Family History and Risk of Second Primary Breast Cancer after In Situ Breast Carcinoma

Incidence rates of in situ breast carcinomas have increased dramatically because the widespread adoption of mammography for breast cancer (1–4). More than 63,000 women are diagnosed with in situ breast cancer every year in the United States, which accounts for approximately 20% of all incident breast cancer diagnoses (4). Compared with the risk women in the general population have of developing a first primary breast cancer, women with a history of in situ breast cancer are at a substantially higher risk of developing a second primary breast cancer. The risk of a second primary in situ tumor is 4.2- to 7.2-fold higher and the risk of a second primary invasive breast cancer is 3.4- to 8.6-fold higher in in situ breast cancer survivors compared with women in the general population (5–7). Risk of a second primary breast cancer among in situ breast cancer survivors varies with patient and clinical characteristics, although current epidemiologic evidence is limited.

Family history of breast cancer has previously been shown to be associated with risk of in situ and invasive breast cancer (8–10). Compared with women without a family history of breast cancer, women with one first-degree affected relative have almost twice the risk of developing breast cancer, and women with more than one first-degree affected relative have three to four times higher risk (8, 10, 11). Younger age at diagnosis of the first-degree relative has also been shown to be associated with higher risk of breast cancer (11). Little is known about the relationship between family history of breast cancer and risk of second primary breast cancer among in situ breast cancer survivors. One previous study found that, among women with a history of in situ breast carcinoma, those with a family history of breast cancer were at a 50% increased risk of developing a second contralateral breast cancer (12). A previous study among women with invasive breast cancer found a nonsignificant increased risk of second invasive contralateral breast cancer among women with a strong family history; a significant association was observed among women with an estrogen receptor (ER)-negative second tumor (13). More studies are needed to further understand the role of family history on risk of developing a second primary breast cancer among women with in situ breast cancer.

Given the growing numbers of newly diagnosed in situ breast cancer, research aimed at identifying factors associated with second breast cancer events is needed in order to develop and/or improve risk prediction and preventive strategies. Using data from a nested case-control study of women with in situ breast cancer, we evaluated the association between first-degree family history of breast cancer and risk of developing a second in situ or invasive breast cancer.

We conducted a population-based nested case–control study designed to evaluate factors associated with risk of second primary breast cancer among women with a previously diagnosed in situ breast carcinoma. The underlying cohort consisted of women identified through the Cancer Surveillance System (CSS), the Surveillance Epidemiology and End Results population–based registry which serves western Washington State, who were diagnosed with in situ breast carcinoma between January 1, 1995, and June 30, 2013, between the ages of 30 and 79 residing in the 13-county area covered by the CSS. Women from the cohort of in situ breast carcinoma patients were classified as cases if they developed an ipsilateral or contralateral second primary breast cancer, either invasive or in situ, at least 6 months following an initial diagnosis. Patients who underwent bilateral mastectomy for their initial in situ breast carcinoma were excluded. Those who did not have a second breast cancer event during the study period were eligible as controls and were individually matched 2:1 to cases on age, year of initial in situ breast carcinoma diagnosis, county of residence at diagnosis, surgical and radiation treatment, histology, and grade of initial in situ breast carcinoma lesion. The case group consisted of 573 incident cases of second primary breast cancer and the control group consisted of 1,096 women with a history of in situ breast carcinoma who did not develop a second primary breast cancer. Among 826 identified eligible cases, 573 (69.4%) were enrolled. Among 1,951 eligible controls, 1,096 (56.2%) were enrolled. Reasons for nonparticipation included women who were unable to communicate, not interested, could not be located (particularly for those diagnosed in earlier years of the study), or did not consider themselves to be diagnosed with breast cancer because they had an in situ tumor. Both ipsilateral and contralateral second breast cancers were included in this study. All contralateral second breast cancers were considered second primary breast cancers. For ipsilateral cases, medical records based on evidence of the classification by the patients' physician were used to determine whether the second tumor was a recurrence or second primary breast cancer event. Written, informed consent was obtained from study participants and the study was approved by the institutional review board at the Fred Hutchinson Cancer Research Center.

Data on demographic, epidemiologic, and clinical factors were collected by trained interviewers via telephone and/or medical record abstraction. Information on epidemiologic risk factors, tumor characteristics, and treatment history was abstracted from medical records. Medical records were sought from all treating physicians and facilities in order to obtain complete medical information. Data were collected across multiple time points including date of first in situ diagnosis and reference date, which was the date of second primary breast cancer diagnosis for cases and assigned reference date for controls. The reference date for controls was based on the interval between the first in situ tumor and the second primary breast cancer event of the matched case. Information on family history of breast cancer was obtained through interview and medical records. Informed consent was required from all participants. After completing the study interview, women were asked to provide consent for medical record access. For deceased enrolled participants, consent was waived for medical record abstraction only. Of participants enrolled in the study, 69% had both interview and medical record data available, whereas 12% had only interview data and 19% had only medical record available.

Using conditional logistic regression, odds ratios (ORs) and their associated 95% confidence intervals (CI) were calculated to evaluate the associations between first-degree family history of breast cancer and risk of second primary breast cancer. Models were implicitly adjusted for matching factors. Other potential confounders listed in Table 1 were considered, but inclusion of these variables did not alter the observed risk estimates by at least 10% and therefore were not included in the final models presented. Potential effect modification by menopausal status, in situ breast carcinoma grade, in situ breast carcinoma treatment, in situ breast carcinoma histology/presence of comedo necrosis, and ER status and laterality of second breast cancer were considered and likelihood ratio tests were used to test these interactions. Continuous variables were used to calculate P-values for trend tests.

For analysis, variables were created using interview data as the primary source and medical review data as supplemental when interview data were missing. After combining both sources, 83 were missing data for family history of breast cancer and were excluded from all analyses. This left 43 controls with no matched case and 10 cases with no matched controls who were subsequently dropped from analyses. This resulted in 539 cases and 994 controls available for analysis. Analyses were conducted using SAS v9.3 (SAS Institute).

Cases and controls were similar with respect to age and year of first breast cancer diagnosis, grade, and treatment of first breast cancer, menopausal status at first diagnosis and reference date, and smoking status (Table 1). Cases were more likely to be overweight or obese at the first breast cancer diagnosis and reference date compared to controls. Of the 539 cases, 68% (n = 368) were invasive second primary breast cancers whereas the remaining cases were in situ tumors. More than half of the cases were diagnosed with contralateral breast cancer (n = 296), 239 were diagnosed with ipsilateral breast cancer, and four cases were diagnosed with bilateral breast cancer.

In situ breast cancer survivors with a first-degree family history of breast cancer were more likely to develop a second primary breast cancer (OR = 1.33; 95% CI, 1.05–1.69; Table 2). Survivors with two or more affected first-degree family members had a greater increased risk (OR = 1.94; 95% CI, 1.15–3.28). Further, in situ survivors whose affected relative was less than 50 years old were more likely to develop a second primary breast cancer (OR = 1.78; 95% CI, 1.24–2.57). Estimates were similar among all cases and among invasive cases only. The observed results were attenuated somewhat when analyses were limited to those women whose first in situ cancer diagnosis was ductal carcinoma in situ (DCIS). DCIS survivors with a first-degree family history of breast cancer were more likely to develop a second primary breast cancer, although it did not reach statistical significance (OR = 1.26; 95% CI, 0.97–1.63). DCIS survivors with two or more affected first-degree family members had a greater increased risk (OR = 1.78; 95% CI, 1.02–3.10) and those with affected relative was less than 50 years old were more likely to develop a second primary breast cancer (OR = 1.56; 95% CI, 1.05–2.33).

When stratified by menopausal status, an increased risk of developing a second primary breast cancer was observed among postmenopausal women (OR = 1.56; 95% CI, 1.13–2.16) but not pre-/peri-menopausal women (OR = 1.15; 95% CI, 0.77–1.71); however, the interaction was not significant (all cases P = 0.31; Table 3). An increased risk of developing a second primary breast cancer was observed for survivors with two or more affected relatives among both pre-/peri-menopausal (OR = 2.30; 95% CI, 0.97–5.48) and postmenopausal women (OR = 1.75; 95% CI, 0.88–3.49), although neither reached statistical significance. A significant increased risk of second primary breast cancer was observed for survivors with an affected relative aged less than 50 at diagnosis among both pre-/peri-menopausal women (OR = 2.02; 95% CI, 1.14–3.59) and postmenopausal women (OR = 1.80; 95% CI, 1.03–3.13).

When stratified by ER status of the second primary breast cancer, associations between first-degree family history of breast cancer and risk of developing a second primary breast cancer were only observed among those cases with ER⁺ tumors (Table 4). A first-degree family history of breast cancer was associated with an increased risk of an ER⁺ second primary breast cancer (OR = 1.49; 95% CI, 1.07–2.07), whereas no association was observed for ER⁻ second primaries (OR = 1.00; 95% CI, 0.49–2.03). Having two or more affected first-degree relatives was associated with a two-fold increased risk of ER⁺ invasive second primary breast cancer (OR = 2.04; 95% CI, 1.03–4.04) but not with ER⁻ invasive breast cancer (OR = 0.79; 95% CI, 0.07–8.97). Similarly, a stronger association among those with an affected first-degree relative diagnosed before age 50 was observed among ER⁺ invasive cases (OR = 2.03; 95% CI, 1.24–3.31) but not ER⁻ invasive cases (OR = 0.67; 95% CI, 0.24–1.86). However, a test of heterogeneity was not significant (P_{heterogeneity} = 0.16). Stratification by grade of the first in situ tumor showed a stronger association between first-degree family history of breast cancer and risk of second primary breast cancer with higher grade tumors than lower grade tumors [grade 1/2 (well differentiated/moderately differentiated): OR = 0.82; 95% CI, 0.43–1.55; grade 3/4 (poorly differentiated/no differentiation): OR = 1.40; 95% CI, 0.95–2.06), although neither reached statistical significance. No differences in risk were observed when the results were stratified by treatment for in situ breast cancer, laterality of the second breast cancer or in situ breast carcinoma histology/presence of comedo necrosis.

In this population-based case–control study among in situ breast cancer survivors, our results suggest that a first-degree family history of breast cancer was associated with an increased risk of developing a second primary breast cancer. Further, those with two or more affected first-degree relatives and those with relatives diagnosed with breast cancer before age 50 were at an even greater risk of developing a second primary breast cancer.

Previous meta-analyses have shown that family history of breast cancer is associated with a two-fold increased relative risk of developing an initial breast cancer (8, 10). Only one previous study was identified which assessed the association between family history of breast cancer and risk of developing a second primary breast cancer after in situ breast carcinoma (12). Similar to our study, this study found an increased risk of second primary breast among in situ breast cancer survivors with a family history of breast cancer. However, this increased risk was limited to contralateral breast cancer and no association was observed among women with subsequent ipsilateral breast cancer. In our study, we found no difference in the observed association by laterality of the second breast cancer. Our results also showed that risk of developing a second breast cancer after an in situ tumor increased with the number of affected relatives and with the presence of relatives affected at a younger age (<50). These factors may give additional information in determining risk for in situ breast cancer survivors.

The association between family history of breast cancer and risk of developing a second primary breast cancer among in situ breast cancer survivors was stronger among postmenopausal women than pre-/peri-menopausal women. However, further analysis showed that an increased risk was observed among all women with two or more affected relatives or an affected relative aged less than 50 years at diagnosis, regardless of menopausal status. These findings suggest that a simple assessment of the presence or absence of any first-degree family history of breast cancer (yes/no) may be insufficient for assessing family history-based risk of a second breast cancer among pre-/peri-menopausal women. More studies are needed to support this finding.

The observed increased risk of breast cancer with positive family history was observed among women whose second primary breast cancer was ER⁺ but not among those with an ER⁻ second primary breast cancer. Family history of breast cancer has been shown to be associated with both ER⁺ and ER⁻ first primary breast cancers (14). A previous study of breast cancer survivors showed that those with a family history of breast cancer had a higher risk of developing a second ER⁻ breast cancer and the association was stronger among those whose first primary breast cancer was also ER−, whereas this association was not observed among those with ER⁺ tumors (13). The authors suggested that use of anti-estrogen therapies among ER⁺ women may explain their findings. Our study primarily included cases with ER⁺ second breast cancers and we may have had limited power to detect an association among those with ER⁻ second breast cancers. We also only observed an increased risk of second breast cancers among women whose first in situ tumor was of higher grade (3 or 4) and not among those with lower grade first in situ tumors (grade 1 or 2). Tumor grade has been shown to be associated with genetic predisposition to developing both in situ and invasive breast cancer (15). Women with a family history of breast cancer may be more likely to develop higher grade tumors than those without a positive family history and therefore may be more likely to develop a second breast cancer.

Current treatment for in situ breast carcinoma typically consists of lumpectomy and radiotherapy or mastectomy. Survival rates for in situ breast carcinoma are extremely high, with one study estimating that 96% to 98% of in situ breast carcinoma patients are alive 10 years after diagnosis (16). It has been suggested that some in situ breast carcinoma patients may be unlikely to have their carcinoma progress to invasive cancer or have a recurrence and that these women may be overtreated by current standard care (17). Currently, there is no way to distinguish among in situ breast carcinoma patients with respect to future breast cancer diagnoses. More studies are needed to identify risk factors for second breast cancers among in situ breast carcinoma patients in order to better inform clinical decision making and surveillance.

Our study is the largest comprehensive, population-based study of in situ breast carcinoma survivors designed to examine risk factors for development of second breast cancers. Major strengths of our study were the large number of second primary breast cancers in our population, the comprehensive collection of data on epidemiological and clinical factors, and centralized histopathological reviews. Patient recall of information related to the first breast cancer diagnosis is a limitation, particularly among older women or women whose first diagnosis was longer ago. Modest response rates may have introduced selection bias into our study and influenced our findings. By including women who were alive as well as deceased, we achieved greater generalizability of our study. Another limitation of our study is that some women may have been unable to report whether their family members had in situ or invasive breast cancer. Future studies which are able to differentiate between family history of in situ or invasive breast cancer are needed to further explore these relationships.

In summary, our results suggest that first-degree family history of breast cancer may be an important risk factor for development of a second primary breast cancer among in situ breast cancer survivors. Further research is needed to confirm these associations and increase our understanding of the role of family history and risk of second primary breast cancer. Given the growing population of in situ breast cancer survivors, a better understanding of risk factors associated with development of a second primary breast cancer is needed to further understand risk for this group of women.

No potential conflicts of interest were disclosed.

Conception and design: K.E. Malone, P. Porter, C.I. Li

Development of methodology: K.E. Malone, P. Porter, C.I. Li

Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): P. Porter, C.I. Li

Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): M.L. Baglia, M.-T.C. Tang, P. Porter, C.I. Li

Writing, review, and/or revision of the manuscript: M.L. Baglia, M.-T.C. Tang, K.E. Malone, P. Porter, C.I. Li

Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): C.I. Li

Study supervision: C.I. Li

This study was funded by the National Cancer Institute (R01-CA097271 to C. Li). M.L. Baglia is funded by T32-CA009168.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.