence Ratios (SIRs) of Second Primary Malignancy (SPM) According to HER2 Status, Stratified by HR Status and Age at Breast Cancer Diagnosis

	HER2+		HER2-		HER2+ versus HER2-
	SIR	95% CI	SIR	95% CI	RR (95% CI)	p-value
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
Negative	1.04	0.97–1.12	1.30*	1.24–1.35	0.80 (0.74–0.88)*	<0.001
Age
<45	1.99*	1.75–2.44	2.12*	1.99–2.25	0.94 (0.82–1.07)	0.347
45–59	1.13*	1.06–1.21	1.28*	1.25–1.32	0.88 (0.82–0.95)*	<0.001
60–74	0.87*	0.81–0.93	1.01	0.99–1.04	0.86 (0.80–0.92)*	<0.001
≥75	0.94	0.85–1.04	1.07*	1.04–1.1	0.88 (0.79–0.98)*	0.02

Note: *p-value<0.05.

Abbreviations: SIR, standardized incidence ratio, CI, confidence interval, RR, relative risk.

Figure 1 Standardized incidence ratios (SIRs) and patient numbers of second primary malignancies (SPM) in specific sites.

Figure 2 Site-specific Standardized incidence ratios (SIRs) and relative risks of developing second primary malignancies (SPM) after HER2+/HER2- BCs.

Table 3 Univariate and Multivariate Proportional Subdistribution Hazard Regression for Second Primary Malignancy (SPM) in Breast Cancer Patients

	Univariate		Multivariate
Characteristics	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

Note: *p-value<0.05.

Abbreviations: sdHR, subdistribution hazard ratios; HR, hormone receptor; HER2, human epidermal growth factor receptor 2.

Figure 3 Cumulative incidence curves for second primary malignancies (SPM) and deaths in HER2+ and HER2- breast cancer patients.

Figure 4 Survival curves of OS and BCSS based on (A and B) SPM occurrence; (C and D) HER2 status in all patients and (E and F) HER2 status in patients with SPMs.