Although adjuvant ET improves breast cancer outcomes, up to half of patients stop therapy early, primarily because of side effects. In this retrospective study, we demonstrated that increased baseline nociplastic pain, as measured by Fibromyalgia Survey Score, was associated with premature discontinuation of ET. This finding suggests that central nervous system dysfunction, rather than peripheral inflammation, may underlie development of some ET-emergent toxicity, which could have implications for management approaches.
In our study, a higher proportion of patients who discontinued ET due to side effects were receiving AI therapy. AI therapy is increasingly used over tamoxifen for adjuvant treatment of hormone receptor-positive breast cancer due to its superior efficacy in reducing breast cancer recurrence and mortality [25]. Despite its demonstrated benefit, many patients experience AIMSS, and up to 30% of patients discontinue their AI due to these side effects [13]. To date, AIMSS has most commonly been attributed to nociceptive pain mechanisms. Some have hypothesized that decreased estrogen and dysfunctional inflammation contribute to microscopic bone and cartilage changes [10, 25]. However, consistent laboratory or radiographic evidence supporting either mechanism has not been found, and AIMSS incompletely responds to treatment with non-steroidal anti-inflammatory medications and opioids [10]. We demonstrated an association between baseline nociplastic pain and ET discontinuation, potentially suggesting a centralized pain mechanism underlying the pathogenesis of AIMSS. Patients who experience AIMSS might benefit from treatment modalities used for nociplastic pain, such as education, cognitive behavioral therapy, acupuncture, and serotonin and norepinephrine reuptake inhibitor (SNRI) therapy [8]. Importantly, both the SNRI duloxetine and acupuncture have been found in randomized clinical trials to be beneficial for improving AIMSS [13–15]. Efficacy of other nociplastic pain treatments for reducing AIMSS have not been reported.
As our understanding of pain evolves, new pain assessment instruments have been created to capture, categorize, and quantify patients’ pain [4, 23, 27]. The BPI, which is one of the most commonly used questionnaires, focuses on overall pain intensity and interference of pain on daily activities [5, 16]. However, BPI has the limitation that the perception of pain intensity varies between patients [7]. The instrument also fails to capture the character of pain (e.g., burning pain or hyperalgesia), timing of pain (episodic versus chronic), or information about locations of pain. These limitations are relevant when characterizing symptoms in patients with widespread, difficult to localize, and centralized pain, such as those with nociplastic pain conditions. The Fibromyalgia Survey was proposed by the American College of Rheumatology in 2010 as a way to address this issue [28]. The instrument has since been validated for evaluation of fibromyalgia, temporomandibular disorders, rheumatoid arthritis, and chronic lower back pain [1, 2, 11]. Studies have demonstrated an association between the Fibromyalgia Survey Score, pain, and disability, even when patients have a Fibromyalgia Score below the threshold for official fibromyalgia diagnosis [2, 11]. Our study found that in patients with breast cancer, an increased Fibromyalgia Score prior to surgery is associated with ET discontinuation, with most patients discontinuing their ET due to side effects. These findings highlight the potential of the Fibromyalgia Survey as a tool to evaluate patients’ underlying risk of ET discontinuation. It is also interesting that patients with hormone receptor-positive disease who did not initiate ET had a higher baseline fibromyalgia score compared to those who initiated ET, although our retrospective study was not designed to examine the clinical implications of this finding.
There were several strengths of this study. The first is that patients were identified from a large, ongoing institutional study in which patient reported outcomes were routinely captured immediately prior to surgery from consecutive, unselected patients, and therefore this cohort is more representative of a real-world population. Second, by limiting our study population to those who did not receive neoadjuvant chemo- or endocrine therapy, we examined a more homogenous population and did not have to account for effects of prior treatment on questionnaire responses. Third, we used validated questionnaires, making our findings more reliable and reproducible. However, patients were recruited from a single cancer center, so results and conclusions might differ in a larger, more diverse population. Also, since the study is retrospective, our conclusions are limited to suggesting association, not causation. Finally, in the MGI project, different questionnaires have been collected over time, resulting in missing data. To minimize errors resulting from missing data, we only included questionnaires completed by at least 75% of patients in our models, although some biases may remain.
In summary, nociplastic pain prior to initiation of any local or systemic breast cancer therapy was associated with premature ET discontinuation. This association suggests a mechanism and potential treatment approaches for ET toxicity, particularly musculoskeletal side effects. In addition, it highlights the Fibromyalgia Survey as a tool to identify patients at increased risk of ET discontinuation. Patients with higher baseline Fibromyalgia Survey scores may benefit from adjustments to the standard ET regimen or proactive side effect management to optimize adjuvant ET adherence and persistence. Further study is necessary to confirm the clinical utility of the Fibromyalgia Survey in a larger, more diverse patient population and to evaluate the impact of other nociplastic pain treatments in patients taking ET.