Oral Aromatase Inhibitor Research Articles

Efficacy and Safety of Letrozole Add-on Injection HMG on Ovulation and Pregnancy: Comparison with Letrozole Alone

Background: Nowadays, Infertility is increasing worldwide. Many regimens are used in the treatment of infertility. Among them, a combination of oral aromatase inhibitor drugs and gonadotropin is recommended as a very effective regimen for inducing ovulation. But there is a scarcity of related data in the Bangladesh context. The present study was designed to compare the effect of letrozole and the combination of letrozole with low-dose intramuscular injection of HMG on ovulation and pregnancy. Methods: This randomized controlled trial was conducted at the department of Obstetrics and Gynaecology in Rajshahi Medical College Hospital from June 2020 to May 2021. A total of 95 patients with a history of infertility were selected as the study population according to inclusion and exclusion criteria. Written informed consent was obtained from each patient. All of them were randomly distributed into two groups, group-A, and group B, by the flipping coin method, where group-A (Experimental group) patients received letrozole with low dose intramuscular injection of HMG (45 patients) and group B (Control group) patients received Letrozole only (50 patients). Relevant investigations were done, along with scheduled follow-ups. Results: Mean age of the study patients was 26.86±3.71 (SD) years, whereas the majority were ≤30 years (74.7%). Age was statistically similar among the patients of both groups. The endometrial thickness, follicular diameter, and a number of mature follicles were statistically higher among patients who received letrozole with low dose intramuscular injection of HMG than the patients who received only letrozole. Maximum follicular diameter ≥18mm (91.1%) in group-A among them (60%) achieved in 1st Cycle. Maximum endometrial thickness was achieved in the first Cycle in both groups (60% vs. 32%) among group-A patients. The positive pregnancy rate was also higher among group-A patients (37.8% vs. 22.0%) in 1st Cycle. Ovarian Hyperstimulation Syndrome was observe

Role of Letrozole in Management of Female Infertility; Review Article

Background: Letrozole is a highly steroidal and selective oral aromatase inhibitor (AI). Serval studies shows that Co-treatment with letrozole significantly reduced gonadotropin consumption and the incidence of Ovarian Hyperstimulation Syndrome in normal/high responders, with pregnancy outcomes comparable to or better than the other groups. In this article we will be looking at role of letrozole in treatment of infertility
 Methodology: A simple systematic review was carried out, searching databases PubMed, Google Scholar, and EBSCO. The authors extracted qualitative data, and then the author's names, year, study type, methodology, and the result were reported.
 Results and Conclusion: Letrozole has effectiveness which is near the usage of the Human Menopausal Gonadotrophin in the numbers of pregnancies per cycle but have much less cost which indicates cost effectiveness of the drug. Furthermore, studies show that administration of the drug is effective in inducing pregnancy, with higher dose more than 5mg and 7.5mg more effective.

Salivary Estrogens Androgens and Aromatase Inhibitors by LC-MS/MS in Breast Cancer Patients Treated With Testosterone Pellets Combined With Aromatase Inhibitors

Introduction: High dose testosterone (T) has been used for treating hormone-sensitive breast cancers for many years. However, a drawback to T therapy is its propensity to convert to estradiol (E2) via aromatase, which can override the growth inhibitory effects of T and stimulate estrogen sensitive tumors. Aromatase is higher in some women than others, particularly those with active tumors, truncal obesity, and inflammatory conditions contributing to and caused by cancer. Oral aromatase inhibitors (AI) have been used to prevent conversion of T to E2. While this effectively reduces E2 burden, systemic oral AI require higher dosing, which often leads to severe side effects. As an alternative to oral AI therapy, researchers have found that T combined with a much lower dose of AI in a solitary pellet implant placed in the subcutaneous (SC) tissue, or alternatively, into the breast adjacent to a primary tumor, is effective in reducing tumor burden and maintaining a low systemic level of E2, while reducing the adverse side effects of very low E2. Study Design: In this case study we report on the use of an LC-MS/MS method to monitor salivary levels of E2, Estrone (E1), T, and the AIs Letrozole (LET) and Anastrozole (ANZ) following T + AI therapy in a breast cancer patient (intolerant of oral LET) with active (measurable) tumor in the breast and metastatic disease. Steroids and AIs were measured in saliva at baseline, 1 week, and 4 weeks after insertion of subcutaneous pellets containing ‘60 mg T + 4 mg ANZ’ and ‘60 mg T + 6 mg LET’. Results: LC-MS/MS (range values-pg/ml) for postmenopausal women, and baseline, week 1 and week 4 post treatment values for each steroid and AI were: E2: (range 0.3-0.9), 0.4, < 0.3, < 0.3; E1: (range 0.9-3.1), 1.0, <0.4, <0.4; T: (range 7-22), 6, 96, 48; ANZ: (range <4), < 4, 2063, 24; LET: (range <4), < 4, 744, 175. Self-reported (Pre/Post Therapy) estrogen deficiency symptoms such as hot flashes, night sweats, vaginal dryness, joint pain, and sleep disturbances were significantly improved post T+AI therapy. In addition, the intramammary tumor decreased in size > 95% by month 5. Summary: These results show that low-dose SC AI therapy (4-6 mg/2-3 months = 0.1 mg/day) with T (120 mg/2-3 months = 1-2 mg/day) increases T to supra-physiological levels, prevents T metabolism to estrogens E2 and E1, reduces estrogen deficiency symptoms, and has beneficial effects on tumor growth inhibition. Simultaneous testing of sex-steroids E2, E1, T, and aromatase inhibitors LET and ANZ by LC-MS/MS provides a convenient means to monitor the bioavailable levels of these analytes and adjust them as necessary to optimize therapeutic efficacy and reduce adverse side effects.

Abstract OT-26-02: Phase III open-label, multicenter, randomized trial of adjuvant palbociclib in combination with endocrine therapy versus endocrine therapy alone for patients with hormone receptor-positive / HER2-negative resected isolated locoregional recurrence of breast cancer - The POLAR Trial

Abstract Background: Isolated local or regional recurrence (ILRR) of breast cancer (BC) after mastectomy or lumpectomy indicates a poor prognosis and patients with ILRR hold a substantial risk of developing subsequent distant metastasis. Limited randomized evidence supports the recommendation of systemic treatment for hormone receptor-positive (HR+) lLRR. Cyclin-dependent kinases 4 and 6 (CDK4/6) inhibitors, such as palbociclib, have shown activity and safety in the first-line treatment of metastatic HR+/HER2-negative BC. The POLAR hypothesis is based on the results of the CALOR trial (IBCSG Trial 27-02), which showed effectiveness of adjuvant chemotherapy among patients with resected HR-negative ILRR, but not for HR+ ILRR. Considering these findings and compelling evidence supporting the activity of the combination of CDK4/6 inhibitors and endocrine therapy (ET), we hypothesize that palbociclib in combination with ET may be effective as adjuvant therapy in patients with HR+/HER2-negative resected ILRR of BC. Trial design: POLAR is a phase III open-label, multicenter, randomized trial of adjuvant palbociclib in combination with standard ET versus standard ET alone for women and men with histologically confirmed HR+/HER2-negative resected ILRR of BC. Protocol treatment consists of palbociclib (125 mg/d orally for 21 days, followed by 7 days rest) for 3 years plus standard ET for at least 3 years (Arm A) or standard ET for at least 3 years (Arm B). Patients must be enrolled within 6 months of complete gross excision of the ILRR. Patients may have started standard ET prior to entry. Randomization (1:1) is stratified according to (1) gender and menopausal status; (2) planned ET (oral aromatase inhibitor or tamoxifen vs. fulvestrant). The primary endpoint, invasive disease-free survival (iDFS), will be compared between treatment groups using a stratified log-rank test. The sample size provides 80% power to detect a 50% reduction in hazard (HR=0.50) for palbociclib plus ET versus ET-alone, using a log-rank test with two-sided α=0.05 test with 66 iDFS events. The 3-year iDFS is assumed to be 76% on the basis of patients in the CALOR trial who had ER+ ILRRs. Accrual: The trial will recruit 400 patients from approximately 50 Centers in Austria, France, Hungary, Italy, Spain and Switzerland. The first patient was randomized in August 2019. Accrual as of mid-June 2020 was 25 patients. The POLAR trial (IBCSG 59-19 / BIG 18-02) is sponsored and coordinated by IBCSG with financial support from Pfizer. The trial is conducted under the BIG umbrella in collaboration with ABCSG, GEICAM, SOLTI, SAKK and Unicancer. NCT03820830 Citation Format: Elisabetta Munzone, Stefan Aebi, Noelia Martínez Jañez, Uwe Güth, Meritxell Bellet, Barbara Pistilli, Marija Balic, Heidi Roschitzki-Voser, Meredith M Regan. Phase III open-label, multicenter, randomized trial of adjuvant palbociclib in combination with endocrine therapy versus endocrine therapy alone for patients with hormone receptor-positive / HER2-negative resected isolated locoregional recurrence of breast cancer - The POLAR Trial [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr OT-26-02.

OR18-4 Beneficial Effect on Sperm Production of Leflutrozole in Men with Obesity-Associated Secondary Hypogonadotropic Hypogonadism: Results from a Phase II Study

Introduction: Excess aromatase activity in adipose tissue has been linked to increased conversion of testosterone (T) to estradiol, resulting in high estradiol levels and suppressing gonadotropins. In obese men, this can cause obesity-associated hypogonadotropic hypogonadism (OHH) with decreased fertility. T replacement therapies frequently result in negative feedback suppression of follicle stimulating hormone (FSH) and luteinizing hormone (LH), further impairing semen fertility. Aromatase inhibition avoids this complication, restoring T without impairing fertility parameters, by reducing inhibitory effects of excess estradiol on LH and FSH. We report the impact of a weekly (QW) oral aromatase inhibitor on hormone levels and semen parameters in patients with OHH. Methods: A 24-wk, multicenter, randomized, double-blind, placebo (PBO)-controlled phase IIb trial (NCT02730169) of 3 doses of leflutrozole QW in obese adult males (BMI 30-50 kg/m2) with morning serum T <300 ng/dL. Exclusion criteria: Type 1 or uncontrolled type 2 diabetes; clinically significant endocrinopathy; prostate disease; recently diagnosed cardiovascular conditions; treatment with confounding medications (including those affecting gonadotropin or T levels). Primary endpoint: normalization (300-1000 ng/dL) of serum T in >75% of patients by end of treatment (EOT) at Wk 24. Secondary endpoints included gonadotropin and estradiol levels; a substudy assessed change in semen parameters. Safety was monitored from 1st dose to 90 days after EOT. Results: 271 patients (means: age 50.9 (±8.7) yrs, BMI 38.1 (±5.3) kg/m2, T 231.1 (±54.6) ng/dL) were randomized to 3 doses of leflutrozole or PBO. All 3 leflutrozole-treated arms met the primary endpoint with normalized T levels by EOT in >75% of patients vs 10% for PBO (p<0.001). Dose-dependent elevations in FSH and LH (p<0.001) and dose-dependent reductions in estradiol were observed at EOT. At Wks 12 and 20, numerical increases in sperm counts were observed in all 3 leflutrozole groups vs PBO, with statistically significant improvements (LS mean difference [95% CI]) in semen volume (1.37 [0.41, 2.34] ml, p=0.006, n=24), spermatozoa (270.084 [65.007, 475.161] x106/ejaculate, p=0.011, n=23), and total motile sperm count (127.711 [12.602, 242.819] 106/ejaculate, p=0.030, n=22) in leflutrozole highest dose group vs PBO. Leflutrozole was generally well tolerated; 24.7% of patients experienced related treatment-emergent adverse events (AEs). Of these, 3.0-7.5% of patients in the 3 leflutrozole dose groups experienced serious AEs, vs 5.2% of patients receiving PBO. Conclusions: In contrast to suppression of spermatogenesis seen with exogenous T therapy, leflutrozole restores normal endogenous physiologic T levels whilst increasing FSH/LH, with positive effects on semen fertility parameters in men with OHH. A 24-wk, blinded extension study is currently ongoing.

Improving medication adherence with adjuvant aromatase inhibitor in women with breast cancer: study protocol of a randomised controlled trial to evaluate the effect of short message service (SMS) reminder

BackgroundMedication adherence refers to whether a patient takes medication according to the frequency prescribed, or continues to take a prescribed medication. Inadequate adherence to medication may cause alterations in risk-benefit ratios, resulting in reduced benefits, increased risks or both, and is significantly associated with adverse clinical outcomes and higher healthcare costs. We aim to examine the effect of a computer generated short message service (SMS) reminder in improving medication adherence, and inhibiting the aromatisation process amongst breast cancer women receiving oral aromatase inhibitor therapy.Methods/DesignIn this randomised controlled trial, eligible patients will be equally allocated to receive either SMS reminder or standard care. The former receives weekly SMS reminder to take medication while the latter does not receive any. The primary endpoint of medication adherence at 1-year is assessed using the Simplified Medication Adherence Questionnaire, and compared using the χ2 test. Adjustment for baseline covariate and potential confounders will be made using the logistic regression. Secondary outcomes involving estrone and androstenedione levels will be compared using the analysis of covariance, whereas the estradiol levels (< 18.4 pmol/L versus ≥18.4 pmol/L) will be compared using the χ2 test, and the logistic regression. Further, the assessment of knowledge, attitude, behaviour, and barriers and facilitating factors of medication adherence will be made via logistic regression.DiscussionThis will be the first study to evaluate short-term clinical outcomes from SMS reminder for breast cancer patients on aromatase inhibitor therapy. Random allocation to SMS reminder or control arm ensures that patients in both arms will be comparable with respect to demographic and clinical characteristics, and any difference in outcomes can be attributed to the intervention. Participants are not blinded to the assignment of intervention, thus there may be potential for bias in outcome assessments.Trial registrationNCT02524548. Retrospectively registered on 17 August 2015.

Abstract P3-12-12: Serum estrogen-levels in women 48-56yrs with hormone receptor-positive breast cancer. Cross-Sectional study using an ultra-sensitive LC-MS/MS-method

Abstract Background and Purpose: Randomized clinical trials in early stage hormone receptor positive breast cancer (HR+BC), have shown that total estrogen suppression (TES) for 5 yrs or after 2-3 yrs of tamoxifen treatment improved outcome over 5 yrs of TAM monotherapy. This relative improvement is in absolute figures most visible in patients with a high relapse risk. To achieve TES, women need to be (rendered) menopausal and treated with an oral aromatase inhibitor (AI). We measured serum estrogens in women of peri-menopausal age with HR+BC starting or on anti-hormonal agents. Methods: Serum estradiol (E2) and estrone (E1) were quantified using a sensitive liquid chromatography-tandem mass spectrometry method (LC-MS/MS; Pauwels et al. JCO 2013) in women 48-56 yrs old with HR+BC starting or on anti-hormonal therapy in a cross sectional observational monocentric study. We report the frequency that (and explore why) AI-users had estrogens above the lower limit of quantification (LLOQ). We measured estrogen levels in TAM users with &amp;gt; 3 months' amenorrhea by previous use of (neo)adjuvant chemotherapy. Finally, we studied the frequency of both estrogens or either alone were &amp;lt; LLOQ in non-users. Statistics are descriptive; biomarkers for estrogen levels were analyzed using linear mixed models. [amendment on study NCT01223833] Results: Estrogen levels were assessed in 566 samples from 401 women; 96 (126 samples) were on AI, 128 (182 samples) on TAM and 217 (258 samples) non-users. Some patients had more than one blood sample in different groups. 13,5% of AI users were above LLOQ for E2 and E1; 7,5% for E1 alone. Some were due to ovarian reactivation. An important proportion (18%) of 83 non-hysterectomized TAM users with amenorrhea had E2 levels &amp;gt;40ng/L; 9,1% and 28.2% respectively in patients who had and didn't have (neo)adjuvant chemotherapy. None of non-users were below LLOQ for E1, while 20.7% were below LLOQ for E2. Conclusions:TES is not always achieved in AI-users; reasons why were multiple. Amenorrhea is no guarantee for TES in TAM users, as a significant proportion had high E2 levels even when previously exposed to (neo)adjuvant chemotherapy. Using LC-MS/MS, undetectable levels for E1 better reflect TES than below LLOQ for E2. Citation Format: Van Houdt M, Neven P, Anneleen L, Ivo J, Dirk V, Jaak B, Annouschka L, Hans W. Serum estrogen-levels in women 48-56yrs with hormone receptor-positive breast cancer. Cross-Sectional study using an ultra-sensitive LC-MS/MS-method [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P3-12-12.

Effects of transdermal testosterone gel or an aromatase inhibitor on serum concentration and pulsatility of growth hormone in older men with age-related low testosterone

This randomized controlled proof-of-concept trial investigated the relative effects of testosterone and estradiol on GH pulsatility and IGF-1 in older men with low testosterone. Thirty-seven men, ≥65years with total testosterone <350ng/dL were randomized to 5g transdermal testosterone gel (TT), 1mg oral aromatase inhibitor (AI) or placebo daily for 12months. Primary outcome was deconvolution and approximate entropy analyses of pulsatile including basal and entropic modes of secretion performed at baseline and 3months. Secondary outcomes included IGF-1 evaluated at baseline, 3 and 6months. At 3months, mean GH and in IGF-1 were similar between the three groups. At 6months, IGF-1 significantly increased by Δ 15.3±10.3ng/ml in the TT-group compared to placebo (P=0.03). Both intervention groups significantly increased GH pulse frequency (TT-group, P=0.04; AI-group, P=0.05) compared to placebo. The GH secretory-burst mode (duration) significantly decreased in the TT-group (P=0.0018) compared to placebo while it remained unchanged in the AI-group (P=0.059). In older men, testosterone increases GH pulse frequency while the aromatization to estradiol is involved in the rise of IGF-1 levels.

Non-adherence and health outcomes in women treated with oral endocrine therapy for breast cancer.

6563Background: Non-adherence (nAdh) with oral selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs) in women with breast cancer (BC) is common. Understanding the impact of n...

Late recurrence of breast carcinoma metastasis to the hypopharynx: a case report.

BackgroundWe report a rare case of a patient with a hypopharyngeal metastasis from breast cancer.Case presentationIsolated breast cancer metastasis to the hypopharynx has been previously reported in only one autopsy case. Herein, we report a 56-year-old woman with metastases to the hypopharynx almost 24 years after receiving a mastectomy and chemotherapy to treat primary breast carcinoma. We believe that she is the first patient to be treated for metastatic breast carcinoma to the hypopharynx. The hypopharyngeal tumor reduced in size after administration of an oral aromatase inhibitor. The patient has remained alive with a preserved larynx for three years.ConclusionsBreast cancer metastasis to the hypopharynx is an extremely rare event.

Effects of Transdermal Testosterone Gel or an Aromatase Inhibitor on Prostate Volume in Older Men.

T replacement is being increasingly offered to older men with age-related low T; hence, monitoring prostate health is important during T therapy. Data suggest that estrogens have an independent effect on the prostate and some effects of T on the prostate might be mediated via its aromatization to estradiol. Although some studies have assessed the effects of T replacement on prostate volume, the differential effects of T and estradiol have not been delineated. The objective of the study was to investigate the relative effects of T and estradiol on prostate volume in older men with low T. Thirty-one men, 65 years old or older with total T less than 350 ng/dL (measured by mass spectrometry) participated in the study. The intervention included randomization to 5 g transdermal T gel (TT), 1 mg oral aromatase inhibitor (AI), or placebo daily for 12 months. The primary outcome was prostate volume measured by transrectal ultrasound at baseline and 12 months. Secondary outcomes included prostate-specific antigen levels and lower urinary tract symptoms score. Serum T levels increased in both intervention groups; estradiol levels increased in the TT group, whereas it decreased in the AI group. At 12 months, prostate volume significantly increased (4.5 ± 1.76 cc, P < .05) only in the TT group. Increase in prostate-specific antigen levels were seen in both intervention groups at 6 months (P < .01 and P < .001). The lower urinary tract symptoms score increased only in the TT group (P < .05). The tropic effects of T on the prostate are mediated via its aromatization to estradiol. Administration of AI for 12 months to older men was not detrimental to the prostate.

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.

Abstract P1-13-09: Sensitive liquid chromatography-tandem mass spectrometry method for serum estradiol and estrone assessment without derivatisation, overcoming cross reactivity with exemestane

Abstract Objective Measuring serum estrogen levels in postmenopausal women on oral aromatase inhibitors is important but challenging. Direct immunoassays are the most widely used techniques for measuring serum estradiol (E2) in research and clinical laboratories. Unfortunately, commercially available immunoassays for E2 lack precision and accuracy in the low range (&amp;lt;20 ng/l) and are susceptible to interference. In addition, particularly in exemestane users biochemical monitoring of E2 is problematic because exemestane metabolites cross react in most immunoassays for E2. We developed a sensitive, routinely applicable liquid chromatography-tandem mass spectrometry (LC-MSMS) method for E2 and estrone (E1) quantification in human serum without the need for derivatization or an extended extraction protocol. Materials and methods Serum E2 levels, assessed with LC-MSMS and electrochemiluminescence estradiol assay (ECLIA) on Modular E170 from Roche Diagnostics, of 10 breast cancer patients treated with exemestane were compared. Limit of quantification (LOQ) was 1.3 ng/l for LC-MSMS (coefficient of variation &amp;lt;20% and signal-to-noise ratio &amp;gt; 10, own validation) and 5 pg/ml for ECLIA (Roche, according to manufacturer). Results Patients treated with exemestane showed much higher E2 levels when measured by ECLIA compared to E2 levels determined by LC-MSMS (Table 1). All patients, but one, had E2 values below LOQ when assessed with LC-MSMS whereas ECLIA measurements showed higher levels with a large variety (mean: 16.5 ng/l; range: 7-33 ng/l). Results for E2 via ECLIA and LC-MSMS for patients treated with exemestanePatientE2 LC-MSMS ng/lE2 ECLIA ng/l1&amp;lt;1.3212&amp;lt;1.373&amp;lt;1.3124&amp;lt;1.3335&amp;lt;1.3156&amp;lt;1.3227&amp;lt;1.398&amp;lt;1.32692.51010&amp;lt;1.310 Conclusion E2 levels in exemestane users measured with ECLIA from Roche are overestimated, probably due to cross reactivity of its metabolites. Therefore, this assay can not be used in these patients. Here, we demonstrate that this hurdle can be overcome by assessment of estrogen values with LC-MSMS. Our group was able to develop such a sensitive method, without derivatization. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-13-09.

Managing the side effects of oral aromatase inhibitors

SUMMARY Aromatase inhibitors (AIs) are increasingly being used to treat postmenopausal estrogen receptor-positive breast cancer. In the short term they enhance or induce menopausal symptoms that compromise AI adherence, while in the long-term they adversely affect bone and probably also cardiovascular health, although this is mainly when compared to tamoxifen, which is cardioprotective. The distinct decrease in estrogen levels following AI administration is believed to be the main reason for the emergence of these side effects, although exact mechanisms remain to be elucidated. As such, management strategies to meet these AI-induced toxicities are still mainly symptomatic. In this review, current treatment options and promising new modalities under research will be discussed.

Undetectable antimüllerian hormone levels and recovery of chemotherapy-induced ovarian failure in women with breast cancer on an oral aromatase inhibitor

Knowledge of the menopause status of a woman with breast cancer is important for good clinical practice. Long-lasting amenorrhea is frequent in this population, often for reasons other than definitive menopause. Antiestrogens like tamoxifen or oral aromatase inhibitors (AIs) may reactivate the ovary causing vaginal bleeding, menstruation, pregnancy, and unopposed endometrial stimulation. In contrast to tamoxifen, AIs are not active against breast cancer in the presence of functional ovaries. Antimüllerian hormone (AMH) is a potential marker of residual ovarian function that can predict not only the onset of menopause but also chemotherapy-induced amenorrhea (CIA) and fertility. We assess the value of AMH in women who recovered from CIA on an AI. This is a series of six women with clinical and biochemical evidence of ovarian recovery during AI treatment. All six were premenopausal at breast cancer diagnosis and developed CIA. AMH, follicle-stimulating hormone, and estradiol levels were measured when patients developed clinical signs of ovarian recovery and/or when a gynecological procedure showed evidence of this. In all six AI-treated women, AMH levels were undetectable despite clinical, biochemical, or pathological evidence of ovarian reactivation after a long period of amenorrhea and sensitive biochemical markers indicating definitive menopause status. Repeated biochemical monitoring of ovarian function remains important in women with breast cancer undergoing AI treatment because ovarian function can recover, AIs are not active with functional ovaries, and amenorrhea does not, by itself, confirm definitive menopause. Undetectable AMH levels do not exclude residual ovarian function in women with breast cancer on an AI.

Cross Reactivity between the Roche Elecsys® Progesterone Assay and Exemestane.

Abstract Background:Oral aromatase inhibitors (AI) and to a lesser extend tamoxifen can promote recovery of ovarian function in postmenopausal breast cancer patients. Biochemical monitoring of ovarian function is important as folliculogenesis may lead to pregnancy, vaginal bleeding and loss of efficacy of the oral AI. Biochemical monitoring of oestradiol in exemestane users is problematic because exemestane metabolites cross react in most immunoassays for oestradiol. Following our finding of luteal phase progesterone levels in serum of some postmenopausal women with vaginal bleeding on exemestane, we assessed potential cross reactivity between exemestane and its 4-OH metabolite in the Roche Elecsys® progesterone assay. We also studied the frequency of such progesterone activity in serum from consecutive exemestane users and correlated values with FSH.Methods:Progesterone concentrations were measured with the Elecsys® assay in blanco serum, blanco serum with pure exemestane and blanco serum with the pure 17-OH-exemestane metabolite. Several concentrations of the purifided 17-OH-exemestane metabolite in DSMO solvent were then prepared using the Elecsys Diluent MultiAssay and progesterone concentration was measured in these samples using the Elecsys® assay. Cross sectional blood samples from 94 exemestane users were measured for progesterone activity with this assay and also for FSH using the Roche Modular E170® (F. Hoffmann-La Roche Ltd, Basel, Switserland).Results:Using this progesterone assay, 41% of exemestane users had luteal phase progesterone levels (&amp;gt;1.7 ng/mL). There is cross reactivity with exemestane but more importantly with the 17-OH metabolite (table). The level of progesterone and cross reactivity for 2 known concentrations of the 17-OH-metabolite are also shown in this table. There is a correlation between progesterone picked up by the Elecsys® assay and FSH which increased with progesterone activity.Elecsys® assay RocheProgesterone (ng/mL)Blanco serum0.030Blanco serum + exemestane0.313Blanco serum + 17-OH-exemestane0.781Blanco serum + 2500 ng-ML 17-OH-exemestane16.20.65 %*Blanco serum + 5000 ng ng/mL 17-OH-exemestane32.50.65%/*(*): percentage of cross reactivityConclusion:Progesterone levels in exemestane users measured with the Elecsys® assay from Roche were often overestimated due to cross reactivity with exemestane and its main metabolite. This progesterone assay can not be used to define menopause or distinguish postmenopausal from menstrual bleeding in exemestane users. Higher FSH levels with higher progesterone activity in this assay suggest a link between circulating exemestane/metabolites and the quantitative downregulation of postmenopausal estrogens by this AI, but serial rather than cross sectional measurements are required to confirm this.We acknowledge Pfizer for providing us with pure exemestane and 17-OH-metabolite. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 5147.

Prospective assessment of the endometrium in postmenopausal breast cancer patients treated with fulvestrant

This prospective study assessed the endometrial effects of fulvestrant, a pure estrogen-receptor antagonist, in postmenopausal women with breast cancer. This single-center study enrolled postmenopausal patients who had an intact uterus at baseline with progressive metastatic breast cancer on tamoxifen followed by an oral aromatase inhibitor (AI). Fulvestrant (250 mg) was administered every 28 +/- 3 days via IM injection. Transvaginal ultrasonography (TVUS) was performed at baseline and after 3 months of therapy. Primary and secondary endpoints were changes from baseline in double endometrial thickness (DET) and uterine volume (UV), respectively. No interventions were performed on any asymptomatic uterine abnormalities that were detected at baseline. In total, 32 women were enrolled. Five patients had no repeat TVUS because of early progression before 3 months, leaving 27 evaluable patients for final analysis. After 3 months therapy, mean DET had significantly decreased by 23.08% (P = 0.010). Mean UV also decreased by 10.88%, although this change was not significant (P = 0.119). After 3 months of therapy, none reported vaginal bleeding, there were no changes noted in most of the uterine pathologies present at baseline and no new uterine abnormalities were detected. We observed that 3 months of fulvestrant treatment resulted in a significant decrease in endometrial growth and a non-significant decrease in UV in postmenopausal women with metastatic breast cancer previously exposed to tamoxifen and AIs. Furthermore, no new uterine pathologies were detected, indicating that fulvestrant behaves as a pure antiestrogen at the uterine level.

Increased Use of Oral Chemotherapy Drugs Spurs Increased Attention to Patient Compliance

Ensuring that patients with breast cancer are taking the oral aromatase inhibitors prescribed as follow-up treatment to surgery is an ongoing concern for oncologists.

Letrozole administration during the luteal phase after ovarian stimulation dramatically reduces estradiol production: A randomized, placebo controlled trial

High estradiol (E2) levels are a consequence of controlled ovarian hyperstimulation. These elevated E2 levels may put at risk patient's health–OHSS, thromboembolic phenomena, … apart from being deleterious for embryo cleavage and implantation. Aromatase inhibitors are very potent drugs that, by inhibiting the conversion of androgens into estrogens, reduce serum levels of estradiol. We performed a pilot study to investigate the effect of letrozole–an oral aromatase inhibitor- on estradiol levels when administered during the luteal phase after oocyte retrieval in IVF/ICSI cycles. Prospective, randomized, placebo controlled trial. Twenty oocyte donors undergoing standardized COH protocols were randomized after successful egg retrieval to receive either 2.5 mg of letrozole (Femara, Novartis, Spain) or a placebo (folic acid tablets). All donors were under IUD contraception. Donors were tested for serum estradiol, progesterone and LH the day of hCG administration and day +4, +7 and +10 after ovum pick up. Significance was set at 0.05. Donors had a comparable serum E2 level on the day of hCG (1989 vs. 1956 pg/mL). Interestingly, levels dramatically dropped 4 days after egg retrieval, finding a statistically significant lower level in those receiving letrozole (177 vs. 965 pg/mL, P<0.001). Again, at the next time points serum E2 levels were significantly lower (day +7: 127 vs. 989 pg/mL, P<0.001, and day +10: 21.5 vs. 296 pg/mL, P<0.01). No significant differences were observed in progesterone or LH levels. The administration of 2.5 mg of letrozole during the luteal phase drastically reduces serum E2 levels. This may be of interest not only for egg donors, but also in patients at high risk of OHSS who freeze all their embryos or who cancel hCG administration, in order to reduce the potential risk that high E2 levels pose to the patient.

Phase II study of letrozole in estrogen receptor (ER) positive relapsed epithelial ovarian cancer (EOC)

5025 Background: Letrozole is a potent oral aromatase inhibitor which rapidly suppresses circulating estrogen levels by 99% in postmenopausal women. By comparison with cytotoxic agents it is very well tolerated. We previously demonstrated an ‘endocrine sensitive’ subgroup of ovarian cancer patients with ER histoscore cutoff of ≥150 (Bowman et al, Clin Can Res 2002). Methods: This was a phase II study with a planned sample size of 33 patients. Eligible patients had relapsed EOC or primary peritoneal cancer with an ER histoscore of ≥150 and a rising CA125 that had progressed according to Rustin’s criteria. Patients were treated with letrozole 2.5mg daily until clinical or marker evidence of disease progression. The primary endpoint was response according to CA125 and RECIST criteria. Biomarker analysis by tissue microarray is also being performed. Results: 46 patients were accrued, 45 of whom were eligible. The median age was 61 (range 39–81). 24, 10 and 10 patients had received 1,2 and &gt;2 previous lines of chemotherapy respectively. Of 43 patients evaluable for CA125 response, 7 (16%) had a response (decrease of &gt;50%) and 16 (37%) patients had not progressed (doubling of CA125) following 12 weeks on treatment. In the CA125 responders, the nadir CA125 ranged from 0.7–49% of baseline (actual % of baseline: 0.7, 2.6, 11.1, 17.6, 23.6, 42.6, 49). Of the 7 responding patients, 5 had received only one previous line of chemotherapy. The time taken to achieve the nadir CA125 value ranged from 10 to 36 weeks, with a median of 13 weeks. Of 33 patients evaluable for radiological response, 3 (9%) had a PR and 14 (42%) had stable disease at 12 weeks. Overall, 11 patients (26%) had a PFS of &gt;6 months and 2 patients (5%) had a PFS of ≥2 years. Conclusions: To our knowledge this is the first study of a hormonal agent in a selected ER +ve population of ovarian cancer patients. Promising efficacy of the agent is demonstrated in this population of pre-treated patients, many with a considerable bulk of disease. Given the median time of 13 weeks to response, we suggest that this strategy should be tested in ER+ve ovarian cancer patients in the adjuvant setting following first line chemotherapy No significant financial relationships to disclose.