Title: The etiology of the aromatase inhibitor-induced musculoskeletal syndrome in breast cancer patients
Other Titles: De etiologie van het aromatase inhibitor-geïnduceerde musculoskeletaal syndroom in borstkankerpatiënten
Authors: Lintermans, Anneleen; S0179349
Issue Date: 22-Sep-2014
Abstract: The third generation aromatase inhibitors (AI) have become an established component of treatment for both early and advanced postmenopausal estrogen receptor-positive breast cancer. Various trials showed an increased disease free survival and overall survival as well as a more favorable long-term toxicity profile with AIs as compared to tamoxifen. Therefore, the long-term use of AIs in the metastatic, adjuvant and probably also preventive setting will further increase worldwide. By blocking the aromatase enzyme responsible for the conversion of androgens to estrogens, AIs substantially suppress the low remaining circulating estrogen levels in postmenopausal breast cancer patients. These women are therefore confronted with exacerbating menopause-related side effects like hot flashes, musculoskeletal problems, sexual dysfunction, cognitive deterioration, changes in lipid metabolism and bone mineral density. Particularly, the AI-induced musculoskeletal syndrome (AIMSS) represents a substantial problem. AIMSS includes carpal tunnel syndrome, arthralgia, myalgia, joint stiffness and paresthesia. Joints that are most commonly affected by AIMSS include hands and wrists, knees, neck, shoulder, feet and back. Also, morning stiffness is frequently reported. Although rates of 35% have been reported in the randomized trials, the real number lies much higher in the clinical setting. We followed a large cohort of 293 AI- and tamoxifen-treated early breast cancer patients during their first year of endocrine therapy, using a validated musculoskeletal questionnaire and grip strength test. 74% of AI users reported new or worsened musculoskeletal complaints compared with 37% in the tamoxifen group. This was translated in a more pronounced grip strength decrease in patients experiencing AI-induced pain opposed to patients without new/worsened complaints. Furthermore, 15% of AI users discontinued therapy due to musculoskeletal symptoms, who were characterized by a larger grip strength reduction than observed in adherent patients. Prior taxane-based chemotherapy, age less than 55 years and a high baseline pain score were confirmed as clinical predictors for AIMSS. Although the prevalence and importance of AIMSS occurring in breast cancer patients has become evident over the last years, there is scarce information that would clearly explain this syndrome and its underlying mechanisms. Although there is no evidence of a systemic inflammatory process, the fluid retention and tendon sheath thickening we demonstrated with AI use mirror local inflammation. This tenosynovial pathology was still present, and even worsened, in the majority of patients after 24 months of AI therapy, underlining the importance of AIMSS. Whether these symptoms are a result of estrogen deprivation or develop in conjunction with other contributing factors is still uncertain. Practically all women on AI therapy have profound estrogen deficiency, as demonstrated with our very sensitive liquid chromatography double mass spectrometry method. However, not all of them develop musculoskeletal symptoms. Therefore, other factors, in addition to estrogen deficiency, likely contribute to these side effects. One of these other factors involved might be the growth hormone/insulin-like growth factor I (GH/IGF-I) axis. We observed elevated IGF-I and decreased IGFBP-3 levels with AI therapy, whereas tamoxifen users were characterized by a decrease in IGF-I levels. AIMSS was associated with a decrease in IGFBP-3 levels and a trend towards an increased IGF-I/IGFBP-3 ratio, reflecting elevated free IGF-I levels. In another part of this PhD thesis we evaluated the potential of the female DBA/1 mouse as a model for mimicking AI-related musculoskeletal toxicity, both in non-inflammatory and arthritis conditions. For the latter, collagen-induced arthritis, a well-established mouse model of human rheumatoid arthritis, was used. The administration of an AI did not affect the outcome of this systemic auto-immune arthritis model suggesting that systemic inflammatory process is not likely to be the factor driving AIMSS. Genetic variability of patients may also contribute to the susceptibility to AIMSS. Several studies have reported possible associations between single nucleotide polymorphisms (SNP) in the aromatase enzyme, as well as in genes responsible for AI and estrogen transport and metabolism. However, due to divergences in definitions of musculoskeletal pain used, the retrospective nature of many trials, different outcomes (pain, discontinuation) and drug-specific variances not all of the reported associations could be confirmed by independent patient populations. Similarly, in our prospective cohort study we were not able to confirm previous findings and the majority of SNPs exhibited a minor allele frequency <0.05 and could not be analyzed. However, we did establish a significant association between the heterozygous genotype (rs2073618) in the osteoprotegerin (OPG) gene and AI-related musculoskeletal adverse events, which has not been published so far. Summarized, we showed the magnitude, impact and severity of AI-related musculoskeletal problems. These symptoms are characterized by tenosynovial abnormalities as well as changes in the GH/IGF-I axis. A genetic variant in the OPG gene was shown to contribute to the susceptibility to AIMSS. Further research in the functional mechanisms of this SNP is warranted. The effects of AIs on bone and joint health, as well as the GH/IGF-1 axis were shown to blunted under severe inflammatory conditions in our DBA/1 mouse model thereby suggesting that a systemic autoimmune reaction is not likely to be the driving force of AIMSS. Clearly, further research in the etiology of this debilitating and complex syndrome is still needed. Especially since musculoskeletal symptoms have been suggested as a biomarker for endocrine treatment efficacy, symptomatic patients seem to have a reduced risk of breast cancer recurrence, increased adherence to AI therapy will probably lead to a significant clinical benefit from this approach. Furthermore, AI-induced joint changes leading to arthralgia may be a surrogate for what happens during the menopausal transition in the general population; AIMSS findings may therefore benefit all postmenopausal women. More in-depth research in the effect of AI therapy on the GH/IGF-I axis, but also on other pathways, and the potential of IGF-I blockers to alleviate and prevent this syndrome is the next step forward.
Publication status: published
KU Leuven publication type: TH
Appears in Collections:Gynaecological Oncology
Organ Systems (+)
Department of Health and Technology - UC Leuven
Clinical and Experimental Endocrinology

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