- Rationale and flexibility of medication grouping and covariates selections using data from electronic healthy records
Both denosumab and bisphosphonates are approved by FDA to treat bone metastatic solid tumors or hematopoietic tumor myeloma involving bone. Those clinical scenarios are excluded from this study by excluding any patients with malignant diagnosis in first encounter, and any cancer diagnosis other than breast carcinoma during follow-up, and applying at least 365-day waiting time in medication groups for breast cancer case counting (any breast cancer cases diagnosed 365 days before medication or 365 days within first encounter were dropped off from analysis).
Denosumab is administrated subcutaneously every 6 months. Bisphosphonates are administered at variable interval of daily, weekly, quarterly or yearly regime. Because of the lingering effect of bisphosphonates and low-frequency standard administration regime for denosumab, we classify the anti-osteoporosis therapy as two category dichotomous binary data, e.g., with or without treatment.
It is natural to ask whether the breast cancer patients in each subgroup have different prognosis. Breast cancer prognosis is currently stratified into 8 groups based on anatomic characters including T (tumor), N(nodes), M (metastasis), and biological types including estrogen/progesterone receptor, HER2 status according to AJCC 8th edition [34]. Furthermore, categorization based on genome, RNA or protein expression profiles are also applied [34]. Such complex stratifications require large number of breast cancer cases for testing of prognosis difference across each subgroup. This question may be addressed in future large-scale studies. Also bearing in mind, relative proportions of cancer subtypes may neither translate into absolute risks nor reveal the underlying tumor biology.
Hormone replacement is required for menopausal symptom control in some patients due to decreased endogenous estrogen level. The hormone replacement may indicate both decreased risk for breast cancer (lower endogenous hormone level) and increased risk (supplemental hormone). We therefore separate this group from our control.
Statins ever users have also been separated from control because of afore mentioned signal pathway overlapping with bisphosphonates.
Well-accepted breast cancer risks include family history, increased hormone level, adiposity (body mass index), alcohol ever use [3]. Smoking is not considered a risk factor for breast cancer [3]. Moreover, diabetes status, which has not been mentioned as a risk factor for breast cancer in WHO Classification of Tumors of the Breast, has been reported to be associated with breast cancer [29-31]. We included those in our covariate analysis, besides age which by itself is a cancer risk. We compared parameters of blood pressure and lipidemia which are related to general health and physical activity. The co-variate analysis showed that there is no significant biomedical difference between the denosumab and bisphosphonates ever use groups.
- Comparison of our results with other studies
There are inconsistent results on association of breast cancer risk and bisphosphonates use. Most previous large cohort studies have shown that bisphosphonates have either a protective effect or no adverse effect in primary breast cancer prevention [15-22]. The only randomized control trials showed that 3–4 years of bisphosphonate treatment did not decrease the risk of invasive breast carcinoma in postmenopausal women [23]. However, the randomized control trials were not initially designed to study breast cancer outcome and they might be at high risk of selective reporting bias. Overall, systemic reviews and meta-analyses agreed upon a significantly decreased risk of primary breast cancer in bisphosphonates users[24-26]. This is in accordance with our findings.
Different from bisphosphonates whose cancer association has been studied for a decade, there is only one paper recently published addressing the relationship between denosumab and breast cancer risk. This first case-control study showed that in a cohort of older women previously treated with bisphosphonates, denosumab use was associated with a 13% decreased breast cancer risk (HR = 0.87; 95% CI 0.76–1.00) [27]. There was no relationship between increasing number of denosumab doses and breast cancer risk (P-trend = 0.15) [27]. Our cohort study, which has a similar length of follow-up to the former study but with a bisphosphonates and denosumab co-medication rate of 2.8% (84/3020=2.8%), did not come to the same conclusion. We showed that breast cancer risk in denosumab users is not significantly different from the control, although our study demonstrated breast cancer lowering effect of bisphosphonates.
The initial epidemiological study on statins and breast cancer association is from the Nurses' Health Study (NHS) cohort [28]. It showed no associated risk of breast invasive carcinoma in statins users, but the co-medication analysis did not include bisphosphonates use. All the cohort and case control studies which focused on the relationship of bisphosphonates and breast cancer did not separate statins use from control group either [15-23]. In our study, statins showed similar breast cancer protective effect as bisphosphonates in consistence with published preclinical research [11-13]. It is possible that the comparable breast cancer protective effect of bisphosphonates or statins might be masked when the control group has co-medication of either of these two drugs.
We also showed that co-medication of denosumab and statins led to lower cancer risk compared to denosumab ever use, although the statistical significance is not applicable due to events (cancer cases) less than 5. Plans are underway for our acquiring even larger medical records data sets to further investigate such concepts.
This healthier biomedical status in the hormone group may explain the lowest breast cancer risk among all the groups despite this group has a higher incidence of breast cancer family history. The absence of increased breast cancer risk may also be related to low dose and formulation of hormone in this group of patients. There is a great discrepancy on breast cancer risk and postmenopausal hormone use [3].
In a contemporary observational cohort study, more than 100,000 women ages 50 to 71 were followed prospectively for 15 years. It showed that long-term hormonal contraceptive use reduced ovarian and endometrial cancer risks by 40% and 34%, respectively, with no increase in breast cancer risk regardless of family history [32].
- Limitation
The electronic health system records individualized personal care, in compliance with standard patient care. It enables us to analyze potential drug interaction among anti-osteoporosis drugs, statins and exogenous hormones in the real world. Our study also has limitations. Age at menarche, breastfeeding history are missing in majority of our electronic health records.
The multi-variate model turned out to be in partial agreement with our univariate and bivariate analysis conclusions, but the main drawback of a multivariate survival analysis here stems from how we counted breast cancer cases within the groups. The multivariate model includes the four main drugs under study: denosumab, bisphosphonates, statins, and hormones. For each patient in the medication group, we needed to compute the last date that any of the four drugs that they took was prescribed and add that number to 365 to determine the threshold after which a breast cancer diagnoses gets counted. This removes that uniformity that we had maintained in the univariate and bivariate analysis.