Co-administration Of Letrozole Research Articles

P-367 Letrozole or Tamoxifen co-administration during fertility preservation of breast cancer patients: a retrospective cohort study

Abstract Study question How do fertility preservation (FP) outcomes differ between breast cancer patients stimulated with FSH and Tamoxifen versus FSH and Letrozole? Summary answer Letrozole and Tamoxifen co-administration yielded similar number of retrieved and cryopreserved oocytes/embryos, as well as similar oocyte maturation and fertilization and rates. What is known already Oocyte/embryo cryopreservation is recommended before initiation of chemotherapy in cancer patients. The co-administration of Tamoxifen, a selective estrogen receptor modulator, or Letrozole, an aromatase inhibitor, during ovarian stimulation with gonadotropins, are used to limit the potentially harmful effects of a supra-physiological rise in estrogen levels on hormone-sensitive cancers. However, the optimal choice between the two is still unclear and with no sound evidence. Study design, size, duration Retrospective cohort study of all FP treatments of newly diagnosed breast cancer patients in two tertiary centers between 2000-2022. Collected data included 354 FP cycles of 290 patients and compared treatment parameters and outcomes of Tamoxifen or Letrozole co-administration. Participants/materials, setting, methods Breast cancer patients who underwent FP before chemotherapy were included. Patients with a history of radiation or gonadotoxic treatment, as well as those undergoing other fertility preservation treatments, such as ovarian tissue cryopreservation were excluded. Main results and the role of chance Overall, 215 Letrozole and 139 Tamoxifen treatment cycles were compared, with no significant demographic differences. Treatments with Letrozole had higher FSH dosages (3970IU vs. 2839IU, p < 0.001) but shorter duration (9.7 vs. 10.5 days, p < 0.001). The Letrozole group achieved lower peak E2 levels and endometrial thickness (1508pmol/L, 8.1mm vs. 8760pmol/L, 9.5mm, p < 0.001). The mean number of retrieved oocytes was comparable between the groups (13.6 with Letrozole vs 14.7 with Tamoxifen, p = 0.06). In 122 Letrozole and 46 Tamoxifen patients that underwent strictly oocytes cryopreservation the mean number of cryopreserved oocytes was comparable (11 vs. 12.1, p = 0.21). Moreover, in embryo cryopreservation cycles of 71 patients treated with Letrozole compared to 76 patients with Tamoxifen, no difference was observed in the number of cryopreserved embryos (6.2 vs. 7.0, p = 0.12). Oocyte maturation rate among strictly oocyte preservation cycles was comparable (86% with Letrozole vs. 83% with Tamoxifen, p = 0.80), as were fertilization rates in embryo cryopreservation cycles (62% vs. 63%, p = 0.8 and 71% vs. 76%, p = 0.3 in IVF and ICSI with Letrozole and Tamoxifen, respectively). Multivariate analysis, controlling for potential confounders showed no significant correlations between Tamoxifen or Letrozole co-administration and the number of retrieved oocytes or oocyte maturation rate. Limitations, reasons for caution The primary limitation of our study is its retrospective design and the variation in treatment duration and gonadotrophin dosages among groups. Wider implications of the findings This study provides reassurance that both Tamoxifen and Letrozole are equally effective options when co-administered in FP treatments of breast cancer patients. Trial registration number not applicable

P-376 Letrozole to minimise exposure to elevated serum estradiol during superovulation for breast cancer patients prior to chemotherapy. Real world experience from a statewide oncofertility service

Abstract Study question How effective is co-treatment with letrozole in supressing peak E2 in a real world setting? Summary answer We observed greater than anticipated supra-physiological serum estadiol concentrations in our cohort. What is known already Breast cancer occurs frequently in women of reproductive age, many of whom request oocyte or embryo cryopreservation before chemo/radiotherapy. Oncofertility treatment requires superovulation with resultant elevation of serum estradiol above concentrations seen physiologically. In order to avoid possible stimulation of estrogen receptor positive breast cancers, co-administration of letrozole is frequently recommended. A 67% lower mean serum estradiol in a letrozole treated group compared with an untreated superovulated comparison group has been reported in the literature, suggesting a protective mechanism. Peak E2 concentration across 4 cohorts of patients co-treated with letrozole has been reported to be 103 – 2350 (mean 564). Study design, size, duration We performed a retrospective cohort study of women referred for fertility preservation following diagnosis of breast cancer to the Fertility Research Centre at The Royal Hospital for Women, Sydney between Jan 2020 and Jan 2024. Women were identified from hospital outpatient paper and electronic medical records. 145 new referrals were received by our centre, with 88 patients undergoing 107 cycles. Participants/materials, setting, methods 145 women aged between 19 and 44 with newly diagnosed breast cancer were referred to our Statewide, multidisciplinary, public oncofertility service for consideration of treatment and review at our fertility multidisciplinary team meeting. Our oncofertility database and outpatient clinical records were used to identify new referrals to the service. Electronic and paper medical records including the ART database were used to obtain cycle information, blood results and demographic information Main results and the role of chance Peak estradiol concentrations (pMol/L) 35% of cycles resulted in peak E2 > 2000. 11% of cycles resulted in peak E2 > 4000 and 2% of cycles resulted in peak E2 > 7000. We calculated a mean E2 of 1837. The mean anti-mullerian hormone was 20.3 pMol/L and mean antral follicle count 19.7. The mean BMI was 24.7. The average stimulation length was 13 days (7-16 days) with an average cumulative gonadotrophin dose of 2769 IU. Average number of MII oocytes per cycle was 7.2. 16 % of patients elected to preserve embryos. The fertilisation rate was 50%, with 61% of fertilised eggs resulting in frozen blastocytes. There have been 2 pregnancies and one live birth to date. 32% of cycles had a germline genetic result prior to OPU, with 20% having a positive BRCA gene mutation. Breast cancer hormone status 56% were Estrogen Receptor positive. 38 % were Progesterone Receptor positive, 18% were HER2 positive, 24% were hormone receptor negative Complications 5% of cycles were cancelled prior to OPU, 8% of cycles resulted in no oocyte or embryo available for freezing. 3% of cycles were reviewed for OHSS symptoms with 2 confirmed cases of OHSS secondary to administration of Zoladex <24hrs following OPU. Limitations, reasons for caution This is a retrospective cohort study in a single academic centre. Our current study duration is too short to permit determination of recurrence rates of breast cancer in the letrozole treated cohort. Wider implications of the findings The impact of short, transient elevation of circulating estradiol during superovulation is uncertain, however it is prudent to try to minimise exposure of ER positive breast cancers to estrogen. Alternative strategies for limiting this phenomenon should be explored, more evidence is needed on oncological and fertility outcomes in this population. Trial registration number N/A

Reassessing the impact of letrozole co-administration in controlled ovarian hyperstimulation: findings from a single-center repeated measures study.

To explore whether letrozole improved outcomes in subsequent controlled ovarian hyperstimulation (COH) cycles. This was a retrospective repeated measures cohort study examining COH cycles. Patients were included if they underwent two cycles for unexplained infertility, male factor infertility, or planned oocyte/embryo cryopreservation. The first cycles for all patients implemented a non-letrozole, conventional gonadotropin protocol. Second cycles for the study group included letrozole (2.5-7.5 mg for 5 days) with no medication change to second cycles amongst controls. Our primary objective was to compare oocyte yield. Cohorts were then subdivided by pursuit of oocyte (OC) or embryo (IVF) cryopreservation. Secondary outcome amongst the OC subgroup was oocyte maturation index (metaphase II (MII)/total oocytes). Secondary outcomes amongst the IVF subgroup were normal fertilization rate (2-pronuclear zygotes (2PN)/oocytes exposed to sperm), blastocyst formation rate (blastocysts/2PNs), and embryo ploidy (%euploid and aneuploid). Fifty-four cycles (n = 27) were included in letrozole and 108 cycles (n = 54) were included in control. Oocyte yield was higher in second cycles (p < 0.008) in the letrozole group but similar in second cycles (p = 0.26) amongst controls. Addition of letrozole did not impact MII index (p = 0.90); however, MII index improved in second cycles amongst controls (p < 0.001). Both groups had similar rates of normal fertilization (letrozole: p = 0.52; control: p = 0.61), blast formation (letrozole: p = 0.61; control: p = 0.84), euploid (letrozole: p = 0.29; control: p = 0.47), and aneuploid embryos (letrozole: p = 0.17; control: p = 0.78) between cycles. Despite improved oocyte yield, letrozole did not yield any difference in oocyte maturation or embryo outcomes.

Effects of letrozole co-treatment on outcomes of gonadotropin-releasing hormone antagonist cycles in POSEIDON groups 3 and 4 expected poor responders.

To evaluate the effects of adjuvant letrozole administration on outcomes of gonadotropin-releasing hormone (GnRH) antagonist cycles with intra-cytoplasmic sperm injection in POSEIDON groups 3 and 4 expected poor responder women. This study was conducted by retrospective analysis of patients with expected poor ovarian response (POSEIDON groups 3 and 4) that underwent GnRH antagonist cycles with intra-cytoplasmic sperm injection between 2010 and 2020. A total of 488 patients with letrozole co-administration and 2564 patients without any adjuvant treatment that underwent GnRH antagonist cycles within the selected period of time were included in the study. Implantation rates, clinical pregnancy rates and live birth delivery rates were significantly higher in letrozole administered patients in comparison to controls among POSEIDON group 3 women (0.39 ± 0.46 vs 0.27 ± 0.40, p = 0.01; 46.1% vs 33%, p = 0.014; 42.7% vs 31.5%, p = 0.034, respectively). Mean total doses of gonadotropins required per cycle were significantly lower in letrozole administered patients among both POSEIDON groups 3 and 4 women (2864.65 ± 878.47IU vs 3757.27 ± 1088.89IU, p < 0.001; 3286.06 ± 770.16IU vs 3666.48 ± 959.66IU, p < 0.001, respectively). Adjuvant letrozole co-administration in intra-cytoplasmic sperm injection cycles following GnRH antagonist protocol appears to improve implantation, clinical pregnancy and live birth delivery rates in women with POSEIDON group 3 expected poor ovarian response.

THE OPTIMAL FOLLICLE SIZE AT OVULATORY TRIGGER IN OVARIAN STIMULATION CYCLES WITH LETROZOLE CO-ADMINISTRATION

Letrozole co-administration during ovarian stimulation minimizes exposure to supraphysiologic estrogen levels for patients with estrogen-sensitive malignancies or those at increased risk for venous thromboembolism. Initial studies describing the use of letrozole as an IVF adjunct noted an improvement in oocyte maturity rates when the ovulatory trigger was administered at larger follicle sizes. We sought to determine the optimal follicle size at the time of ovulatory trigger to maximize oocyte maturity rates in women undergoing IVF with letrozole co-administration. We performed a single-center retrospective study of women undergoing ovarian stimulation with letrozole co-administration from 2010 to 2019. Cycles were divided into seven groups based on the size of the lead and 2nd largest follicles on the day of ovulatory trigger (≥24 mm, 22-23.9 mm, 20-21.9 mm, 17-19.9 mm). The reference group was comprised of cycles in which the lead follicle was ≥20 mm and the 2nd largest follicle was 17-19.9 mm. The primary outcomes were the number of MII oocytes retrieved and the proportion of MII oocytes. Comparisons between groups were made using the Student’s t-test. 309 patients were identified for analysis. The most common indications for letrozole co-administration were breast cancer (n=219, 71.6%), BRCA mutation (n=17, 5.6%), history of venous thromboembolism (n=13, 4.4%), and endometrial hyperplasia/cancer (n=12, 3.9%). The number of oocytes retrieved was highest when both the lead and 2nd largest follicle were 22-23.9 mm (19.9, p < 0.01) and lowest in the reference group (12.0). The proportion of MII oocytes was lowest in the reference group (67.1%) when compared to all groups where both the lead and 2nd largest follicle were ≥20 mm. The highest proportion of MII oocytes occurred when the lead follicle was ≥24 mm and the 2nd largest follicle was 22-23.9 mm (77.0%, p=0.03), and when the lead follicle was ≥24 mm and the 2nd largest follicle was 20-21.9 mm (79.4%, p=0.07). In ovarian stimulation cycles where letrozole is co-administered, pushing lead follicles to advanced sizes (≥20 mm) before ovulatory trigger increases the proportion of MII oocytes. Oocyte maturity rates were highest when the lead follicle was ≥24 mm and the 2nd largest follicle was 20-23.9 mm.

Abstract PS13-03: Fertility preservation for breast cancer patients before chemotherapy

Abstract Background: Various strategies of fertility preservation for breast cancer patients have been purposed for women at childbearing age. Ovarian stimulation protocols for oocyte/embryo cryopreservation are common means, but are introduced differently and detail regimens vary widely. Protocols for better oocyte cryopreservation outcomes and patients’ hormone stability remain to be determined. Research Objectives and Rationale: To compare oocyte/embryo cryopreservation outcomes after random-start ovarian stimulations with conventional ones as well as to investigate the effects after double ovarian stimulation cycles, co-administration of aromatase inhibitors or tamoxifen on stabilizing breast cancer patients’ estrogen level, the efficiency of oocyte in vitro maturation for fertilization and the impact of patients' genetic background on fertility preservation outcomes. Methods: A systematic review followed by a meta-analysis was performed to identify all relevant studies published before June 2020. The primary outcomes were the numbers of retrieved oocytes. The secondary outcomes were the numbers of mature oocytes and peak serum estradiol levels. Outcomes: A total of 29 studies met the inclusion criteria. Random-start ovarian stimulations resulted in comparable numbers of retrieved oocytes as conventional protocols did (retrieved oocytes: 503 patients, weighted mean difference [WMD]: -0.01, 95% CI: -2.08 - 2.06, P = 0.99; I2= 0%). Two cycles of ovarian stimulation have significant higher numbers of total retrieved oocytes compared to a single cycle (102 patients, WMD: 7.91, 95% CI: 3.42 -12.40, P = 0.0006; I2= 0%). Both co-administration of letrozole and tamoxifen showed similar results of retrieved oocytes compared to those without (letrozole versus without: 681 patients, WMD: -0.68, 95% CI: -1.96 - 0.61, P = 0.30; I2= 0%) (tamoxifen versus without: 87 patients, WMD: 0.67, 95% CI: -1.29 - 2.64, P = 0.50; I2= 45%). Significant lower peak serum estradiol level was observed in letrozole-based groups compared to letrozole-free groups (301 patients, WMD: -1.05, 95% CI: -1.21 - -0.89, P &amp;lt; 0.00001; I2= 0%). No significant differences were found in peak serum estradiol level between those co-treated with tamoxifen and those without (87 patients, WMD: 0.21, 95% CI: -0.01 - 0.43, P = 0.07; I2= 26%). Regarding breast cancer patients with different BRCA gene background, lower AMH levels were discovered in those with BRCA mutations (831 patients, WMD: -0.63, 95% CI: -1.18 - -0.08, P = 0.03; I2= 47%); however, no significant differences were found in the numbers of retrieved oocytes (retrieved oocytes: 550 patients, WMD: -1.33, 95% CI: -2.72 - 0.05, P = 0.06; I2= 0%). Wider implications: We systematically investigated various aspects of ovarian stimulation for oocyte retrieval in breast cancer patients undergoing fertility preservation prior to chemotherapy, our review indicated that (1) random-start controlled ovarian stimulation protocol showed comparable oocyte yields with minimal delays of referral to initiate ovarian stimulation; (2) two ovarian stimulation cycles results in higher numbers of retrieved oocytes while back-to-back and conventional two cycles showed no significant differences; (3) combinations with letrozole demonstrated a safer way over tamoxifen and anastrozole in terms of lowering estradiol level during stimulation processes; (4) in vitro maturation of immature oocytes can maximize the numbers of oocytes for cryopreservation; and (5) regarding patients’ genetic backgrounds, those with BRCA mutations have lower AMH levels, but similar in numbers of retrieved oocytes to those without BRCA mutations. Nonetheless, we look forward to higher evidence-level studies to understand the clinical relevance of these protocols for ovarian stimulation in breast cancer patients desiring fertility preservation before chemotherapy. Citation Format: Chih-Ning Chen, Lu-Te Chang, Ka-Wai Tam. Fertility preservation for breast cancer patients before chemotherapy [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 PS13-03.

1829P - Efficacy and safety of controlled ovarian stimulation with or without letrozole co-administration for fertility preservation: A systematic review and meta-analysis

BackgroundMature oocyte vitrification and storage is currently used to help patients preserving their ability to have offspring either for fertility preservation (FP) before gonadotoxic treatment such as chemotherapy or for elective purposes. Our meta-analysis investigated whether letrozole co-administration during controlled ovarian stimulation (COS) for FP is effective and safe. MethodsA literature search using PubMed was conducted up to March 8th, 2019 to retrieve information from studies that compared the performance of COS with or without letrozole co-administration for FP. Mean or median values and 95% confidence intervals (CIs) or standard deviations (SDs) were collected for efficacy (number of collected oocytes, number of mature oocytes, maturation rate) and safety (peak estradiol levels [E2], total gonadotropin dose, number of stimulation days) endpoints. Statistical analysis was conducted with random-effects model. ResultsA total of 10 articles were eligible including 1930 patients undergoing COS with or without letrozole. Studies compared COS with and without letrozole in cancer or infertile cohorts (N=9) and infertile cohort only (N=1). The total number of oocytes and mature oocytes collected were similar between letrozole and no letrozole groups while the peak estradiol was significantly higher in the standard COS without letrozole (Table).Table1829PTableMR (letrozole vs no letrozole)95% CIP-valueCollected oocytes1.020.90-1.160.748Mature oocytes0.980.83-1.160.830Maturation rate0.940.86-1.030.181Peak E20.270.22-0.32<0.001Total gonadotropin0.970.86-1.100.676Length of stimulation1.000.95-1.040.849 ConclusionsLetrozole co-administration during COS resulted to be as effective as standard COS but with significantly decreased peak estradiol levels, suggesting its increased safety especially for hormone-sensitive cancer patients. Legal entity responsible for the studyThe authors. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Letrozole supplementation during controlled ovarian stimulation in expected high responders: a pilot randomized controlled study

BackgroundAlmost all of the previous studies related with co-administration of letrozole in IVF cycles were performed in poor responders and letrozole may reduce the total gonadotropin dose required for ovarian stimulation, and the pregnancy rate did not decrease in poor responders. This study aimed to assess whether high responders co-treatment with letrozole reduced supraphysiological late follicular phase estradiol levels and the incidence of premature progesterone elevated at the end of the follicular phase, thereby impacting positively on endometrial receptivity.MethodsA randomized parallel controlled study in a university-affiliated center include 130 high responders between October 2015 and August 2016. The patients were randomized on the first stimulation day of the IVF cycle and from stimulation day 5 receive letrozole (group A) or without letrozole treatment (group B).ResultsAlthough estradiol levels were significantly lower in the letrozole group (group A) (P < 0.001), progesterone elevation (> 1.5 ng/mL was considered as a rise) on the day of hCG triggering (15.4, 7.7%) was not statistically significant (P = 0.170). RecFSH, the recovery rate of eggs, the high-quality embryo rate, and the thickness of endometrium (P = 0.776) were similar between the letrozole group(group A) and control groups (group B). Clinical pregnancy rates were 53.1% (26/49) and 72.9% (35/48) in the letrozole and control groups, respectively, with a statistical significance (P = 0.043).Live birth rates were 42.9% (21/49) and 62.5% (30/48),showed a marginally significant difference (P = 0.053). The miscarriage rate did not significantly differ between the two groups.ConclusionsIn this pilot study, letrozole supplementation could not reduce the incidence of premature progesterone rise during the late follicular phase in stimulated in vitro fertilization cycles in expected high responders, producing a harmful effect on the pregnancy outcome.Trial registrationChina Clinical Trial Registration Center: ChiCTR-IPR-15006211 URL of the trial registry record: http://www.chictr.org.cn/showproj.aspx?proj=10731. Trial registration date: 8 April, 2015. Date of first patient’s enrolment: 5 October, 2015.

Effect of letrozole added to gonadotropins in controlled ovarian stimulation protocols on the yield and maturity of retrieved oocytes

We aimed to evaluate the effect of co-administration of letrozole and gonadotropins during ovarian stimulation on oocyte yield and maturation in breast cancer patients prior to chemotherapy. A retrospective cohort design was used comparing oocyte cryopreservation cycles among patients with breast cancer patients with other oncological indications and women undergoing elective oocyte cryopreservation. All patients were treated with GnRH antagonist protocol using GnRH agonist for final oocyte maturation. The breast cancer group was additionally treated with letrozole (5 mg/d) from the first day of treatment until the day of oocyte retrieval. The cohort included 418 patients: 145 breast cancer patients, 168 with other oncological indications, and 105 patients who chose to undergo elective oocyte cryopreservation. There were no significant differences among the groups in the number of retrieved oocytes or proportion of mature oocytes. On multivariate linear regression models, co-treatment with letrozole was not a significant factor for the number of retrieved oocytes or for oocyte maturation rate after controlling for age, body mass index (BMI), and FSH dose. We conclude that the addition of letrozole to gonadotropins does not increase the number of oocytes retrieved or the oocyte maturation rate.

Does daily co-administration of letrozole and gonadotropins during ovarian stimulation improve IVF outcome?

BackgroundFor the last year we have been treating normal responders with gonadotropins and letrozole during the whole stimulation in order to improve response to FSH by increasing the intrafollicular androgen concentration, and to reduce circulating estrogen concentrations. The aim of this study was to compare the IVF outcome of normal responders treated with letrozole and gonadotropins during ovarian stimulation with patients treated with gonadotropins only.MethodsA single centre retrospective cohort study of 174 patients (87 in each group).ResultsThe age of the patients was comparable between the groups. Estradiol levels were significantly higher in the control group (6760 pmol/L vs. 2420 pmol/L respectively, p < 0.01), and the number of follicles ≥15 mm at the trigger day was significantly lower in the control group (7.9 vs. 10, p = 0.02). The number of retrieved oocytes (10 vs. 14.5, p < 0.01), MII oocytes (7.9 vs. 11.2, p < 0.01) and blastocysts (2.7 vs. 4.0, p = 0.02) was significantly higher in the study group. We found no significant differences in the cumulative pregnancy outcome between the two groups (65.2% vs 58.3% p = NS).ConclusionsWe conclude that co-treatment with letrozole improves the IVF outcome in normal responders in terms of increased number of blastocysts obtained without increasing the pregnancy rate or the risk of OHSS.

The safety and efficacy of controlled ovarian hyperstimulation for fertility preservation in women with early breast cancer: a systematic review.

Can controlled ovarian hyperstimulation (COH) for fertility preservation be effectively conducted in women with breast cancer without worsening their prognosis? COH with co-administration of letrozole suppresses oestradiol levels without significantly impacting oocyte yield or decreasing disease-free survival rates. Oestradiol has the capacity to stimulate the proliferation of breast cancer cells. COH can cause oestradiol levels to rise by an order of magnitude above physiological levels. Concern exists regarding the effect of supra-physiological oestradiol levels in women with a recent diagnosis of breast cancer. A systematic review of the literature was performed using MEDLINE (PubMed database), EMBASE and the Cochrane Library. The search was restricted to articles written in English. No restrictions regarding the date of publication were applied. Safety was assessed in terms of relapse rates and cancer-related mortality rates. Peak oestradiol concentrations were recorded for different stimulation protocols. Efficacy was measured in terms of the total number of oocytes collected and proportion of mature oocytes. The primary outcome was mortality/recurrence in premenopausal women with Stage I-IIIB breast cancer who underwent COH in the immediate post-operative period, prior to chemotherapy. This is a systematic review of randomized control trials (RCTs), case control and cohort studies reporting on the primary outcome of mortality/recurrence after COH in women with early breast cancer, or secondary outcomes of oocyte yield and peak oestrogen concentration. Owing to the small number of RCTs available, other study types were included. The last electronic search was run in April 2016. Two prospective non-randomized studies reported relapse and breast cancer-related mortality rates in 397 women with breast cancer, of whom 149 underwent COH. Twelve studies reported the peak oestradiol concentrations of 882 women undergoing COH with letrozole co-administration. Four studies compared the oocyte yield of 248 women who underwent COH plus letrozole with 254 women who underwent standard COH. Two studies compared peak oestradiol concentrations and oocyte yield in 61 women who underwent COH with tamoxifen co-administration and 49 women who underwent COH without tamoxifen. One study compared letrozole and tamoxifen co-administration, and another study compared the co-administration of letrozole and anastrozole. The search identified 1002 records of which 15 were included in the final analysis. There was no evidence of a decline in relapse-free survival rates in the two studies of women with breast cancer who received COH with letrozole co-administration compared with women who did not undergo fertility preservation procedures. The largest of these studies reported recurrences in 6/120 (5.0%) women who received COH plus letrozole compared with 12/217 (5.5%) women who did not undergo COH (mean follow-up 5.0 versus 6.9 years; hazard ratio for recurrence 0.77, 95%CI 0.28-2.13). Conclusions regarding women with breast cancer who received tamoxifen during COH could not be made due to insufficient data. Peak oestradiol concentrations (338-829 pg/ml) were suppressed by letrozole when commenced on Days 2-3, with no decrease in oocyte yield. Tamoxifen does not suppress oestradiol concentrations, but may convey protection via its inhibitory action on the oestrogen receptor. Any statements regarding the safety of COH in women with breast cancer are based on a limited number of observational studies. High quality evidence is unlikely to become available for ethical and practical reasons. Whilst available data do not indicate a decline in disease-free survival, a small effect cannot be excluded. Breast cancers are heterogeneous in their genetic profile and receptor status, making the results of studies difficult to generalize to individual cases. The implication of alterations in other hormone levels such as androgens, progestins or vascular endothelial growth factor secondary to COH in women with breast cancer has not been quantified. The co-administration of 5 mg of letrozole daily commencing on Day 2 and continuing throughout COH is recommended as it reduces peak oestradiol concentrations without significantly decreasing oocyte yield. The use of a GnRH agonist trigger is beneficial as oestradiol concentrations rapidly decrease post-administration and rates of ovarian hyperstimulation are lower than with an hCG trigger, without a corresponding reduction in clinical pregnancy or live birth rates in cryopreservation cycles. The protective effect of tamoxifen has not been evaluated although theoretically may be of benefit due to its action on the oestrogen receptor. None. None.

Controlled ovarian hyperstimulation with sequential letrozole co-treatment in normo/high responders

Objective: To investigate the effect of co-administration of letrozole in an ovarian stimulation protocol using recombinant FSH and GnRH antagonists for ICSI in normo/high responders.Methods: Computerized data of 320 antagonist ICSI/ET cycles with or without letrozole were retrospectively analyzed. In 105 cases, letrozole (5 mg/day) was started at the second day of the cycle continued for 5 days. At the second day of letrozole, gonadotropins were added. The remaining 215 cases were stimulated with recombinant FSH only. In all cases on day 6, GnRH antagonist was started. Ovarian stimulation protocols with or without letrozole were compared for cycle outcome parameters.Results: In cycles with letrozole, significantly lower gonadotropin consumption and lower peak estradiol levels were found. In cycles with letrozole, mean number of metaphase II and fertilized oocytes retrieved were significantly higher compared to cycles without letrozole. The pregnancy and clinical pregnancy rates were similar.Conclusion: Should the number of oocytes retrieved being higher in letrozole group might indicate that letrozole might contribute to successful ovarian stimulation with a lower dosage of gonadotropins. Despite the lower peak estradiol levels, pregnancy rates being similar to other group also support the idea that letrozole can contribute to normal potential of implantation.

The case for aromatase inhibitors use in Oncofertility patients. Should aromatase inhibitors be combined with gonadotropin treatment in Breast Cancer patients undergoing ovarian stimulation for fertility preservation prior to chemotherapy? A debate

Breast cancer is one of the hormone-dependent cancers that may be adversely affected by elevated oestrogen or progesterone concentrations, particularly the endocrine active (hormone receptor positive) breast cancers.Treatment for breast cancer patients aimed at fertility preservation, includes ovarian hyperstimulation, the harvest of oocytes, and subsequent cryopreservation of oocytes or embryos. Classically, gonadotrophins have been used effectively for ovulation induction, a treatment often accompanied by high blood oestrogen concentrations produced by the hyperstimulated granulosa cells. Despite the uncertainty which surrounds this issue and the lack of clear-cut clinical evidence, it is still of major concern that these ensuing high hormone levels might be associated with a high risk of recurrence of the cancer.A growing number of clinical studies have strongly suggested the benefits of using aromatase inhibitors in infertility treatment, both as single agents or as adjuncts to FSH-containing ovulation induction regimes in reproductive medicine. Combining gonadotrophins with aromatase inhibitors would augment the stimulation effect, with a reduced increase in serum concentrations of estradiol. We propose to open a debate over the use of aromatase inhibitors in combination with FSH in ovulation induction treatment of breast cancer oncofertility patients.As the safety of aromatase inhibitors such as letrozole has recently been demonstrated in several studies, and there is growing concern over the possible detrimental effects of high estradiol levels on breast cancer cells (at least in mouse models), the co-administration of letrozole in these patients would reduce both the high supraphysiologic serum levels of estradiol and the intratumoral in situ production of oestrogen. However, since it is unlikely that a well-founded evidence-based justification of this treatment will be formulated in the near future, based on well-designed prospective randomised controlled trials, we advocate a wider use of aromatase inhibitors in combination with gonadotrophins in breast cancer patients, especially those with hormone-receptor-positive tumours.

Reduced Methadone Clearance During Aromatase Inhibition

Methadone is increasingly used in pain management and is a cornerstone in the treatment of opiate withdrawal. It is subject to highly variable clearance among patients. The complete metabolic disposition of methadone is likely to involve a number of enzymes, including specifically CYP2B6. Previous studies in vitro suggest that metabolism by aromatase may also contribute. Single-dose methadone pharmacokinetics (2 mg, intravenous) were studied in 15 healthy postmenopausal women in the presence and absence of a potent aromatase inhibitor, letrozole. A sequential design was used, involving a control period followed by treatment with letrozole (2.5 mg/d, 11 days), in which each subject served as her own control. On average, letrozole treatment reduced methadone systemic clearance by 22% (P = 0.001), increased methadone AUC by 23% (P = 0.007), and increased elimination half-life by 21% (P = 0.042). The plasma parent-to-metabolite ratio also increased (P = 0.009), and there was a linear relationship (R2 = 0.74) between change in this plasma ratio and change in methadone AUC0-∞. In contrast, there was no such association with change in apparent urinary methadone clearance. Letrozole did not change methadone distribution half-life or its volume of distribution. Overall, these data demonstrate a significant decrease in methadone clearance during coadministration of letrozole, consistent with decreased metabolism brought about by aromatase inhibition. An involvement of aromatase in the disposition of methadone may help explain the difficulty in methadone dosing and suggests a broader role for this catalyst of endogenous steroid metabolism in xenobiotic drug disposition.

Methadone adverse reaction presenting with large increase in plasma methadone binding: a case series

IntroductionThe use of methadone as an analgesic is on the increase, but it is widely recognized that the goal of predictable and reproducible dosing is confounded by considerable variability in methadone pharmacokinetics, and unpredictable side effects that include sedation, respiratory depression and cardiac arrhythmias. The mechanisms underlying these unpredictable effects are frequently unclear. Here, to the best of our knowledge we present the first report of an association between accidental methadone overexposure and increased plasma protein binding, a new potential mechanism for drug interactions with methadone.Case presentationWe describe here the cases of two patients who experienced markedly different responses to the same dose of methadone during co-administration of letrozole. Both patients were post-menopausal Caucasian women who were among healthy volunteers participating in a clinical trial. Under the trial protocol both patients received 6 mg of intravenous methadone before and then after taking letrozole for seven days. One woman (aged 59) experienced symptoms consistent with opiate overexposure after the second dose of methadone that were reversed by naloxone, while the other (aged 49) did not. To understand the etiology of this event, we measured methadone pharmacokinetics in both patients. In our affected patient only, a fourfold to eightfold increase in methadone plasma concentrations after letrozole treatment was observed. Detailed pharmacokinetic analysis indicated no change in metabolism or renal elimination in our patient, but the percentage of unbound methadone in the plasma decreased 3.7-fold. As a result, the volume of distribution of methadone decreased approximately fourfold. The increased plasma binding in our affected patient was consistent with observed increases in plasma protein concentrations.ConclusionsThe marked increase in the total plasma methadone concentration observed in our patient, and the enhanced pharmacodynamic effect, appear primarily due to a reduced volume of distribution. The extent of plasma methadone binding may help to explain the unpredictability of its pharmacokinetics. Changes in volume of distribution due to plasma binding may represent important causes of clinically meaningful drug interactions.

Final 5‐year results of Z‐FAST trial

Postmenopausal breast cancer (BC) patients receiving adjuvant aromatase inhibitor therapy are at risk of progressive bone loss and fractures. Zoledronic acid inhibits osteoclastic bone resorption, is effective in maintaining bone health, and may therefore be beneficial in this setting. Overall, 602 postmenopausal women with early, hormone receptor-positive BC receiving adjuvant letrozole were randomized (301 each group) to receive upfront or delayed-start zoledronic acid (4 mg intravenously every 6 months) for 5 years. The primary endpoint was the change in lumbar spine (LS) bone mineral density (BMD) at month 12. Secondary endpoints included changes in LS BMD, total hip BMD, and bone turnover markers at 2, 3, and 5 years; fracture incidence at 3 years; and time to disease recurrence. At month 61, the adjusted mean difference in LS and total hip BMDs between the upfront and delayed groups was 8.9% and 6.7%, respectively (P < .0001, for both). Approximately 25% of delayed patients received zoledronic acid by month 61. Only 1 patient experienced grade 4 renal dysfunction; no confirmed cases of osteonecrosis of the jaw were reported. Fracture rates (upfront, 28 [9.3%]; delayed, 33 [11%]; P = .3803) and Kaplan-Meier disease recurrence rates (upfront, 9.8 [95% confidence interval (CI), 6.0-10.3]; delayed, 10.5 [95% CI, 6.6-14.4]; P = .6283) were similar at month 61. Upfront zoledronic acid seems to be the preferred treatment strategy versus delayed administration, as it significantly and progressively increases BMD in postmenopausal women with early BC receiving letrozole for 5 years, and long-term coadministration of letrozole and zoledronic acid is well tolerated.

The effect of tamoxifen on the pharmacokinetics of letrozole in female rats

The effects of single doses of tamoxifen (TAM; 0.5-5 mg/kg, i.v.) and chronic pretreatment with TAM (0.1-5.0 mg/kg/day, i.p. for 7 consecutive days) on letrozole (0.5 mg/kg, i.v.) pharmacokinetics were evaluated in female Sprague-Dawley rats. The plasma concentration-time profiles of letrozole (0.1-2.0 mg/kg) after single i.v. doses were analysed by the non-compartment model with terminal half-lives (t(1/2,lambdaz)) ranging from 34.3 to 37.5 h. The volume of distribution at the terminal phases (Vd(lambdaz)) ranged from 1.9 to 2.1 l/kg and clearance (CL) varied from 0.036 to 0.042 l/(h.kg). After co-administration of TAM and letrozole intravenously, the t1/2, Vd(lambdaz) and CL of letrozole were not significantly altered. Chronic pretreatment with TAM significantly decreased the t1/2 of letrozole by about 33%, and increased its clearance by an average of 40%. However, TAM pretreatment did not significantly affect the Vd(lambdaz) of letrozole in female rats. Co-administration of letrozole and TAM orally increased the absorption half-life of letrozole threefold although the absolute bioavailability remained unchanged. These observations suggest that single oral doses of TAM delay the absorption of letrozole while chronic pretreatment with TAM accelerates the elimination of letrozole, probably due to induction of cytochrome P450 enzymes in rats.