The etiology of the aromatase inhibitor-induced musculoskeletal syndrome in breast cancer patients

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 favorablelong-term toxicity profile with AIs as compared to tamoxifen. Therefore, the long-term use of AIs in the metastatic, adjuvant and probably alsopreventive 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 patientsexperiencing 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 becomeevident over the last years, there is scarce information that would clearly explain this syndrome and its underlying mechanisms. Although thereis 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 contributingfactors 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. Oneof 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-3ratio, 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 humanrheumatoid 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 allof the reported associations could be confirmed by independent patient populations. Similarly, in our prospective cohort study we were not ableto confirm previous findings and the majority of SNPs exhibited a minorallele frequency 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.status: publishe

The UZ Leuven Policy for Extended Adjuvant Anti-estrogen Therapy in Women With Early Estrogen Receptor-Positive Breast Cancer

Opinion statement: Five years after adjuvant endocrine treatment for estrogen receptor (ER)-positive breast cancer, patients have a 2 to 20 % risk of metastatic relapse during the next 5 years. Extended adjuvant endocrine therapy seems to further lower this. In UZ Leuven, extended endocrine therapy is now discussed unless the tumor was a grade 1-2, pT1N0, ER-positive, progesterone receptor (PR)-positive, HER2-negative lesion. After 5 years of adjuvant tamoxifen treatment for ER-positive breast cancer, we encourage women to take another 5 years of tamoxifen. If the tumor was lymph node-positive at diagnosis and patients are menopausal after the first 5 years of tamoxifen, we advise to take prolonged treatment with an oral aromatase inhibitor (AI). For this particular group, available data for extending endocrine therapy with an AI after 5 years of tamoxifen are strongest and more convincing for letrozole than for anastrozole or exemestane. Under these conditions, letrozole is reimbursed for 3 years in Belgium. If women are postmenopausal at diagnosis and already used an oral AI at any time during the first 5 years, we discuss an extra 5 years of tamoxifen. Results from ongoing clinical trials will tell us whether in these cases prolonged AI use is better than tamoxifen so that therapy can be adapted. Benefit from extended adjuvant endocrine therapy is likely larger with better compliance and potential side effects of extended endocrine therapy need to be discussed. Therefore, when advising extended adjuvant endocrine treatment, a balance should always be made between relapse risk and treatment tolerance/compliance.status: publishe

GPR39, a Receptor of the Ghrelin Receptor Family, Plays a Role in the Regulation of Glucose Homeostasis in a Mouse Model of Early Onset Diet-Induced Obesity

GPR39, which may function as a Zn2+ sensor, is a member of the G protein-coupled receptor family that also includes the receptor for the hunger hormone ghrelin. The down-regulation of GPR39 mRNA in adipose tissue of obese type 2 diabetic patients suggests that GPR39 may contribute to the pathogenesis of the disease. The present study aimed to investigate the role of GPR39 in the regulation of energy balance and glucose homeostasis in wild-type (GPR39+/+) and GPR39 knockout mice (GPR39-/-) with obesity-related type 2 diabetes. GPR39 mRNA levels in adipose tissue of fasted GPR39+/+ mice fed a high-fat diet (HFD) for 30 weeks were reduced and correlated positively with blood glucose levels. Body weight, fat percentage and energy intake were increased in the HFD group but did not differ between both genotypes. Within the HFD group, blood glucose levels were lower in GPR39-/- than in GPR39+/+ mice, despite significant reductions in prandial plasma insulin levels. The latter may not be a result of changes in beta-cell hyperplasia because immunohistochemical staining of pancreata of mice on a HFD showed no differences between genotypes. The lower blood glucose levels may involve alterations in insulin sensitivity as revealed by glucose tolerance tests and respiratory quotient measurements that showed a preference of obese GPR39-/- mice for the use of carbohydrates as metabolic fuel. The increase in plasma ghrelin levels in GPR39-/- mice fed a HFD may contribute to the alterations in glucose homeostasis, whereas changes in gastric emptying or intestinal Zn2+ absorption are not involved. The results obtained in the present study suggest that GPR39 plays a role in the pathogenesis of obesity-related type 2 diabetes by affecting the regulation of glucose homeostasis.Verhulst P.J., Lintermans A., Janssen S., Loeckx D., Himmelreich U., Buyse J., Tack J., Depoortere I., ''GPR39, a receptor of the ghrelin receptor family, plays a role in the regulation of glucose homeostasis in a mouse model of early onset diet-induced obesity'', Journal of neuroendocrinology, vol. 23, no. 6, pp. 490-500, June 2011.status: publishe

Need for Estradiol Assays With a Lower Functional Sensitivity in Clinical Studies Examining Postmenopausal Women Treated With Aromatase Inhibitors

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Ultra-low-dose estriol and Lactobacillus acidophilus vaginal tablets (Gynoflor(®)) for vaginal atrophy in postmenopausal breast cancer patients on aromatase inhibitors: pharmacokinetic, safety, and efficacy phase I clinical study

Phase I pharmacokinetic (PK) study assessed circulating estrogens in breast cancer (BC) patients on a non-steroidal aromatase inhibitor (NSAI) with vaginal atrophy using vaginal ultra-low-dose 0.03 mg estriol (E3) and Lactobacillus combination vaginal tablets (Gynoflor(®)). 16 women on NSAI with severe vaginal atrophy applied a daily vaginal tablet of Gynoflor(®) for 28 days followed by a maintenance therapy of 3 tablets weekly for 8 weeks. Primary outcomes were serum concentrations and PK of E3, estradiol (E2), and estrone (E1) using highly sensitive gas chromatography-mass spectrometry. Secondary outcomes were clinical measures for efficacy and side effects; microscopic changes in vaginal epithelium and microflora; and changes in serum FSH, LH, and sex hormone-binding globulin. Compared with baseline, serum E1 and E2 did not increase in any of the women at any time following vaginal application. Serum E3 transiently increased after the first application in 15 of 16 women, with a maximum of 168 pg/ml 2-3 h post-insertion. After 4 weeks, serum E3 was slightly increased in 8 women with a maximum of 44 pg/ml. The vaginal atrophy resolved or improved in all women. The product was well tolerated, and discontinuation of therapy was not observed. The low-dose 0.03 mg E3 and Lactobacillus acidophilus vaginal tablets application in postmenopausal BC patients during AI treatment suffering from vaginal atrophy lead to small and transient increases in serum E3, but not E1 or E2, and therefore can be considered as safe and efficacious for treatment of atrophic vaginitis in BC patients taking NSAIs.status: publishe

Associations Between Patient and Anthropometric Characteristics and Aromatase Inhibitor Discontinuation

Toxicity can lead to noncontinuation of adjuvant endocrine therapy. We hypothesized that endocrine therapy-induced changes in grip strength would predict for early discontinuation of therapy because of musculoskeletal toxicity and would be associated with a patient's body mass index.status: publishe