The title of the article to be reviewed is “Association of Non-Genetic Factors with Breast Cancer Risk in Genetically Predisposed Groups of Women in the UK Biobank Cohort.”
The introduction of the article provides important statistics about the subject of breast cancer. For instance, breast cancer is the most common type of cancer in women. It is also the second most common cause of cancer-related deaths in women with more than 55,000 new cases of breast cancer being registered every year in the UK.
The causes of these breast cancers can be linked to genetic factors. Evidence has shown that breast cancer is linked to highly penetrant rare gene variants, such as in the BRCA1 and BRCA2 genes.
Here is something we should know about the genes associated with cancer.
The BRCA1 and BRCA2 genes cause most of the inherited breast cancers.
The BRCA genes repair damaged cells and ensure the normal growth of cells in the breast and ovary. These genes can be passed from generation to generation. When they are passed with mutations, they do not function normally leading to an increase in the risk of breast cancer. 1 out of every 10 breast cancer cases is as a result of mutations in the BRCA genes.
Single-nucleotide variations have also been linked to the development of breast cancer. The effects of all such single-nucleotide variations associated with breast cancer are referred to as a polygenic risk score. Statistics show that about 88% of breast cancer patients have an aggregated polygenic risk score.
Lifestyle and behavioral factors can also increase or decrease the risk of breast cancer. However, while genetic factors are not modifiable, lifestyle factors can be modified. That is, regardless of the polygenic risk score of an individual, the overall risk of breast cancer can be decreased through a healthy lifestyle.
This section introduces the methodology used in the study. The study used a longitudinal cohort research design. The cohort data was obtained from the UK Biobank and included 502,650 men and women aged between 39 and 71 years.
Three coding systems were used in the identification of patients with breast cancer and those serving as controls:
International Statistical Classification of Disease-Related Health Problems
International Classification of Diseases
The diagram here shows the process of filtering the study’s participants. The first inclusion criterion was white women aged between 40 and 71 years. The second inclusion criterion was postmenopausal women who did not report a history of hysterectomy or bilateral oophorectomy and reported no longer menstruating. Deceased participants and those with other cancers were excluded. After the filtering process, the number of eligible participants was 96,086.
The eligible participants were divided into three groups: incident (2,728), prevalent (4,869), and controls (88,489).
The incident groups consisted of participants who had been diagnosed with cancer.
The control group were women without a history of any cancer.
The prevalent group was defined by the 3 coding system.
Breast cancer risk factors are categorized as either modifiable or non-modifiable
Modifiable factors include:
Oral contraceptive use
Hormonal replacement therapy
The scoring system based on the modifiable factors was as follows:
Favorable lifestyle: ≥4 healthy factors present
Intermediate lifestyle: 2 or 3 healthy factors present
Unfavorable style: ≤1 healthy factor present
Polygenic risk scores for the eligible participants was derived based on the Mavaddat score. The scores were constructed using 313 single-nucleotide variations.
Single-nucleotide variations rs10764337 was triallelic and excluded leaving 305 single-nucleotide variations. This data was then used to group participants by their level of polygenetic risk.
Classifications based on the tertile genetic risk classification using standardized polygenic risk scored was developed as follows:
Low (1st tertile up to 33.33%)
Intermediate (2nd tertial between 33.34% and 66.67%)
High (3rd tertile from 66.68% to 100%)
The study used a binomial generalized linear regression model to conduct a statistically analyze basic risk factors.
Hazard ratios of the lifestyles and breast cancer risks were assessed using Cox proportional hazards regression. All analyses were adjusted for age and family history.
This section presents the results and findings of the study.
Table 1 shows the criteria for healthy lifestyle classification
Participants were divided into three categories:
If there are more than four health factors classified as favorable lifestyle
Two or three health factors classified as intermediate lifestyle
1 or less health factors were classified as unfavorable lifestyle
Table 2 shows the relative risks for basic characteristics, lifestyles, and genetic categories
A one-year increase in age is linked to a 2.3% increase in breast cancer risk. Women who have either a mother or sister with breast cancer have a 48.6% increase in breast cancer risk. If both the mother and sister had breast cancer, then the risk of breast cancer doubles when compared to women without a family history of cancer.
Additionally, an unhealthy weight is also linked with a 13.9% increase in the risk of breast cancer while a lack of physical activity increases breast cancer risk by 12.2%. Alcohol consumption of three or more times a week increases the risk of breast cancer by 10.7%. Similarly, using HRT for five years or more increases the risk by 22.9%. However, there is no association between breast cancer risk and oral contraceptives.
Table 2 also shows that 23.3% of the women followed a favorable lifestyle while 68% and 8.6% followed intermediate and unfavorable lifestyles respectively. Unfavorable and intermediate lifestyles had higher risks of breast cancer compared to favorable lifestyles.
An analysis of the PRS tertile groups shows that the gradient of breast cancer risk increases across the tertiles. That is, women in the third tertile, which represents the highest genetic risk group, are at a considerably higher risk of breast cancer in comparison with women in lower tertiles. Furthermore, members of the intermediate risk group demonstrate a moderate increase in risk in comparison with those in the low genetic risk group.
Table 3 shows breast cancer hazard ratios based on lifestyles, stratified by the genetic risk group.
Significant increases in hazard ratios can be observed in the low genetic risk group for both the unfavorable and intermediate lifestyle groups in comparison with favorable lifestyle groups. Significant increases in hazards ratios can also be seen in the intermediate genetic risk group for both the unfavorable and intermediate lifestyle groups in comparison with favorable lifestyle groups. Finally, in the higher genetic risk group, a significant hazard ratio is seen in only the unfavorable lifestyle groups compared to favorable lifestyle groups. These results demonstrate that less healthy lifestyles within any of the genetic risk groups increase the risk of breast cancer.
Figure 2 shows a ten-year cumulative breast cancer incidence rate of the UK Biobank postmenopausal women classified according to genetic and lifestyle factors.
From the figure, it can be observed that the lowest ten-year cumulative breast cancer incidence rates across all genetic groups is associated with favorable lifestyles compared to intermediate and unfavorable lifestyles. On the other hand, unfavorable lifestyles had the highest ten-year cumulative breast cancer incidence rates across all genetic groups compared to intermediate and favorable lifestyles. This trend indicates incremental rates of breast cancer risk across all genetic risk groups from favorable to intermediate to unfavorable lifestyles.
Moving on to the discussion section of the article, it has estimations indicate that breast cancer can be prevented in 23% of patients in the UK.
The purpose of the study was to investigate the relationship between genetic and lifestyle factors with breast cancer risk.
The hypothesis that was tested was that breast cancer risk in postmenopausal women can be modified or reduced by improving lifestyle habits, even for the highest genetic risk group
The findings of the study thus showed that an intermediate and unfavorable lifestyle resulted in an increased risk of breast cancer when compared to favorable lifestyles.
The findings demonstrate that adherence to healthy lifestyles across all genetic risk groups leads to a decrease in breast cancer risk, regardless of the effect size of polygenic risk scores.
Therefore, the study proves that the risk of breast cancer can be reduced by following favorable lifestyles even in women with high genetic risk.
The strengths of this study include:
The use of a large sample size spread across the UK which reinforces the generalizability of the findings.
The assessments of phenotypic exposure conducted by the UK Biobank were comprehensive, robust, and of high-quality
Using a prospective study design enabled the assessment of phenotypic exposures before breast cancer developed in the cohort.
The limitations of the study are:
The study only used white women which limits its generalizability to other racial groups.
There is a need for additional validation of these polygenic risk scores for other populations.
Only postmenopausal women were analyzed which means that the results cannot be generalized to premenopausal women.
The study failed to investigate sub-types of breast cancer such as ER-positive and negative, PR positive and negative, and ERBB2 positive and negative.
In conclusion, the findings of this study suggest that healthy lifestyles involving regular exercise, healthy weight, no or limited alcohol intake, and avoidance of hormonal replacement therapy should be encouraged to reduce the risk of Breast Cancer.
This further demonstrates the importance of lifestyle factors in genetically inherited diseases such as breast cancer.