By Jeffrey T. Jensen, MD, MPH
Leon Speroff Professor and Vice Chair for Research, Department of Obstetrics and Gynecology, Oregon Health & Science University, Portland
Dr. Jensen reports he receives grant/research support from and is a consultant for ObstetRx, Bayer, Merck, and Sebela Pharma; is a consultant for AbbVie, Mithra, and Daré Bioscience; and receives grant/research support from CooperSurgical and Population Council.
In a pooled analysis of prospective studies, researchers found an increased risk of breast cancer among parous women that persists for more than 20 years after childbirth. Breastfeeding did not modify this pattern.
Nichols HB, Schoemaker MJ, Cai J, et al. Breast cancer risk after recent childbirth: A pooled analysis of 15 prospective studies. Ann Intern Med 2018; Dec 11. doi: 10.7326/M18-1323. [Epub ahead of print].
In prior research evaluating the association of parity to breast cancer risk, investigators have found an increased risk during and shortly after giving birth, followed by protection. Although the increase in risk following pregnancy persists for several years, the roles of breastfeeding, family history, and specific tumor types remain controversial. To better define these relationships, the research team led by Nichols and Schoemaker used data from the Premenopausal Breast Cancer Collaborative Group, a pooling project involving 20 prospective cohort studies.1 The authors of the participating studies followed women without breast cancer younger than 55 years of age through direct contact or linkage with cancer registries. All the studies provided information on important confounders such as age, demographic characteristics, lifestyle factors, reproductive history, medical conditions, and first-degree family history of breast cancer. From this group of studies, the authors identified 15 cohorts that provided information on women’s ages at childbirth and pooled these results for a reanalysis. Information about breastfeeding status was available in 12 studies, family history in 12 studies, and tumor stage or estrogen receptor status in 13 studies.
The investigators used Cox proportional hazards regression to calculate hazard ratios (HRs) and 95% confidence intervals [CIs] for the association between time since most recent birth and breast cancer, using attained age as the underlying time scale. They adjusted these HRs for age at first birth, parity, and breastfeeding. They considered first-degree family history an effect modifier, and conducted separate analyses for positive and negative family history. The pooled results included 889,944 women who contributed 9,625,727 person-years of follow-up (mean,10.8 years; standard deviation, 6.4 years). At enrollment, 81% of the cohort were parous and an additional 8% gave birth during follow-up. The mean age at study entry was 41.8 years (range, 16.0-54.9 years). Overall, women who reported a family history of breast cancer contributed 12.4% of person-years of follow-up. Among parous women, women who reported breastfeeding contributed 72.9% of the person-years.
Compared with nulliparous women, the overall HR for breast cancer among parous women peaked 4.6 years after the most recent birth (HR, 1.80; 95% CI, 1.63-1.99). The point estimate of risk did not change from elevated to reduced until 23.6 years (CI, 21.9-25.0) after birth, decreasing to its lowest observed point (HR, 0.77; 95% CI, 0.67-0.88) 34.5 years after birth. Although the effect of a positive family history only modestly increased the risk of breast cancer among parous women (HR, 1.82; 95% CI, 1.48-2.24 at 4.9 years), the risk increased substantially (HR, 3.53; 95% CI, 2.91-4.29 at 4.9 years) using a comparison group that only included nulliparous women without a family history.
The age of first birth influenced the pattern of risk. The authors found no increased risk among women who had their first birth before age 25 years (HR, 1.06; 95% CI, 0.67-1.66 at < 1 year), but weak associations for those with first births at 25-34 years of age (HR, 1.25; 95% CI, 1.11-1.40 at 4.6 years) and 35-39 years of age (HR, 1.40; 95% CI, 1.14-1.72 at 6.4 years). In contrast, breastfeeding history did not change the overall patterns.
Tumor type only modestly influenced risk patterns for parous women relative to nulliparous. The peak HR for estrogen receptor-positive breast cancer (HR, 1.88; 95% CI, 1.62-2.20 at 5.3 years after most recent birth) crossed the null value at 25.0 years (HR, 0.90; 95% CI, 0.74-1.09). For estrogen receptor-negative breast cancer, the HR peaked at 2.2 years after birth (HR, 1.77; 95% CI, 1.34-2.33), but never crossed over to protection (HR, 1.38; 95% CI, 1.01-1.88 even 34.5 years after birth).
COMMENTARY
Nichols et al combined individual-level data from almost 1 million women collected from 15 prospective cohort studies to investigate breast cancer risk in reproductive-aged women. They found that compared to nulliparous women, parous women had an elevated breast cancer risk that peaked around five years after childbirth and lasted about 20 years. The persistence of the elevation of risk and the absence of a protective effect from breastfeeding represent novel findings. The pooling of results from several prospective studies provides a large number of subjects with incidence data on breast cancer, allowing for the calculation of hazard ratios. A notable strength is the availability of data on the number and timing of pregnancy. Breastfeeding history was available in only 12 of the 15 cohorts, making these conclusions less reliable. The large number of subjects provides sufficient statistical power to yield tight confidence intervals around the HRs. However, it is important to note that the point estimates for most of the HRs reported are under 2.0, suggesting weak associations. Although the investigators made careful and transparent efforts to reduce bias by considering potential confounders and effect modifiers, these factors were not collected in all of the studies. Thus, a careful reviewer should interpret these results with caution.
So why did I decide to highlight this study? In the February 2018 issue of OB/GYN Clinical Alert, I reported on the results of a prospective study published by Mørch et al that used Danish databases to evaluate breast cancer risk associated with the use of hormonal contraception.2 These authors reported results based on 11,517 cases of invasive breast cancer that occurred over 19.6 million woman-years of follow-up during the interval of study. Compared to never users of hormonal contraception, current and recent users of hormonal contraception showed a small increase in risk (relative risk [RR], 1.20; 95% CI, 1.14-1.26). This risk was not increased with less than one year of use (RR, 1.09; 95% CI, 0.96-1.23), but became significant after one year, peaking at 1.38 (95% CI, 1.26-1.51) after 10 years of use. Overall, the increased risk stopped rapidly after discontinuation of a hormonal method, although one analysis suggested that women using hormonal contraception for five to 10 years maintained a small increased risk up to 10 years following discontinuation (RR, 1.3; 95% CI, 1.06-1.58). Similar to the study of Nichols et al, I noted that the Mørch et al study provided some interesting results, but with weak associations that should be interpreted with extreme caution.3
The two studies demonstrate a consistent relationship. Mørch et al reported a small increased risk of breast cancer confined to current/recent but not past users of hormonal contraception. This supports the hypothesis that hormonal therapy may promote the growth of pre-existing breast cancers leading to early detection. This result was first described in the Collaborative Reanalysis study from 1996.4 The rapid disappearance of excess risk after discontinuation of use among women who used hormonal contraception for short periods is what you would expect to see if early detection is occurring with short-term use. Nichols et al provided evidence that pregnancy increases the risk of breast cancer and that the risk remains elevated for many years.
In my opinion, a notable weakness of studies evaluating breast cancer risk associated with hormonal contraceptive use has been the exclusion of pregnant women from the reference group. It now appears that both hormonal contraception and pregnancy likely accelerate the growth of prevalent breast cancers leading to earlier diagnosis. Presenting information on breast cancer risk associated with pregnancy may help frame the discussion of cancer risk associated with hormonal contraception. Fortunately, the overall excess risk remains very low.
REFERENCES
- Nichols HB, Schoemaker MJ, Wright LB, et al. The Premenopausal Breast Cancer Collaboration: A pooling project of studies participating in the National Cancer Institute Cohort Consortium. Cancer Epidemiol Biomarkers Prev 2017;26:1360-1369.
- Mørch LS, Skovlund CW, Hannaford PC, et al. Contemporary hormonal contraception and the risk of breast cancer. N Engl J Med 2017;377:2228-2239.
- Grimes DA, Schulz KF. Bias and causal associations in observational research. Lancet 2002;359:248-252.
- Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormonal contraceptives: Collaborative reanalysis of individual data on 53 297 women with breast cancer and 100 239 women without breast cancer from 54 epidemiological studies. Lancet 1996;347:1713-1727.
