Tamoxifen + Letrozole for Fertility Preservation in Breast Cancer

(TALES Trial)

Overseen By Rebecca Wong

Age: 18 - 65

Sex: Female

Trial Phase: Phase 3

Sponsor: University of California, San Francisco

Must be taking: Letrozole, Tamoxifen

Disqualifiers: Recurrent breast cancer, Stage IV, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Pivotal Trial (Near Approval) This treatment is in the last trial phase before FDA approval

Prior Safety Data This treatment has passed at least one previous human trial

Compensation: Varies

Number of Visits: 1

309 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores methods to help women with estrogen-receptor-positive breast cancer preserve fertility before chemotherapy. It compares two treatments: letrozole (a hormone therapy) plus gonadotropin and tamoxifen (another hormone therapy) plus gonadotropin, to determine which yields more oocytes (eggs). Women newly diagnosed with breast cancer who have not started chemotherapy and wish to preserve their eggs may be suitable candidates. The trial aims to enhance the quality of life for breast cancer survivors who hope to have children in the future. As a Phase 3 trial, it represents the final step before FDA approval, offering participants the opportunity to contribute to a potentially groundbreaking fertility-preserving treatment.

Do I have to stop taking my current medications for this trial?

The trial protocol does not specify whether you need to stop taking your current medications. However, since the trial involves ovarian stimulation and oocyte retrieval, it's best to discuss your current medications with the trial team or your doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research has shown that both letrozole and tamoxifen are safely used in fertility treatments for breast cancer patients. Studies have found that combining letrozole with hormones that stimulate the ovaries does not significantly increase the risk of cancer recurrence. This combination is generally well-tolerated and considered safe for women who wish to preserve their fertility.

Similarly, tamoxifen is safe for fertility preservation and does not negatively affect fertility treatment outcomes. Although it acts like estrogen, it does not increase the risk of uterine cancer. Overall, both treatments have strong safety records and are commonly used to help preserve fertility. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about using tamoxifen and letrozole for fertility preservation in breast cancer patients because these drugs offer a unique approach to tackling estrogen receptor-positive breast cancer while also safeguarding fertility. Unlike traditional chemotherapy which can impact fertility, these treatments work by manipulating hormone levels; tamoxifen blocks estrogen receptors, while letrozole reduces estrogen production. This dual action not only targets cancer cells more precisely but also allows women to undergo fertility preservation procedures like egg retrieval without the same risk of harm to their reproductive potential. This innovative approach could represent a significant advancement in maintaining quality of life for young breast cancer patients concerned about future fertility.

What evidence suggests that this trial's treatments could be effective for fertility preservation in breast cancer patients?

Research has shown that both letrozole and tamoxifen can help preserve fertility in breast cancer patients. In this trial, participants will receive either letrozole or tamoxifen alongside hormones that stimulate the ovaries. Letrozole has increased pregnancy rates to 75%, higher than some other methods, and helps prevent cancer recurrence by lowering estrogen levels. Tamoxifen can increase the number of mature eggs and embryos, with promising pregnancy rates of 74%. Both treatments offer good options for preserving fertility, each with distinct benefits. ^{1 3 6 7 8}

Who Is on the Research Team?

Mitchell Rosen, M.D.

Principal Investigator

University of California, San Francisco

Are You a Good Fit for This Trial?

This trial is for adults over 18 who have been newly diagnosed with breast cancer and wish to preserve fertility before starting chemotherapy. They must want to undergo ovarian stimulation and egg retrieval.

Inclusion Criteria

New breast cancer diagnosis

Has not yet begun chemotherapy

Desires to undergo ovarian stimulation and oocyte retrieval prior to cancer treatment

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Ovarian Stimulation

Participants undergo ovarian stimulation with either letrozole-gonadotropin or tamoxifen-gonadotropin to preserve fertility

Up to 2 weeks

Daily monitoring visits

Oocyte Retrieval

Oocytes are retrieved for cryopreservation after completion of the stimulation cycle

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after oocyte retrieval

4 weeks

What Are the Treatments Tested in This Trial?

Interventions

• Letrozole
• Tamoxifen

Trial Overview The study is testing the effectiveness of two drugs, Tamoxifen and Letrozole, in increasing the number of eggs retrieved for preservation from patients with estrogen-sensitive tumors before they start cancer treatment.

How Is the Trial Designed?

Group I: Randomized ER Positive Participants (Tamoxifen) Experimental Treatment 1 Intervention

Participants will receive 20 mg of tamoxifen with the first day of non-investigational gonadotropin (tamoxifen-gonadotropin) and stopped on the day of oocyte retrieval

Group II: Randomized ER Positive Participants (Letrozole) Experimental Treatment 1 Intervention

Participants will receive 5 mg of letrozole with the first day of non-investigational gonadotropin (letrozole-gonadotropin) and stopped on the day of oocyte retrieval.

Group III: ER Negative (ER-) Participants Active Control 1 Intervention

Participants whose disease is ER negative will be consented and used as a reference cohort and will receive no study related medication. The Gonadotropin received is non-investigational and part of usual care.

Letrozole is already approved in United States, European Union, Canada for the following indications:

Approved in United States as Femara for:

• Breast cancer in postmenopausal women
• Increasing the chance of ovulation in women with polycystic ovary syndrome

Approved in European Union as Letrozole for:

• Early breast cancer in postmenopausal women
• Advanced breast cancer in postmenopausal women

Approved in Canada as Letrozole for:

• Adjuvant treatment of postmenopausal women with hormone receptor-positive early breast cancer
• First-line treatment of postmenopausal women with hormone receptor-positive advanced breast cancer

Who Is Running the Clinical Trial?

University of California, San Francisco

Lead Sponsor

Trials

2,636

Recruited

19,080,000+

Published Research Related to This Trial

Letrozole has been fully approved by the FDA for treating postmenopausal women with hormone receptor-positive early breast cancer, showing a significant improvement in disease-free survival compared to tamoxifen, with a hazard ratio of 0.87 in the adjuvant trial.

While letrozole is effective, it is associated with a higher risk of bone fractures and myocardial infarction compared to tamoxifen, which has its own risks such as endometrial cancer and thromboembolic events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Approval summary: letrozole (Femara® tablets) for adjuvant and extended adjuvant postmenopausal breast cancer treatment: conversion of accelerated to full approval. Cohen, MH., Johnson, JR., Justice, R., et al.[2021]

In a study of 1086 women with early-stage breast cancer who were disease-free after 5 years of tamoxifen, those with more positive lymph nodes (N1 and N2) had significantly higher risks of recurrence and death, indicating the importance of lymph node status in predicting long-term outcomes.

The study provides annual breast cancer risk estimates for years 6 to 10 post-tamoxifen, which can help guide decisions about extended hormonal therapy, particularly for women with varying tumor and lymph node characteristics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Late risk of relapse and mortality among postmenopausal women with estrogen responsive early breast cancer after 5 years of tamoxifen. Kennecke, HF., Olivotto, IA., Speers, C., et al.[2022]

A novel ovarian stimulation protocol using letrozole and tamoxifen for fertility preservation in 40 women with estrogen-positive breast cancer resulted in an average of 11.78 collected oocytes and 9.72 vitrified oocytes, indicating effective oocyte retrieval.

The protocol demonstrated efficiency with a mean stimulation duration of 10.03 days and a mean estradiol level of 623.10, suggesting it is a safe option for women undergoing neoadjuvant chemotherapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A specific controlled ovarian stimulation (COS) protocol for fertility preservation in women with breast cancer undergoing neoadjuvant chemotherapy. Cavagna, F., Pontes, A., Cavagna, M., et al.[2022]

In a study of 5,187 postmenopausal women with early breast cancer, letrozole significantly improved disease-free survival (DFS) in patients younger than 60 years, but showed similar efficacy across all age groups, including those aged 70 and older.

There were no significant differences in toxicity or quality of life between letrozole and placebo in patients aged 70 and older, suggesting that letrozole can be safely considered for extended treatment in this age group after completing 5 years of tamoxifen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy, toxicity, and quality of life in older women with early-stage breast cancer treated with letrozole or placebo after 5 years of tamoxifen: NCIC CTG intergroup trial MA.17. Muss, HB., Tu, D., Ingle, JN., et al.[2022]

In a study of 118 breast cancer patients undergoing fertility preservation, letrozole and tamoxifen did not significantly affect the number of retrieved or mature oocytes compared to standard protocols, but there were notable differences in embryo quality.

Tamoxifen was associated with a lower rate of top-quality embryos (25% vs 39.4% in controls), and letrozole was linked to a higher abnormal fertilization rate (7.8% vs 3.6% in controls), suggesting potential negative impacts on fertilization and embryo quality during fertility preservation treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of letrozole or tamoxifen coadministered with a standard stimulation protocol on fertility preservation among breast cancer patients. Shulman, Y., Almog, B., Kalma, Y., et al.[2022]

In the BIG 1-98 trial, letrozole demonstrated a 19% reduction in the risk of disease-free survival events compared to tamoxifen, indicating its superior efficacy as an adjuvant therapy for early breast cancer.

Letrozole significantly reduced the risk of distant metastases (hazard ratio 0.73), establishing it as a standard treatment option for postmenopausal women with hormone-sensitive breast cancer.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The evolving role of letrozole in the adjuvant setting: first results from the large, phase III, randomized trial BIG 1-98. Monnier, A.[2022]

In a study involving 6182 postmenopausal women with hormone-receptor-positive breast cancer, sequential treatment with tamoxifen and letrozole did not significantly improve disease-free survival compared to letrozole monotherapy, indicating that letrozole alone may be sufficient for treatment.

The updated analysis showed no statistically significant difference in overall survival between letrozole and tamoxifen monotherapy, suggesting that both treatments have similar long-term outcomes, with adverse events consistent with previous reports.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. Mouridsen, H., Giobbie-Hurder, A., Goldhirsch, A., et al.[2022]

Letrozole is highly effective and well-tolerated as a neoadjuvant therapy for postmenopausal women with ER-positive early breast cancer, with 76.8% of patients showing an objective response.

The study suggests that an optimal treatment duration of 4 to 6 months is sufficient to achieve maximum response, with modest benefits observed if treatment is extended beyond this period.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Phase II trial with letrozole to maximum response as primary systemic therapy in postmenopausal patients with ER/PgR[+] operable breast cancer. Llombart-Cussac, A., Guerrero, Á., Galán, A., et al.[2022]

In a study of 4,922 postmenopausal women with hormone receptor-positive early breast cancer, letrozole significantly improved overall survival (OS) compared to tamoxifen, with an 18% reduction in the risk of death.

Letrozole also demonstrated better disease-free survival (DFS) and time to distant recurrence (TDR), indicating it is a more effective adjuvant treatment option for this patient group.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Analyses adjusting for selective crossover show improved overall survival with adjuvant letrozole compared with tamoxifen in the BIG 1-98 study. Colleoni, M., Giobbie-Hurder, A., Regan, MM., et al.[2022]

In a study of 907 postmenopausal women with advanced breast cancer, letrozole was found to be more effective than tamoxifen, showing a longer time to progression (TTP) in both younger (<70 years) and older (≥70 years) patients.

Letrozole also demonstrated a significantly higher objective response rate (ORR) in older patients (38% vs. 18% for tamoxifen), while the ORR in younger patients was similar for both treatments (26% for letrozole vs. 22% for tamoxifen).

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of first-line letrozole versus tamoxifen as a function of age in postmenopausal women with advanced breast cancer. Mouridsen, H., Chaudri-Ross, HA.[2018]

Citations

1. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC4880171/

Long-Term Safety of Letrozole and Gonadotropin ... This prospective non-randomized controlled study showed no increased recurrence risk in breast cancer patients who pursued fertility preservation via ...

2. sciencedirect.com sciencedirect.com/science/article/pii/S1472648325000859

Letrozole or tamoxifen co-administration during fertility ... Letrozole was also found to be effective in preventing cancer recurrence among post-menopausal women by drastically lowering oestrogen concentration (Loibl et ...

3. pubmed.ncbi.nlm.nih.gov pubmed.ncbi.nlm.nih.gov/26101247/

Fertility Preservation Success Subsequent to ... - PubMed Embryo cryopreservation after ovarian stimulation with the letrozole and follicle-stimulating hormone protocol preserves fertility in women with breast cancer.

4. academic.oup.com academic.oup.com/humrep/article/40/Supplement_1/deaf097.1073/8170422

P-769 Pregnancy outcomes after ovarian stimulation with or ... Pregnancy rates in the tamoxifen group were lower (56%) compared to letrozole (75%) and standard stimulation (70%). However, live birth rates were equal, ...

5. acsjournals.onlinelibrary.wiley.com acsjournals.onlinelibrary.wiley.com/doi/full/10.1002/cncr.33601

The impact of fertility preservation on the timing of breast ... FP after a breast cancer diagnosis delays the time to treatment by a small amount, but this delay does not lead to inferior IDFS or OS.

6. academic.oup.com academic.oup.com/humrep/article/32/5/1033/3054473

The safety and efficacy of controlled ovarian hyperstimulation ... A prudent approach to fertility preservation using COH in a woman with breast cancer would be to administer letrozole (5 mg/day) from Day 2 of stimulation, with ...

7. fertstert.org fertstert.org/article/S0015-0282(13)02996-8/fulltext

Safety and feasibility of performing two consecutive ovarian ... To investigate the safety and feasibility of performing two consecutive ovarian stimulation cycles with the use of letrozole protocol for fertility ...

8. ascopubs.org ascopubs.org/doi/abs/10.1200/JCO.2007.14.8700

Safety of Fertility Preservation by Ovarian Stimulation With ... Ovarian stimulation with gonadotropins and letrozole for the purpose of fertility preservation is unlikely to cause substantially increased recurrence risk.