Reassess Young Breast Cancer Risk Factor in Mainland of Penang, Malaysia

Until today, there is no clear cut off point for age in young breast cancer. Multiple studies have shown that breast cancer among women diagnosed before age of 40 is increasing in trend and have poorer survival rate. Incidence rate among Malaysian breast cancer from the age of 25 and below 40 is also increasing in trend. This is rst paper in Malaysia to ascertain the risk factors among young breast cancer in mainland of Penang state, Malaysia Method This is a retrospective study which includes young women diagnosed with breast cancer from 1 st January 2015 until 31 st December 2019, from HSJ cluster hospitals. Inclusion criteria are 40 years old and below at the age of diagnosis of breast cancer, female and complete sociodemographic data. Result This study has shown that 17.07% of women with young breast cancer are age before 31 years old and most are age from 36 to 40 years old. Young age at menarche (12 years old and below), positive family history of breast cancer, use of oral contraceptive pill, breastfeeding history and pregnancy history (parity at least 1 and above) are strongly associated with increased risk of young breast cancer with P-value<0.05. This is a small-scale study on young breast cancer patient. Larger population study should be performed to conrm this ndings and dwell further on other possible risk factors. menarche study, is higher control There is signicant correlation between young breast menarche age with P-value of 0.026. common to seen in young age. in study by et nd there is no signicant association between breastfeeding and risk of hormonal-receptor positive breast cancer. (21) In our study, P value between breastfeeding and breast is 0.038 shows that breastfeeding is a risk factor associated with increased risk of young breast cancer. A similar correlation been found in study by Felix Essiben et (24) The longer the duration of breastfeeding (at least 12 months) has associated with higher risk of young breast cancer with P-value of 0.002. Hence, breastfeeding is not a protective factor in young breast cancer.


Introduction
Until today, there is no clear cut off point for the age of young breast cancer. In study by Carey et al, women diagnosed before age of 40 years old has shown to have poorer survival rate. Young breast cancer account for more than 40% of cancer at this age group.

Method
A case-control retrospective study was conducted which included women diagnosed with breast cancer from 1 st January 2015 until 31 st December 2019, from HSJ cluster hospitals. Inclusion criteria are 40 years old and below at the age of diagnosis of breast cancer, female, complete sociodemographic data and histopathological con rmed breast cancer. Exclusion criteria are breast cancer diagnosed after age of 40 years old, incomplete data and patients with unspeci ed laterality of tumors. We compare women diagnosed with breast cancer age 40 years old and below (cases) during this period with control of same age range who came in for consultation and/or treated in this service with sonographic evidence of negative for breast lesions. Each case was compared with 1 control. Socio-demographic data (age, ethnics) and clinical characteristics (age of menarche, oral contraceptive use, family history of breast cancer, gravidity, parity, age at rst pregnancy, history of breast feeding, duration of breast feeding) were collected from patients' medical record and breast cancer registry.
A total of 82 patients (41 cases and 41 controls) were recruited into this study. Women diagnosed with breast cancer at 40 years old and below (cases) are compared with women of same range of age who came for consultation and/or treated in these facilities with sonographic evidence of negative breast lesions. Sample size was calculated by using StatCalc from Centre for Disease Control and Prevention (CDC). Odd ratio of 10.11 is quoted from variable (family history of breast cancer) in study by Felix Essiben et. Al. Two-sided con dence level is 95% with power of study 98%. Each case was opposed with 1 control. Minimum sample size obtained was 41 cases and 41 controls.

Statistical analysis
Statistical analysis was done by using Statistical Product and Service Solutions (SPSS) version 24. Chi square test has been used to analyze the differences between cases and controls. The signi cance threshold was set at 0.05. Logistic regression was performed to eliminate confounders. has shown that risk increase by 5% with each year younger at menarche. (6) In another study, risk is 2.2 times higher among attain menarche at age of 10 or 11 as compared to those attain menarche at 12 years old and elder. (7) The earlier onset of ovulatory cycle has led to younger age of menarche and this has increases the period of exposure to estrogen. The exposure to estrogen has increased the risk of onset of breast cancer in women. (8) In our study, women with younger menarche age in case group is 41.2% higher than in control group. There is signi cant correlation between young breast cancer and early menarche age with P-value of 0.026.

Pregnancy
In a meta-analytical study, breast cancer risk with each full-term pregnancy reduces by 3%. (10) The propose mechanism is that pregnancy lead to full cell differentiation in the gland of breast cancer and reduce the risk of carcinogenesis (11) Our study has shown a different result. 87.80% of women in our study are pregnant before and 66.67% of them have their rst pregnancy before age of 25. Our data has shown a totally different data and pregnancy is strongly associated as a risk of young breast cancer. The P-value is 0.003 and is similar with study conducted by Felix Essiben et al. with P-value of <0.001. (24) Hence, pregnancy may be a risk factor in increasing the risk of young breast cancer but a protective factor in reducing risk of breast cancer in older age group.

OCP
A study by Morch LS et. Al shown that breast cancer risk is higher among women ever use contraceptive than women never use contraceptive before.
There is approximately 1 extra breast cancer for every 7680 women using hormonal contraception for 1 year. (12) In another study by Collaborative Group on Hormonal Factors in Breast Cancer, it concluded that there is increase in relative risk of having breast cancer diagnosed among women using combined oral contraceptives. The risk is reduced after oral contraceptives are stopped for more than 10 years. (13) However, there are few cohort studies showing that neither current nor past long term usage of oral contraception are associated with increased risk of breast cancer. (14,22) There are 68.29% of young breast cancer women in our study ever use oral contraceptive. It is approximately 1.7 times higher as compared to another study in Jordan by Sanaa et. Al which show 39.01% of breast cancer of all age group ever use oral contraceptive and this study show a strong correlation between oral contraception and breast cancer risk. (23) In our study, P-value is less than 0.001 and is the lowest among all variables to show that there is signi cant correlation between usage of OCP and young breast cancer. Further study narrowing down to association between young breast cancer risk and oral contraception should be done because there is controversy seen among studies of breast cancer in all age groups.

Breast feeding
Breast feeding has been a protective effect against breast cancer. In an Icelandic cohort study by Tryggcadottir et al., the women ever lactating are associated with decreased risk of developing breast cancer as compared to women who have never breastfed. (19) The protective effect is better observed in another analysis data of 47 epidemiological studies. This study estimates 4.7% risk reduction in developing breast cancer with every 12 months of breastfeeding. (20) Multiple studies have shown that breastfeeding in particular is signi cant inversely associated with risk of hormonalreceptor negative breast cancer which is more common to seen in young age. (15,21) However, in study by Islami et al. nd out that there is no signi cant association between breastfeeding and risk of hormonal-receptor positive breast cancer. (21) In our study, P value between breastfeeding and young breast cancer is 0.038 which shows that breastfeeding is a risk factor strongly associated with increased risk of young breast cancer. A similar correlation has been found in study by Felix Essiben et al. (24) The longer the duration of breastfeeding (at least 12 months) has been associated with higher risk of young breast cancer with P-value of 0.002. Hence, we concluded breastfeeding is not a protective factor in young breast cancer.

Family history of breast cancer
Multiple studies have shown a strong correlation of family history of breast cancer with breast cancer risk. There is about 12.9% to 18.77% of women affected by breast cancer having affected rst degree relative (mother, daughter or sister). (16,17,18) In an analysis data of 52 epidemiologic studies, the breast cancer risk associated with family history is signi cantly increased with the number of rst degree relative with breast cancer. (17) A similar trend of presentation is observed in a statistic by American Cancer society. 24 out of 100 women will get breast cancer if she has at least 1 rst degree relative with breast cancer and 36 out of 100 women will get breast cancer if she has at least 2 rst degree relative with breast cancer. (25) In our study, 31.71% of women with young breast cancer have primary family history of breast cancer and it is at least 1.6 times higher than studies mentioned above. Young breast cancer has a more signi cant correlation with primary family history of breast cancer as compared with breast cancers of all age group. P-value is 0.002 and young breast cancer is signi cantly correlated with positive family history of breast cancer.

Limitations Of Study
This is a retrospective hospital based study with lots of extra data are not available (lifestyle, body mass index, environmental hazzard and etc.). A small number of cases can be recruited even though 5 years study had been conducted. A large populations study should be conducted in multiple centers in order to ascertain the risk factors among young breast cancer.

Declaration Ethical Approval
This study uses available data of patient in respective hospital. Hospital ethical committee has reviewed this study and has approve the study. No ethical committee references number available.

Consent for publication
Not applicable in this study Availability of data and materials The datasets generated during and/or analysed during the current study are not publicly available due data con dentiality protection reason are available from the corresponding author on reasonable request.

Competing Interests and Funding
There is no competing interest in this study and it is self-funding by the authors and co-authors.

Authors contribution
Authors and co-authors contributing in this study by designing the study, data collection and analysis and manuscript preparation.