Tamoxifen Metabolism and Efficacy in Breast Cancer: A Prospective Multicenter Trial.

Purpose: Levels of endoxifen, the most active metabolite of tamoxifen, vary by the highly polymorphic cytochrome P450 (CYP) 2D6 enzyme. We prospectively investigated tamoxifen efficacy by serum endoxifen levels and the tamoxifen activity score (TAS).Experimental Design: A prospective observational multicenter study included postmenopausal women with an estrogen receptor-positive breast cancer receiving first-line tamoxifen, 20 mg daily in the neoadjuvant or metastatic setting, recruited between February 2009 and May 2014. The primary endpoint was the objective response rate (ORR) using RECIST criteria 1.0. Secondary endpoints were clinical benefit (CB), progression-free survival (PFS), and tolerability of tamoxifen. The main analysis used logistic regression to relate ORR to serum endoxifen levels after 3 months. Endpoints were also related to other tamoxifen metabolites and to TAS.Results: Endoxifen levels were available for 247 of all 297 patients (83%), of which 209 with target lesions (85%). Median follow-up time for PFS was 32.5 months, and 62% progressed. ORR and CB were 45% and 84%, respectively. ORR was not related to endoxifen, and the OR of ORR was 1.008 per µg/L increase in endoxifen (95% confidence interval, 0.971-1.046; P = 0.56). In general, none of the endpoints was associated with endoxifen levels, tamoxifen metabolites, or TAS.Conclusions: Under the prespecified assumptions, the results from this prospective clinical trial do not suggest therapeutic drug monitoring of endoxifen to be of clinical value in postmenopausal women treated with tamoxifen for breast cancer in the neoadjuvant or metastatic setting. Clin Cancer Res; 24(10); 2312-8. ©2018 AACR.

Associations Between Patient and Anthropometric Characteristics and Aromatase Inhibitor Discontinuation.

BACKGROUND: 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. PATIENTS AND METHODS: Postmenopausal women with breast cancer starting a new adjuvant endocrine therapy were enrolled in the present study. The patients were monitored for 12 months to assess their symptoms, endocrine therapy adherence and change in grip strength and baseline body mass index. The association between the change in grip strength and interval to discontinuation was assessed using a joint longitudinal and survival model. RESULTS: Of the 93 aromatase inhibitor (AI)-treated and 22 tamoxifen-treated patients, 40.9% and 9% discontinued endocrine therapy within 12 months because of toxicity, respectively (P = .019). A trend was seen toward a greater decrease in grip strength in the AI-treated patients over time (P = .055); however, the decrease was not significantly associated with the interval to discontinuation (P = .96). Receipt of an AI (hazard ratio, 5.49; P = .019) and baseline pain (hazard ratio, 1.19; P = .004) significantly decreased the interval to discontinuation. CONCLUSION: In contrast with the findings from previous reports, the change in grip strength in our study was not associated with the interval to discontinuation of AI therapy. Future research should focus on proactive treatment of patients at increased risk of AI intolerance, such as those with high levels of pre-existing pain.

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.

Safety of aromatase inhibitor therapy in breast cancer.

INTRODUCTION: Aromatase inhibitor (AI) therapy is the current preferred choice of endocrine therapy in postmenopausal estrogen receptor-positive breast cancer patients thanks to their improved effectiveness compared to tamoxifen. Despite the absence of increased endometrial pathology and deep venous thrombosis seen in tamoxifen-users, the safety profile of AIs consists of a variety of bothersome side effects negatively influencing daily functioning. AREAS COVERED: Besides the well-known adverse effects on joints and bone and the vasomotor system, more neglected and latent toxicity like cognitive problems and vulvovaginal atrophy will be discussed. Concern has been raised in terms of increased risk of fractures and cardiovascular events with chronic AI use. EXPERT OPINION: Placebo-controlled long-term studies carefully monitoring these adverse events, together with more extensive research in the etiologies, are warranted.

Arthralgia induced by endocrine treatment for breast cancer: A prospective study of serum levels of insulin like growth factor-I, its binding protein and oestrogens.

BACKGROUND: Aromatase inhibitors (AIs) frequently induce or enhance musculoskeletal problems (AI-induced musculoskeletal syndrome (AIMSS)) which sometimes are debilitating. Apart from low oestrogen levels, underlying mechanisms are unknown and likely multiple. We previously hypothesised a role for the growth hormone/insulin like growth factor-I (IGF-I) axis. Here, we report the effect of tamoxifen and AI on IGF-I, IGF binding protein-3 (IGFBP-3) and oestrogen levels from a prospective study. MATERIALS AND METHODS: Postmenopausal women with an early breast cancer scheduled to start adjuvant endocrine therapy with an AI or tamoxifen were recruited. A rheumatologic questionnaire was completed and serum was collected for assessment of IGF-I, IGFBP-3 and oestrogen levels. Re-evaluation was done after 3, 6 and 1 2months of therapy. RESULTS: 84 patients started on tamoxifen (n=42) or an AI (n=42). 66% of the latter group experienced worsening of pre-existing or de novo complaints in joint and/or muscle, compared to 29% of tamoxifen-treated patients. AI therapy resulted in elevated IGF-I levels with a statistically significant increase at 6months (p=0.0088), whereas tamoxifen users were characterised by a decrease in IGF-I levels at all follow-up times (p<0.0004). No effect on IGFBP-3 was seen in the latter group. AI-users, however, showed decreased IGFBP-3 levels at 12 months (p=0.0467). AIMSS was characterised by a decrease in IGFBP-3 levels (p=0.0007) and a trend towards increased IGF-I/IGFBP-3 ratio (p=0.0710). CONCLUSION: These findings provide preliminary evidence that AI-induced musculoskeletal symptoms are associated with changes in the growth hormone (GH)/IGF-I axis.

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.

Aromatase inhibitors in the breast cancer clinic: focus on exemestane.

Breast cancer is the most prevalent type of cancer in women and responsible for significant female cancer-related mortality worldwide. In the Western world, over 80% of breast cancers are hormone-receptor positive for which endocrine therapy is administered. The main anti-estrogen treatments in use consist of selective estrogen-receptor modulators, such as tamoxifen, and third-generation aromatase inhibitors (AIs), such as exemestane, letrozole, and anastrozole. In this review, the focus will lie on exemestane, its clinical use, and its side-effect profile. Exemestane is the only third-generation steroidal AI. Its efficacy as a first-line treatment in metastatic breast cancer has been demonstrated. Therefore, exemestane could be considered a valid first-line therapeutic option, but it also can be used in second-line or further situations. Exemestane is mostly used as part of sequential adjuvant treatment following tamoxifen, but in this setting it is also active in monotherapy. Furthermore, this AI has been studied in the neoadjuvant setting as presurgical treatment, and even as chemoprevention in high-risk healthy postmenopausal women. It may reverse side effects of tamoxifen, such as endometrial changes and thromboembolic disease but may also cause some inconvenient side effects itself. Additionally, there is a lack of total cross-resistance between exemestane and nonsteroidal AIs as far as their anti-tumoral efficacy is concerned; moreover the two classes of AIs display a nontotal overlapping toxicity profile. Taking together, exemestane can be considered as a useful treatment option at all stages of breast cancer.

Sensitive routine liquid chromatography-tandem mass spectrometry method for serum estradiol and estrone without derivatization.

The need for a routinely applicable assay to measure low estradiol levels in adult men, postmenopausal women, and young adolescents was recently discussed in an Endocrine Society position statement. Our aim was to develop a sensitive liquid chromatography-tandem mass spectrometry method for estradiol and estrone in human serum without the need for derivatization or extended extraction protocols. After protein precipitation of serum with a mixture of methanol/acetonitrile (85/15) (v/v) containing isotopic internal standards (17ß-estradiol-16,16,17-d 3 and estrone-2,3,4-(13)C), we quantified estradiol and estrone by two-dimensional liquid chromatography-tandem mass spectrometry with electrospray ionization in the negative mode monitoring 5 × 271.20→145.00 (17ß-estradiol) and 269.20→145.00 (estrone). Sensitivity was increased by using fluoride and summation of 5 identical transitions for estradiol. Our method was analytically validated, compared against direct immunoassays using serum of 25 adult men, and clinically tested by measuring samples of 3 men at baseline and after chemical castration, 30 postmenopausal women and 15 patients receiving aromatase inhibitors. Total imprecision was below 20% for the low quality controls. Limit of quantification was 1.3 ng/L (4.8 pmol/L) for estradiol and 1.2 ng/L (4.4 pmol/L) for estrone. Estradiol in Certified Reference Material BCR-576 was within specified uncertainty limits. No significant ion suppression or interference was observed. Our method showed modest correlation with direct immunoassay for estradiol (r(2) = 0.64) but no correlation for estrone (r(2) = 0.12). Patient sample results were within expected ranges. In conclusion, we developed a routinely applicable liquid chromatography-tandem mass spectrometry method for estradiol and estrone measurement which is sensitive enough for use in men, postmenopausal women, and young adolescents.

Pharmacology of arthralgia with estrogen deprivation.

BACKGROUND: The third generation aromatase inhibitors (AIs) have become an established component of postmenopausal estrogen receptor positive breast cancer therapy. Unfortunately, up to half of AI-users experience the AI-induced musculoskeletal syndrome (AIMSS) (arthralgia, carpal tunnel syndrome, start pains, stiffness, etc.), which can severely impact quality of life and treatment compliance. We have previously demonstrated that loss of hand grip strength is part of AIMSS and involves tenosynovial changes and fluid retention in joints. REVIEW OF LITERATURE AND HYPOTHESIS GENERATING FINDINGS: Our presentation during this AI-symposium focuses on available literature regarding AIMSS with new data from a prospective study generating a hypothesis for its pathogenesis. Profound estrogen deprivation as a consequence of AI-use is thought to be the underlying reason but the exact pathway remains unknown. A potential hypothesis is that the growth hormone/insulin like growth factor-I (GH/IGF-I) pathway may be involved. This possibility is based on the non-linear association between body mass index (BMI) and loss of hand grip strength that we observed. It appears that in lean and overweight women, hand grip strength decreases most following intake of an AI. This observation suggests an underlying biological process which probably evolves through the GH/IGF-I pathway, controlled by sex steroids. CONCLUSION: Estrogen deprivation leads to incapacitating AIMSS and hampers treatment compliance. In our search for the missing link between 'lowering postmenopausal estrogens' and 'arthralgia' we here report on AI-induced changes in grip strength by BMI which we believe are hypothesis generating for an effect of AIs on the GH/IGF-I axis. This needs to be explored prospectively.

Drug safety evaluation of exemestane.

INTRODUCTION: Hormone-dependent breast cancer can be successfully treated by either blocking the estrogen receptor, as with tamoxifen, or reducing the production of estrogens, as with aromatase inhibitors. Exemestane is a third-generation aromatase inhibitor used in the treatment of estrogen-receptor-positive breast cancer in postmenopausal women. In various trials, exemestane has shown superiority over tamoxifen in both efficacy and safety. Furthermore, aromatase inhibitors are gaining territory in the metastatic, as well as the early, setting for treating patients with breast cancer. AREAS COVERED: The authors describe the mechanism of action and pharmacokinetic/pharmacodynamic characteristics of exemestane and discuss its efficacy and safety within the framework of currently approved and potential new indications. The reader can expect a full update on the characteristics of exemestane, including its efficacy and safety profile compared with tamoxifen and other third-generation aromatase inhibitors. EXPERT OPINION: Exemestane is a safe drug due to its steroidal structure, which blocks aromatase at a different site to nonsteroidal AIs (eg., anastrozole and letrozole). Noncross-resistance with nonsteroidal aromatase inhibitors makes it an attractive alternative for all clinical indications of aromatase inhibitors in patients with breast cancer.