Abstract
Patients with preeclampsia have a reduced risk of breast cancer, but it is not clear if the protective effect extends to all types of breast tumors. Our objective was to determine the association of preeclampsia with ductal, lobular, and other breast cancer histology. We conducted a longitudinal cohort study of 1,459,716 patients who had pregnancies between 1989 and 2022 in Quebec, Canada. The main exposure measure was preeclampsia. The outcome was breast cancer, including ductal, lobular, and other histological subtypes diagnosed up to 34 years after childbirth. We included in situ, localized invasive, and metastatic breast cancer. We used Cox regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between preeclampsia and breast cancer histology, adjusted for maternal characteristics. Patients with preeclampsia had a lower incidence of breast cancer than patients without preeclampsia (82.1 vs. 111.7 per 100,000 person‐years). Preeclampsia was associated with a 16% lower risk of breast cancer compared with no preeclampsia (HR 0.84, 95% CI 0.79–0.89), including a 14% lower risk of ductal (HR 0.86, 95% CI 0.81–0.93) and 31% lower risk of lobular tumors (HR 0.69, 95% CI 0.55–0.87). The protective association was present for in situ, localized invasive, and metastatic breast tumors. Preeclampsia was not associated with mucinous, medullary, papillary, or other breast cancer histology. We conclude that patients with preeclampsia are less likely to develop ductal and lobular breast cancer than patients with normotensive pregnancies, but do not have a reduced risk of other types of breast cancer.
Keywords: breast neoplasms, ductal breast carcinoma, histology, lobular carcinoma, pre‐eclampsia
What's New?
Preeclampsia is protective against breast cancer, but it is not clear if the effect extends to all breast tumors. This study examined the association between preeclampsia and breast tumor histology. The findings suggest that the protective effect of preeclampsia is concentrated among ductal and lobular tumors, but not other tumors. Patients with preeclampsia may have antiangiogenic characteristics that contribute to lowering the risk of highly vascularized breast cancers, such as ductal and lobular tumors.
Abbreviations
- CI
confidence interval
- HELLP
hemolysis, elevated liver enzymes, and low platelet count
- HR
hazard ratio
- ICD‐O‐3
International Classification of Diseases for Oncology, 3rd edition
- PlGF
placental growth factor
- sFlt‐1
soluble fms‐like tyrosine kinase 1
- VEGF
vascular endothelial growth factor
1. INTRODUCTION
Patients with preeclampsia, a hypertensive disorder of pregnancy, tend to have a reduced risk of breast cancer over their lifetime. 1 A number of studies have found that patients with preeclampsia are up to 20% less likely to develop breast cancer overall. 2 , 3 The reason for the protective effect is uncertain, but impaired angiogenesis and endothelial dysfunction are hallmarks of preeclampsia, 4 and patients with preeclampsia have been found to have poor vascular function even after pregnancy. 5 Preeclampsia could potentially reduce the risk of breast cancer by hindering the development of tumors that are highly vascularized, such as ductal and lobular tumors. 6 , 7 Tumor blood vessel formation involves processes such as angiogenesis, vasculogenesis, and neovascularization that are regulated by angiogenic factors. 6 , 8 , 9 , 10 Patients with preeclampsia typically have lower levels of proangiogenic growth factors, which may impede vascularization and decrease the chance of developing ductal and lobular breast tumors. 6
The possibility that preeclampsia may protect patients against the development of breast tumors that are more vascularized has not been considered. Researchers have instead focused on the hormone receptor status of breast tumors. However, preeclampsia seems to be just as protective against estrogen receptor positive as estrogen receptor negative tumors. 11 , 12 , 13 A study of 55,044 parous women in which 2496 developed breast cancer found that preeclampsia reduced the risk of both receptor positive and negative tumors by 20%, 11 while two reports with a combined total of 5065 women with breast cancer found that preeclampsia reduced the risk of both tumors by around 15%. 12 , 13 Moreover, analyses of premenopausal and postmenopausal tumors are conflicting, suggesting that the pathway between preeclampsia and breast cancer is not hormonal. 13 , 14 To explore the possibility that angiogenic pathways may connect preeclampsia with a reduced risk of breast cancer, we sought to determine if preeclampsia was more protective against breast tumors with ductal or lobular histology, as these tumors tend to be highly vascularized. 7
2. MATERIALS AND METHODS
2.1. Study design and population
We conducted a longitudinal retrospective cohort study of 1,459,716 pregnant women who had an in‐hospital delivery in the province of Quebec, Canada, between April 1, 1989, and March 31, 2022. We obtained information on the cohort from the Maintenance and Use of Data for the Study of Hospital Clientele registry, which contains hospital discharge records for 98% of deliveries in Quebec. The registry includes day and overnight stays for diagnostic procedures, radiation, chemotherapy, and surgery for cancer. 15
We identified pregnant patients at their first delivery and followed them over time to retrieve subsequent hospitalizations for breast cancer, with follow‐up ending March 31, 2023. The cohort excluded patients diagnosed with breast cancer prior to their first delivery.
2.2. Exposure
The main exposure measure was preeclampsia, defined as new onset of elevated blood pressure (≥140/90 mmHg) with proteinuria or involvement of neurological, hematological, uteroplacental, or other organ dysfunction after 20 weeks of gestation. 16 We classified preeclampsia as mild, severe, or superimposed. 17 Severe preeclampsia was defined as a blood pressure of 160/110 mmHg or higher and included eclampsia or HELLP (hemolysis, elevated liver enzymes, and low platelet count) syndrome. 17 Mild preeclampsia was defined as hypertension with blood pressure ranging from 140/90 to 159/109 mmHg. 17 Superimposed preeclampsia was defined as preexisting hypertension with new or worsening proteinuria or other multiorgan complications. 17
We identified patients who developed preeclampsia during their first or any subsequent pregnancy. We further categorized preeclampsia by onset (early onset before 34 weeks of gestation, late onset at 34 weeks or more), first occurrence (first pregnancy, second or later pregnancy), and recurrence (recurrent, nonrecurrent). 18 We used diagnostic codes from the ninth and tenth revisions of the International Classification of Diseases to identify patients with preeclampsia. 19
2.3. Outcome
The main outcome measure was the occurrence of breast cancer up to 34 years after pregnancy. We determined the histological subtype, including ductal, lobular, mixed ductal and lobular, mucinous, tubular, comedocarcinoid, medullary, papillary, micropapillary, neuroendocrine, cribriform, Paget's, adenocarcinoid, epithelial, sarcoma, and other rare or unspecified breast tumors. 20 Ductal and lobular tumors are the most common types of breast cancer and are known for their greater vascular involvement. 6 , 8
Additionally, we classified breast cancers by stage, including in situ, localized invasive, and metastatic tumors. We used topological and morphological codes from the third edition of the WHO International Classification of Diseases for Oncology (ICD‐O‐3) to determine the histology and tumor stage (Table S1). 20
2.4. Covariates
We accounted for potential confounding factors at the first pregnancy, including maternal age (<25, 25–29, 30–34, ≥35 years), comorbidity defined as preexisting or gestational diabetes, obesity, dyslipidemia, and alcohol, tobacco, or other substance use disorders (any vs. none), socioeconomic disadvantage (yes, no, unknown), and time period (1989–1999, 2000–2010, 2011–2022). We defined socioeconomic disadvantage as the bottom fifth of the population with the lowest levels of education, employment, and income based on neighborhood data from the Canadian census. 21
2.5. Statistical analysis
We calculated rates of ductal, lobular, and other breast cancers for patients with and without preeclampsia. We used Cox proportional hazards regression models to estimate hazard ratios (HR) and 95% confidence intervals (CI) for the association between preeclampsia and the risk of breast cancer, adjusted for maternal age, comorbidity, socioeconomic disadvantage, and time period. We examined the association of preeclampsia with breast cancer overall, as well as with breast cancer histology and stage. We used the number of days from first delivery to the first breast cancer hospitalization as the time scale, as the first admission for breast cancer approximates the time of diagnosis. 22 We censored patients who died or never developed breast cancer by the end of the study and analyzed preeclampsia as a time‐fixed exposure, as underlying endothelial dysfunction tends to be present throughout a patient's lifetime and not only during pregnancy. 23 We verified the proportional hazard assumption using survival curves. We conducted data analysis using SAS statistical software, version 9.4 (SAS Institute Inc., Cary, NC).
3. RESULTS
There were 1,459,716 patients in this study, including 74,415 (5.1%) with preeclampsia (Table 1). Patients with preeclampsia were more likely to be younger than 25 years (28.8% vs. 25.4%), have a comorbidity (16.3% vs. 9.0%), and be socioeconomically disadvantaged (21.6% vs. 18.9%) compared with no preeclampsia. Mean length of follow‐up was 17.3 years (standard deviation 9.5) for patients with preeclampsia and 19.1 years (standard deviation 10.1) for patients without preeclampsia. A total of 30,573 patients were hospitalized for breast cancer during 27,722,071 person‐years of follow‐up, with 1056 cases (1.4%) occurring among patients with preeclampsia and 29,517 (2.1%) among patients without preeclampsia.
TABLE 1.
Characteristics of patients with and without preeclampsia.
| No. patients (%) | ||
|---|---|---|
| Preeclampsia | No preeclampsia | |
| Maternal age, years | ||
| <25 | 21,464 (28.8) | 352,566 (25.4) |
| 25–29 | 26,194 (35.2) | 509,882 (36.8) |
| 30–34 | 17,549 (23.6) | 362,879 (26.2) |
| ≥35 | 9208 (12.4) | 159,974 (11.5) |
| Maternal comorbidity a | ||
| Yes | 12,140 (16.3) | 124,411 (9.0) |
| No | 62,275 (83.7) | 1,260,890 (91.0) |
| Socioeconomic disadvantage | ||
| Yes | 16,068 (21.6) | 261,239 (18.9) |
| No | 53,720 (72.2) | 1,014,464 (73.2) |
| Time period at first delivery | ||
| 1989–1999 | 23,482 (31.6) | 575,292 (41.5) |
| 2000–2010 | 26,211 (35.2) | 392,137 (28.3) |
| 2011–2022 | 24,722 (33.2) | 417,872 (30.2) |
| Total | 74,415 (100.0) | 1,385,301 (100.0) |
Preexisting or gestational diabetes, obesity, dyslipidemia, or substance use disorder.
Patients with preeclampsia had a lower incidence of breast cancer than patients without preeclampsia (Figure 1). By the end of follow‐up, there was a cumulative incidence of 41.2 breast cancers per 1000 patients with preeclampsia (95% CI 37.8–44.8), compared with 51.0 breast cancers per 1000 patients without preeclampsia (95% CI 50.1–51.8). On average, patients with preeclampsia had a lower breast cancer rate than patients without preeclampsia (82.1 vs. 111.7 per 100,000 person‐years).
FIGURE 1.
Cumulative incidence of breast cancer for patients with and without preeclampsia.
Preeclampsia was associated with a lower risk of breast cancer in adjusted regression models (Table 2). Compared with no preeclampsia, preeclampsia was associated with a 16% lower risk of any breast cancer (HR 0.84, 95% CI 0.79–0.89). Nearly all subtypes of preeclampsia were associated with a reduced risk of breast cancer compared with no preeclampsia. Severe (HR 0.84, 95% CI 0.75–0.94) and mild preeclampsia (HR 0.84, 95% CI 0.78–0.90) were both associated with a 16% lower risk of breast cancer. Patients with late onset preeclampsia, as well as primiparous or multiparous patients with nonrecurrent preeclampsia, all had similarly decreased risks of breast cancer.
TABLE 2.
Risk of breast cancer among patients with and without preeclampsia.
| Total no. women | No. with breast cancer | Rate per 100,000 person‐years | Hazard ratio (95% CI) | ||
|---|---|---|---|---|---|
| Unadjusted | Adjusted a | ||||
| Preeclampsia | |||||
| Yes | 74,415 | 1056 | 82.1 | 0.80 (0.75–0.85) | 0.84 (0.79–0.89) |
| No | 1,385,301 | 29,517 | 111.7 | Reference | Reference |
| Severity of preeclampsia | |||||
| Severe | 21,287 | 312 | 82.5 | 0.81 (0.72–0.90) | 0.84 (0.75–0.94) |
| Superimposed | 3792 | 60 | 95.0 | 0.94 (0.73–1.21) | 0.86 (0.67–1.11) |
| Mild | 49,336 | 684 | 80.9 | 0.79 (0.73–0.85) | 0.84 (0.78–0.90) |
| No preeclampsia | 1,385,301 | 29,517 | 111.7 | Reference | Reference |
| Onset of preeclampsia | |||||
| Early <34 weeks | 6860 | 125 | 102.9 | 0.99 (0.83–1.18) | 0.97 (0.82–1.16) |
| Late ≥34 weeks | 67,555 | 931 | 79.9 | 0.78 (0.73–0.84) | 0.82 (0.77–0.88) |
| No preeclampsia | 1,385,301 | 29,517 | 111.7 | Reference | Reference |
| Timing of preeclampsia | |||||
| First pregnancy | 59,526 | 866 | 86.6 | 0.85 (0.79–0.91) | 0.85 (0.80–0.91) |
| Second pregnancy or later | 14,889 | 190 | 66.2 | 0.65 (0.56–0.74) | 0.79 (0.68–0.91) |
| No preeclampsia | 1,385,301 | 29,517 | 111.7 | Reference | Reference |
| Recurrence of preeclampsia | |||||
| Recurrent, multiparous | 6308 | 80 | 70.6 | 0.81 (0.65–1.01) | 0.84 (0.68–1.05) |
| Nonrecurrent, multiparous | 42,091 | 531 | 67.7 | 0.74 (0.68–0.81) | 0.76 (0.70–0.83) |
| Preeclampsia, primiparous | 26,016 | 445 | 114.4 | 1.26 (1.15–1.38) | 0.90 (0.82–0.99) |
| No preeclampsia, primiparous | 580,512 | 14,088 | 133.8 | 1.30 (1.28–1.33) | 0.96 (0.94–0.98) |
| No preeclampsia, multiparous | 804,789 | 15,429 | 97.0 | Reference | Reference |
Adjusted for maternal age, comorbidity, socioeconomic disadvantage, and delivery period.
Preeclampsia was associated with a lower risk of breast cancer across all tumor stages (Table 3). Compared with no preeclampsia, patients with preeclampsia had a lower risk of in situ (HR 0.81, 95% CI 0.68–0.96), localized invasive (HR 0.87, 95% CI 0.79–0.94), and metastatic (HR 0.82, 95% CI 0.74–0.91) breast cancer. The protective association across different breast cancer stages was present whether preeclampsia was classified by severity, onset, timing, or recurrence, although not all reached statistical significance.
TABLE 3.
Association between preeclampsia and breast cancer stage.
| Rate per 100,000 person‐years | Hazard ratio (95% CI) a | |||||
|---|---|---|---|---|---|---|
| In situ | Localized invasive | Metastatic | In situ | Localized invasive | Metastatic | |
| Preeclampsia | ||||||
| Yes | 10.4 | 40.8 | 30.7 | 0.81 (0.68–0.96) | 0.87 (0.79–0.94) | 0.82 (0.74–0.91) |
| No | 15.0 | 54.6 | 41.5 | Reference | Reference | Reference |
| Severity of preeclampsia | ||||||
| Severe | 10.0 | 41.6 | 30.5 | 0.78 (0.57–1.08) | 0.88 (0.76–1.03) | 0.81 (0.68–0.97) |
| Superimposed | 12.6 | 50.5 | 31.5 | 0.87 (0.44–1.74) | 0.96 (0.68–1.35) | 0.75 (0.48–1.17) |
| Mild | 10.4 | 39.6 | 30.6 | 0.82 (0.66–1.01) | 0.85 (0.76–0.95) | 0.83 (0.73–0.94) |
| No preeclampsia | 15.0 | 54.6 | 41.5 | Reference | Reference | Reference |
| Onset of preeclampsia | ||||||
| Early <34 weeks | 12.3 | 52.5 | 37.7 | 0.88 (0.53–1.46) | 1.03 (0.81–1.32) | 0.94 (0.70–1.25) |
| Late ≥34 weeks | 10.2 | 39.5 | 29.9 | 0.80 (0.67–0.96) | 0.85 (0.77–0.93) | 0.81 (0.72–0.90) |
| No preeclampsia | 15.0 | 54.6 | 41.5 | Reference | Reference | Reference |
| Timing of preeclampsia | ||||||
| First pregnancy | 10.6 | 43.3 | 32.4 | 0.80 (0.66–0.97) | 0.88 (0.80–0.97) | 0.83 (0.75–0.93) |
| Second pregnancy or later | 9.4 | 32.0 | 24.7 | 0.87 (0.60–1.27) | 0.79 (0.65–0.97) | 0.76 (0.60–0.96) |
| No preeclampsia | 15.0 | 54.6 | 41.5 | Reference | Reference | Reference |
| Recurrence of preeclampsia | ||||||
| Recurrent, multiparous | 7.0 | 27.3 | 36.1 | 0.66 (0.33–1.33) | 0.69 (0.49–0.98) | 1.09 (0.80–1.48) |
| Nonrecurrent, multiparous | 9.4 | 34.7 | 23.4 | 0.82 (0.65–1.03) | 0.82 (0.73–0.93) | 0.68 (0.58–0.78) |
| Preeclampsia, primiparous | 13.3 | 56.8 | 43.7 | 0.78 (0.59–1.03) | 0.94 (0.83–1.08) | 0.90 (0.77–1.05) |
| No preeclampsia, primiparous | 18.3 | 66.5 | 48.1 | 0.95 (0.89–1.02) | 0.98 (0.95–1.02) | 0.93 (0.90–0.97) |
| No preeclampsia, multiparous | 12.8 | 46.7 | 37.1 | Reference | Reference | Reference |
Adjusted for maternal age, comorbidity, socioeconomic disadvantage, and delivery period.
Patients with preeclampsia mainly had a lower risk of ductal and lobular breast cancer (Table 4). Compared with no preeclampsia, preeclampsia was associated with a 14% lower risk of ductal (HR 0.86, 95% CI 0.81–0.93) and a 31% lower risk of lobular breast cancer (HR 0.69, 95% CI 0.55–0.87). Preeclampsia was not associated with a lower risk of mucinous, medullary, papillary, or other types of breast cancer, although the number of patients with these tumors was low. Excluding women with multiple births led to similar results (Table S2).
TABLE 4.
Association between preeclampsia and specific type of breast cancer.
| Preeclampsia | No preeclampsia | Hazard ratio (95% CI) a | ||||
|---|---|---|---|---|---|---|
| No. women | Rate per 100,000 person‐years | No. women | Rate per 100,000 person‐years | Unadjusted | Adjusted b | |
| Ductal | 853 | 66.2 | 23,004 | 86.8 | 0.83 (0.78–0.89) | 0.86 (0.81–0.93) |
| Lobular | 77 | 6.0 | 2741 | 10.3 | 0.65 (0.52–0.82) | 0.69 (0.55–0.87) |
| Mixed ductal and lobular | 54 | 4.2 | 1495 | 5.6 | 0.81 (0.61–1.06) | 0.88 (0.67–1.16) |
| Mucinous | 12 | 0.9 | 216 | 0.8 | 1.24 (0.69–2.22) | 1.28 (0.71–2.29) |
| Tubular | 5 | 0.4 | 263 | 1.0 | 0.44 (0.18–1.07) | 0.49 (0.20–1.20) |
| Comedocarcinoid | 9 | 0.7 | 254 | 1.0 | 0.72 (0.37–1.41) | 0.89 (0.46–1.72) |
| Medullary | <5 | 0.3 | 123 | 0.5 | 0.65 (0.24–1.77) | 0.79 (0.29–2.15) |
| Papillary | 10 | 0.8 | 229 | 0.9 | 1.00 (0.53–1.89) | 1.07 (0.57–2.02) |
| Micropapillary | 11 | 0.8 | 322 | 1.2 | 0.80 (0.44–1.45) | 0.79 (0.43–1.43) |
| Neuroendocrine | <5 | 0.2 | 37 | 0.1 | 1.19 (0.29–4.93) | 1.12 (0.27–4.67) |
| Cribriform | 25 | 1.9 | 538 | 2.0 | 1.09 (0.73–1.62) | 1.12 (0.75–1.68) |
| Paget's disease | 5 | 0.4 | 214 | 0.8 | 0.51 (0.21–1.25) | 0.56 (0.23–1.36) |
| Adenocarcinoid | 23 | 1.8 | 530 | 2.0 | 0.94 (0.62–1.42) | 1.01 (0.66–1.53) |
| Epithelial | 27 | 2.1 | 922 | 3.5 | 0.64 (0.43–0.93) | 0.69 (0.47–1.01) |
| Sarcoma | 5 | 0.4 | 109 | 0.4 | 0.97 (0.40–2.39) | 0.99 (0.40–2.44) |
| Other | 39 | 3.0 | 1406 | 5.3 | 0.62 (0.45–0.85) | 0.65 (0.47–0.89) |
Hazard ratio for preeclampsia compared with no preeclampsia.
Adjusted for maternal age, comorbidity, socioeconomic disadvantage, and delivery period.
4. DISCUSSION
In this longitudinal cohort study of nearly 1.5 million patients followed for up to 34 years after pregnancy, preeclampsia was associated with a lower risk of breast cancer compared with no preeclampsia. This finding was present for most variants of preeclampsia, especially severe, mild, and late onset preeclampsia. Preeclampsia was associated with a decreased risk of ductal and lobular breast cancer, while there was no association with medullary, mucinous, papillary, or other types of breast tumors. As ductal and lobular tumors tend to be highly vascularized, 7 the findings support the possibility that preeclampsia reduces the risk of breast cancer by inhibiting angiogenesis, vasculogenesis, or other processes required for neovascularization and tumor vasculature. Overall, the protective association between preeclampsia and breast cancer appears to apply primarily to ductal and lobular tumors.
A recent systematic review of more than 7 million patients from 11 different cohort studies found that preeclampsia was associated with an 11% reduction in the risk of breast cancer. 24 Yet, there is less literature on why the effect may be protective. Some investigators have explored the molecular characteristics of tumors, hypothesizing that preeclampsia might involve hormonal pathways. 11 , 12 , 13 However, an analysis of 2496 patients with breast cancer suggested that preeclampsia was equally protective against estrogen receptor positive and receptor negative tumors. 11 Studies of the timing of breast cancer also provide limited support for an underlying hormonal pathway as results have been conflicting. 13 , 14 A case–control study of 2695 parous patients demonstrated that preeclampsia was associated with lower odds of postmenopausal but not premenopausal breast tumors. 14 However, a cohort study of 1969 patients with breast cancer found that risks were lower for premenopausal but not postmenopausal tumors. 13 These mixed findings make it unclear if hormonal pathways explain the connection between preeclampsia and breast cancer.
Vascular pathways may be more plausible. 4 , 5 , 23 Preeclampsia is a systemic vascular disorder in which impaired placental development leads to an imbalance of circulating angiogenic factors with subsequent endothelial dysfunction. 4 Levels of antiangiogenic biomarkers such as soluble fms‐like tyrosine kinase 1 (sFlt‐1) increase, while proangiogenic biomarkers such as placental growth factor (PlGF) and vascular endothelial growth factor (VEGF) decrease. 5 The biomarker sFlt‐1 binds and reduces circulating levels of VEGF and PlGF, factors that are normally needed for endothelial integrity. 4 , 5 A number of studies suggest that patients with preeclampsia have an antiangiogenic predisposition throughout their lifetime, including elevated levels of sFlt‐1, sensitivity to vasoactive factors such as angiotensin II, and signs of endothelial activation as indicated by elevated levels of vascular cell adhesion molecule‐1 and intercellular adhesion molecule‐1. 23 Persistent endothelial impairment after pregnancy is thought to explain why patients with preeclampsia have an increased risk of cardiovascular disease later in life. 4 , 5 , 23
However, there have been limited efforts to examine whether the vascular phenotype of patients with preeclampsia could explain the lower incidence of breast cancer. Angiogenesis is a necessary component of tumor growth, as blood vessels are necessary to supply nutrients and oxygen for tumor development. 7 Angiogenesis drives the increase in microvessel density observed in breast carcinoma, particularly in large tumors, and differentiates malignant from benign breast disease. 25 Breast tumor angiogenesis is facilitated by agents such as VEGF and fibroblast growth factor, 26 which promote endothelial cell proliferation, migration, and vasculature formation. 7 , 27 These proangiogenic growth factors tend to be more concentrated in patients with breast cancer than in healthy individuals or patients with benign breast tumors. 7 Research has shown that VEGF expression is upregulated in malignant breast tissue, 7 , 27 especially in patients with aggressive tumors and advanced breast cancer. 26 , 28 VEGF expression is particularly high in ductal breast tumors, but is also elevated in lobular breast tumors. 7 , 29 , 30
In our study, preeclampsia was associated with a 14% lower risk of ductal and a 31% lower risk of lobular breast cancer, compared with no preeclampsia. While prior studies have not examined how preeclampsia relates to ductal and lobular breast cancer, there is evidence that angiogenic biomarker levels vary between these two types of breast tumors. 6 , 8 , 29 A study of 42 patients from the United Kingdom, including 28 patients with ductal and 10 with lobular breast tumors, found that VEGF expression in tissues was higher for ductal than lobular breast cancer. 29 VEGF levels correlate with vascular density in patients with ductal tumors. 29 In contrast, a study of 162 patients with lobular and 121 patients with ductal breast cancer from Japan found that lobular tumors had a higher quantity of immature blood vessels and that microvessel density was greater compared with ductal tumors, 8 while a study of 75 patients with ductal and 10 patients with lobular breast cancer from Poland found that levels of the soluble form of VEGF receptor type 2, which binds VEGF and inhibits angiogenic signaling, were greater for lobular than ductal tumors. 6 There is some evidence that levels of the soluble form of VEGF receptor type 2 are reduced in preeclampsia, 31 which may relate to the greater decrease in risk of lobular cancer in our study.
In the present analysis, most variants of preeclampsia were associated with a decreased risk of breast cancer. Previous analyses support the possibility that any preeclampsia reduces the risk of breast cancer, including a study from researchers in the United Kingdom where a protective effect was present regardless of the number of preeclamptic pregnancies or whether preeclampsia occurred at the first or last pregnancy. 13 In Sweden, joint analyses of data from two separate cohorts have shown that patients who have preeclampsia only once in their lifetime have a similar reduction in breast cancer risk as patients with recurrent preeclampsia. 11 The findings led the investigators to suspect that genetic factors were involved, as breast density tended to be lower for patients who had a sister with preeclampsia compared with patients whose sister did not have preeclampsia. 11 The investigators raised the possibility that variants in genes such as VEGF and FLT1 could reduce the density of breast tissue and consequently breast cancer risk. 11
Emerging recognition of the role of angiogenesis in breast tumor development has led researchers to investigate strategies to inhibit this process in order to reduce the risk of breast cancer. 32 Findings are particularly promising for bevacizumab, a monoclonal antibody targeting VEGF. 33 Bevacizumab has been shown to decrease microvessel density, restrict invasion of tumor‐associated macrophages, and inhibit the growth of breast tumors. 33 In patients with advanced breast cancer, bevacizumab can improve survival when combined with other therapies. 27 Several clinical trials have found that adding bevacizumab to neoadjuvant chemotherapy regimens results in a favorable treatment response. 28 A meta‐analysis of three phase III clinical trials found that first‐line treatment with bevacizumab combined with chemotherapy significantly improved response rates and progression‐free survival in patients with metastatic breast cancer. 34 These findings support the possibility that the antiangiogenic phenotype of patients with preeclampsia contributes to reducing the risk of breast cancer.
This study had some limitations. We used administrative hospital data which may be subject to coding errors and misclassification of variables. Misclassification of the exposure or outcome may have attenuated the associations and led to conservative associations. We did not have data on estrogen receptor status, tumor size, and genetic or molecular subtypes of breast cancer. Future research should assess the possibility that the angiogenic pathways in preeclampsia interact with the receptor status of breast tumors. We lacked data on ethnicity, breastfeeding, family history, age at menarche, menopausal status, and hormone replacement therapy. Covariates such as obesity, smoking, and alcohol use may be underreported, thus we cannot rule out residual confounding. Precision was limited for very rare types of breast cancer such as medullary and neuroendocrine tumors. Our findings are representative of a large multicultural Canadian population with publicly funded healthcare, but generalizability to other settings remains uncertain.
5. CONCLUSION
In this longitudinal cohort study of nearly 1.5 million women with more than 27,000,000 person‐years of follow‐up, preeclampsia was associated with a reduced risk of ductal and lobular breast cancer after pregnancy. The reduction in risk was more pronounced for lobular breast cancer. Preeclampsia was not associated with other types of breast tumors. As ductal and lobular tumors have elevated vascular requirements, the findings suggest that antiangiogenic mechanisms present in preeclampsia may be partially responsible for reducing the risk of certain types of breast cancer. Future research on the mechanisms linking preeclampsia with different tumors may contribute to the development of new therapeutic strategies to prevent or treat breast cancer.
AUTHOR CONTRIBUTIONS
Shu Qin Wei: Conceptualization; writing – original draft; methodology; writing – review and editing; formal analysis. Valérie Leduc: Writing – review and editing; methodology; conceptualization. Brian Potter: Writing – review and editing. Gilles Paradis: Writing – review and editing. Aimina Ayoub: Methodology; writing – review and editing; conceptualization. Jessica Healy‐Profitós: Methodology; writing – review and editing; conceptualization. Amanda Maniraho: Conceptualization; methodology; writing – review and editing. Antoine Lewin: Writing – review and editing. Nathalie Auger: Conceptualization; methodology; writing – original draft; writing – review and editing; funding acquisition; supervision.
CONFLICT OF INTEREST STATEMENT
The authors have declared no conflicts of interest.
ETHICS STATEMENT
The study adhered to the ethical guidelines of the Tri‐Council Policy Statement on Ethical Conduct for Research Involving Humans in Canada. The institutional review board of the University of Montreal Hospital Centre provided an ethics waiver, as the data were de‐identified. Informed consent was not required.
Supporting information
Data S1
ACKNOWLEDGEMENTS
This work was supported by the Heart and Stroke Foundation of Canada (G‐22‐0031974). NA acknowledges a career award from the Fonds de recherche du Québec‐Santé (296785). The sponsors were not involved in study design; in the collection, analysis, and interpretation of data; in the writing of the report; and in the decision to submit the article for publication.
Wei SQ, Leduc V, Potter B, et al. Preeclampsia and risk of breast cancer: A longitudinal cohort study of tumor histology. Int J Cancer. 2025;157(10):2025‐2032. doi: 10.1002/ijc.70025
DATA AVAILABILITY STATEMENT
The data that support the study findings are property of the Ministry of Health and Social Services of Quebec. Researchers can access the Maintenance and Exploitation of Data for the Study of Hospital Clientele registry (https://publications.msss.gouv.qc.ca/msss/document-000170/) by submitting a request to the Quebec Statistics Institute (https://statistique.quebec.ca/en/institut/services-for-researchers/submitting-a-request). Further information is available from the corresponding author upon request.
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Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Data S1
Data Availability Statement
The data that support the study findings are property of the Ministry of Health and Social Services of Quebec. Researchers can access the Maintenance and Exploitation of Data for the Study of Hospital Clientele registry (https://publications.msss.gouv.qc.ca/msss/document-000170/) by submitting a request to the Quebec Statistics Institute (https://statistique.quebec.ca/en/institut/services-for-researchers/submitting-a-request). Further information is available from the corresponding author upon request.