Aromatase Inhibitor-Associated Musculoskeletal Pain: Taking ‘Aim‘ at a Symptom in Breast Cancer Survivors

Breast cancer is the most common cancer affecting women in the USA, with almost 200,000 new cases diagnosed each year [101]. Depending on the stage of disease at diagnosis and the subtype of the cancer, patients undergo treatment with surgical resection, radiation therapy, chemotherapy and/or targeted treatments such as anti-estrogen therapy. In the setting of non-metastatic breast cancer, these therapies are administered with the intention of curing the disease, but all can be associated with both short-term toxicity and long-term morbidity, including pain, which can be difficult to manage.

As a medical oncologist, two of my primary goals when treating a patient with early-stage breast cancer are to maximize breast cancer survival while minimizing the impact of the therapies on her quality of life. Approximately three-quarters of women diagnosed annually with breast cancer have hormone-sensitive disease, and anti-estrogen therapies such as tamoxifen and aromatase inhibitors are routinely recommended for treatment based on strong data demonstrating improved breast cancer outcomes. However, multiple studies have shown that, although overall survival is increased with at least 5 years of treatment, almost half of women with breast cancer discontinue these therapies prematurely, in part owing to side effects associated with the medications [1]. Failure to complete the full course of the medication can obviously compromise the chance of cure.

During the past decade, the aromatase inhibitor class of anti-estrogen therapy has become the standard of care for postmenopausal women with breast cancer, in part owing to improved outcomes compared with the previous standard treatment, tamoxifen [2]. However, although these medications were initially thought to be well-tolerated, subsequent studies in real world settings have demonstrated a high treatment discontinuation rate caused by side effects [3]. Joint and muscle aches are the most common toxicity, affecting approximately half of treated women and leading to premature discontinuation of therapy in up to 20%. Since the underlying prevalence of arthralgias is high in this postmenopausal population and there are no pathognomonic findings, diagnosis can be challenging. Withdrawal of the medication frequently leads to symptomatic improvement, but reinitiation of aromatase inhibitor therapy can lead to recurrence of symptoms. Despite numerous studies conducted to elucidate the etiology of this pain, the underlying mechanism remains poorly understood, although some have proposed it is caused by profound estrogen deprivation [3]. Management of the pain can also be challenging, as it is typically poorly responsive to standard analgesics.

Working with our chronic pain colleagues at the University of Michigan (MI, USA), we designed a prospective clinical study to further characterize the aromatase inhibitor-associated musculoskeletal toxicity of anti-estrogen therapy [4]. Clinical and laboratory assessment of affected patients revealed a lack of evidence of significant local or systemic inflammation. For example, no subjects had examination findings consistent with synovitis, or laboratory results suggestive of autoimmune or inflammatory conditions. Similar to other chronic pain conditions, such as fibromyalgia, there was discordance between clinical presentation and the degree of pain and functional impairment in many women. In these other chronic pain conditions, standard analgesics are frequently ineffective, but adjunctive therapies, such as tricyclic antidepressants, serotonin norepinephrine reuptake inhibitors and gabapentin, have shown promise [5]. For example, duloxetine has been approved by the US FDA for the management of fibromyalgia, painful diabetic peripheral neuropathy and chronic musculoskeletal pain. Therefore, based on management approaches for these other chronic pain disorders, we conducted a pilot clinical trial to evaluate the efficacy of the serotonin and norepinephrine reuptake inhibitor duloxetine for treatment of aromatase inhibitor-associated arthralgias.

As we recently presented at the San Antonio Breast Cancer Symposium, we treated 29 evaluable women who had been treated with an aromatase inhibitor for at least 2 weeks and who had developed new or worsening arthralgias rated at least four on a ten point scale with duloxetine for 8 weeks [6,102]. Results from this pilot clinical trial demonstrated a mean decrease in average pain of approximately 60%, as well as substantial improvement in functional status and pain interference. Although these data are promising, given the prominent placebo response previously noted in randomized studies of duloxetine and similar medications, as well as the potential for duloxetine-associated side effects, evaluation in a randomized, placebo-controlled clinical trial is necessary to determine the true benefit of the medication. In addition, it will be important to identify predictors for which subset of patients are more likely to benefit from the treatment with minimal toxicity.

The ultimate goal is to enable breast cancer survivors to receive potentially curative breast cancer therapy with minimal negative impact on their quality of life, in order to optimize adherence and persistence with therapy for the recommended duration. The addition of a medication such as duloxetine may sufficiently alleviate aromatase inhibitor-associated pain to permit a proportion of survivors to continue to take the anti-estrogen therapy with minimal toxicity. In addition, breast cancer survivors frequently experience depression, anxiety and hot flashes, and preliminary data from our pilot study suggest that these conditions may also be improved with duloxetine [6]. However, a subset of treated patients experienced bothersome side effects from the therapy, which outweighed any potential benefits. Conduct of correlative studies evaluating predictive factors, such as pharmacogenetics, may enable clinicians to determine a priori which patients are likely to experience pain relief from the addition of duloxetine and which are more likely to experience significant toxicity, which could lead to the tailoring of therapy for individual patients.

In addition to aromatase inhibitor-associated musculoskeletal pain, which usually resolves upon discontinuation of medication, patients with breast cancer can experience treatment-related chronic pain that requires management. Chronic chest wall pain following surgery can be disabling for a subset of patients. Those treated with certain types of chemotherapy, especially taxanes, can experience painful peripheral neuropathy that can be long-lasting in a minority of patients. The Cancer and Leukemia Group B (CALGB) Cooperative Group is currently conducting a randomized, placebo-controlled study of duloxetine for treatment of chemotherapy-associated painful neuropathy [103], based on existing data which demonstrate that duloxetine is effective for treatment of diabetic peripheral neuropathic pain. Additional studies of adjunctive analgesics will hopefully lead to improvements in the management of long-term painful sequelae of cancer treatments.

Identification of effective treatment modalities for all of these conditions is important, and adjuvant treatments such as serotonin norepinephrine reuptake inhibitors may play a key role in pain management in the future. Additional research is warranted to better understand the etiology of the pain, to identify which patients are predisposed to developing pain, and to develop more effective and well-tolerated cancer treatment and pain management regimens. Through this approach, we hope to improve the lives of breast cancer survivors.

Financial & competing interests disclosure

The author has received funding to conduct clinical trials from Eli Lilly, AstraZeneca, Sanofi-Aventis and Exelixis. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.