August 19, 2008 — Researchers have identified several risk factors that increase the risk for joint symptoms in postmenopausal women with breast cancer who are receiving endocrine treatment. The finding is reported in the August 13 Online First issue of The Lancet Oncology.

The risk for joint symptoms is increased by 12.1% by previous use of hormone replacement therapy, 7.3% by hormone receptor positivity, 6.5% by previous chemotherapy, 6.2% by obesity, and 4.9% by treatment with anastrozole vs tamoxifen.

The presence of multiple risk factors also increased the risk for joint symptoms that include arthralgia and arthritis. "The effects of these risk factors are additive, so having multiple factors will have a big impact on the likelihood of experiencing symptoms," study author Jack Cuzick, PhD, from Cancer Research UK, Wolfson Institute of Preventive Medicine, London, United Kingdom, told Medscape Oncology.

Estrogen deficiency and postmenopausal status have been associated with the development of joint pain and other symptoms in the general population. In addition, patients with breast cancer who received chemotherapy have also shown joint symptoms and other joint or muscle-related problems, but tamoxifen use appears to have limited effect on the incidence of joint symptoms.

In this trial, Dr. Cuzick and colleagues investigated the relative importance of several risk factors for joint symptoms in women who were enrolled in the Arimidex Tamoxifen Alone or in Combination (ATAC) trial and then evaluated if the identified risk factors act differently in the presence of anastrozole treatment.

The ATAC trial randomly selected 9366 postmenopausal women with early breast cancer to either anastrozole 1 mg/day, tamoxifen 20 mg/day, or to a combination of both agents. Of this cohort, 5433 women (anastrozole group: n = 2698; tamoxifen group: n = 2735) who did not report joint symptoms at entry into the trial were included in the analysis, which was based on data from case reports for these patients.

For the study authors' analysis, joint symptoms were defined as any report of arthralgia, arthrosis, arthritis, or joint disorder on a case-report form, and joint disorders included reports of cervical spondylosis, osteoarthritis, and disk herniation.

The investigators found that women in the anastrozole group reported significantly more joint symptoms vs women in the tamoxifen group (949 [35.2%] of 2698 vs 829 [30.3%] of 2735 women, respectively). In both groups, the majority of joint symptoms were mild or moderate, and the intensity of symptoms was similar across both groups. Of patients who reported joint symptoms, 60% received treatment, and 90% used a nonsteroidal anti-inflammatory drug alone or in combination with a mild analgesic.

Of the 1914 women who used hormone replacement therapy before entry into the trial, 777 (40.6%) went on to have joint symptoms vs 1001 (28.4%) of 3519 women who had not used hormonal therapy. Patients with hormone receptor–negative breast cancer had significantly fewer joint symptoms vs patients with hormone receptor–positive tumors (124 [26.9%] of 461 vs 1556 [34.2%] of 4548 patients, respectively).

Previous chemotherapy and high body mass index (BMI) were also associated with an increase in risk factors. Women who initially underwent chemotherapy had significantly more joint symptoms than those who did not undergo chemotherapy (461 [37.8%] of 1219 vs 1317 [31.3%] of 4214 women, respectively). Patients with a BMI of more than 30 kg/m² reported more joint symptoms vs patients who had a BMI of 25 to 30 kg/m² (504 [37.2%] of 1354 vs 502 [31.3%] of 1926 women) or a BMI of less than 25 kg/m² (592 [31.0%] of 1908 women).

The researchers noted that the effect of previous hormone replacement therapy was especially striking because most women had stopped using it within 6 months before they entered the study. However, the effect was similar in patients who had halted hormonal therapy earlier. The effects of hormone replacement therapy also appeared to be additive, resulting in an 18.1% increase in joint symptoms in women with both previous use of hormone replacement therapy and who were receiving anastrozole vs women receiving tamoxifen with no previous hormone replacement therapy.

Women who recently used hormone replacement therapy were more likely to have experienced a greater decrease in estrogen concentrations with endocrine treatment than women who stopped use more than 6 months ago, the study authors write, and most studies have shown that these women are more likely than never-users to have estrogen receptor–positive tumors.

In most patients, the risk for joint symptoms does not override the clear benefits of anastrozole vs tamoxifen in decreased tumor recurrence rates and fewer other major adverse effects. "This is a clinical judgment but even one factor should be enough to prompt oncologists to counsel patients about the possibility of joint symptoms and the likelihood that they will be mild and transient," said Dr. Cuzick.

"If symptoms are severe or persistent, tamoxifen should be considered instead of an aromatase inhibitor," he added.

This study was funded by Cancer Research UK and AstraZeneca. Dr. Cuzick has received research funds from AstraZeneca and acted as a consultant to AstraZeneca and Novartis. Four of the other study authors have disclosed various financial relationships with AstraZeneca. Another study author has received honoraria and other research grants from AstraZeneca, Pfizer, Genentech, Lilly, Taiko, and Amgen.

Lancet Oncol. Published online August 13, 2008.

Clinical Context

Study Highlights

• Women eligible for study participation were postmenopausal and had completed primary surgical or radiation therapy for invasive breast cancer. All women were candidates to receive hormonal adjuvant therapy. Women with metastatic breast cancer were excluded from study participation.
• The ATAC trial was a double-blind, randomized study comparing treatment with anastrozole 1 mg daily, tamoxifen 20 mg daily, or a combination of both treatments.
• The current study included only women who reported no joint symptoms at the outset of the study.
• The main outcome of the current study was the incidence of joint symptoms during active study treatment or within 14 days of its discontinuation. These data were drawn from case reports completed by participating study centers.
• Joint symptoms could be defined as arthralgia, arthrosis, arthritis, or joint disorder. Joint disorders were defined as cervical spondylosis, osteoarthritis, and disk herniation.
• 2085 of 6186 women in the current analysis reported treatment-emergent joint symptoms, and case reports from 5433 women were evaluated after the application of exclusion criteria. Most joint symptoms were mild to moderate in severity, and the rate of treatment withdrawal because of joint symptoms was only 1%.
• 35.2% of women receiving anastrozole experienced joint symptoms vs 30.3% of women receiving tamoxifen (odds ratio, 1.25).
• The rates of joint symptoms in women who previously did and did not receive hormone replacement therapy before the diagnosis of breast cancer were 40.6% and 28.4%, respectively (odds ratio, 1.72).
• 26.9% of women with hormone receptor–negative breast tumors experienced joint symptoms vs 34.2% of women with hormone receptor–positive tumors (odds ratio, 0.71).
• The use of previous chemotherapy increased the risk for joint symptoms by 34%.
• Obesity, defined as a BMI of more than 30 kg/m², increased the risk for joint symptoms vs women with a BMI of less than 25 kg/m².
• Age and a history of radiotherapy had no independent effect on the risk for joint symptoms.

Pearls for Practice

• Joint symptoms are most prominent in women in the fifth decade of life, and women who are postmenopausal are more likely to experience joint symptoms vs premenopausal or perimenopausal women of the same age. Hormonal therapy with estrogen can relieve these joint symptoms, whereas third-generation aromatase inhibitors promote joint symptoms.
• In the current study of women with breast cancer, the use of anastrozole instead of tamoxifen, previous use of hormone replacement therapy, hormone receptor–positive tumors, and obesity increased the risk for incident joint symptoms. However, age and previous radiotherapy had no independent effect on the risk for the development of joint symptoms.

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