|Ahead of print publication
Infertility as a risk factor for breast cancer: Results from a hospital-based case–control study
Maryam Ghanbari Andarieh1, Mouloud Agajani Delavar1, Dariush Moslemi2, Mahmoud Haji Ahmadi3, Ebrahim Zabihi4, Sedighe Esmaeilzadeh1
1 Infertility and Reproductive Health Research Center, Health Research Institute, Babol University of Medical Science, Babol, Iran
2 Cancer Research Center, Babol University of Medical Sciences, Babol, Iran
3 Noncommunicable Pediatric Diseases Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
4 Cellular and Molecular Biology Research Center, Health Research Institute, Babol University of Medical Sciences, Babol, Iran
Department of Obstetrics and Gynecology, Infertility and Reproductive Health Research Center, Health Research Institute, Babol University of Medical Sciences, Ganjafroz Street, Babol
Source of Support: None, Conflict of Interest: None
Context: Breast cancer is the most common cancer in women worldwide and its prevalence is increasing.
Aims: The aim of this study was to investigate the extent to which a history of infertility can present as risk factors for breast cancer.
Settings and Design: This was a hospital-based case–control study.
Subjects and Methods: In this study, 1177 women with breast cancer were participated for assessing the risk for this cancer. The control was 1204 women with self-reported free-cancer history who were matched in terms of age and residence.
Statistical Analysis Used: Using logistic regression, it was examined whether infertility is a risk factor of case–control status in addition to marriage age, menarche age, body mass index, number of pregnancies, family history of breast cancer, and previous oral contraceptive use. The data were considered significant at P ≤ 0.05.
Results: Infertility history was reported in 12.5% (n = 147) of the cases and 5.8% (n = 70) of the controls. Infertility history was a relevant risk for case–control study in addition to other risk factors (odds ratio: 2.43; 95% confidence interval, 3.34–1.77).
Conclusions: This study found that infertility may be as the main risk factor for breast cancer in Iranian women, therefore, doing breast screening in women who have one or more risk factors, must receive more emphasis.
Keywords: Breast cancer, case–control study, family medical histories, infertility risk factor
|How to cite this URL:|
Andarieh MG, Delavar MA, Moslemi D, Ahmadi MH, Zabihi E, Esmaeilzadeh S. Infertility as a risk factor for breast cancer: Results from a hospital-based case–control study. J Can Res Ther [Epub ahead of print] [cited 2019 Sep 15]. Available from: http://www.cancerjournal.net/preprintarticle.asp?id=264707
| > Introduction|| |
Despite the many advances in medical science, breast cancer is still one of the most common cancers in women and is the cause of death in almost 20% of women. It is also known to be one of the most expensive diseases worldwide. The cumulative incidence of breast cancer in lifetime is about 1 in every 9 people.,,, The average age at diagnosis in western societies is 48 years; however, the current statistics suggest that it is younger in Iran, indicating an urgent need for care and further investigations aimed at timely diagnosis and treatment. It is also imperative that people care more for diagnoses and medical studies.,, Studies showed that 20%–30% of newly diagnosed breast cancers cases are accompanied by its known risk factors. About 10% of breast cancer cases are caused by mutations in breast cancer susceptibility genes.
Increased survival depends on screening methods, risk factor identification, early detection, and treatment procedures. Despite various interventions such as hormone therapy, chemotherapy, radiotherapy, and surgery, 5-year survival in breast cancer is 50%, and most of these therapies are associated with numerous side effects, reducing the quality of life of these patients significantly.,, Quality of life is an important factor that is affected in breast cancer condition. Factors affecting the quality of life in physical aspect include digestive disorders, immunodeficiency, hair loss, vaginal dryness, menopause, irregular periods, spotting, pain and swelling in the hands, fatigue, and reduced ability to perform daily activities. Factors in the social emotional dimension include adaptation with the disease with a spiritual approach, body image disorders, lack of psychosocial support, lack of or inadequacy of insurance coverage, expensive chemotherapy drugs and other medical expenses, depression, and anxiety that affect quality of life patient and families not only in the course of chemotherapy but also long after it. Because breast cancer affects many women's lives, and its exact cause is not yet known, timely detection of risky behaviors and promotion of public awareness through education and care planning in changing behavior can be effective in controlling the incidence of breast cancer. It should be noted that, if detected early, breast cancer is one of the most preventable cancers., By considering to high prevalence of infertility in Babol, Iran, and the traditional thoughts of Iranian families that persuade the majority of couples to have their first child after marriage and therefore they have to undergo infertility treatments using assisted reproduction technology. This exposure to infertility drugs can be an increased risk for a number of malignancies. The objective of the present study was the extent to which a history of infertility may be present as a risk factor for breast cancer in addition to marriage age, menarche age, body mass index (BMI), number of pregnancies, family history of breast cancer, and previous oral contraceptive use that may be present.
| > Subjects and Methods|| |
The cases of this study were all patients with the histological confirmed of all types of breast cancer in the Cancer Center of Shahid Rajaee Hospital, Babolsar (North of Iran) between March 2014 and May 2016. The inclusion criteria included the following conditions: (a) the diagnosis of any clinical staging of the breast cancer was histologically and cytologically confirmed; (b) there was no suspicion of breast metastases from a different tumor; and (c) women who had received consents from their physicians.
A total number of 1410 medical records were fully assessed based on which 1177 were found to have inclusion criteria. Finally, all these selected patients were interviewed and were requested to fill out the questionnaire (contribution rate 83.4%).
For each breast cancer case, there was one control, which was matched in terms of age and residence. A total number of 1204 controls participated in this study (contribution rate: 85.4%). They were selected randomly from women who had any other types of cancers and inclusion criteria for the study using refer to the cases' residential areas. The women free of any other cancers were done based on the screening checklists.
A structured questionnaire was designed and piloted in two groups, and modification was made based on the results achieved. The questionnaire including lifestyle, the reproductive history comprising the menarche age, the age of marriage, pregnancy history, breastfeeding, the previous use of hormonal contraceptive, and the family history of reproductive cancer was filled out by the patients and completed with in-person interviews from two groups by the trained interviewer. A history of infertility in a “yes/no” form was obtained in controls and cases when fill out the questionnaire.
The Ethics Committee of Babol University of Medical Sciences, Iran, approved this case–control study or ethics in medical research and all of the participants for two groups signed written informed consent.
The term parity was defined as nulliparity (those who have never births) and parous (those who had experienced at least one live or stillbirth).
The age and weight of patients in case group were their age and weight at diagnosed with breast cancer, and the age and weight of women in the control group were their age and weight at interview time. The BMI was calculated as weight (in kilograms) divided by the square of height (in meters).
The data were analyzed using the Statistical Package for the Social Sciences version 16.0 (SPSS Inc., Chicago, IL, USA) through descriptive and analytical statistics. Normality of variables was determined by Kolmogorov–Smirnov test, and quantitative variables were compared with t-test. Characteristics of women with and without breast cancer were compared using descriptive and Chi-squared statistics. To test the associations between the breast cancer and the risk factors, bivariate conditional logistic regression analyses at P = 0.2 were used. The potentially important risk factors were assessed with stepwise multivariate conditional logistic regression analysis. Odds ratios using maximum likelihood and 95% confidence intervals were estimated by univariate and multivariate models. P ≤ 0.05 was considered statistically significant.
| > Results|| |
A total of 2381 women were included in the analyses, of whom 217 (9.1%) had history of infertility, 1177 were women with breast cancer (case group), and 1204 were free of breast cancer (control group). The mean ± standard deviation age of cases and controls was 48.8 ± 8.5 years and 48.2 ± 9.6 years, respectively. There were no significant differences between cases and controls with regard to age. Characteristics of the study participants are shown in [Table 1]. A history of infertility was noted by 12.5% of the cases (n = 147) and by 5.8% of the controls (n = 70). There was a higher proportion of marriage age ≥30 years (P = 0.002), BMI ≥25 kg/m2 (P = 0.003), smoking (P = 0.027), menarche age <12 years (<0.001), nulliparity (P < 0.038), the history of using hormonal contraception (P < 0.0001), the positive family history of breast cancer (P < 0.0001), and lower education (P < 0.001) in the case group as compared with those of the control group. There was no significant difference between the percentages of women in the case group and those of the control group in terms of alcohol consume and the history of breastfeeding.
[Table 2] shows the odds ratios (ORs) of breast cancer risk factors using univariate and multiple logistic regression models with the likelihood of 95% confidence interval (CI) in patients with breast cancer and those in the control group. The unadjusted OR for history of infertility was 2.31 (95% CI, 1.72–3.11). After adjusting the variables, menarche age <12 years (OR: 1.85, 95% CI, 1.37–2.50), oral contraceptive use (OR: 3.83 95% CI, 3.21–4.58), and positive family history of breast cancer (OR: 2.11, 95% CI, 1.62–2.74) were found to be associated with an increased risk of breast cancer. A history of infertility, after adjustment for confounding variables, was identified as the most effective factors in breast cancer (OR: 2.43, 95% CI, 1.77–3.34).
|Table 2: Logistic regression analyses, showing adjusted odds ratios* with the 95% confidence intervals|
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| > Discussion|| |
In this case–control study, a history of infertility was confirmed as a risk factor for breast cancer. In addition, other already well-known risk factors for breast cancer such as early menarche age, contraception use, and family history of breast cancer were confirmed. The findings presented here showed that marriage age in the case group was significantly higher than the controls; these findings seem to be consistent with Motie et al.'s study that the marriage age in breast cancer patients was significantly higher than the control group; however, in Motie et al.'s researches in Gorgan city, Iran, the marriage age was not significantly different between breast cancer patients with controls that is most likely due to a small sample size of study. With regard to the findings from the present study, BMI in breast cancer cases in Mazandaran was significantly higher than the controls. Borghesan et al. in Brazil investigated, on 100 patients with breast cancer and 500 controls, that BMI ≥30 kg/m2 was introduced as a risk factor for breast cancer, or evidence from the USA also suggested that BMI ≥30 kg in breast cancer patients can reduce the survival rate; hence, according to these results, effect of BMI as a risk factor for breast cancer should be considered. The findings presented here showed that the percentage of cases whose menarche age was before 12 years in cases was significantly higher than the controls, and this association was significant statistically. Huo et al. in Nigeria also reported that the menarche age higher or equal to 17 years old was associated with risk 0.72, which suggests a protective effect of menarche age and it is in line with our findings. Low menarche age due to increased reproductive period for women can expose them on risk; however, Motie et al. showed that the menarche age was not significantly different between breast cancer patients and controls that is probably due to small sample size in their study. Our investigation revealed that the contraceptive pills used in breast cancer patients were significantly higher than the controls, that is, this association was statistically significant. Bethea et al. also found that contraceptive pill use was one of the risk factors for breast cancer, whereas Ichida et al. found that there was no significant association between contraceptive pill use and breast cancer in Japanese women that is probably due to differences of race and genetic influences.
Although alcohol consumption has been associated with an increased risk of breast cancer consistently in different studies; our study did not identify alcohol as a risk factor. This result is due to the low number of women who consumed alcohol because of their religious beliefs.
We demonstrated that a family history of breast cancer in the study group was higher than the controls significantly (18.4% vs. 9.2%), and this association was statistically significant. Sifuentes-Álvarez et al.'s study also reported that breast cancer risk in women with a family history of breast cancer was 5.1 times more than controls, which are similar to our findings.
Some investigators have indicated an association between long-term use of ovulation-stimulating hormone drugs and the prevalence of female-specific cancers.,,, Another study has shown that increasing the number of menstrual cycles with regular ovulation may increase the risk of breast cancer. In addition, another survey showed that the peak of mitotic activity in breast cells occurs during the luteal phase. Thus, increasing the number of menstrual cycle periods with ovulation will expand mitotic activity in the breast. In our study, the women with the history of infertility were approximately involved with breast cancer-and-a-half times as much as those without the history of infertility. It is suggested that infertility drugs, as a confounding element, may have a greater malignancy risk than the infertility itself and may be increase the incidence of breast cancer.
| > Conclusions|| |
There have been few studies regarding relationship between breast cancer and infertility, and it is needed to a cohort study to confirm characterization of infertility as a risk factor for breast cancer, especially to examine the pathogenesis of infertility drugs and breast cancer. Finally, this study, despite its overall aims, there are some limitations such as insufficient data to assess the effect of the confounding variables such as genetic mutations in the few genes which cause breast cancer, physically activity on breast cancer alone; therefore, our results should be interpreted with much caution.
Financial support and sponsorship
This study was supported by Babol University of Medical Sciences.
Conflicts of interest
There are no conflicts of interest.
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[Table 1], [Table 2]