Managing Adverse Events with Endocrine Therapy: What Patients Need to Know
Presentation by Dr Naomi Dempsey, MD, Miami Cancer Institute
At the 2024 West Oncology Conference in Memphis, Tennessee, Dr Naomi Dempsey from Miami Cancer Institute presented on the topic of managing adverse events associated with endocrine therapy, particularly in the setting of breast cancer. A majority of patients with breast cancer present with tumors that are ‘hormone responsive’, defined as having expression of the estrogen and progesterone receptors (ER+/PR+). As such, after surgical removal of their tumor, and depending on their overall risk for a recurrence, such patients may be candidates for adjuvant endocrine therapy (ET) using agents like tamoxifen (in premenopausal women) or the aromatase inhibitors (in postmenopausal women).
The main purpose of ET is to inhibit the actions of estrogen, and thereby block a major biologic pathway that breast cancers depend on in order to grow. The inhibition of estrogen, however, also results in several undesirable adverse events (AEs), which is a major factor in poor adherence and compliance over the duration of ET (typically 5 years, but up to 10 years in some cases). Dr Dempsey noted that the adherence to ET decreases over time, in one study of tamoxifen, declining from 83% at year 1 to 50% by year 4, with younger age and Black race being the major predictors of non-adherence to ET. Another study found that both younger <40 and older >75 patients were more likely to discontinue or be non-adherent to their ET. The lack of adherence to ET is important, because it has been shown that an adherence level <80% results in significantly poorer overall survival in women with Stage I to III breast cancers (80.7% versus 73.6%; P<0.0001). While multiple factors including personal (e.g., health beliefs, social support), treatment related (e.g., side effects of ET), and healthcare system related (e.g., lack of insurance coverage, satisfaction with care), Dr Dempsey noted that AEs were one of the most important factors that result in patients stopping or being non-adherent to their ET.
Vasomotor Symptoms (Hot Flashes)
Vasomotor symptoms (VMS), or hot flashes, are one of the most common symptoms associated with ET, and Dr Dempsey noted that while hormone replacement therapy (HRT) with estrogen is an effective treatment option, its use in the setting of ET for breast cancer is contraindicated, as more than one clinical study has shown a higher incidence of breast cancer events in patients receiving HRT versus those not on treatment. As such, there has been a greater focus on the use of non-hormonal treatments for patients on ET experiencing VMS (BOX 1).
Box 1. Non-Hormonal Treatment Options for Hot Flashes
Antidepressant medications (e.g., venlafaxine)
Gabapentin
Oxybutynin
Clonidine
Acupuncture
Cognitive Behavioral Therapy
Fezolinetant (Veozah)
Based upon data from randomized, placebo-controlled clinical trials, Dr Dempsey noted that fluoxetine, clonidine, and venlafaxine all reduced hot flashes over 6 weeks of treatment. She further noted evidence from clinical trials of a large placebo effect, meaning that, although patients on therapies like antidepressant medications experienced a greater benefit in terms of symptom reduction, patients on placebo also experienced some reduction in their hot flashes.
In a study comparing venlafaxine and gabapentin in breast cancer patients using a crossover design (where patients received one treatment or the other first for 4 weeks, then crossed over to the other treatment for another 4 weeks with a 2 week “washout period” in between treatments), both agents reduced hot flashes to a similar degree, but there was a greater patient preference for venlafaxine (68% vs. 32%). Dr Dempsey also reviewed data for acupuncture in treating hot flashes, as she noted many of her patients don’t like the idea of “taking a pill to combat the side effects of another pill” and are therefore more receptive to acupuncture as a treatment option. One study she reviewed further showed that acupuncture outperformed venlafaxine in reducing hot flashes.
Fezolinetant (Veozah) is a neurokinin 3 receptor antagonist type drug and was recently approved for VMS associated with menopause, however, it has also been used in the setting of ET. Side effects such as abdominal pain, diarrhea, and liver toxicity (transaminitis) may occur, and Dr Dempsey noted it is important to check that there are no drug interactions with any medications the patient may be on when using this agent; one notable interaction is ribociclib, a CDK4/6 inhibitor drug also used in breast cancer.
Summarizing, Dr Dempsey noted that at present her preferred treatment for VMS associated with ET is venlafaxine at a dose of 37.5 mg. Gabapentin is another option, at gradually increasing (“titrated”) doses of up to 900 mg, either split up during the day or at bedtime. Other agents like fezolinetant can also be considered, but it is important to check for possible drug interactions. She also considers acupuncture to be a very viable non-pharmacologic option for treating VMS that patients may want to try.
Arthralgias
Arthralgias are commonly seen in patients on aromatase inhibitor (AI) based ET, and can manifest as bone pain, joint stiffness, or carpal tunnel syndrome. Arthralgias can be severe in about one third of cases and result in treatment discontinuation in up to 20% of patients on AIs. Dr Dempsey noted patients frequently report the symptoms like “I feel like I’ve aged 30 years in just one month…” and “Everything’s stiff… I feel awful”. She highlighted exercise, duloxetine, and acupuncture as the three most effective treatments for arthralgias, also referred to as AI-induced musculoskeletal syndrome (AIMSS). In the HOPE Trial, women with breast cancer on AIs who reported arthralgias and not exercising at baseline were randomized to exercise consisting of aerobic and strength training or not, and pain scores before and after 3, 6, 9, and 12 months were assessed. Dr Dempsey noted significant benefits in the trial in terms of reducing worst pain and pain severity, and independent of the study, she highlighted the additional known benefits of exercise, including weight loss and reducing recurrence risk for breast cancer patients – “There’s a lot of good reasons to recommend exercise…”. Duloxetine, an antidepressant medication was also more effective than placebo in reducing pain scores in at least one study, but there was also a significant placebo effect observed in this study (BOX 2), with more than half of patients on placebo experiencing at least a 2 point drop in their pain score by 12 weeks. Lastly, she noted a benefit, again, of acupuncture in this setting, highlighting one study in which patients received either true acupuncture or a “sham” acupuncture procedure, which showed a significant improvement in worst pain scores with the true acupuncture procedure.
BOX 2. Duloxetine Versus Placebo for AIMSS: Percent of Patients with a Drop in Average Pain of At Least 2 Points
| Time (Weeks) | Duloxetine | Placebo |
|---|---|---|
|
2
|
52% | 40% |
| 6 | 68% | 49% |
| 12 | 68% | 59% |
Summarizing, Dr Dempsey noted exercise as one of the top interventions patients should try for arthralgias, as well as nonsteroidal anti-inflammatory drugs (NSAID) pain medications like ibuprofen. Duloxetine (initially 30 mg daily for one week, then 60 mg) is another option, and, as with VMS, she also highlighted the efficacy of acupuncture in this setting. For patients having more resistant arthralgia symptoms on one type of AI, Dr Dempsey suggested stopping the AI for a 2 week period and then starting a different AI, or switching to tamoxifen. As a final option, she also suggested reconsidering the overall benefit of ET (in terms of preventing recurrence for that patient) as weighed against the overall burden of arthralgia symptoms which can be debilitating and impair quality of life – “Patients may not always feel that the benefits outweigh the side effects…”
Vaginal Dryness
Dr Dempsey noted vaginal dryness is an important side effect of ET to ask about, because patients don’t always bring it up, and it can significantly diminish sexual function and enjoyment. Vaginal estrogen creams have been shown to be effective for this symptom, but, as with hot flashes, because of the risk for increased recurrence with estrogens in patients with breast cancer, the data remain controversial, and Dr Dempsey does not recommend this for her patients. Instead, she suggests non-hormonal vaginal mositurizers such as Replens and Revaree. She noted that some companies will provide samples that can be useful for patients to try, and that it is important to instruct patients to apply regular lubricants at the time of intercourse for best results. She also noted some data for vaginal laser based therapy as a means to improve dryness, itching, and burning as well as sexual function but she had not had any patients thus far who had tried the therapy for these ET-related symptoms.
Bone Health
While addressing all ET-associated adverse events is important to ensure optimal compliance and adherence to treatment, Dr Dempsey noted that bone health, particularly for patients on AI therapy, is especially important, as it can be the most impactful for patients’ health, and its potential impacts are not as easily reversed. She noted that any patient beginning therapy with an AI should have a bone density scan to assess their risk for bone loss.
While there are a number of options for bone supportive therapy including oral agents (e.g., alendronate, ibandronate) and subcutaneous treatments such as denosumab (Prolia), Dr Dempsey noted she prefers using intravenous zoledronic acid bisphosphonate therapy (brand names Reclast or Zometa) for her patients on AIs. Zoledronic acid has also been shown to have the added benefit of reducing the incidence of breast cancer recurrences (metastases) occurring in bone. In one large, pooled analysis of 26 trials with nearly 12,000 women, there was a significant reduction of about 2.2% in the incidence of bone recurrences for patients with breast cancer on zoledronic acid bisphosphonate medications versus control (6.6% vs. 8.8%; P=0.0002), and fewer deaths, with the benefits limited to postmenopausal women.
Summarizing her recommendations for bone health, Dr Dempsey noted that all patients should undergo a bone density assessment prior to beginning AI therapy. Indications for bone density scan are shown in BOX 3. She noted that adjuvant bisphosphonate therapy should be offered to postmenopausal women on ET, particularly those whose breast cancer was severe enough to require chemotherapy. Her current preference for bisphosphonate therapy is zoledronic acid, at a dose of 4 mg, administered every 6 months to complete three years of treatment. In addition, any woman with osteoporosis should be offered bisphosphonate therapy (zoledronic acid, 5 mg annually), and should be referred to endocrinology for further evaluation. Bone density scans should also be repeated every 2 years.
Box 3. Indications for Bone Density Scanning in Women
Women >65, regardless of clinical risk factors.
Younger postmenopausal women, or women transitioning to menopause, who have clinical risk factors for fracture.
Any woman having a fracture after age 50.
Any woman with a clinical condition (e.g., arthritis) or on medications (e.g., AIs for breast cancer) associated with low bone mass or bone loss.
Practice Points
Dr Dempsey noted some general practice points for clinicians when managing patients who are experiencing side effects of ET. She recommends pairing with a good acupuncture group so that patients be offered this non-pharmacologic option which can be quite effective for managing their ET associated adverse events. In addition, she recommends obtaining patient samples whenever possible, so patients can try other non-hormonal treatments and supplements at home for their ET associated events like vaginal dryness and hot flashes.
Speaker Disclosure Information: Dr Dempsey noted some off-label use of medications in her presentation, and the following disclosures: Consulting: Gilead, Novartis, MJH Life Sciences, OncLive, Ashfield Healthcare, PrecisCa, Curio Science; Speaker’s Bureau: Seattle Genetics.
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