Monday, September 25, 2023

Risk factors for the development of triple-negative breast cancer versus non-triple-negative breast cancer: a case–control study – Scientific Reports

Our results in a breast cancer patient cohort from two tertiary care cancer centres in urban India suggest that triple negative breast cancer constitutes a higher proportion of cases compared with that reported from developed countries and that TNBC phenotype is not significantly differentially associated with reproductive or body size related risk factors, compared with non-TNBC phenotype. This is one of the few studies that has prospectively analysed the association of breast cancer receptor-based subtypes with risk factors in a case-case analysis.

It is worth noting that our study was designed to evaluate the association of risk factors using TNBC patients as cases and non-TNBC patients as controls, which was meant to bring out differential predispositions, if any, to these subtypes of breast cancer in the Indian population. This also means that our results cannot be directly compared with other studies that tested the associations between patients with specific breast cancer subtypes using women without breast cancer as controls. Importantly, our results imply that risk factor modification strategies do not need to be specifically tailored for breast cancer subtypes and that a broad strategy is likely to be effective in modifying the population-level predisposition to all types of breast cancer, with the possible exception of parity, as discussed below.

One important previous study has suggested that high parity could be a risk factor for triple negative breast cancer9, although it is traditionally considered a protective factor for breast cancer. Our results suggest that parity is not significantly differentially associated with triple negative breast cancer compared with non-TNBC although the OR was 1.35. Given the limited power of finding risk factor associations in a case-case analysis, high parity being associated with TNBC remains a possibility, based on our results. There was no significant differential association of other reproductive risk factors like age at first full term pregnancy, age at menarche and breast feeding with TNBC, suggesting that these factors are likely to be similarly operative in predisposition to all types of breast cancer.

We did not find BMI to be differentially associated with TNBC compared with non-TNBC while a lower waist-to-hip ratio was borderline significantly associated with TNBC compared with non-TNBC. Some studies have suggested that a higher waist-to-hip ratio is associated with the risk of hormone receptor-positive breast cancer. In our study, we have reported that a lower waist-to-hip ratio was associated with the risk of TNBC. This is because ours was a case–control study wherein TNBC patients were cases and non-TNBC patients were controls. Therefore, all risk factor associations are preferential associations with TNBC compared with the non-TNBC subtype. An association of lower waist-to-hip ratio with TNBC in our study is consistent with literature reports of higher waist-to-hip ratio being associated with estrogen receptor-positive breast cancer. However, this would still be consistent with an overall association of a higher waist-to-hip ratio with the risk of TNBC when healthy individuals are used as controls, albeit to a lesser extent than estrogen receptor-positive disease. The Carolina study10 found an association of waist-hip ratio with TNBC among both premenopausal and post-menopausal women. It is likely that central obesity as measured by waist-to-hip ratio is a more accurate descriptor of the underlying metabolic predisposition to breast cancer compared with BMI because it considers not only the total body fat composition but also its distribution11. Other studies have variably found an association of TNBC with various measures of body weight12,13,14,15,16,17. Since our study used non-TNBC patients as control, the association of waist circumference and waist-to-hip ratio in our results suggests that central obesity is preferentially associated with non-TNBC, especially hormone receptor-positive disease, which constituted a high proportion of our non-TNBC controls in our study.

We also collected data on tobacco chewing, a somewhat unique form of tobacco used in India. It was not significantly associated with breast cancer subtypes. Interestingly, lower socioeconomic status was borderline associated with TNBC, the reasons for which are unclear but could reflect the impact of other factors. However, since this association was not statistically significant in univariable and multivariable analyses, it could result from chance.

Our study confirms previous reports that triple-negative breast cancer phenotype constitutes a higher proportion of patients6 in India. We also found that a high proportion of TNBC tumors express the immunohistochemical markers, i.e. CK5/6, CK14, CK17 or EGFR of basal-like cancers. A previous report in a subset of patients from this study reported a high prevalence of Epstein–Barr Virus (EBV) in the tumor cells of TNBC tumors18.

Our study has several strengths. It was a prospective study with a large sample size that included patients who presented to two large tertiary care hospitals. The tissue samples were processed by a central laboratory, and all the tumours were subtyped by a single experienced pathologist at a tertiary cancer centre.

Nevertheless, our study also had a few limitations. Because women with non-TNBC cancers were used as controls, the odds ratios in our study indicate the association of each risk factor with these phenotypes. The absolute risk association of each factor with TNBC can only be analysed in a study that includes healthy persons as the control population. Moreover, we did not perform germline sequencing for variants that predispose to breast cancer, like BRCA1 and BRCA2 pathogenic variants. This information might be useful in evaluating the interaction between germline predisposition and risk factors.

In conclusion, the results of our case–control analysis of the association of risk factors with breast cancer phenotypes suggests that lower waist-to-hip ratio, lower socio-economic status and possibly high parity could be differentially associated with triple-negative breast cancer compared with non-TNBC cancers, although these associations were not statistically significant. Most other reproductive and non-reproductive risk factors showed no significant association with breast cancer phenotypes. Broad risk factor modification strategies are likely to be useful as population-level interventions.

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