Aromatase Inhibitor Therapy for Breast Cancer

(NAOMI Trial)

Recruiting at 1 trial location

Overseen By Research Nurse

Age: 18+

Sex: Female

Trial Phase: Phase 2

Sponsor: Dartmouth-Hitchcock Medical Center

Must be taking: Aromatase inhibitors

Must not be taking: Endocrine therapy

Disqualifiers: Pregnancy, Lactation, others

Stay on Your Current Meds You can continue your current medications while participating

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

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 1

Duration: 4-24 weeks

137 Participants Needed

Trial Summary

What is the purpose of this trial?

This is a single-arm, open-label study testing the effects of neoadjuvant therapy with the aromatase inhibitor letrozole in post-menopausal women with Stage I-III ER+, HER2- breast cancer. Eligible subjects will be treated with letrozole therapy for 4 to 24 weeks prior to surgical resection of the tumor. Tumor specimens obtained at baseline (diagnostic biopsy) and at surgery (surgical specimen) will be compared using molecular analyses. A subset of subjects will be asked to provide an optional research tumor biopsy prior to treatment for molecular analysis. Subjects will be evaluated for treatment adherence and provide feedback via survey questionnaires to identify potential causes of non-adherence.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, you cannot have had any endocrine therapy for cancer in the last 10 years, and other neoadjuvant therapies for breast cancer are not allowed.

What data supports the effectiveness of the drug Letrozole for breast cancer?

Research shows that Letrozole, an aromatase inhibitor, is more effective than tamoxifen in improving disease-free survival in postmenopausal women with early breast cancer. It is also more effective in treating metastatic breast cancer and in the neoadjuvant setting (before main treatment) compared to tamoxifen. ^{1 2 3 4 5}

Is letrozole safe for humans?

Letrozole is generally safe for humans, with most side effects being mild, such as hot flashes, joint pain, nausea, and fatigue. However, long-term use may lead to bone loss and increased fracture risk. ^{1 6 7 8 9}

How is the drug Letrozole unique in treating breast cancer?

Letrozole is a highly potent aromatase inhibitor (a drug that blocks estrogen production) that is more effective than tamoxifen in treating hormone-responsive breast cancer in postmenopausal women. It offers greater suppression of estrogen and is used both as an initial treatment and after tamoxifen therapy to improve disease-free survival. ^{1 2 10 11 12}

Research Team

Mary D. Chamberlin

Principal Investigator

Dartmouth-Hitchcock Medical Center

Eligibility Criteria

The NAOMI trial is for post-menopausal women over 18 with Stage I-III ER+ and HER2- breast cancer. Participants must have a tumor ≥1cm, not received prior endocrine therapy for any cancer, and meet specific blood criteria. Pregnant or lactating women are excluded.

Inclusion Criteria

Ability to give informed consent

Your blood tests show a normal level of white blood cells and platelets, and your liver function is within normal limits.

Your tumor must be at least 1 centimeter in size to provide enough tissue for testing.

Exclusion Criteria

Pregnant or lactating women

I have received hormone therapy for cancer.

I am receiving initial treatment for breast cancer, but I can take bisphosphonates for bone symptoms.

Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive neoadjuvant letrozole therapy for 4 to 24 weeks prior to surgical resection of the tumor

4-24 weeks

Regular visits for treatment adherence and feedback

Surgery

Surgical resection of the tumor is performed after neoadjuvant therapy

1 day

1 visit (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment, including assessments at 1 year and 3 years post-surgery

3 years

Periodic visits for assessments

Treatment Details

Interventions

• Letrozole

Trial Overview This study tests Letrozole as pre-surgery treatment in eligible women to see how the drug affects their breast tumors. It involves taking Letrozole for 4 to 12 weeks before surgery, with molecular analysis of tumor samples before and after treatment.

Participant Groups

Group I: Treatment Experimental Treatment 1 Intervention

Letrozole 2.5mg tablet administered once daily for 4 to \~12 weeks (window of + 4 weeks for surgical scheduling flexibility) final dose taken the day of surgery.

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?

Dartmouth-Hitchcock Medical Center

Lead Sponsor

Trials

548

Recruited

2,545,000+

Findings from Research

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]

In a study involving 8010 postmenopausal women with hormone-receptor-positive breast cancer, letrozole significantly improved disease-free survival compared to tamoxifen, with a 5-year survival rate of 84.0% versus 81.4%.

Letrozole reduced the risk of disease recurrence, particularly distant recurrence, by 19% compared to tamoxifen, although it was associated with a higher incidence of skeletal and cardiac events.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. Thürlimann, B., Keshaviah, A., Coates, AS., et al.[2022]

Letrozole is an effective and well-tolerated aromatase inhibitor used to treat metastatic breast cancer in postmenopausal women, with confirmed efficacy in both adjuvant and neoadjuvant settings based on clinical trials.

The review highlights the potential for future advancements in treatment by combining letrozole with new biologic agents and personalizing therapy through gene expression profiling.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole. Dellapasqua, S., Colleoni, M.[2018]

In a study of 40 postmenopausal women with locally advanced breast cancer, both Letrozole and Tamoxifen were found to be effective as neoadjuvant hormone therapies, with 25% of patients on Tamoxifen and 20% on Letrozole not achieving a complete response, leading to subsequent radiotherapy.

The study indicated that neoadjuvant hormone therapy was generally well-tolerated, with side effects occurring in 55% of patients on Letrozole and 60% on Tamoxifen, suggesting that these treatments could improve clinical outcomes and allow for successful radical mastectomy in patients with better prognoses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Letrozole vs. tamoxifen as neoadjuvant therapy for postmenopausal patients with hormone-dependent locally-advanced breast cancer]. Novoa Vargas, A., Font López, KC., Amador, DD.[2018]

In a study of 3887 post-menopausal patients with hormone receptor-positive early breast cancer, over 85% persisted with letrozole treatment for 12 months, but 14.6% discontinued, primarily due to side effects.

Musculoskeletal symptoms and sleep disorders were the most significant adverse events leading to treatment discontinuation, with hazard ratios of 2.55 and 1.95, respectively, indicating a strong need for targeted compliance programs to support patients experiencing these issues.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Influence of side-effects on early therapy persistence with letrozole in post-menopausal patients with early breast cancer: Results of the prospective EvAluate-TM study. Nabieva, N., Fehm, T., Häberle, L., 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]

Anastrozole and letrozole are effective oral treatments for advanced breast cancer in postmenopausal women, especially when other therapies like tamoxifen have not worked.

Both drugs are claimed to be more effective and less toxic than the standard treatment, megestrol acetate, although the review assesses the validity of these claims.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

New aromatase inhibitors for breast cancer. [2019]

Letrozole is a new non-steroidal aromatase inhibitor approved in Japan for treating postmenopausal women with breast cancer, particularly effective for those with steroid receptor positive or receptor-unknown locally advanced or metastatic cases.

The drug is generally well-tolerated, with mostly mild side effects such as hot flashes and fatigue, and has shown beneficial results in large international studies for post-surgical endocrine therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

[Introduction of new drug: letrozole, a new non-steroidal aromatase inhibitor for the treatment of postmenopausal women with breast cancer]. Tsukagoshi, S.[2018]

In a study of 1065 postmenopausal women with early breast cancer receiving letrozole, immediate treatment with zoledronic acid significantly increased lumbar spine bone mineral density (BMD) by 5.7% compared to a delayed treatment strategy, which resulted in bone loss.

Both immediate and delayed zoledronic acid regimens were well tolerated, but the immediate group experienced more bone pain due to acute-phase reactions, highlighting the need for monitoring during treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST Study results. Bundred, NJ., Campbell, ID., Davidson, N., et al.[2022]

Letrozole is more effective than tamoxifen for adjuvant therapy in postmenopausal women with hormone-responsive early breast cancer, and it is well tolerated by patients.

Extended therapy with letrozole after tamoxifen treatment is more effective than placebo, making it a valuable treatment option while ongoing trials investigate the best duration and comparison with other aromatase inhibitors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Letrozole: a review of its use in the treatment of postmenopausal women with hormone-responsive early breast cancer. Keating, GM.[2021]

Letrozole is a highly potent third-generation aromatase inhibitor that effectively blocks estrogen production, showing greater potency and selectivity compared to other aromatase inhibitors like anastrozole and exemestane.

Clinical trials have demonstrated that letrozole provides significant benefits for postmenopausal women with hormone-responsive breast cancer, outperforming the previous standard treatment, tamoxifen.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The discovery and mechanism of action of letrozole. Bhatnagar, AS.[2022]

Aromatase inhibitors like anastrozole, letrozole, and exemestane are now the preferred hormonal treatments for estrogen-receptor-positive, postmenopausal metastatic breast cancer, replacing older therapies such as tamoxifen.

Recent studies have confirmed the effectiveness of these aromatase inhibitors in managing breast cancer, highlighting their critical role in targeting the hormonal pathways involved in the disease's progression.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Nonsteroidal and steroidal aromatase inhibitors in breast cancer. Hamilton, A., Volm, M.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. [2022]

3. England pubmed.ncbi.nlm.nih.gov

Letrozole. [2018]

4. Mexico pubmed.ncbi.nlm.nih.gov

[Letrozole vs. tamoxifen as neoadjuvant therapy for postmenopausal patients with hormone-dependent locally-advanced breast cancer]. [2018]

5. England pubmed.ncbi.nlm.nih.gov

Influence of side-effects on early therapy persistence with letrozole in post-menopausal patients with early breast cancer: Results of the prospective EvAluate-TM study. [2022]

6. Netherlands 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. [2022]

7. England pubmed.ncbi.nlm.nih.gov

New aromatase inhibitors for breast cancer. [2019]

8. Japan pubmed.ncbi.nlm.nih.gov

[Introduction of new drug: letrozole, a new non-steroidal aromatase inhibitor for the treatment of postmenopausal women with breast cancer]. [2018]

9. United States pubmed.ncbi.nlm.nih.gov

Effective inhibition of aromatase inhibitor-associated bone loss by zoledronic acid in postmenopausal women with early breast cancer receiving adjuvant letrozole: ZO-FAST Study results. [2022]

10. New Zealand pubmed.ncbi.nlm.nih.gov

Letrozole: a review of its use in the treatment of postmenopausal women with hormone-responsive early breast cancer. [2021]

11. Netherlands pubmed.ncbi.nlm.nih.gov

The discovery and mechanism of action of letrozole. [2022]

12. United States pubmed.ncbi.nlm.nih.gov

Nonsteroidal and steroidal aromatase inhibitors in breast cancer. [2018]