Underweight Indian Women at a Risk for Developing Breast Cancer: A Retrospective Study

development 5]. Various studies a Abstract Background: Breast cancer is the leading cancer diagnosed in Indian women. Lifestyle related factors such as high body mass index (BMI) and obesity have been recognized as major risk factors for the development of breast cancer. However, India has higher proportion of underweight population and recently positive correlation has been reported between underweight and increased risk of breast cancer. We have attempted to study an association between low BMI and total body fat percentage with breast cancer risk by performing retrospective analysis on a small sample size of 41 female patients diagnosed with breast cancer. The data was collected from Department of Oncology, Bharati Vidyapeeth Hospital and Research Centre (BVHRC), Pune, India. Methods : Binary logistic regression was performed to estimate odds ratios (ORs) and to examine the predictive effect of each factor on the breast cancer risk. Results: It was observed that underweight population displayed higher risk of breast cancer development based on BMI (OR-15.40) and body fat % (OR-1.33). Conclusion: This pilot study suggests that low body mass index may be related to poor prognosis in breast cancer and thus warrants further studies on a larger sample size to establish a positive correlation. between obesity and incidence of breast cancer that would affect the survival of postmenopausal women with breast cancer [6-8]. However, several studies have suggested that breast cancer patients who are underweight could be at a higher risk than normal weight for recurrence and mortality [4, 9-11]. Recently, low BMI in young breast cancer patients with lymph node metastases, was reported to be of prognostic significance [12]. It has been hypothesized that a low BMI may result in lack of breast fat resulting into lower levels of ovarian hormones in the early adult life, which may lead to increased risk of breast cancer [13]. Thus, the present study has attempted to establish a correlation between lower BMI and total body fat with


Introduction
India has the highest number of underweight adults in the world [1]. Epidemiological studies conducted in different geographical areas of India have suggested an association between low body mass index and increased risk of mortality and health-related quality of life [2]. In India, breast cancer is the leading cancer diagnosed in women. According to Indian Council of Medical Research (ICMR) report, based on cancer registries from different parts of India, number of breast cancer cases were predicted to rise by 85% in 2020 [3]. Lifestyle related risk factors such as high body mass index (BMI) and obesity have been recognized as independent risk factors for the development of breast cancer by many researchers [4,5]. Various studies have demonstrated a positive correlation Abstract Background: Breast cancer is the leading cancer diagnosed in Indian women. Lifestyle related factors such as high body mass index (BMI) and obesity have been recognized as major risk factors for the development of breast cancer. However, India has higher proportion of underweight population and recently positive correlation has been reported between underweight and increased risk of breast cancer. We have attempted to study an association between low BMI and total body fat percentage with breast cancer risk by performing retrospective analysis on a small sample size of 41 female patients diagnosed with breast cancer. The data was collected from Department of Oncology, Bharati Vidyapeeth Hospital and Research Centre (BVHRC), Pune, India. Methods: Binary logistic regression was performed to estimate odds ratios (ORs) and to examine the predictive effect of each factor on the breast cancer risk. Results: It was observed that underweight population displayed higher risk of breast cancer development based on BMI (OR-15.40) and body fat % (OR-1.33). Conclusion: This pilot study suggests that low body mass index may be related to poor prognosis in breast cancer and thus warrants further studies on a larger sample size to establish a positive correlation. between obesity and incidence of breast cancer that would affect the survival of postmenopausal women with breast cancer [6][7][8].

Keywords: Breast cancer-body mass index-body fat percentage
However, several studies have suggested that breast cancer patients who are underweight could be at a higher risk than normal weight for recurrence and mortality [4,[9][10][11]. Recently, low BMI in young breast cancer patients with lymph node metastases, was reported to be of prognostic significance [12]. It has been hypothesized that a low BMI may result in lack of breast fat resulting into lower levels of ovarian hormones in the early adult life, which may lead to increased risk of breast cancer [13]. Thus, the present study has attempted to establish a correlation between lower BMI and total body fat with

Study population
The present retrospective study included 41 females diagnosed with breast cancer (cases) and 24 healthy females (control), who visited Department of Surgery and Oncology, Bharati Vidyapeeth Hospital and Research Centre (BVHRC), Pune, India during the period of 2014-2016 (Ethics approval no.-BVDU/MC/02).

Data collection
Information on anthropometric factors of cases such as age, weight, height and body fat percentage was collected from the hospital records of Department of Surgery and Oncology, BVHRC. BMI was calculated as weight in kilograms divided by height in meters square (kg/m 2 ). Controls were selected among females who visited awareness camp organized by BVHRC. Females aged below 30 and above 80, diagnosed with gynecological malignancies were excluded from the control study population.

Statistical analysis
Descriptive statistics was used to describe the data. For quantitative variables, mean with standard deviation and for qualitative variables, frequency with percentage was used to describe the data. Chi-Square test and independent sample t test were performed to assess the significance of age, weight, height, BMI and total body fat percentage between breast cancer patients and controls. Binary logistic regression was performed to estimate odds ratios (ORs) and to examine the predictive effect of each factor on the risk for breast cancer. All the statistical assessments were two-sided and considered to be significant with p-value <0.05. All the statistical analysis were performed by using STATA15 software.

Characteristics of the study population
In this study, mean age of breast cancer cases and controls was 54.12 ± 13.42 and 49.54 ± 11.98 years, respectively (Table 1). Mean height of cases and controls was 156.8 ± 4.74 cm and 150.3 ± 6.25 cm, respectively. The study cases weighed between 42-79 kg while the controls weighed between 33.5-77 kg, thereby showing that the mean weights were similar for both the groups (51.76 kg and 52.47 kg, respectively) (p= 0.2307). Mean BMI of breast cancer cases and controls was 21.03 ± 4.00 and 23.17 ± 4.01, respectively whereas mean body fat % was 25.85 ± 5.24 and 27.93 ± 8.67, respectively.

BMI as a risk factor for breast cancer
Among the breast cancer cases, 53.65% showed low BMI (<18.5), 24.39% showed normal BMI (18.5-24.9%) and 21.95% showed high BMI (25-29.9/≥30) and the cases were categorized into underweight, normal and overweight/ obese groups, respectively (Table 2). Odds ratio above 1 demonstrated the predictive effect of high risk for each factor. Based on BMI, underweight population displayed nearly 15-fold higher risk (OR = 15.40 and p <0.0005) of developing breast cancer compared to overweight cases (OR= 1.57 and p <0.477). Thus, BMI classification showed a significant association with breast cancer occurrence.

Body fat percentage as a risk factor for breast cancer
The number of underweight breast cancer cases showing low body fat percentage were 60.97%, which was higher than the number of healthy underweight controls (33.33%) with an OR of 1.33 (p<0.0636) ( Table 3). However, number of overweight breast cancer cases constituted 21.95% compared to 54.17% of healthy overweight controls with an odds ratio of 0.30 (p <0.136). Thus, based on body fat percentage too, underweight population displayed a higher risk of developing breast cancer.

Discussion
In this study, we have attempted to find an association between BMI and body fat levels as risk factor for breast cancer. The study was conducted on a pilot scale and the cases have not been stratified with respect to hormone receptor or menopausal status. We found that underweight (BMI <18.5) breast cancer cases displayed nearly 15-fold higher risk for the disease. Based on body fat percentage, the proportion of underweight females was higher among breast cancer patients than among healthy controls.
The complex relationship between obesity and breast cancer has been studied at various levels such as BMI, different measures of obesity, hormonal or menopausal status in patients, ethnicity, stage of cancer and so on. Overweight women have been reported to have increased risk for developing breast cancer (OR =2.29) compared to women with normal BMI in both pre-and post- Mumbai, India has reported a positive association between low BMI and increased breast cancer risk with high odds-ratio [4]. A multicentric study has shown association between low BMI and high risk of premenopausal breast cancer with increase in hazard ratios [29]. Underweight premenopausal women (BMI <18.5) with Luminal A and HER2 subtypes have shown risk for breast cancer [11]. A retrospective study in Chinese patients has suggested adverse outcomes in young underweight BMI (<18.5) patients (under 40 years old) with lymph node metastasis [12]. Various mechanisms have been proposed underlying the association between underweight and breast cancer risk, out of which malnutrition is one of the important factors [30]. Malnutrition often leads to immune system dysfunction that may hamper tumor surveillance by immune cells and may also influence the efficacy of systemic antitumor therapies, thereby resulting into tumor dysregulation [31].
Our findings have important implications wherein a positive association was observed between low BMI, low total body fat and increased breast cancer risk. This underlines the significance of body fat in underweight population, which until now was not considered as a major risk factor. The present study has several limitations, the main one being the sample size. This pilot study warrants further studies on a larger sample size. Secondly, the patients need to be stratified based upon pre-and post-menopausal status, stage of cancer and hormone receptor status. This would strengthen our findings and further reiterate the significance of low BMI and low total body fat as important prognostic factors for management of breast cancer.
In conclusion, our study suggests that underweight status, based upon both low BMI and low total body fat, menopausal cases [14]. Many studies have shown that there was a higher risk of breast cancer incidence among postmenopausal women with high BMI [6][7][8]15]. Based on ethnicity, a positive association between high BMI and increased breast cancer incidence has been observed in the Asia Pacific group than in the European-Australian or North-American group [16]. In India, few studies have shown a positive correlation between body mass index and breast cancer risk [17][18][19][20]. Using only BMI as an indicator for weight status overshadows other parameters such as body composition, adiposity, and adipose distribution [21]. Asian population have higher levels of total body fat, more abdominal fat and less-lean mass than other ethnic groups [22]. High central obesity (measured by waist to hip ratio) was reported to be the most important risk factor of BCa, irrespective of menopausal and hormonal receptor status [4,23]. Postmenopausal women with a normal BMI but high body-fat levels [24] or high central obesity [8] were shown to have an elevated risk of breast cancer.
In the current work, we have categorized the sample population into underweight, normal and overweight/ obese, based upon BMI and body fat percentage. We observed that low BMI and low total fat in underweight cases, positively correlated with breast cancer risk. Although most of the studies have underlined a positive association between high BMI and increased risk of breast cancer, few reports have indicated that underweight pose a high risk for developing breast cancer. Underweight patients were reported to be at an increased risk of local recurrence among all types of breast cancer [9]. Women with low BMI have increased risk for premenopausal breast cancer compared to those with healthy BMI [25][26][27][28]. A hospital based case control study conducted in   should be considered as a high-risk factor for breast cancer development and thus strategies should be developed accordingly for the prevention and management.