Anneleen Lintermans

Management of menopausal symptoms in breast cancer patients.

In breast cancer patients, menopausal symptoms such as hot flashes, urogenital problems, musculoskeletal symptoms and cognitive dysfunction are common, regardless of age at diagnosis. They affect quality of life and systemic therapy will worsen this. Endocrine and/or chemotherapy may induce temporary or permanent ovarian failure and can exacerbate these symptoms. Hormone therapy (HT) has been studied in breast cancer survivors, but safety has been questioned. The HABITS trial investigating estrogen-based HT, as well as the LIBERATE trial investigating tibolone, found a reduction in disease-free survival for those treated. Alternative strategies are needed, as menopause symptoms may reduce compliance with breast cancer treatments. This article reviews recently published strategies to tackle menopausal problems in breast cancer patients. Antidepressants may help with hot flashes. Acupuncture and hypnosis can also be used but the evidence is conflicting. For urogenital problems vaginal moisturizers or topical estrogens can be employed. A musculoskeletal syndrome induced by aromatase inhibitors (AIs) is frequently encountered and currently there are no effective treatment strategies. Bisphosphonates reduce AI-induced bone resorption and can also increase disease-free and overall survival. Standard-dose endocrine and chemotherapy are associated with a decline in cognitive function.

Aromatase inhibitor-induced loss of grip strength is body mass index dependent: hypothesis-generating findings for its pathogenesis.

BACKGROUND Our preliminary results showed that tenosynovial changes and decrease in grip strength are associated with the aromatase inhibitor-induced musculoskeletal syndrome (AIMSS). Here, we report the final results and assess the relationship between grip strength and body mass index (BMI). PATIENTS AND METHODS We conducted a prospective study including postmenopausal early breast cancer patients receiving either an aromatase inhibitor (AI) or tamoxifen. Primary end point was change from baseline in tenosynovial abnormalities. Secondary end points were changes from baseline in morning stiffness, intra-articular fluid and grip strength and its association with BMI. RESULTS After 6 months of therapy, 74% [95% confidence interval (CI) 51% to 89%] of AI-treated patients had worsened tenosynovial abnormalities, 56% (95% CI 34% to 75%) had increased intra-articular fluid, and 22% (95% CI 9% to 45%) had increased morning stiffness. Grip strength decreased 8% for the left hand (95% CI 2% to 21%) and 11% for the right (95% CI 4% to 17%). Regression analysis suggested that grip strength decreased more for subjects with high or with low BMI. CONCLUSIONS AIMSS is characterized by tenosynovial changes, intra-articular fluid and morning stiffness. We hypothesize that the quadratic association between BMI and loss of grip strength reflects AI-induced changes on the endocrine control of the growth hormone insulin-like growth factor-I pathway.

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.

Vaginal estriol–lactobacilli combination and quality of life in endocrine-treated breast cancer

Abstract Objective We investigated the effect of a combination of vaginal ultra-low-dose estriol with lactobacilli on the sexual functioning domain of quality of life during the treatment of breast cancer survivors on an aromatase inhibitor with vaginal atrophy. Subjects and methods This was an open-label, bicentric, exploratory, clinical study in 16 postmenopausal breast cancer survivors on aromatase inhibitors suffering from vaginal atrophy-induced sexual disorders. Atrophy symptoms were assessed by scoring with an 11-point estimation scale (0 = not at all, 10 = worst imaginable feeling). Sexuality parameters of quality of life and medication adherence were recorded in a patients diary and in the Female Somatic Sexual Experience Instrument (FSSEI) questionnaire. Patients underwent an initial treatment for 4 weeks (one vaginal tablet of Gynoflor® containing 0.03 mg estriol daily), followed by maintenance therapy (three vaginal Gynoflor® tablets weekly) for 8 weeks. Results Vaginal dryness continuously improved from a median score of 8 at entry to a score of 4 at the end of initial therapy, and a median score of 2 at the end of maintenance therapy. Normal sexual activity before breast cancer diagnosis was reported by 14 women (88%). At study entry, only three women (19%) were sexually active. At the end of the Gynoflor® regimen, ten women (63%) reported sexual activity, of which seven (44%) reported sexual intercourse. The FSSEI demonstrated a non-significant trend of improvement of parameters related to sexuality. Conclusions Local vaginal therapy with Gynoflor® in breast cancer survivors on aromatase inhibitors reporting atrophic vaginitis could be considered as a useful treatment for the quality of sexual life.

Prospective study to assess fluid accumulation and tenosynovial changes in the aromatase inhibitor-induced musculoskeletal syndrome: 2-year follow-up data

BACKGROUND Aromatase inhibitors (AIs) frequently lead to the AI-induced musculoskeletal syndrome (AIMSS). Looking into its pathophysiology, 6 months of AI therapy thickens the tendon sheath with intra-articular fluid (IAF) retention and loss of grip strength. We here report 24-month follow-up data. PATIENTS AND METHODS A prospective cohort study of 33 postmenopausal breast cancer patients received adjuvant endocrine therapy; 27 received an AI and 6 received tamoxifen. At baseline, 6 and 24 months patients had a rheumatologic examination, including a grip strength test, and magnetic resonance imaging of both hands and wrists. The primary end point was tenosynovial changes; secondary end points were changes in morning stiffness, grip strength and IAF. RESULTS Twenty-three AI and 5 tamoxifen patients completed all investigations. Between month 6 and 24, IAF further increased in AI users (P = 0.04) but not in tamoxifen users, and grip strength further decreased in both groups. The worsened tenosynovial changes were strongly correlated with a decrease in grip strength. At 24 months, morning stiffness continued to be present in over a third of AI users. CONCLUSION AIMSS represents a substantial problem in breast cancer patients. It is associated with tenosynovial changes, IAF retention, joint stiffness and loss of grip strength that do not improve with prolonged use.

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.

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

TO THE EDITOR: In their recently published study, Folkerd et al found that in postmenopausal women with early estrogen receptor– positive breast cancer who are treated with aromatase inhibitors (AIs), suppressed levels of estradiol and estrone sulfate are related to body mass index. If confirmed, this observation is of great interest, not only because it would explain why treatment with an AI results in a better outcome compared with tamoxifen in lean patients but not in obese patients, but also because it might open the way toward individualized AI treatment by adapting the dose of AIs on the basis of the plasma estradiol and estrone sulfate concentration. Although the measurement of AIs using mass spectrometry is not so difficult, the measurement of estrogens, particularly estradiol, is quite challenging. As reported by the authors, most on-treatment values for estradiol were below 3 pmol/L, which was the “conventional sensitivity” limit of the assay used. Conventional sensitivity was defined by the authors as the 95% CI of the zero standard, which corresponds more or less to the limit of blank (LoB) as defined by the Clinical and Laboratory Standards Institute. The LoB is the highest apparent analyte concentration that is expected to be found when replicates of a sample containing no analyte are tested. The limit of detection is the lowest analyte concentration likely to be reliably distinguished from the LoB and at which detection is feasible. The limit of quantitation, which is defined as the lowest concentration at which the analyte can not only be reliably detected but also measured with an acceptable degree of imprecision, is usually significantly higher (and cannot be lower) than the LoB and the limit of detection. Functional sensitivity is usually defined as the concentration that results in a coefficient of variation (CV) of 20%. The authors reported a between-run CV of 12% for a concentration of 37 pmol/L for their estradiol assay, suggesting that the functional sensitivity of their assay is significantly higher than 3 pmol/L, given that the CV increases exponentially around the limit of quantitation. Such a functional sensitivity is insufficient to allow a reliable quantification of estradiol concentrations in individual postmenopausal women who are treated with AIs. For estrone sulfate, there is a similar problem, although to a lesser extent. The functional sensitivity is most likely also significantly higher than 15 pmol/L, given that the authors reported a CV of 11% at 130 pmol/L, but in contrast to estradiol, a majority of on-treatment values were above the conventional sensitivity defined by the authors. Toexaminetherelationbetweenestrogenconcentration,bodymass index, and outcome, and to open the way toward individualized AI treatment, clinical studies should use estrogen assays with a better functional sensitivity, particularly for estradiol. Unfortunately, the only estradiol assays that currently have a functional sensitivity of less than 3 pmol/L are labor-intensivemassspectrometrymethodsthatrequireextensivesample pretreatmentincludingliquid/liquidextraction.Asimplemassspectrometrymethodnotrequiring liquid/liquidextraction,derivatization,or large volumes of serum (eg, 500 L) is therefore needed.

Tamoxifen metabolism and efficacy in breast cancer- a prospective multicentre 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.

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.

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.