Risk factors of developing contralateral breast cancer after first primary breast cancer treatment

Abstract Background Breast cancer (BC) is the most common cancer among women worldwide. Increased survival of primary BC (PBC) has increased contralateral breast cancer (CBC) and become a health problem. Aims This study aimed to determine the effect of disease‐free interval (DFI), risk factors and PBC characteristics on the progression of CBC within primary BC survivors. Methods and Results This retrospective study identified 5003 women diagnosed with breast cancer between 2000 and 2020 in the cancer research center. The study included 145 CBC and 4858 PBC survivors, with CBC diagnosed at least 6 months after the detection of primary BC. ER+, PR+, and HER2+ were reported in 72.13%, 66.67%, and 30% of CBC patients. Invasive ductal carcinoma (IDC) BC was reported in 69.57% of patients, and 81.90% and 83.64% of the patients were treated with adjuvant chemotherapy and external radiotherapy. The Kaplan–Meier method indicated that the median time interval between PBC and CBC was 3.92 years, and the 5‐year DFI was 97%. The Cox proportional hazard regression model indicated that although more than half of the participants had no family history of BC (69.57%), women 60 years and older were negatively associated with CBC. Conclusion This study provides the first investigation of CBC and DFI risk factors among PBC survivors in Iran. Age was found to be negatively associated with CBC development particularly after the age of 60, indicating the necessity of tracking CBC survivors carefully in this age group.

patients. 3,4Genetic susceptibility, long-term effects of PBC treatment, and shared risk factors between the first and second BCs are likely to contribute to this increased risk. 5The number of PBC survivors is increasing, and the increased survival time has led to a significant increase in the chance of CBC. 6 Second primary cancers can occur due to environmental risk, genetic, lifestyle, or treatment-related factors. 7The most important risk factors for CBC include reproductive factors, lobular histology, mutation of BRCA1/BRCA2, and family history of BC. 8 However, breast cancer is a heterogeneous disease, and environmental risk factors affect CBC development, leading to the necessity of studies within distinct environmental populations.
Although many studies have been conducted on the risk factors and epidemiology of breast cancer, 3,9 less research has been published on the related factors of CBC particularly within Iran.Therefore, this study aims to address the risk factors of developing CBC after treating the PBC in Iran.The study assesses the DFI of patients with PBC as well as the incidence, clinicopathologic features, and DFI of CBC, providing necessary insight into PBC monitoring.Based on prior reports, DFI is categorized into the first 5 years after the primary tumors detection (short DFI) and the following years (long DFI).Long DFI is associated with a better prognosis and favorable outcomes. 10

| Inclusion and exclusion
For this study, we followed patients treated for PBC to detect CBC and calculate DFI.
• The study focused on metachronous breast cancers, defined as tumors that manifested at least 6 months after the initial tumor diagnosis. 11The patients who had synchronous or metachronous tumors at the time of admission were excluded from the study.
• Patients with bilateral synchronous BC (the presence of cancer in both breasts diagnosed within a short interval of time, usually within 3-6 months) were also excluded from the study.
• Individuals with a follow-up period of less than 180 days were excluded from the study.

| Data analysis
Descriptive analysis was conducted on the total sample of 5003 participants enrolled in the study.The chi-square test was used for categorical variables, and the t-test was used for continuous variables.
Variables investigated include age, tumor size, ER and PR status, HER2 status, breast histology, chemotherapy, radiotherapy, lymph vascular invasion, family history, lymph node metastasis, hormone therapy, type of surgery, triple negative status, stage, and grade.All the variables with a p-value less than .2or most of the levels had a p-value less than .2 in univariable analysis were included in the multivariable analysis.
The Kaplan-Meier curve was plotted to estimate the probabilities of 1-, 5-, 10-, and 20-year DFI.The proportional hazards assumption was tested using the Schoenfeld residual test followed by the Cox proportional hazard regression model was adopted to estimate the crude and adjusted hazard ratio (HR) and its confidence interval for the risk of CBC.The results of the multivariable analysis were expressed as HR and 95% CI.The significance level of 5% was considered for a statistically significant association.
Stata (version 14.0; Stata Corp., Texas, USA) software was used to for all statistical tests.

| Study characteristics
A total of 5515 women diagnosed with PBC during the study's follow-up time were reviewed.We excluded 375 bilateral synchronous breast cancer patients and 137 patients with incomplete profiles.
In total, this allowed us to study 5003 PBC patients.
Of the selected patients, 145 (2.9%) progressed to CBC within the following years after treatment.The median age of these patients was 47 (range 17-78).All the other 4858 patients with a median age of 48 (range 17-90) were considered the PBC group.The median time interval between PBC and CBC was 3.92 years (confidence interval: 3.55-4.49).Of the patients who developed CBC, 36.92% were younger than 45 years old and more than half of the patients (57.65%) had a tumor size of 2-4 cm.Compared to patients with PBC, 61.54% of tumors in patients with CBC were 2-4 cm in size.
Invasive ductal carcinoma (IDC) is the most common type of breast cancer histology among CBC patients (69.57%).Of the CBC patients, 72.13% and 66.67% had ER+ and PR+ tumors, respectively, but 70% had negative HER2.For 74.63% of PBC, adjuvant chemotherapy was used.Nearly all (83.53%) subjects were treated with external radiotherapy, and 61.53% of patients had negative lymph vascular invasion.Of the patients with CBC, 69.57% did not have a family history of breast cancer (in first or second degrees).
T A B L E 1 Clinical characteristics of the unilateral and contralateral breast cancer in the study patients.F I G U R E 1 Kaplan-Meier curve of 1-, 5-, 10-, and 20-year disease-free interval for contralateral breast cancer after primary breast cancer treatment.
The prevalence of hormone therapy in patients with CBC was 89.62%.Of the patients who developed CBC, 45.26% had a mastectomy, and only 10.34% were triple negative (Table 1).

| The DFI between PBC and CBC
For PBC, the probability of having a 1-year DFI was 99%, while the probability for 5-year, 10-year, and 20-year DFI was 97%, 96%, and 88%, respectively (Figure 1).The probability of DFI was higher in patients older than 60 years compared to other age groups (those under 45 years and those between 45 and 60 years; Figure 2).

| DISCUSSION
Despite extensive research on breast cancer that has led to successful treatment and increased survival rates, the development of CBC after treatment of PBC remains a major issue that requires further research.
The present study found that the mean age of patients was 49 years, which is in contrast to another study that reported a mean age of 61.2 years at the first breast cancer diagnosis. 5The median time interval between PBC and CBC was 3.92 years, which differs from other studies that reported median time intervals of 6.2-6.7 years. 12,13These differences in median age and time interval between PBC and CBC may be due to differences in the population's age composition.Previous research suggests that people with PBC can develop CBCs more than 5 years after diagnosis. 13The reported incidence of CBC was 3% after 5 years, which is comparable to other studies, which range in rate from 3% to 41.5%. 3,12The possible reasons for differences in the frequency of incidence of CBC in the present and previous studies could be due to several factors, including differences in study design, patient characteristics, follow-up duration, or differences in treatments.
Our study found that patients older than 60 had a lower chance of developing CBC.There is inconclusive reports regarding the effect of age on the progression of CBC, with some studies reporting a positive association between age and CBC and some reporting a negative association. 3,12,14 We believe our results are an accurate representation of the young age pyramid in Iran, where diagnosed CBC was more common among younger people.
In the present study, a family history of BC in the second degree was associated with a 59% increased risk of CBC, while the family history of BC among first-degree relatives was not associated with an increased risk of developing CBC.This finding is consistent with Yoon et al and Vichapat et al. 15,16 However, other studies have suggested that women with a strong family history of BC are at higher risk of developing CBC. 17,18[21] Also consistent with literature, we found that radiotherapy had no statistically significant effect on the incidence of CBC. 22However, another study found contradictory results. 23Of course, this is related to a kind of surgery such as mastectomy or saving the breast.Hence, it is not a scientific statement about irradiation effectiveness.In Yadav et al's study, 18 adjuvant chemotherapy had no significant effect on the risk of second malignancy.In Alkner et al, chemotherapy given after BC made a difference in the progression of the disease and disease-free interval (DFI).In this study, chemotherapy after BC was a negative prognostic factor. 13In the present study, adjuvant or neoadjuvant chemotherapy was not significantly protective or promotive for the CBC.
Although invasive lobular carcinoma is the second most prevalent type of breast cancer pathology, 24 there are still conflicting results about its effect on CBC.According to a study by Tong et al, 25 patients with invasive lobular carcinoma or a mixture of IDC and invasive lobular carcinoma had a higher likelihood of developing CBC compared to IDC alone. 24Glas et al revealed a higher risk of CBC in patients with lobular tumor morphology. 26In our study, the ILC was 10.14% versus 5.78% in CBC and PBC groups, respectively, and IDC was a protective factor for CBC.
The overall disease-free interval estimates among contralateral breast cancer patients by age.
Breast cancer, as a significant health concern in Iran, has an agestandardized incidence rate (ASR) of about 34.53 per 100 000 in 2014. 27This rate is lower than the global age-standardized incidence rate of breast cancer in females, estimated to be 48/100 000. 28According to the results of immunohistochemical studies, 10%-20% of breast cancer cases are triple-negative.This subtype is characterized by significant proliferative activity and growth rate aggressive clinical course.
Triple-negative breast cancer (TNBC) is a specific subtype of breast cancer that does not express estrogen receptor (ER), progesterone receptor (PR), or human epidermal growth factor receptor 2 (HER-2).TNBC has clinical features that include high invasiveness, metastatic potential, relapse potential, and poor prognosis. 29,30 This study was the first to investigate CBC and DFI risk factors among BC survivors in Iran.This information will help clinicians identify patients at higher risk of CBC and develop appropriate surveillance and treatment plans.By identifying risk factors for CBC and DFI, patient outcomes will be improved by enabling more personalized treatment plans for high-risk patients who may benefit from more aggressive treatment or closer surveillance.
In this retrospective cohort study, patient data were obtained from the cancer research center of Shahid Beheshti University of Medical Sciences in Tehran, Iran, from 2000 to 2020.The cancer research center registers breast cancer patients who undergo required investigations and routine clinical examinations.Following approval from the ethical committee of our institute, Shahid Beheshti University of Medical Sciences (No: IR.SBMU.CRC.REC.1400.048),we conducted a study to assess the risk factors of developing CBC including the interval between treatments of PBC after the identification of CBC or DFI.

Table 2
contains the results of univariable and multivariable Cox proportional hazards regression models.Most variables were protective.The age group of 60 years and higher (HR = 0.53; 95% CI: 0.30-0.94)and the IDC type of pathology (HR = 0.61; 95% CI: 0.38-0.97)were negatively associated with CBC progression.A history of breast cancer in the second degree was associated with a 59% increased likelihood of developing CBC (HR = 1.59; 95% CI: 1.01-2.51).
Hazard ratios for (multivariable cox regression analysis) CBC risk factors among patients.
death criteria in order to adjust for those potentially confounding risk factors.Furthermore, the lack of significance in several variables may be attributed to the limited sample size and the absence of measurement or recognition of potential confounding factors and study conditions.In future studies, we plan to employ a larger number of participants and obtain all demographic variables of the BC patient.T A B L E 2 (Continues) T A B L E 2 (Continued) *p-Value less than .2included in the multivariate analysis.