There will be a dramatic increase in the number of BC cases based on the aging of the population of US women. Standard risk factors for recurrence and prognosis focus on the tumor stage and the biological characteristics of the tumor, [41
] as well as the receipt of appropriate adjuvant therapies. The extent to which other comorbid conditions and their associated medications influence BC recurrence and mortality is an area of recent interest.[13
] Factoring these exposures into BC recurrence prediction may be important and potentially affect follow-up care. In addition, medications that are implicated in the prevention of recurrence may become candidates for use in primary prevention and adjuvant therapy settings. [26
The findings from the LACE cohort provide a window on the biology of BC recurrence in a diverse population of women who are insured and have access to care in a group model health maintenance organization, with access to both specialist and generalist care. In this setting, there is no evidence of racial disparity in BC outcomes for Black women controlling for cancer specific variables (stage, treatment), demographic and chronic disease variables (age, obesity, diabetes, hypertension), as well as the medications studied. Consistent with an expanding literature on host lifestyle factors, diabetes was significantly associated with greater hazard for overall mortality, as in the general population of women. However, in this patient sample there was no association of diabetes with BC recurrence or cause-specific mortality. Among other findings, being overweight or obese was not statistically significantly associated with recurrence, cause-specific mortality or mortality, which likely relates to the access to care in this setting as well as the control for other chronic disease variables that may be in the causal pathway.
What about the relationship between the pharmacological agents studied and the risk for BC recurrence? We did not find a statistically significant relationship between use of BB and any of the BC outcomes. This evaluation is hampered by the small number of women who took a non-selective BB, i.e. propanolol (14% of BB sample), which would be the best therapeutic agent to affect the beta-2-adrenergic receptor implicated as a therapeutic target in BC metastasis preclinical models.[30
] While one recent study has suggested clinical benefit from both selective beta 1 adrenergic antagonists as well as non-selective BB therapy,[33
] another study of a large BC sample only found benefit in women receiving a non-selective BB.[34
] In our analyses, it is noteworthy that women receiving BB therapy had lower HR for recurrence and cause- specific mortality, although these findings were not statistically significant given the low event rate in the LACE cohort. In contrast, we found that use of ACEi therapy was associated with an increased hazard of recurrence (HR 1.56, 95% CI 1.02, 2.39, p=0.04), but not for cause-specific mortality or overall mortality. Interestingly, patients on both a BB and an ACEi did not have an increased hazard of recurrence (HR 1.14, 95% CI 0.61, 2.14, p=0.69), suggesting that the addition of the BB to ACEi therapy may have a beneficial effect on recurrence.
The present data indicate divergent effects of two commonly prescribed anti-hypertensive medication classes (BB and ACEi) on the risk of BC recurrence. Such results and those from previous BB studies [33
] suggest that the observed alterations in recurrence risk are unlikely to stem from reductions in hypertension per se, and instead likely reflect differences in the biological pathways through which those agents act. Preclinical studies suggest that BBs can influence the progression of solid epithelial tumors (including experimental BC) by inhibiting macrophage recruitment and neovascularization within the primary tumor. [29
] Those effects are mediated predominately by inhibition of beta-2 adrenergic receptor signaling in tumor cells, vascular endothelial cells, and monocyte/macrophages, resulting in reduced signal transduction to support the expression of pro-metastatic and pro-angiogenic genes. [29
] Beta adrenergic signaling may also support the survival of disseminated carcinoma cells (anoikis). [47
] The reduced BC recurrence observed here in BB-treated patients, although not reaching statistical significance in this cohort, is thus consistent with BB biological processes observed in preclinical experimental data and other BB epidemiological studies in BC. [33
In contrast, the mechanisms by which ACEi might increase BC recurrence are more obscure. Such effects are unlikely to stem from antihypertensive effects per se, and more likely to involve the specific biology of angiotensin and its receptor system. Angiotensin is therapeutically manipulated chiefly to modulate vasoconstriction, but this oligopeptide has a diverse array of other physiologic effects on other aspects cardiovascular function, neural function (including brain regulation of thirst and salt balance, and peripheral sympathetic norepinephrine outflow), and aldosterone production by the adrenal cortex. The increased hazard of BC recurrence observed here in ACEi-treated patients is consistent with previous reports linking these drugs to inflammation;[48
] however, most studies of ACEi, as well as a recent study of angiotensin receptor blocker (ARB) exposure have focused on cancer incidence rather than progression or metastases.[50
] Given that ACEi and ARB medications target different specific molecules but are associated with similar effects on cancer risk, there could be a specific protective effect of angiotensin signaling on BC-related biology. Identifying the biological mechanisms by which BC biology is regulated by angiotensin signaling and its pharmacologic modulation by ACEi medications represents an important area for further preclinical research.
Strengths of this study include careful case ascertainment and follow-up for disease recurrence and mortality in the LACE cohort, an ethnically diverse patient sample, and access to a pharmacy database capturing medication use before and after BC diagnosis. Without the latter, questions related to potential benefits or harms of BB and ACEi therapy could not have been examined. However, caution should be used in interpreting the drug exposure findings, as we cannot exclude confounding of medication use with indication (e.g., heart disease and ACEi) or other types of bias in this observational study setting. In addition, there are other limitations that relate specifically to the cohort, including access to treatment for many chronic conditions that might favorably influence survival and BC specific outcomes. These access factors may have influenced the lack of survival disparities for Black women, although we may have reduced potential for observing disparities by controlling for diabetes and hypertension which are more prevalent in Black women.
Nevertheless, the findings from this study are provocative, and raise concerns about the potential harm of commonly prescribed ACEi therapy. Although the low event rates and small number of patients on BB limited our power to detect the potential benefits of individual BB medications, the main findings for BB are consistent with the hypothesis that this class of drugs may be risk reducing. However, our sensitivity analysis findings of decreasing risk with decreasing days of supply of medication, while only exploratory due to sample size, would argue against a causal association. Finally, the findings of an association of ACEi exposure with poor outcomes are hypothesis generating only, as they were not specified a priori, and were in fact counter to suggestions in the literature. Thus, they need further corroboration in other clinical databases and, if confirmed, their potential mechanism for adverse outcomes needs more detailed examination in the laboratory.