Correlation between family history and characteristics of breast cancer

Family history is a major risk factor for breast cancer; approximately 5–10% cases of breast cancer are associated with a family history. Herein, we investigated the link between family history and breast cancer features to elucidate the importance of family history in the diagnosis and treatment of breast cancer. Data from 10,549 patients with breast cancer were collected from 2014 to 2017. Detailed information about the family history of the patients including the degree and number of relatives affected and the types of cancer was recorded. The tumors were pathologically and clinically classified based on the stage, grade, ER, PR, HER2, Ki-67 status, and subtypes, according to standard guidelines. Data were analyzed using χ2 test and multiple logistic regression. Patients with a family history of other cancer types were significantly older at diagnosis than patients with a family history of breast/ovarian cancer (p = 0.002) and those without a family history of cancer (p < 0.001). Patients without a family history of cancer were typically diagnosed at a later stage, including high frequency in N2 (p = 0.035) and TNM stage III (p = 0.015). Compared with patients with second-/third-degree relatives, those with first-degree relatives having breast/ovarian cancer had a higher median age (54.1, p < 0.001) at diagnosis and showed more advanced disease. No significant difference was found between ER, PR, and HER2 status in patients with and without a family history of cancer. Family history of breast cancer can influence the cancer characteristics of the patients at diagnosis, especially patient age, tumor stage, and grade.

www.nature.com/scientificreports/ cancer. In total, 2039 patients (19.3%) in our cohort had no family history of breast cancer but had other types of cancer, and 7734 patients (73.3%) had no family history of cancer. Patients were grouped based on a family history of breast/ovarian cancer (FHBO), family history of other cancer (FHO), and no family history of cancer (non-FH), and the pathological and clinical features of breast cancer were compared between these three groups.
The median age of patients in the FHO group was 54.1 years, which was significantly higher than that of patients in the FHBO (52.5 years) and non-FH (52.3 years) groups. No significant difference in age was found between patients in FHBO and non-FH groups. Histological grading showed more patients with grade I in non-FH group than in FHBO and FHO groups (p = 0.019). As the majority of patients were negative for lymph node metastasis, similar findings were observed in all three groups. Approximately 60% of patients in all three groups were classified as stage N0 (no tumor in axillary and nearby lymph nodes). Significant differences between groups were observed in the percentage of patients classified as stage N2 (4-9 axillary lymph nodes or internal mammary lymph nodes positive for tumor). Fewer patients in the FHBO group (6.8%) were classified as N2 stage, compared with the FHO (7.3%) and non-FH groups (8.8%). Further, based on the TMN staging system, patients in non-FH group (19.2%) had a significantly high proportion of stage III cancer, compared with patients in the FHBO (15.7%) and FHO (16.8%) groups. These data suggest a lower stage of cancer at diagnosis among patients who had a family history of breast/ovarian cancer and other types of cancer, compared with patients without a family history of cancer. The ER, PR, and HER2 statuses of the patients' tumors were evaluated, and no significant difference was observed between these three groups. However, the percent of luminal B subtype of breast cancer was slightly higher in the non-FH group (51.9%) than in the other groups (50.6% and 49.3%, p = 0.037). Detailed analysis is shown in Table 3.
Effect of degree of relatives in family history on breast cancer features of patients. The effect of degree of relatives with a history of breast cancer on the characteristics of breast cancer is described in  16.4% in multiple-FH) ( Table 5). A similar finding was noted when the single-FH and non-FH groups were compared. Compared with the non-FH group, the single-FH group had a higher percentage of patients with stage N0 (p = 0.042), lower percentage of patients with stage TNM-III (p = 0.016), but higher percentage of patients with higher-histological-grade tumors (p = 0.014) and those with the most aggressive subtype of breast cancer, namely TNBC (p = 0.046) ( Table 5).
Effect of number of relatives with breast/ovarian cancer on breast cancer features of patients. As previously published, having more relatives with a history of breast/ovarian cancer further increases the risk of developing breast cancer 4 . Among 617 patients with a family history of only breast/ovarian cancer, we further analyzed the relationship between the number of relatives with breast/ovarian cancer and the breast cancer features of the patients (Table 6). In total, 576 patients had only one relative with a history of breast/ ovarian cancer, and 41 patients had multiple relatives with a history of breast/ovarian cancer. Patients who had multiple family members with breast/ovarian cancer tended to have higher primary tumor stage and histologic grade, including increased percentage of T3 stage (14.6% vs. 6.6% and 6.5%, p = 0.062 and 0.05) and a greater trend of increased percentage of histologic grade III (31.7% vs. 24.1% and 20.5%, p > 0.05). Patients who had a single family member with breast/ovarian cancer had a significantly enriched TNBC subtype, compared with patients without a family history of cancer (p = 0.048; Table 6).
Comprehensive effects of all three aspects of family history. To further analyze the contribution of degree, cancer type, and number of relatives on the breast cancer features of the patients, multiple logistic regression was performed using these three factors (  18 . Family history is one of the major risk factors for developing breast cancer 3 . In this study, we collected data from 10,549 patients with breast cancer, including their tumor features and family history of cancer, and investigated the link between family history and the breast cancer characteristics of the patients. In our cohort, 7.4% of patients had a family history of breast/ovarian cancer, of which 95.9% patients had a family history of breast cancer only, a percentage that was much higher than that of patients with a family history of ovarian cancer only (3.1%) or that of both cancer types (1%). As the incidence rate of breast cancer (> 100  21 . However, in a study on the Turkish population, 23.5% of patients had a family history of breast/ovarian cancer 22 , and in a study on the European population, 32.7% of patients had a family history of breast cancer 23 . These data suggest that the percentage of patients with a family history of breast/ovarian cancer could depend on the cohort size and population. The percentage of patients with a family history of breast/ovarian cancer in our cohort falls in the normal range. Another interesting finding from our cohort is the regional aggregation of patients with breast cancer who had a family history of cancer. Significantly higher percentages of patients with family history of breast/ovarian and other types of cancer were found in patients from coastal cities, compared with those in non-coastal cities. www.nature.com/scientificreports/ The effect of coastal regions on breast cancer is still unclear. Reports by other groups have also shown a higher incidence rate of cervical cancer in coastal regions than in non-coastal regions 24 , which might be attributed to the economic prosperity of coastal cities, leading to better health care and higher diagnosis rate. Moreover, living habits, especially dietary habits, could differ between people living in coastal and non-coastal cities, which could also contribute to the different rates of a family history of breast/ovarian cancer between the two areas. In our analysis, age at diagnosis was affected the most by having a family history of cancer. We found that patients with a family history of other types of cancer had a slight but significantly higher median age than that of patients with a family history of breast/ovarian cancer or those without a family history of cancer. We also found that patients who had first-degree relatives with a history of breast/ovarian cancer were much more significantly older at diagnosis than patients who had second-/third-degree relatives with a history of breast/ovarian cancer (median age 54.1 vs. 46 years), which is consistent with other published data 22,25 . Besides the age difference, breast cancer tends to be diagnosed early (low primary tumor and TNM stages, similar tumor histologic grade) in patients with second-/third-degree relatives who have breast/ovarian cancer history, compared with patients with first-degree relatives who do not have a breast/ovarian cancer history and patients without a family history www.nature.com/scientificreports/ of cancer. Current reports mainly focus on the risk of a family history of breast cancer within first-or second-/ third-degree relatives, with a breast cancer history of first-degree relatives related to more significantly increased risk of breast cancer 26,27 . To the best of our knowledge, this is among the first reports to analyze the tumor characteristics of patients with a family history of breast cancer within first-or second-/third-degree relatives. This early diagnosis could be linked with the patients' young age and a family history of breast cancer in their second-/third-degree relatives. With around 8 years of difference in age between them and their relatives, those patients could have better access to medical service and be more educated about breast cancer. The underlying reason of the much younger age at diagnosis in patients with a family history of breast cancer in their second-/ third-degree relatives and how or whether their age could contribute to their early diagnosis of breast cancer are still unclear and warrant further investigation. www.nature.com/scientificreports/ A family history of breast/ovarian cancer has a significant impact on tumor grade and stage. Patients without a family history of cancer had the highest percentage of histologic grade I tumors (p = 0.019); however, they also had a significantly higher percentage of lymph node staging N2 (8.8% vs. 6.8% and 7.3%) and TNM staging III. These data suggest that the breast tumors of patients without a family history of cancer tend to be less aggressive, but the staging at diagnosis tends to be higher than that of patients with a family history of breast/ovarian or other types of cancer. Similar results were found in other studies. In a cohort study published by Jannot et al. on the European population, women who had a family history of breast/ovarian cancer had favorable tumor features and greater overall survival 23 . Another study focused on breast cancer in young women also showed that patients with a family history of breast cancer had smaller tumors and less lymph node positivity at diagnosis 28 . This could be attributed to the possibility that patients who have a family history of cancer are more cautious about their health, leading to early detection of their breast cancers. The degree of relatives that have a history of cancer also impacts the cancer staging of the patient at diagnosis. A significantly lower percentage of T0, N0, and TNM0 staging has been observed in patients with first-degree relatives with a history of breast/ovarian cancer, compared with those with second-/third-degree relatives with a history of breast/ovarian cancer. These data suggest a potential positive effect of the degree of relatives on cancer progression.
The effect of the type of cancer and number of relatives with cancer history on the tumor characteristics of the patients was also analyzed. Increased percentage of tumor histologic grade III was found in patients whose relatives had only breast/ovarian cancer, compared with patients whose relatives had breast/ovarian cancer and other types of cancer, and patients without a family history of cancer. Compared with patients without a family history of cancer, patients with a single relative with breast and ovarian cancer showed higher TNM stage, histologic grade, and TNBC subtype. Patients with multiple relatives with breast and ovarian cancer showed no significant difference from the other two groups. However, owing to the small number of patients during subcategorizing, there were insufficient data to provide a firm conclusion regarding the link between the number of relatives who had breast/ovarian cancer, and the cancer features of the patients.
Although the ER, PR, HER2, and Ki-67 status of the patients' tumors was not affected by their family history (degree, type, number), the breast cancer molecular subtypes were affected. Patients without a family history of cancer had a slightly increased percentage of luminal B subtype of breast cancer compared with patients without a family history of cancer (51.9% vs. 49.3%, p = 0.037). After subcategorizing, compared with patients without a family history of cancer, those with a family history of only breast/ovarian cancer had an increased percentage Table 7. Multiple logistic regression test on degree, type, and number of relatives with family history of cancer, and patients' tumor characteristics. Comparison degree: second-/third-degree versus first-degree relatives, Type family history of multiple types of cancer versus breast/ovarian cancer only, Number family breast/ovarian cancer history of multiple members versus single member. www.nature.com/scientificreports/ of TNBC (17.2% vs. 20.4%, p = 0.046), and patients with single relatives with a history of breast/ovarian cancer also had an increased percentage of TNBC (17.2% vs. 20.5%, p = 0.048). Family history could influence breast cancer subtypes potentially owing to the enrichment of inherited genetic mutations such as BRCA1 and BRCA2, which account for 30%-50% of the known mutations that cause breast cancer 29,30 . Several studies have reported that breast cancers caused by mutations in BRCA1/2 genes have specific characteristics. A study on 187 patients reported that BRCA1 mutation was associated with TNBC subtype (52.5%), and BRCA2 mutation was associated with luminal B subtype (39.8%) 31 . Another study with a cohort of 425 patients showed similar findings; the most frequently classified subtype for patients with BRCA1 mutation was TNBC (65%), and that for patients with BRCA2 mutation was luminal B subtype (40%) 32 . The increased level of TNBC and luminal B subtypes of breast cancer in patients with a family history of breast cancer in our cohort supported the rationale of enrichment of breast cancer-specific inherited mutations.
One of the major advantages of our study is the large patient cohort. We collected data from 10,549 patients to study the link between family history and breast cancer features. However, as few patients had a family history of breast/ovarian cancer (4-20%, based on literature reports), and owing to our detailed subcategorization to further characterize the degree, type, and number of relatives in breast cancer family history, the number of patients in some groups was too low to draw conclusions. In our future practice, more patient data will be collected to increase the number of patients in each subgroup of patients with a family history of breast/ovarian cancer, which will substantially enhance the strength of our analysis and help strengthen our data.
One limitation of our study is that all the patient cancer history data came from self-reporting of the patients and were not normalized to the patients' family size. Further, other types of gynecological cancer history can be mistaken for ovarian cancer history during self-reporting by patients. These factors could introduce error to the database. We were unable to analyze the relationship between patient survival and family history of cancer owing to the lack of survival data of patients. We plan to collect patient survival data from this cohort in our future studies. Another long-term study and patient follow-up are currently underway to further investigate the potential role of family history in predicting the progression-free and overall survival of patients. Another limitation of our study is that we did not have genetic mutation testing data for each patient in our cohort, so we could not make direct comparisons of the family history status between patients with or without common mutations. As stated above, considering that we found increased TNBC percentage (around 3%) in patients with a family history of breast/ovarian cancer, and BRCA1 mutation is linked with increased TNBC percentage, common genetic mutations could potentially influence our results. Further in-depth analysis with larger cohort and more family history-related data will be performed in the future.

Conclusion
After analyzing data from 10,549 patients with breast cancer, we found that patients with a family history of other types of cancer were older at diagnosis than patients with a family history of breast/ovarian cancer or those without a family history of cancer. Patients without a family history of cancer were diagnosed with more advanced disease. Patients with first-degree relatives having breast/ovarian cancer were older and diagnosed at a later stage than patients with second-/third-degree relatives with cancer were. In summary, family history of breast cancer mainly influenced patient age, tumor stage, and grade at diagnosis in our cohort.

Patients and methods
Patient data collection. In  www.nature.com/scientificreports/ Pathological and clinical classification. Surgically resected tissues or core biopsy samples that were formalin fixed and paraffin embedded were used for analysis. Cancer staging was performed based on the staging system published by the American Joint Committee on Cancer (AJCC) in 2016. Histologic grading was performed using Black's method. Breast cancer subtypes were classified by immunohistochemistry (IHC) staining of ER, PR, and HER2. ER or PR was defined as positive when more than 1% tumor cells were positive for either markers. HER2 positive was defined when the tumor IHC score of HER2 was 3+ , or when a 2+ HER2 score with HER2 gene amplification was detected by fluorescence in situ hybridization. Ki-67 high was defined when more than 20% tumor cells were positive for Ki-67 in the primary tumor, and Ki-67 low was defined when less than 20% tumor cells were positive. Breast cancer subtype classification was analyzed following St. Gallen classification of breast cancer 2017 33 . Briefly, luminal A was defined as ER and or PR (≥ 20% positive) positive, HER2 negative, and Ki-67 low. Luminal B was defined as ER and or PR positive, HER2 negative, and Ki-67 high or ER and or PR positive, HER2 positive, and any Ki-67 expression. HER2 positive subtype was defined as ER and PR negative, and HER2 positive. Triple negative breast cancer (TNBC) subtype was defined when ER, PR, and HER2 were all negative in the tumor cells.
Statistical analysis. All statistical analyses were performed using IBM SPSS 20 software. Non-parametric test was used to analyze the age differences between the patients. The χ 2 test was used to compare the tumor features (tumor stage, lymph node status, TNM stage, histologic grade, ER, PR, HER2, Ki-67 status, and molecular subtypes) of the patients. Multiple comparison was performed using Tamhane T2, with significant results indicated in the tables. Multiple logistic regression was used to analyze the independent family history variables that contributed to the differences between the tumor features of the patients. Data were considered significant when p < 0.05.

Ethics approval. This study was approved by the ethical committee of Tianjin Medical University Cancer
Institute & Hospital (bc2020070). All methods were carried out in accordance with relevant guidelines and regulations.
Informed consent. Informed consent was obtained from all participants.

Data availability
The datasets during and/or analyzed during the current study are available from the corresponding author on reasonable request.