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NPJ Breast Cancer logoLink to NPJ Breast Cancer
. 2022 Jul 14;8:82. doi: 10.1038/s41523-022-00447-5

Mortality after second malignancy in breast cancer survivors compared to a first primary cancer: a nationwide longitudinal cohort study

Zhengyi Deng 1, Miranda R Jones 1,2, Mei-Cheng Wang 3, Kala Visvanathan 1,2,4,
PMCID: PMC9283416  PMID: 35835760

Abstract

Limited information exists about survival outcomes after second primary cancers (SPCs) among breast cancer survivors. Studies suggest that mortality after certain SPCs may be higher than mortality after first primary cancers (FPCs) of the same type. A cohort study was conducted among 63,424 US women using the Surveillance, Epidemiology, and End Results 18 database (2000–2016) to compare mortality after a SPC among breast cancer survivors to mortality among women after a FPC using Cox proportional hazard regression. Propensity scores were used to match survivors with SPCs to women with FPCs 1:1 based on cancer type and prognostic factors. During a median follow-up of 42 months, 11,532 cancer deaths occurred after SPCs among survivors compared to 9305 deaths after FPCs. Cumulative cancer mortality was 44.7% for survivors with SPCs and 35.2% for women with FPCs. Survivors with SPCs had higher risk of cancer death (hazard ratio (HR): 1.27, 95% CI: 1.23–1.30) and death overall (HR: 1.18, 95% CI: 1.15–1.21) than women with FPCs. Increased risk of cancer death after SPCs compared to FPCs was observed for cancer in breast, lung, colon and/or rectum, uterus, lymphoma, melanoma, thyroid, and leukemia. Estrogen receptor status and treatment of the prior breast cancer as well as time between prior breast cancer and SPC significantly modified the mortality difference between women with SPC and FPC. A more tailored approach to early detection and treatment could improve outcomes from second cancer in breast cancer survivors.

Subject terms: Cancer epidemiology, Outcomes research

Introduction

In the US, the number of breast cancer survivors is estimated to reach close to 5 million by 20301. Second primary cancer (SPC) of all types can be a life-threatening event for survivors. The estimated cumulative incidence of SPC among women with breast cancer is 20% at 25 years2,3. The incidence of SPC in breast cancer survivors is 4–40% higher than the incidence of developing a first primary cancer (FPC) among women in the general population2,47. Breast cancer survivors are at elevated risk for multiple cancer types including second breast cancer, lung cancer, endometrial cancer, ovarian cancer, and leukemia2,4. Shared genetic and environmental risk factors, as well as the toxicant effects from cancer treatments, are hypothesized to contribute to the elevated risk2,4,812.

Some studies suggest that breast cancer survivors diagnosed with a SPC may have a worse prognosis compared to a FPC of the same type13,14. There is, however, limited data on survival outcomes after a second cancer. More information is needed to determine whether survivors require a more tailored approach to early detection and treatment of second cancers. To address this knowledge gap, we used data from Surveillance, Epidemiology, and End Results (SEER) program to compare cancer and all-cause mortality after a SPC in female breast cancer survivors to women who developed a FPC over the same time period (see study design schema in Fig. 1).

Fig. 1. Study design using second colorectal cancer as an example.

Fig. 1

Colorectal cancer is one of the top 10 cancers we studied. FPC first primary cancer, SPC second primary cancer.

Results

Descriptive characteristics

The FPC and SPC groups were well matched based on propensity scores as shown in Table 1. Half of the second cancers were diagnosed within 5 years of the prior breast cancer. Prior breast cancers were primarily ER-positive (69.1%) and diagnosed at local stage (66.8%). Night-five percent of the prior breast cancers had tumor size ≤50 mm, 54% of them had negative lymph node status, and 96.4% of them received surgery. In a subgroup of 3184 breast cancer survivors diagnosed after 2010, when HER2 status was available, 68.4% of their prior breast cancers were luminal A molecular subtype (ER-positive and/or PR-positive and HER2-negative). The median follow-up time was 44 and 40 months for FPC and SPC group respectively. A comparison of FPC and SPC in the original unmatched cohort is shown in Supplementary Table 1.

Table 1.

Demographic and clinical characteristics of propensity score-matched study population identified from the SEER database.

Characteristics 1:1 PS-matched
FPC (N = 31,712), No. (%)
SPC among breast cancer survivors
(N = 31,712), No. (%)
Age of diagnosis, mean (SD), years 66.5 (13.2) 66.6 (13.1)
Race
White 26279 (82.9%) 26094 (82.3%)
Black 3442 (10.9%) 3501 (11.0%)
Other 1991 (6.3%) 2117 (6.7%)
Primary site
Breast 13903 (43.8%) 13931 (43.9%)
Lung 4900 (15.5%) 4850 (15.3%)
Colorectal 3424 (10.8%) 3351 (10.6%)
Uterus 2335 (7.4%) 2392 (7.5%)
Lymphoma 1202 (3.8%) 1191 (3.8%)
Thyroid 1237 (3.9%) 1268 (4.0%)
Melanoma 1240 (3.9%) 1261 (4.0%)
Ovary 1113 (3.5%) 1095 (3.5%)
Pancreas 1093 (3.4%) 1130 (3.6%)
Leukemia 1265 (4.0%) 1243 (3.9%)
Tumor stage
Local 16760 (52.9%) 16739 (52.8%)
Regional 7579 (23.9%) 7591 (23.9%)
Distant 7373 (23.2%) 7382 (23.3%)
Year of diagnosis
2000–2004 3397 (10.7%) 3393 (10.7%)
2005–2009 10600 (33.4%) 10592 (33.4%)
2010–2014 17715 (55.9%) 17727 (55.9%)
Surgerya
No/Unknown 8682 (27.4%) 8755 (27.6%)
Yes 23030 (72.6%) 22957 (72.4%)
Chemotherapya
No/Unknown 21497 (67.8%) 21476 (67.7%)
Yes 10215 (32.2%) 10236 (32.3%)
Radiotherapya
No/Unknown 24792 (78.2%) 24585 (77.5%)
Yes 6920 (21.8%) 7127 (22.5%)
Characteristics of the prior breast cancer
Age of diagnosis (year)
≤50 1922 (22.3%)
>50 29790 (77.7%)

Time interval between

prior breast cancer and SPC

6 months-5 years 17077 (53.9%)
>5 years 14635 (46.1%)
Tumor stage
Local 21176 (66.8%)
Regional 9441 (29.8%)
Distant 658 (2.1%)
Unknown 437 (1.4%)
Tumor grade
Grade 1 6481 (20.4%)
Grade 2 12279 (38.7%)
Grade 3&4 10289 (32.4%)
Unknown 2663 (8.4%)
Tumor size (mm)
≤10 7843 (24.7%)
>10 and ≤20 11286 (35.6%)
>20 and ≤50 8362 (26.4%)
>50 1694 (5.3%)
Unknown 2527 (8.0%)
Lymph node status
Negative 19582 (61.7%)
Positive 8785 (27.7%)
Unknown 3345 (10.5%)
ER status
Negative 6190 (19.5%)
Positive 21920 (69.1%)
Unknown 3602 (11.4%)
PR status
Negative 9088 (28.7%)
Positive 18563 (58.5%)
Unknown 4061 (12.8%)
Molecular subtypeb
ER+ or PR+/HER2− (Luminal A) 2178 (68.4%)
ER+ or PR+/HER2+ (Luminal B) 256 (8.0%)
ER- and PR−/HER2+ (HER2 Enriched) 120 (3.8%)
ER- and PR−/HER2− (Triple Negative) 359 (11.3%)
Unknown 271 (8.5%)
Surgerya
No/Unknown 1134 (3.6%)
Yes 30578 (96.4%)
Chemotherapya
No/Unknown 19567 (61.7%)
Yes 12145 (38.3%)
Radiotherapya
No/Unknown 14617 (46.1%)
Yes 17095 (53.9%)

FPC first primary cancer, SPC second primary cancer, ER estrogen receptor, PR progesterone receptor, HER2 human epidermal growth factor receptor 2, +: positive, −: negative.

aThis indicates initial treatment.

bThis variable is limited to data from 2010 and onwards (N = 3184), because HER2 status is only available after 2010.

Relative difference in the risk of death comparing SPC to FPC

During the follow-up of 197 months, 12,935 deaths (9305 from cancer) and 14,735 deaths (11,532 from cancer) occurred in FPC and SPC groups respectively. The hazard of death for SPC was greater than that for FPC for both cancer and all-cause death, although the hazard functions of two groups did begin to converge with increasing follow-up time (Fig. 2a, b). Breast cancer survivors with SPC experienced 27% increased risk of cancer death (HR:1.27, 95% CI: 1.23, 1.30) and 18% increased risk of all-cause death (HR:1.18, 95% CI: 1.15, 1.21), compared with their first cancer counterparts. Further adjustment for five racial/ethnic groups did not change the estimates. Subdistribution HR of cancer death was consistent with the HR from the Cox regression (Supplementary Table 2).

Fig. 2. Hazard function and cumulative mortality comparing SPC to matched FPC.

Fig. 2

Non-parametric hazard functions with hazard ratios (HRs) and 95% confidence intervals (CIs) for cancer mortality (a) and all-cause mortality (b). Cumulative mortality functions for cancer mortality (c) and all-cause mortality (d). SPC and FPC were matched by propensity scores calculated from race, age at diagnosis, cancer type, year of diagnosis, surgery, chemotherapy, and radiotherapy. Shaded areas in c and d show the 95% CIs of cumulative mortality. The absolute differences in 5 year, 10 year and overall mortality are provided below the figures. FPC first primary cancer, SPC second primary cancer.

The risk of dying from cancer comparing SPC to FPC for the top 10 cancer types is shown in Table 2. Increased risk of death was observed for second breast cancer (HR: 1.82, 95% CI: 1.71, 1.94), colorectal cancer (HR: 1.11, 95% CI: 1.02, 1.21), uterine cancer (HR: 1.40, 95% CI: 1.24, 1.58), lymphoma (HR: 1.15, 95% CI: 1.00, 1.32), thyroid cancer (HR: 3.09, 95% CI: 2.06, 4.61), melanoma (HR: 1.51, 95% CI: 1.18, 1.92), and leukemia (HR: 1.53, 95% CI: 1.37, 1.70). Decreased risk of death was observed for second lung cancer (HR: 0.95, 95% CI: 0.91, 1.00) even after adjustment of subtype. There was no difference in risk of death for second ovarian (HR: 1.02, 95% CI: 0.92, 1.14) and pancreatic cancer (HR: 0.97, 95% CI: 0.89, 1.06).

Table 2.

Hazard ratios (HRs) comparing cancer mortality after the second primary cancer (SPC) in breast cancer survivors to cancer mortality after the first primary cancer (FPC) for different types of cancer.

Number of cases Person-months Number of deaths HR (95% CI)a
Breast cancer 13,903 903004.5 1815 1.00 (Reference)
BC + BC 13,931 825131.5 3198 1.82 (1.71, 1.94)
ER-positive BC + BC 9069 534883.5 1842 1.77 (1.65, 1.90)
ER-negative BC + BC 3184 183208 889 1.98 (1.81, 2.17)
Lung cancer 4900 121576 3283 1.00 (Reference)
BC + Lung cancer 4850 120105 3339 0.95 (0.91, 1.00)
ER-positive BC + Lung cancer 3414 87507 2260 0.92 (0.87, 0.97)
ER-negative BC + Lung cancer 880 20057.5 659 1.10 (1.01, 1.20)
Colorectal cancer 3424 181289.5 1079 1.00 (Reference)
BC + Colorectal cancer 3351 173083 1171 1.11 (1.02, 1.21)
ER-positive BC + Colorectal cancer 2466 128772 838 1.07 (0.98, 1.18)
ER-negative BC + Colorectal cancer 515 24758.5 186 1.17 (1.00, 1.36)
Uterine cancer 2335 147537.5 433 1.00 (Reference)
BC + Uterine cancer 2392 144851.5 669 1.40 (1.24, 1.58)
ER-positive BC + Uterine cancer 1752 104264 507 1.43 (1.26, 1.63)
ER-negative BC + Uterine cancer 380 23595 88 1.30 (1.03, 1.64)
Lymphoma 1202 60396.5 391 1.00 (Reference)
BC + Lymphoma 1191 55653 448 1.15 (1.00, 1.32)
ER-positive BC + Lymphoma 921 42804.5 335 1.09 (0.95, 1.27)
ER-negative BC + Lymphoma 153 7048 66 1.51 (1.16, 1.97)
Thyroid cancer 1237 86451.5 32 1.00 (Reference)
BC + Thyroid cancer 1268 85812.5 107 3.09 (2.06, 4.61)
ER-positive BC + Thyroid cancer 926 61235 66 2.44 (1.59, 3.76)
ER-negative BC + Thyroid cancer 217 15688 24 5.05 (2.93, 8.68)
Melanoma 1240 81894.5 106 1.00 (Reference)
BC + Melanoma 1261 83854 181 1.51 (1.18, 1.92)
ER-positive BC + Melanoma 956 62150.5 129 1.34 (1.03, 1.74)
ER-negative BC + Melanoma 197 13689.5 30 2.06 (1.36, 3.10)
Ovarian cancer 1113 49886 631 1.00 (Reference)
BC + Ovarian cancer 1095 48083.5 667 1.02 (0.92, 1.14)
ER-positive BC + Ovarian cancer 684 28563 437 1.03 (0.91, 1.16)
ER-negative BC + Ovarian cancer 275 13461.5 145 1.00 (0.83, 1.20)
Pancreatic cancer 1093 12472.5 959 1.00 (Reference)
BC + Pancreatic cancer 1130 13716 999 0.97 (0.89, 1.06)
ER-positive BC + Pancreatic cancer 832 9953 742 0.97 (0.88, 1.06)
ER-negative BC + Pancreatic cancer 161 2012 139 0.99 (0.82, 1.18)
Leukemia 1265 53258 576 1.00 (Reference)
BC + Leukemia 1243 38144 753 1.53 (1.37, 1.70)
ER-positive BC + Leukemia 900 28404.5 533 1.45 (1.29, 1.63)
ER-negative BC + Leukemia 228 6510.5 144 1.79 (1.49, 2.16)

Estrogen receptor (ER) status is missing for some breast cancers.

HRs for overall, ER-positive, and ER-negative breast cancer survivors are presented separately.

FPC first primary cancer, SPC second primary cancer, HR hazard ratio, CI confidence interval, BC breast cancer, ER estrogen receptor.

aModels adjusted for race, year of diagnosis, age at diagnosis, tumor stage, and treatments (surgery, chemotherapy, and radiotherapy). For breast cancer, we further adjusted for ER status. For leukemia, we omitted surgery (it was not a treatment option) and tumor stage (all leukemia were distant stage).

The risk of cancer death differed by tumor characteristics of the prior breast cancer. The increased risk of cancer death after a SPC was accentuated in ER-negative vs ER positive breast cancer survivors when compared to FPC except for uterine cancer, which had a greater association in ER-positive survivors (Table 2). The decreased risk after second lung cancer was only observed in ER-positive survivors. In a subgroup of women diagnosed after 2010, we found a greater risk of cancer death in survivors with a second breast cancer diagnosed initially with a luminal A (HR: 2.16, 95% CI: 1.73, 2.69), luminal B (HR: 3.29, 95% CI: 1.98, 5.48), and triple negative (HR: 2.57, 95% CI: 1.85, 3.57) prior breast cancers, as compared to women with only one breast cancer (Supplementary Table 3).

We observed similar increased risk of cancer death for second breast cancers diagnosed ≥1 year (HR: 1.78, 95% CI: 1.67, 1.89), particularly for contralateral breast cancer (HR: 1.90, 95% CI: 1.78, 2.03) (Supplementary Table 4).

Relative difference in the risk of death comparing SPC to FPC restricted to survivors with local stage breast cancer

The increased risk of cancer death persisted when limited to breast cancer survivors diagnosed with local stage disease and who received surgery (N = 20,820). The followings are the type specific HRs of cancer death: second breast cancer (HR: 1.30, 95% CI: 1.20, 1.40), uterine cancer (HR: 1.27, 95% CI: 1.10, 1.45), thyroid cancer (HR: 1.87, 95% CI: 1.15, 3.04), and leukemia (HR: 1.29, 95% CI: 1.14, 1.47) (Table 3). A stronger association was observed for SPC in women initially diagnosed with an ER-negative cancer (Table 3). The associations also varied by time between prior breast cancer and SPC (Supplementary Table 5). When further restricted to survivors treated by chemotherapy (N = 5139), a greater increase in risk of cancer death was observed for second breast cancer (HR: 1.57, 95% CI: 1.40, 1.75), colorectal cancer (HR: 1.27, 95% CI: 1.06, 1.54), uterine cancer (HR: 1.82, 95% CI: 1.44, 2.29), thyroid cancer (HR: 5.18, 95% CI: 2.74, 9.82), and leukemia (HR: 1.96, 95% CI: 1.62, 2.38) (Table 4). Sensitivity analysis assuming all ER-negative survivors received chemotherapy yielded similar results (Supplementary Table 6). Among survivors treated by chemotherapy, the increased risk of cancer death became similar for ER-positive and ER-negative survivors for second breast cancer, thyroid cancer, and leukemia, but not for second lung cancer and lymphoma (Table 4). Among survivors treated by radiotherapy alone, we did not observe a greater increase in risk of cancer death after SPC. The risk of cancer death after second breast cancer, uterine cancer, and lymphoma increased further among survivors who previously received both radiotherapy and chemotherapy (Supplementary Table 7).

Table 3.

Hazard ratios (HRs) comparing cancer mortality after the second primary cancer (SPC) in breast cancer survivors (restricted to survivors with prior breast cancer of local stage and received surgery) to cancer mortality after the first primary cancer (FPC) for different types of cancer.

Number of cases Person-months Number of deaths HR (95% CI)a
Breast cancer 13,903 903004.5 1815 1.00 (Reference)
BC + BC 9000 571431 1338 1.30 (1.20, 1.40)
ER-positive BC + BC 6076 378583 798 1.24 (1.13, 1.35)
ER-negative BC + BC 1936 122156.5 373 1.50 (1.33, 1.70)
Lung cancer 4900 121576 3283 1.00 (Reference)
BC + Lung cancer 3358 83597.5 2281 0.93 (0.89, 0.99)
ER-positive BC + Lung cancer 2435 62588.5 1590 0.90 (0.85, 0.95)
ER-negative BC + Lung cancer 556 12672.5 420 1.11 (1.00, 1.23)
Colorectal cancer 3424 181289.5 1079 1.00 (Reference)
BC + Colorectal cancer 2172 118342 672 0.97 (0.88, 1.07)
ER-positive BC + Colorectal cancer 1607 88011.5 483 0.91 (0.82, 1.02)
ER-negative BC + Colorectal cancer 347 17424 116 1.17 (0.97, 1.42)
Uterine cancer 2335 147537.5 433 1.00 (Reference)
BC + Uterine cancer 1631 102150.5 403 1.27 (1.10, 1.45)
ER-positive BC + Uterine cancer 1200 73089 304 1.25 (1.07, 1.45)
ER-negative BC + Uterine cancer 250 16398 55 1.40 (1.05, 1.86)
Lymphoma 1202 60396.5 391 1.00 (Reference)
BC + Lymphoma 849 40474.5 308 1.09 (0.94, 1.27)
ER-positive BC + Lymphoma 662 31506.5 227 1.02 (0.87, 1.21)
ER-negative BC + Lymphoma 102 4598 47 1.48 (1.09, 2.01)
Thyroid cancer 1237 86451.5 32 1.00 (Reference)
BC + Thyroid cancer 772 53027.5 43 1.87 (1.15, 3.04)
ER-positive BC + Thyroid cancer 567 37790 27 1.52 (0.87, 2.64)
ER-negative BC + Thyroid cancer 127 9265 8 2.93 (1.31, 6.54)
Melanoma 1240 81894.5 106 1.00 (Reference)
BC + Melanoma 824 54725 92 1.02 (0.76, 1.37)
ER-positive BC + Melanoma 633 40854.5 67 0.87 (0.63, 1.21)
ER-negative BC + Melanoma 127 8920.5 14 1.47 (0.83, 2.61)
Ovarian cancer 1113 49886 631 1.00 (Reference)
BC + Ovarian cancer 737 33072 434 0.95 (0.84, 1.08)
ER-positive BC + Ovarian cancer 479 20143 295 0.96 (0.83, 1.10)
ER-negative BC + Ovarian cancer 177 8923.5 92 0.94 (0.75, 1.17)
Pancreatic cancer 1093 12472.5 959 1.00 (Reference)
BC + Pancreatic cancer 777 8898 696 0.96 (0.87, 1.06)
ER-positive BC + Pancreatic cancer 587 6597 531 0.97 (0.88, 1.08)
ER-negative BC + Pancreatic cancer 108 1317 94 0.97 (0.78, 1.20)
Leukemia 1265 53258 576 1.00 (Reference)
BC + Leukemia 700 23418.5 396 1.29 (1.14, 1.47)
ER-positive BC + Leukemia 512 17983.5 279 1.20 (1.04, 1.38)
ER-negative BC + Leukemia 127 3350 80 1.74 (1.37, 2.20)

Estrogen receptor (ER) status is missing for some breast cancers.

HRs for overall, ER-positive, and ER-negative breast cancer survivors are presented separately.

FPC first primary cancer, SPC second primary cancer, HR hazard ratio, CI confidence interval, BC breast cancer, ER estrogen receptor.

aModels adjusted for race, year of diagnosis, age at diagnosis, tumor stage, and treatments (surgery, chemotherapy, and radiotherapy). For breast cancer, we further adjusted for ER status. For leukemia, we omitted surgery (it was not a treatment option) and tumor stage (all leukemia were distant stage).

Table 4.

Hazard ratios (HRs) comparing cancer mortality after the second primary cancer (SPC) in breast cancer survivors (restricted to survivors with prior breast cancer of local stage and received surgery and chemotherapy) to cancer mortality after the first primary cancer (FPC) for different types of cancer.

Number of cases Person-months Number of deaths HR (95% CI)a
Breast cancer 13,903 903004.5 1815 1.00 (Reference)
BC + BC 2483 156591.5 451 1.57 (1.40, 1.75)
ER-positive BC + BC 1194 73886 210 1.63 (1.40, 1.91)
ER-negative BC + BC 1103 69579.5 207 1.57 (1.34, 1.84)
Lung cancer 4900 121576 3283 1.00 (Reference)
BC + Lung cancer 661 17218 470 1.05 (0.95, 1.15)
ER-positive BC + Lung cancer 352 9948 244 1.02 (0.89, 1.16)
ER-negative BC + Lung cancer 260 5967 190 1.12 (0.97, 1.30)
Colorectal cancer 3424 181289.5 1079 1.00 (Reference)
BC + Colorectal cancer 395 21137.5 130 1.27 (1.06, 1.54)
ER-positive BC + Colorectal cancer 211 11318 69 1.34 (1.05, 1.72)
ER-negative BC + Colorectal cancer 159 8238.5 53 1.16 (0.87, 1.53)
Uterine cancer 2335 147537.5 433 1.00 (Reference)
BC + Uterine cancer 412 26563 97 1.82 (1.44, 2.29)
ER-positive BC + Uterine cancer 248 15667 59 1.77 (1.34, 2.35)
ER-negative BC + Uterine cancer 137 8734 32 1.86 (1.29, 2.68)
Lymphoma 1202 60396.5 391 1.00 (Reference)
BC + Lymphoma 132 7611.5 39 1.27 (0.90, 1.78)
ER-positive BC + Lymphoma 84 4966.5 19 0.97 (0.61, 1.56)
ER-negative BC + Lymphoma 42 2213 19 1.88 (1.17, 3.02)
Thyroid cancer 1237 86451.5 32 1.00 (Reference)
BC + Thyroid cancer 259 17760.5 17 5.18 (2.74, 9.82)
ER-positive BC + Thyroid cancer 157 10312 8 4.58 (2.01, 10.42)
ER-negative BC + Thyroid cancer 87 6364 7 4.68 (1.97, 11.13)
Melanoma 1240 81894.5 106 1.00 (Reference)
BC + Melanoma 223 15083.5 17 1.30 (0.74, 2.28)
ER-positive BC + Melanoma 143 9516 10 1.11 (0.54, 2.29)
ER-negative BC + Melanoma 72 4967.5 6 1.56 (0.67, 3.62)
Ovarian cancer 1113 49886 631 1.00 (Reference)
BC + Ovarian cancer 219 10552.5 121 1.01 (0.82, 1.23)
ER-positive BC + Ovarian cancer 87 3924.5 54 1.18 (0.89, 1.56)
ER-negative BC + Ovarian cancer 118 5963 61 0.94 (0.72, 1.23)
Pancreatic cancer 1093 12472.5 959 1.00 (Reference)
BC + Pancreatic cancer 133 2042.5 119 1.05 (0.86, 1.28)
ER-positive BC + Pancreatic cancer 76 1208 68 1.06 (0.82, 1.36)
ER-negative BC + Pancreatic cancer 45 558.5 41 1.09 (0.79, 1.50)
Leukemia 1265 53258 576 1.00 (Reference)
BC + Leukemia 222 6548.5 141 1.96 (1.62, 2.38)
ER-positive BC + Leukemia 127 4093.5 77 1.80 (1.41, 2.31)
ER-negative BC + Leukemia 83 2253.5 54 2.00 (1.50, 2.66)

Estrogen receptor (ER) status is missing for some breast cancers.

HRs for overall, ER-positive, and ER-negative breast cancer survivors are presented separately.

FPC first primary cancer, SPC second primary cancer, HR hazard ratio, CI confidence interval, BC breast cancer, ER estrogen receptor.

aModels adjusted for race, year of diagnosis, age at diagnosis, tumor stage, and treatments (surgery, chemotherapy, and radiotherapy). For breast cancer, we further adjusted for ER status. For leukemia, we omitted surgery (it was not a treatment option) and tumor stage (all leukemia were distant stage).

Absolute difference in cumulative mortality comparing SPC to FPC

Cumulative cancer and all-cause mortality were 44.7% and 67.5% for SPC vs 35.2% and 60.4% for FPC during entire follow-up (Fig. 2c, d). For both cancer and all-cause mortality, the curves begin to diverge at 6 months post diagnosis. A greater overall cancer mortality was observed for all types of SPCs except lung and pancreatic cancer, with the absolute difference between SPC and FPC ranging from 3.7 to 15.1% (Table 5). Cumulative 5-year and 10-year cancer mortality and the absolute mortality difference between SPC and FPC by cancer type are also shown in Table 5.

Table 5.

Cumulative cancer mortality of second primary cancer (SPC) compared to first primary cancer (FPC) at 5 years, 10 years, and end of follow-up since diagnosis for different types of cancer.

5-year mortality (95% CI) (%) 10-year mortality (95% CI) (%) Overall mortality (95% CI) (%)
BC + BC 21.7 (20.9, 22.4) 30.7 (29.6, 31.7) 33.1 (31.4, 34.8)
Breast cancer 12.1 (11.6, 12.7) 17.0 (16.2, 17.8) 20.0 (18.6, 21.3)
Absolute mortality differencea 9.5 (8.6, 10.5) 13.7 (12.8, 14.6) 13.1 (11.0, 15.3)
BC + Lung cancer 69.7 (68.3, 71.0) 73.9 (72.3, 75.4) 75.4 (73.2, 77.7)
Lung cancer 67.9 (66.5, 69.3) 71.5 (70.0, 73.0) 72.7 (70.1, 75.3)
Absolute mortality difference 1.8 (−0.2, 3.7) 2.4 (0.4, 4.3) 2.7 (−0.7, 6.1)
BC + Colorectal cancer 33.7 (32.0, 35.4) 40.2 (38.2, 42.1) 40.6 (38.5, 42.6)
Colorectal cancer 30.7 (29.1, 32.3) 34.9 (33.1, 36.7) 36.9 (34.3, 39.5)
Absolute mortality difference 3.0 (0.7, 5.3) 5.3 (3.0, 7.6) 3.7 (0.4, 7.0)
BC + Uterine cancer 27.1 (25.2, 29.0) 32.3 (30.1, 34.6) 36.3 (32.3, 40.3)
Uterine cancer 18.9 (17.2, 20.5) 20.7 (18.9, 22.5) 21.2 (19.2, 23.1)
Absolute mortality difference 8.2 (5.7, 10.7) 11.6 (9.1, 14.1) 15.1 (10.7, 19.5)
BC + Lymphoma 36.4 (33.5, 39.2) 43.3 (39.8, 46.7) 47.8 (41.5, 54.0)
Lymphoma 32.0 (29.3, 34.7) 36.4 (33.2, 39.6) 37.6 (33.7, 41.6)
Absolute mortality difference 4.4 (0.4, 8.3) 6.9 (2.9, 10.8) 10.1 (2.7, 17.6)
BC + Thyroid cancer 7.6 (6.1, 9.2) 12.0 (9.4, 14.7) 14.2 (10.1, 18.3)
Thyroid cancer 2.3 (1.4, 3.2) 3.3 (1.9, 4.7) 4.2 (2.0, 6.4)
Absolute mortality difference 5.3 (3.5, 7.1) 8.7 (6.9, 10.5) 10.0 (5.3, 14.6)
BC + Melanoma 14.0 (11.9, 16.0) 19.0 (16.3, 21.7) 19.0 (16.3, 21.7)
Melanoma 8.4 (6.7, 10.0) 10.7 (8.6, 12.7) 12.1 (8.7, 15.5)
Absolute mortality difference 5.6 (2.9, 8.2) 8.3 (5.6, 11.0) 6.9 (2.5, 11.3)
BC + Ovarian cancer 57.3 (54.2, 60.5) 70.6 (67.2, 74.0) 73.1 (69.3, 76.9)
Ovarian cancer 55.1 (52.0, 58.2) 64.6 (61.1, 68.1) 66.2 (62.5, 69.8)
Absolute mortality difference 2.3 (−2.1, 6.7) 6.0 (1.6, 10.4) 6.9 (1.7, 12.2)
BC + Pancreatic cancer 89.6 (87.7, 91.5) 89.8 (87.9, 91.7) 92.4 (89.5, 95.3)
Pancreatic cancer 88.7 (86.8, 90.7) 89.7 (87.7, 91.6) 89.7 (87.7, 91.6)
Absolute mortality difference 0.9 (−1.9, 3.6) 0.1 (−2.6, 2.8) 2.7 (−0.8, 6.2)
BC + Leukemia 59.9 (57.1, 62.7) 63.9 (60.9, 67.0) 66.7 (62.4, 71.0)
Leukemia 44.4 (41.6, 47.3) 50.7 (47.4, 53.9) 52.4 (48.4, 56.5)
Absolute mortality difference 15.4 (11.5, 19.4) 13.2 (9.3, 17.2) 14.2 (8.4, 20.1)

FPC first primary cancer, SPC second primary cancer, CI confidence interval, BC breast cancer.

aAbsolute mortality difference = Mortality of SPC – Mortality of FPC.

Discussion

This large diverse population-based study examined cancer and all-cause mortality after a second cancer in breast cancer survivors and compared these risks with mortality after a first cancer matched on cancer type, race, and prognostic factors. The cumulative cancer mortality and all-cause mortality after SPCs among breast cancer survivors was 9% and 7% higher than the comparable FPCs over the same time period. The cumulative mortality curves are together at diagnosis but begin to diverge ~6 months later. Increases in cumulative mortality for survivors with SPC by cancer type ranged from 3.7 to 15.1%. Based on Cox proportional hazard models, up to a threefold elevation in risk of cancer death was observed for second cancers in the breast, lung, colon and/or rectum, uterus, lymphoma, melanoma, thyroid, and leukemia. Chemotherapy and radiotherapy treatment of the prior breast cancer, ER status, and the time between prior breast cancer and SPC significantly modified the mortality difference between women with SPC and FPC for specific cancer types.

Several prior studies have demonstrated an increased mortality among individuals with two vs one cancer. However, these studies did not stratify by type of first cancer. Zhou et al. reported an increase in all-cause mortality between 17 and 56% for second cancers with a prior history of any adulthood cancer compared to their first cancer counterparts14. Keegan et al. reported a higher mortality after SPC than FPC, with the largest increase in adolescent and young adult cancer survivors15. Studies among breast cancer survivors have been limited to second breast cancers in the contralateral breast. Consistent with our observations, some studies13,1618, although not all1922, showed that women who developed contralateral breast cancer (CBC) had increased mortality compared to those with a unilateral breast cancer, particularly if the second cancer occurred close in time to the first cancer diagnosis.

In our study, the difference in cancer mortality between second and first cancer was not observed for second ovarian and pancreatic cancer. This is likely due to the fact that patients with these two cancers often survive <6 months which is when we begin to observe a mortality difference. Zhou et al. reported a similar result for all-cause mortality14. Zhou et al. also observed that second thyroid cancer, uterine cancer, breast cancer, melanoma, and colorectal cancer had a greater all-cause mortality compared to their FPCs counterparts, which is consistent with our findings.

Treatment of the first breast cancer is one factor that could contribute to the higher mortality observed after second cancers. In our study, mortality difference between second and first breast cancer, uterine cancer, colorectal cancer, thyroid cancer, and leukemia was even larger among survivors who received chemotherapy for their first breast cancer. Radiotherapy alone however was not associated with a higher mortality difference between SPC and FPC. Further, the largest mortality difference between second and first breast cancer, uterine cancer, and lymphoma was observed among women who received both chemotherapy and radiotherapy. For second breast cancer, thyroid cancer, and leukemia, the receipt of chemotherapy explained the greater mortality difference between FPC and SPC among ER-negative survivors than ER-positive survivors, while for second lymphoma and lung cancer, there will likely be additional factors.

There are several biological explanations for a chemotherapy-associated increase in cancer mortality. Chemotherapy-related neoplasms can present with a more aggressive phenotype than sporadic cancer. A prior population-based study that compared chemotherapy and/or radiotherapy-induced acute myeloid leukemia (AML) to sporadic AML found that patients with treatment-induced AML were more likely to have adverse cytogenetics, worse response to treatment, and poor prognosis23. Clonal hematopoiesis can occur as a direct result of both chemotherapy and radiotherapy and is also associated with an increase in mortality24,25. An increased mortality was also found after a second uterine cancer among ER-positive survivors compared to a first uterine cancer. ER-positive survivors likely received hormone treatment including tamoxifen, which has been observed to cause uterine cancers that have unfavorable tumor characteristics (i.e., p53-positive, ER-negative, advanced FIGO stage, and higher grade) and a worse prognosis compared to sporadic uterine cancer2628.

In addition to direct treatment effects, other potential explanations for the mortality disparity we observed include the fact that patients diagnosed with a second cancer could receive less intensive therapy and/or for shorter duration due to worry about their health status. It is plausible that women with SPCs have greater cumulative exposure to environmental/lifestyle risk factors of cancer such as obesity or smoking that can impact both cancer incidence and mortality29. Some of the women who developed SPCs may also have an inherited genetic susceptibility associated with more aggressive cancer phenotypes30. Interestingly, our results indicate that ER-positive survivors diagnosed with a second lung cancer had a reduced mortality than women with a first lung cancer. Laccetti et al. also found that prior cancer history was associated with improved survival among advanced stage lung cancer31. This reduction in mortality could be due to the fact that cancer survivors are more likely to stop smoking compared to cancer-free individuals32.

This study has several limitations. We were not able to adjust for or stratify by lifestyle factors such as body mass index, smoking, and alcohol, that could be different between FPC and SPC. Since there could be significant misclassification among patients classified as receiving no/unknown chemotherapy, we did not compare groups with and without chemotherapy. We chose not to present cancer-specific hazard ratios (HRs), given the potential for misclassification to have occurred in recording the cause of death among women with two cancers33.

The strengths of this national study using the SEER database include the large sample size, long-term follow-up, high-quality ascertainment of cancer diagnosis and mortality, and use of propensity-score matching. This study demonstrates that breast cancer survivors with a SPC have worse survival outcomes compared to women with a FPC. Treatment for the prior breast cancer appear to only partially contribute to the worse prognosis after SPC, suggesting that there are other yet unrecognized factors that impact the survival disparity. Future studies are needed to identify those novel drivers of this large absolute difference in mortality between SPC and FPC and possibly to test different early detection and treatment strategies among subgroups of survivors based on ER status and previous treatment.

Methods

Study population and study design

The study population was identified from the SEER 18 database34. SEER is a US national program that has been in existence since 1973 that collects patient data from cancer registries. Data on race/ethnicity, multiple primary cancers, tumor characteristics, and first course of treatment was extracted from medical records by experienced cancer registrars at each registry site. Starting from 2000, SEER has expanded its coverage from 13 to 18 cancer registries across the country which represents 27.8% of the population (SEER 18).

A cohort study was conducted to compare cancer and all-cause mortality between breast cancer survivors who developed a second cancer (SPC group) and individuals who developed only one primary cancer of the same type (FPC group). Figure 1 describes the study design. The SPC group included women 18 years or older diagnosed with incident breast cancer followed by a second cancer between January 1st, 2000 and December 31st, 2014. Second cancer was defined as the diagnosis of one of ten cancers at least 6 months after the initial breast cancer. Prior studies have used varying time intervals between first and second cancer diagnosis ranging from 2 months to 1 year2,7,35. The ten cancers are the most frequent types and represent more than 80% of second cancers diagnosed in breast cancer survivors. They include breast cancer, lung cancer, colorectal cancer, uterine cancer, lymphoma, melanoma, thyroid cancer, pancreatic cancer, ovarian cancer, and leukemia. The FPC group included women diagnosed with one primary invasive cancer during the same time period. The end of follow-up for both groups was December 31st, 2016, 2 years after the date of last cancer diagnosis. Women who developed another cancer after 2014 were excluded from the analysis.

Ascertainment of cancer and tumor characteristics

Data on cancer was extracted from pathology records based on the North American Association of Central Cancer Registries’ (NAACCR) Data Standards. SEER variable “behavior code” was used to identify all invasive cancers diagnosed between January 1st, 2000 and December 31st, 2014, followed by “site recode” to classify cancer type. The “site recode” variable was created based on International Classification of Diseases for Oncology, Third Edition (ICD-O-3) histology36. The variable “sequence number” was used to determine the number of cancers.

Information was available on age, year of diagnosis, and the following tumor characteristics: stage, grade, size, lymph node status, estrogen receptor (ER) status (for breast cancer), progesterone receptor (PR) status (for breast cancer), human epidermal growth factor receptor 2 (HER2) status (for breast cancer after year of 2010), surgery (yes vs no/unknown), initial chemotherapy (yes vs no/unknown), and initial radiotherapy (yes vs no/unknown). Of note, the SEER database cannot distinguish between patients who did not have treatment and those in whom the data on treatment was missing for chemotherapy and radiotherapy, thus the original variable was classified as “no/unknown”.

Ascertainment of vital status and cause of death

SEER obtained vital status, survival time, as well as cause of death from the National Center for Health Statistics37. We excluded 6% of patients with missing data on FPC/SPC race, ethnicity, tumor stage, cause of death, or survival time for analysis.

Statistical analysis

Propensity-score matching was conducted to balance the distribution of known prognostic factors between SPC and FPC. Propensity scores were generated based on race (White, Black, and Other), age at diagnosis (continuous), calendar year of diagnosis (2000–2014), cancer types, summary tumor stage (local, regional, and distant), and treatments (surgery, chemotherapy, and radiotherapy) in women with personal breast cancer history compared to women without. Nearest-neighbor matching was conducted to match one SPC to one FPC that has the closest propensity score38. The distribution of propensity score in each group and the standardized mean difference of matched variables were generated to check the matching. Similar propensity score distribution between groups and a standardized mean difference below 0.1 indicated excellent matching.

Means (standard deviation) and proportions were calculated to summarize the demographic and tumor characteristics for the SPC group, compared with the FPC group. Among breast cancer survivors, tumor characteristics of the prior breast cancer were also described.

Time-to-event analyses were conducted to compare the mortality after SPC to FPC. The outcome variable was person-time in months from time of diagnosis of the index cancer (second cancer in the SPC group and first cancer in the FPC group) to the date of death from cancer (any type of cancer), which could be censored by date of death from other conditions, date of last contact, or December 31st, 2016, whichever came first. A half month of follow-up time was added to women with survival time of 0 month. In the matched cohort, we used R package “bshazard” to generate the non-parametric hazard functions for cancer and all-cause death comparing SPC with FPC. Hazard ratio (HR) for cancer and all-cause death with 95% confidence intervals (CI) comparing SPC with FPC were estimated from Cox proportional hazard regression. The proportional hazard assumption was checked by graphing the Schoenfeld residuals, and we did not observe major violations.

HRs for cancer death were calculated for each of the top 10 cancers (breast cancer, lung cancer, colorectal cancer, uterine cancer, lymphoma, melanoma, thyroid cancer, pancreatic cancer, ovarian cancer, and leukemia). In addition, to address potential residual confounding we also adjusted for the matching variables [race, age at diagnosis, calendar year of diagnosis, cancer type, summary tumor stage, treatments, and ER status (only in regression for second breast cancer)]. A similar analysis was completed stratified by ER status of the prior breast cancer. For second breast cancer alone in women diagnosed after 2010 we also evaluated differences by molecular subtype of their prior breast cancer (luminal A, luminal B, triple negative, and HER2 enriched). For second lung cancer, we further adjusted for tumor histology (small cell vs non-small cell lung cancer) in the Cox model.

In order to minimize the impact of the prior breast cancer on mortality outcomes, similar analyses as described above were conducted limited to breast cancer survivors diagnosed with local stage disease and received surgery. Additional analysis was also conducted by time between prior breast cancer and SPC (≤5 vs >5 years). To explore the effect that chemotherapy for their prior breast cancer may have on mortality, we further limited to survivors with local stage disease who received surgery and chemotherapy for their prior breast cancer. We could not directly compare survivors with and without chemotherapy, because patients in the “no/unknown” chemotherapy group could have received chemotherapy but this was missed by the registry. To explore the additional effect of prior radiotherapy after surgery, we conducted separate analyses among survivors with local stage disease who received surgery and radiotherapy for their first breast cancer and those who received surgery, radiotherapy, and chemotherapy.

To understand the cumulative risk of death after SPC, we graphed the cumulative mortality curves and quantified the cumulative cancer and all-cause mortality (5-year, 10-year, and overall) and mortality difference comparing SPC to FPC. Competing risk of death from other conditions was considered for cancer mortality.

The following sensitivity analyses were performed. (1) In the matched cohort, categorical variable of race/ethnicity (Non-Hispanic White, Non-Hispanic Black, Non-Hispanic American Indian or Alaska Native, Non-Hispanic Asian or Pacific Islander, and Hispanic) and locations of 18 cancer registries were further adjusted for in the model. (2) Fine and Gray model was used to obtain subdistribution HR for cancer death. (3) To evaluate the possible misclassification of recurrence as a second primary, we conducted analysis among women with second breast cancer diagnosed ≥1 year, and for ipsilateral and contralateral breast cancer separately. (4) Considering that chemotherapy is underreported in SEER, we assumed all survivors with a first ER-negative breast cancer received chemotherapy and repeated the subgroup analysis for survivors with local stage disease who received surgery and chemotherapy.

All analyses were performed in software R (version 3.6.1). Two-sided p values < 0.05 were considered statistically significant in hypothesis testing.

Ethical approval

Ethical approval is not required as data used for this study were taken from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program, which is a public database.

Supplementary information

Supplementary Tables (221.2KB, pdf)

Acknowledgements

This work was supported by the Breast Cancer Research Foundation. K.V. has received research funds from Cepheid Inc. for work unrelated to this paper and also has an ongoing research collaboration with Optra Health Inc. for work unrelated to this paper. K.V. and M.R.J are supported by P30CA006973.

Author contributions

Z.D. and K.V. conceived and designed the study. Z.D. prepared the database and conducted the analysis. Z.D. and K.V. drafted the paper. All authors contributed to the interpretation of the results and critical revision of the paper. All authors finally approved the paper.

Data availability

The data analyzed in this study were obtained from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program at https://seer.cancer.gov/.

Code availability

Codes used to generate the data are available upon reasonable request.

Competing interests

The authors declare no competing interests.

Footnotes

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

The online version contains supplementary material available at 10.1038/s41523-022-00447-5.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

Supplementary Tables (221.2KB, pdf)

Data Availability Statement

The data analyzed in this study were obtained from the National Cancer Institute Surveillance, Epidemiology, and End Results (SEER) program at https://seer.cancer.gov/.

Codes used to generate the data are available upon reasonable request.


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