Introduction: Nine randomized trials in early breast cancer(EBC) have demonstrated an advantage of aromatase inhibitors(AI’s) over tamoxifen in disease-free survival. Joint symptoms are common toxicities and lead to treatment interruption in up to 20% in case of severe aromatase-induced arthralgia(AIA). During menopause levels of markers of inflammation such as IL-1b, TNF-alpha and IL-6 increase. We hypothesized that estrogen deprivation by aromatase inhibition could be associated with similar changes in these markers and that this could play a role in AIA. In an earlier study, similar toxicities were observed in patients(pts) treated with a recombinant form of IL-6. In several cell types it has been shown that ligand activated estrogen receptor blocks nuclear factor kappa beta controlled gene transcription of IL-6.

Aim of the study: We initiated a prospective open-label study to examine the role of inflammatory cytokines and other serum markers(CRP and hormones) in the pathogenesis of AIA.

Methods: 29 evaluable postmenopausal pts with hormone sensitive, Her 2 negative EBC stage I-III, with baseline G0-1 arthralgia were included. Before chemotherapy, at baseline, at month 3, 6, 9, 12 and 18 after AI initiation, serum samples were taken for CRP and hormones (estradiol, androstenedion) and cytokines were analyzed with a human cytokine 25-plex panel. A detailed rheumatologic questionnaire and Visual Analog Scale(VAS) was performed at each visit. Arthralgia grading was assessed using the CTCAE criteria 4.0. The T-test and the Wilcoxon Signed Rank test were used to look for the difference in terms of IL-6, Il-1b, IL-8, TNF, CRP, estradiol and androstenedion between G0 versus G1-2-3 arthralgia.

Results: The mean age was 56 yrs. (34-72yrs). All patients were treated with surgery followed by concomitant chemoradiation and letrozole (31) or anastrazole (1). In 16 pts G1 arthralgia was present before the start of the chemotherapy. Grade 2 and 3 arthralgia appeared at mth 3. The proportion of pts with grade 2 remained more or less the same, while grade 3 pts declined from month 6 onwards and disappeared at month 18.

Grade of arthralgia at different time points

Arthralgia mth o mth 3 mth 6 mth 9 mth 12 mth 18 
G0 45 23 19 11 18 
G1 55 39 54 61 59 55 
G2 23 19 22 29 27 
G3 15 
Arthralgia mth o mth 3 mth 6 mth 9 mth 12 mth 18 
G0 45 23 19 11 18 
G1 55 39 54 61 59 55 
G2 23 19 22 29 27 
G3 15 

There was a significant correlation between the grade of arthralgia and the VAS score at all-time points (p<0.05). CRP levels were significantly higher in the patients with arthralgia at month 3 (p<0.001) and 6 (p<0.005). Patients with G2-3 arthralgia had higher estradiol levels at mth 3 (p<0.001) and 6 (p<0.001).Cytokine results are currently available for the first 12 patients only. In these preliminary data, IL-6 levels were significant higher in the pts with arthralgia before initiation of AI ‘s. The examination of correlations during AI treatment needs the analysis of the full cohort.

Conclusion: This study indicates that both menopause and AIA have inflammatory mediators (IL6 and CRP) that correlate with the degree of lowering of estradiol levels. This is consistent with the regulation of IL-6 by the ligand activated ER through NFkB in vitro.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-06.