Persistence to extended adjuvant endocrine therapy following Breast Cancer Index (BCI) testing in women with early-stage hormone receptor-positive (HR +) breast cancer

Patients with early stage hormone receptor positive (HR +) breast cancers have a risk of distant recurrence that remains high over a prolonged period, with approximately 50% of recurrences occurring more than 5 years after diagnosis despite optimal locoregional and standard adjuvant systemic therapies [1‐3]. Several randomized clinical trials established that extending ET beyond the standard 5 years of tamoxifen, an aromatase inhibitor (AI) or a combination of the two, offers superior protection against late recurrences [4‐11]. The ideal duration of EET in all-comers remains unclear with some studies suggesting equivalent survival in patients taking 7 or 8 years of total ET compared with 10 years [12, 13], however, certain high risk patients may benefit from longer duration of EET.

The absolute benefit of EET is modest – approximately 3–5% across studies – which must be weighed against added toxicities. An increased number or rare but serious side effects including endometrial cancer and thromboembolic disease were seen in trials of extended tamoxifen. A meta-analysis including seven trials and a total of 16,349 patients analyzed toxicity of EET with AIs [13]: longer treatment was associated with increased rates of cardiovascular events, bone fractures and discontinuation of treatment due to adverse events. In the ABCSG-16/SALSA trial [12] of extended ET, there was an increased risk of bone fractures in the 5-year versus the 2-year group with a hazard ratio (HR) of 1.35 (95% confidence interval [CI], 1.00–1.84).

Studies have shown that early discontinuation of adjuvant ET is associated with increased mortality [14], hence there is growing interest in studying non-compliance, adherence and persistence to ET. Differences between these terms are subtle but they are not interchangeable. Rates of adherence, defined as the extent to which patients take medications as prescribed, measured over the first 5 years of adjuvant therapy are estimated to range from 41 to 72% in one systematic review [15], which included data from 29 retrospective studies. In a series of randomized controlled trials of adjuvant ET, early discontinuation rates ranged from 8 to 28% [6, 16‐18]. Data on medication taking behaviors beyond 5 years is scarce. Non-compliance, defined as early discontinuation of letrozole for any reason, excluding death or breast cancer recurrence, was 18.4% at 2.5 years of EET in the IDEAL trial [19, 20]. One retrospective study examined real-world persistence, defined as the time from initiation to discontinuation of treatment, to EET after 5 years in 89 patients who were offered extended therapy based on clinicopathologic risk and found a high rate (78%) of persistence [21].

Breast Cancer Index (BCI) is a multigene-expression based assay that consists of two functional biomarker panels – the Molecular Grade Index (MGI) and the HOXB13/IL17BR ratio (H/I) – that interrogate proliferation and estrogen signaling pathways. BCI has been validated in multiple randomized trial cohorts [22‐26] as a prognostic tool for risk of late distant recurrence and predictive of benefit from EET [22‐24, 27]. We previously reported on the impact of BCI testing on patient decisions regarding EET [28, 29]. In this study, we aimed to characterize patient experiences and examine persistence rates to EET over a 5-year period after BCI testing at two academic centers in the United States.

This study provides data from long-term follow-up on our previously reported prospective assessment of the decision-making impact of the BCI assay in routine clinical practice in patients who face the important and difficult decision to continue ET or stop after completing 5 years [28]. This is the first study to also assess EET persistence in this context. The results show that patients who elect to continue ET based on BCI testing have a high likelihood of EET persistence: the observed rate of persistence at 75% is similar to a previously reported rate of 71.9% in what is, to the best of our knowledge, the only other study assessing EET persistence in a real-world setting [21]. Perhaps even more impactful is the finding that those patients for whom BCI predicted a high likelihood of benefit from EET had even higher persistence rate to EET at 81%; the difference in persistence rates between the (H/I)-high and -low groups was statistically significant (p = 0.0243). This study confirms our prior findings in a larger cohort demonstrating that the majority of BCI (H/I)-high patients (81%) chose to extend ET after BCI testing and discussion with their oncologist. However, BCI test results indicating a low prognostic risk of recurrence and high likelihood of benefit from EET could increase non-compliance with treatment recommendations, i.e., the decision to stop ET despite continued treatment benefit, which we observed in our study.

While the ideal duration of adjuvant ET in all-comers with early-stage HR + breast cancer remains unclear, there is ample evidence for preferential benefit from EET in patients with high BCI (H/I) ratio. (H/I)-high tumor biology corresponds to an approximately 58–67% relative risk reduction from EET in three large cohorts. In MA.17 (n = 249), (H/I)-high status was associated with a decrease in late recurrences (odds ratio [OR)] = 0.35; 95% CI, 0.15–0.73; p = 0.007) and with an absolute recurrence risk reduction of 16.5% at 5 years [23]. Similarly, in Trans-aTTom (n = 789), those patients classified as BCI (H/I)-high derived a significant benefit from 10 versus 5 years of tamoxifen (HR 0.33; 95% CI, 0.14–0.75; 9.7% absolute risk reduction; p = 0.016) [32]. Additionally, in 908 patients in the IDEAL trial, high BCI (H/I) significantly predicted benefit from 5 versus 2.5 years of extended letrozole in the overall cohort (HR 0.42; 95% CI, 0.21–0.84; p = 0.011) and in the subset of patients who received any AI during the first 5 years of ET (HR 0.34; 95% CI, 0.16–0.73; p = 0.004) [27].

In order to achieve the risk reductions above, patients must take their medication as close as possible to as prescribed; available evidence points to early discontinuation of adjuvant ET being associated with increased mortality [14]. Most of the data on adherence and persistence comes from studies done in the first 5 years of adjuvant ET. In a systematic review including data from 29 studies [15], non-adherence over greater than 4 years of therapy with adjuvant ET ranged from 28 to 59%, while non-persistence after 5 years of treatment ranged from 31 to 73%. Our results, and those of Myrick et al. [21] suggest higher persistence rates to EET after 5 years of adjuvant therapy. Since our study only included patients who had BCI testing, our cohort is enriched for patients who were likely persistent and adherent to ET during the initial 5 years and thus, is limited to studying this particular population that is possibly more likely to be adherent and persistent over longer follow-up. However, our results of higher persistence in those with BCI (H/I)-high results suggests the test result itself may be a tool to improve the behaviors associated with medication-taking behaviors.

There has been much interest in various strategies to improve adherence and persistence to adjuvant ET. Most early efforts focused on one-time or short-term educational interventions that emphasized the benefits of treatment; however, these studies demonstrated no improvement in adherence [33, 34]. More recently, mobile health has emerged as a strategy to improve medication adherence in multiple disease settings. For example, the SWOG S1105 randomized trial aimed to use one-way text messaging to increase adherence and persistence to adjuvant AIs and used urine metabolite assays to monitor adherence [34]. Observed adherence rates at three years, irrespective of prior adherence status, were similar in both the text messaging and no text messaging arms at around 55%. Perhaps most strikingly, by year three, 81.9% of patients in the text messaging and 85.6% in the no text messaging arms had an adherence failure event (a urine AI metabolite under a specified level or no submitted specimen). Overall, this study showed high rates of non-adherence to ET within the first 5 years and did not show any improvement with one-way text messaging reminders. There are currently efforts to use bi-directional text messaging that also tracks adherence and collects patient-reported information on side effects and other barriers to taking the medication, which can trigger alerts and interventions [35, 36].

In this study, we show that patients who had prognostic and, in particular, predictive information, from BCI testing had high rates of persistence to EET. Whether availability of BCI results improves persistence is unclear as our study only included patients who were persistent after the initial 5 years of therapy and were motivated to potentially continue ET. Based on our prior results that among patients recommended for EET, 82% reported they were more likely to comply with treatment based on BCI results [29] and with new data from this study, we hypothesize that BCI testing may help motivated patients remain persistent with treatment. This raises the question of whether BCI testing could be incorporated into the armamentarium of strategies improving adherence and persistence earlier during therapy to create an individualized, risk-stratified, treatment plan. Like individualized care plans in the survivorship setting, adjuvant care plans may give patients a roadmap to their adjuvant treatment over 5–10 years. For example, most patients with early-stage HR + breast cancers fall into the BCI low risk and BCI (H/I)-low category and for them, adjuvant care plans would emphasize the goal of 5 years of ET and follow-up with focus on strategies to promote adherence and persistence over those 5 years. Upon completion, they could “graduate” from traditional oncology follow-up to a survivorship program. On the other hand, for patients with BCI high risk and BCI (H/I)-high results, individualized treatment plans would include 10 years of ET and they may require more frequent follow-up or additional strategies to mitigate side effects such as more aggressive management of bone loss or cardiovascular risk factors for those on AIs. Treatment plans for patients with equivocal, i.e., Prognostic High/Predictive Low or Prognostic Low/Predictive High BCI results would be less clear, although BCI (H/I) status has been shown consistently to predict benefit from EET. Whether adjuvant treatment plans incorporating information from BCI testing early in the course of therapy would improve adherence/persistence or lead to reduced anxiety and improved quality of life will need to be tested in future research.

After 10 years of follow-up from diagnosis, there were six patients who experienced distant breast cancer recurrence, consistent with the overall excellent outcome of patients with early-stage HR + breast cancers. Given the small number of recurrences, no conclusions can be drawn regarding the association of BCI results and EET persistence with long-term outcomes. Overall, women who elected to extend ET had more bone density scans performed compared with those who stopped ET at around 5 years, and had numerically higher proportion of patients with osteoporosis, which can lead to increased health care cost. We previously reported on BCI-related projected net savings that were estimated to be US $5,190/patient [29], primarily driven by targeted use of EET.

Our study has several limitations. First, all patients received BCI testing and thus, it represents a population more likely to be persistent with ET in the first 5 years of therapy who are possibly more motivated to continue being persistent. Second, our cohort is small, yet it does include patients from two U.S. institutions servicing a diverse demographic region, which increases generalizability. Third, information on persistence was obtained from prescriptions entered into the electronic health record and from provider notes. In the future, studies incorporating urine metabolite testing to assess adherence to ET after BCI testing should be undertaken.

In summary, our multi-institutional study found high rates of persistence to EET after BCI testing, particularly in patients with (H/I)-high results, which is the population most likely to benefit from 10 years of ET. BCI is commercially available in the United States for all early-stage HR + breast cancer patients with up to 3 positive lymph nodes and is included in the National Comprehensive Cancer Network (NCCN) and American Society for Clinical Oncology (ASCO) guidelines. It is covered by Medicare and many private payors. It is also available in select international locations. The test is typically offered after 5 years of primary adjuvant therapy to help physicians and patients make informed decisions on the benefit of extending endocrine therapy to 10 years. Additionally, there is an ongoing large, population-based prospective BCI Registry study to evaluate long-term clinical outcome, clinical impact, medication adherence and quality of life in patients with HR + early-stage breast cancer receiving BCI testing as part of routine clinical care to inform extended endocrine therapy. Adjuvant, risk-stratified treatment care plans incorporating BCI testing earlier during treatment, along with other strategies, may increase the likelihood of persistence and adherence to ET, which has the potential to improve long-term outcomes in patients with early-stage HR + breast cancers.

In patients with early-stage HR + breast cancer who received BCI testing after approximately 5 years of adjuvant ET, rates of persistence to extended ET were high, particularly in patients with predicted high likelihood of benefit from EET. BCI can be a clinically valuable tool, in addition to clinicopathologic information, in guiding discussions with patients and decision-making regarding extending adjuvant endocrine therapy.