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Letrozole (Monograph)

Brand name: Femara
Drug class: Antiestrogens
- Aromatase Inhibitors
VA class: AN900
Chemical name: 4,4′-(1H-1,2,4-triazol-1-ylmethylene)bis-benzonitrile
Molecular formula: C17H11N5
CAS number: 112809-51-5

Medically reviewed by Drugs.com on May 25, 2023. Written by ASHP.

Introduction

Antineoplastic agent; selective aromatase inhibitor.1 2 3 6 11 13 15

Uses for Letrozole

Initial, Sequential, or Extended Adjuvant Therapy for Postmenopausal Women with Early-Stage Hormone Receptor-Positive Breast Cancer

Adjuvant treatment in postmenopausal women with early-stage hormone receptor-positive breast cancer.1 39 40 41 52 82 10029 10053

Extended adjuvant treatment in postmenopausal women with early-stage breast cancer who have received 5 years of adjuvant tamoxifen therapy.1 25 50 Efficacy of letrozole as extended adjuvant therapy based on analysis of disease-free survival in patients receiving the drug for a median of 5 years.1

ASCO states that postmenopausal women with node-positive hormone receptor-positive breast cancer should be offered extended adjuvant endocrine therapy with one of the following: aromatase inhibitor therapy for up to a total of 10 years; tamoxifen for 10 years; tamoxifen for 5 years, then an aromatase inhibitor for 5 years; or tamoxifen for 2–3 years, then an aromatase inhibitor for 7–8 years.10019 Women with node-negative breast cancer may also be offered extended adjuvant endocrine therapy for up to a total of 10 years, but benefits are likely narrower due to lower risk for recurrence.10019

Consider adverse effects, patient preference, and preexisting conditions when selecting an adjuvant regimen; during the course of adjuvant therapy, patients who are intolerant of one treatment may be switched to a different treatment.10075

Adjuvant Therapy for Early-Stage Breast Cancer in Premenopausal Women

Use of endocrine therapy (i.e., anastrozole, exemestane, letrozole, tamoxifen) in combination with ovarian suppression† [off-label] as adjuvant therapy in premenopausal women† [off-label] with early-stage hormone receptor-positive breast cancer may be considered a reasonable choice (accepted).10010 10011 10012 10013 10023 10026 10028

Advanced Breast Cancer in Postmenopausal Women

First-line therapy for hormone receptor-positive or hormone receptor-unknown locally advanced or metastatic breast cancer in postmenopausal women.1 20 21

Second-line therapy for advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy (e.g., tamoxifen).1 7 8 19 22 84

In combination with lapatinib for treatment of hormone receptor-positive metastatic breast cancer that overexpresses the human epidermal growth factor receptor type 2 (HER2) protein in postmenopausal women who are candidates for hormonal therapy.44 49 53

In combination with ribociclib for initial treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in postmenopausal women.75 76 78 81

According to ASCO, combination therapy with a nonsteroidal aromatase inhibitor (e.g., letrozole, anastrozole) and a cyclin-dependent kinase (CDK) 4/6 inhibitor should be offered first line to postmenopausal patients with treatment-naive hormone receptor-positive metastatic breast cancer; for some patients, monotherapy with an aromatase inhibitor may be appropriate.4000 Choice of second-line hormonal therapy should take into account prior treatment exposure and response to previous endocrine therapy; options for second-line therapy include tamoxifen, an aromatase inhibitor, or fulvestrant with or without everolimus.4000

Advanced Breast Cancer in Pre-/Perimenopausal Women and Men

In combination with ribociclib and a gonadotropin-releasing hormone (GnRH) agonist for the initial treatment of hormone receptor-positive, HER2-negative advanced or metastatic breast cancer in adult patients, including pre-/perimenopausal women and men.76 80

For first-line treatment of most premenopausal women, ASCO recommends combination therapy with a nonsteroidal aromatase inhibitor (e.g., letrozole, anastrozole) and a CDK 4/6 inhibitor, in conjunction with chemical ovarian function suppression.4000 Ovarian suppression or ablation in combination with hormonal therapy should be offered to premenopausal women with metastatic hormone receptor-positive breast cancer; patients without prior exposure to hormonal therapy may be treated with tamoxifen or ovarian suppression/ablation alone, but combination therapy is preferred.4000 In men with advanced or metastatic hormone receptor-positive, HER2-negative breast cancer, ASCO recommends endocrine therapy (i.e., tamoxifen, an aromatase inhibitor combined with a GnRH agonist, or fulvestrant) first line except in cases of visceral crisis or rapidly progressing disease; as in women, CDK 4/6 inhibitors may be used with endocrine therapy.10056

Letrozole Dosage and Administration

General

Pretreatment Screening

Patient Monitoring

Dispensing and Administration Precautions

Administration

Oral Administration

Administer orally once daily without regard to meals.1

Dosage

Adults

Breast Cancer
> Initial, Sequential, or Extended Adjuvant Therapy for Postmenopausal Women with Early-Stage Hormone Receptor-Positive Breast Cancer
Oral

2.5 mg once daily.1 25 Discontinue if relapse occurs.1 25

Initial adjuvant therapy: Median duration of treatment in clinical study was 5 years.1 Optimal duration unknown.1

Extended adjuvant therapy: Initiate letrozole after completion of 5 years of adjuvant tamoxifen therapy.1 25 41 Median duration of letrozole treatment in clinical study was 5 years;1 71% of patients completed ≥3 years and 58% completed ≥4.5 years of treatment.1 Optimal duration unknown.1 25

ASCO states that postmenopausal women with node-positive hormone receptor-positive early breast cancer should be offered extended adjuvant endocrine therapy with one of the following: aromatase inhibitor therapy for up to a total of 10 years; tamoxifen for 10 years; tamoxifen for 5 years, then an aromatase inhibitor for 5 years; or tamoxifen for 2–3 years, then an aromatase inhibitor for 7–8 years.10019 Women with node-negative breast cancer may also be offered extended adjuvant endocrine therapy for up to a total of 10 years, although benefits are likely narrower due to lower risk for recurrence.10019

Adjuvant Therapy for Early-stage Breast Cancer in Premenopausal Women† [off-label]
Oral

2.5 mg once daily for 5 years has been used in combination with ovarian suppression† [off-label].10026

Advanced Breast Cancer in Postmenopausal Women
Oral

2.5 mg once daily.1 Continue therapy until tumor progresses.1

Advanced Breast Cancer in Pre-/Perimenopausal Women and Men
Oral

2.5 mg once daily in combination with ribociclib.76 These patients should also be treated with a luteinizing hormone-releasing hormone (LHRH) according to current clinical practice standards.76

Special Populations

Hepatic Impairment

Cirrhosis and severe hepatic impairment (Child-Pugh class C): Decrease dosage to 2.5 mg every other day.1

Mild to moderate hepatic impairment: No dosage adjustment recommended.1

Renal Impairment

Clcr ≥10 mL/minute: No dosage adjustment necessary.1

Geriatric Patients

No dosage adjustment necessary.1

Detailed Letrozole dosage information

Cautions for Letrozole

Contraindications

Warnings/Precautions

Bone Effects

May cause reduction in bone mineral density (BMD).1 In the adjuvant studies, decreases in BMD at the lumbar spine and hip were greater among patients receiving letrozole compared to patients receiving tamoxifen.1 Osteoporosis and fractures occurred more frequently among patients receiving letrozole compared to patients receiving tamoxifen.1

Consider BMD monitoring in patients receiving letrozole.1

Cholesterol

Hypercholesterolemia and use of antilipemic agents reported more frequently in patients receiving letrozole versus tamoxifen as initial adjuvant therapy.1

Consider cholesterol monitoring in patients receiving letrozole.1

Hepatic Impairment

Patients with cirrhosis and severe hepatic impairment experienced twice the exposure to letrozole as healthy volunteers with normal liver function.1 Dosage reduction recommended in this population.1

Effect of hepatic impairment on letrozole exposure in cancer patients with elevated bilirubin levels not determined.1

Fatigue and Dizziness

Fatigue, dizziness, and somnolence reported.1 Caution advised when driving or using machinery.1

Laboratory Test Abnormalities

Moderate decreases in lymphocyte counts observed in some patients, but of uncertain clinical importance and transient in about half of those affected.1

Thrombocytopenia reported but causality is unclear.1

Fetal/Neonatal Morbidity and Mortality

May cause fetal harm.1 Embryotoxic, fetotoxic, and teratogenic in animals.1 Contraindicated in pregnancy.1 Test for pregnancy prior to initiation of the drug.1 Advise females of reproductive potential to use effective contraceptive methods during therapy and for ≥3 weeks after discontinuance of the drug.1 If used during pregnancy or patient becomes pregnant, apprise of fetal hazard.1

Specific Populations

Pregnancy

May cause fetal harm.1 Embryotoxic, fetotoxic, and teratogenic in animals.1 Spontaneous abortion and congenital birth defects reported during postmarketing experience in pregnant women, but data are insufficient to inform a drug-associated risk of adverse pregnancy-related outcomes.1

Contraindicated in pregnancy.1 Test for pregnancy prior to initiation of the drug.1 If used during pregnancy or patient becomes pregnant, apprise of fetal hazard.1

Lactation

Not known whether letrozole is distributed into human milk; effects on nursing infant and milk production also unknown.1 Discontinue nursing during therapy and for ≥3 weeks after drug discontinuance.1

Females and Males of Reproductive Potential

May cause fetal harm.1 Contraindicated in pregnancy.1 Test for pregnancy prior to initiation of the drug.1 Advise females of reproductive potential to use effective contraceptive methods during therapy and for ≥3 weeks after discontinuance of the drug.1

May impair female and male fertility.1

Pediatric Use

Safety and efficacy not established in pediatric patients.1

Geriatric Use

Initial adjuvant therapy in postmenopausal women: 36% of study patients were ≥65 years of age and 12% were ≥75 years of age.1 Adverse effects generally more common in geriatric patients regardless of their assigned study treatment; however, no overall differences in safety and efficacy of letrozole versus tamoxifen were observed between geriatric patients and younger adults.1

Extended adjuvant therapy in postmenopausal women: 41% of study patients were ≥65 years of age and 12% were ≥75 years of age.1 No substantial differences in safety and efficacy relative to younger adults, but increased sensitivity cannot be ruled out.1

First- and second-line treatment in postmenopausal women: Median patient age in all studies was 64–65 years; one-third were ≥70 years of age.1 In the first-line clinical study, patients ≥70 years of age experienced longer time to tumor progression and higher response rates than patients <70 years of age.1

Hepatic Impairment

Dosage reduction recommended in patients with cirrhosis and severe hepatic impairment.1 Effect of hepatic impairment on drug exposure in noncirrhotic cancer patients with increased bilirubin concentrations not determined.1

Renal Impairment

Letrozole pharmacokinetics not altered in individuals with varying renal function.1 No dosage adjustment is necessary in patients with Clcr ≥10 mL/minute.1

Common Adverse Effects

Adverse effects occurring in >20% of patients: hot flashes, arthralgia, flushing, asthenia, edema, headache, dizziness, hypercholesterolemia, increased sweating, bone pain, and musculoskeletal effects.1

Drug Interactions

Metabolized by CYP3A4 and CYP2A6.1 Inhibits CYP2A6 and, to a lesser extent, CYP2C19 in vitro.1

Specific Drugs

Drug

Interaction

Comments

Antineoplastic agents

No clinical experience with concomitant use to date1

Cimetidine

No clinically important effect on letrozole pharmacokinetics1

Estrogens

Antagonistic pharmacologic effects14 37

Concomitant use not recommended14 37

Tamoxifen

Decreased plasma letrozole concentrations1

Therapeutic effect of letrozole not impaired if used immediately after tamoxifen1

Warfarin

No clinically important effects on warfarin pharmacokinetics1
Letrozole drug interactions (more detail)

Letrozole Pharmacokinetics

Absorption

Bioavailability

Rapidly and completely absorbed after oral administration.1

Onset

Plasma estradiol, estrone, and estrone sulfate reduced by 75–95% within 2–3 days with daily dosages of 0.1–5 mg.1

Duration

Estrogen suppression maintained throughout therapy in patients receiving ≥0.5 mg daily.1

Food

Food does not affect absorption.1

Distribution

Extent

Not known if distributed into milk.1

Plasma Protein Binding

Weakly bound.1

Elimination

Metabolism

Principally metabolized to inactive carbinol metabolite by CYP3A4 and CYP2A6.1

Elimination Route

Excreted in urine as glucuronide of carbinol metabolite (≥75%), unidentified metabolites (about 9%), and unchanged drug (6%).1

Half-life

2 days.1

Special Populations

Renal function did not affect the pharmacokinetics of a single 2.5-mg dose in adults with varying renal function.1 Renal impairment (Clcr 20–50 mL/minute) did not affect steady-state plasma concentrations in patients with advanced breast cancer.1

AUC was increased twofold and clearance was decreased in adults with cirrhosis and severe hepatic impairment (Child-Pugh class C); higher letrozole concentrations are expected in breast cancer patients with severe hepatic impairment compared with patients with normal liver function.1

AUC was increased (37%) in adults with moderate hepatic impairment (e.g., cirrhosis, Child-Pugh class A and B); drug exposure was within range observed in patients without hepatic impairment.1

No age-related differences in pharmacokinetics observed in patients ranging from 35 to >80 years of age.1 Age-related differences between adults and children or race-related differences in the pharmacokinetics of letrozole not evaluated.1

Stability

Storage

Oral

Tablets

20–25°C (excursions permitted between 15–30°C).1

Actions

Advice to Patients

Additional Information

The American Society of Health-System Pharmacists, Inc. represents that the information provided in the accompanying monograph was formulated with a reasonable standard of care, and in conformity with professional standards in the field. Readers are advised that decisions regarding use of drugs are complex medical decisions requiring the independent, informed decision of an appropriate health care professional, and that the information contained in the monograph is provided for informational purposes only. The manufacturer’s labeling should be consulted for more detailed information. The American Society of Health-System Pharmacists, Inc. does not endorse or recommend the use of any drug. The information contained in the monograph is not a substitute for medical care.

Preparations

Excipients in commercially available drug preparations may have clinically important effects in some individuals; consult specific product labeling for details.

Please refer to the ASHP Drug Shortages Resource Center for information on shortages of one or more of these preparations.

* available from one or more manufacturer, distributor, and/or repackager by generic (nonproprietary) name

Letrozole

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Tablets, film-coated

2.5 mg*

Femara

Novartis

Letrozole Tablets
Letrozole Combinations

Routes

Dosage Forms

Strengths

Brand Names

Manufacturer

Oral

Kit

Letrozole 2.5 mg (28 film-coated tablets)

Ribociclib succinate 200 mg (of ribociclib) (21, 42, or 63 film-coated tablets)

Kisqali Femara Co-Pack

Novartis

AHFS DI Essentials™. © Copyright 2024, Selected Revisions May 25, 2023. American Society of Health-System Pharmacists, Inc., 4500 East-West Highway, Suite 900, Bethesda, Maryland 20814.

† Off-label: Use is not currently included in the labeling approved by the US Food and Drug Administration.

References

1. Novartis. Femara (letrozole) tablets prescribing information. East Hanover, NJ; 2020 May. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=82b77d74-085f-45ac-a7dd-1f5c038bf406

2. Ingle JN, Johnson PA, Suman VJ et al. A randomized phase II trial of two dosage levels of letrozole as third-line hormonal therapy for women with metastatic breast carcinoma. Cancer. 1997; 80:218-24. http://www.ncbi.nlm.nih.gov/pubmed/9217033?dopt=AbstractPlus

3. Lonning PE. Aromatase inhibition for breast cancer treatment. Acta Oncol. 1996; 35(Suppl 5):38-43. http://www.ncbi.nlm.nih.gov/pubmed/9142963?dopt=AbstractPlus

4. Higa GM, AlKhouri N. Anastrazole: a selective aromatase inhibitor for the treatment of breast cancer. Am J Health-Syst Pharm. 1998; 55:445-52. http://www.ncbi.nlm.nih.gov/pubmed/9522927?dopt=AbstractPlus

5. Winer EP, Morrow M, Osborne CK et al. Malignant tumors of the breast. In: DeVita VT Jr, Hellman S, Rosenberg SA eds. Cancer: principles and practice of oncology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2001:1651-717.

6. Iveson TJ, Smith IE, Ahern J et al. Phase I study of the oral nonsteroidal aromatase inhibitor CGS 20267 in postmenopausal patients with advanced breast cancer. Cancer Res. 1993; 53:266-70. http://www.ncbi.nlm.nih.gov/pubmed/8417819?dopt=AbstractPlus

7. Dombernowsky P, Smith I, Falkson G et al. Letrozole, a new oral aromatase inhibitor for advanced breast cancer: double-blind randomized trial showing a dose effect and improved efficacy and tolerability compared with megestrol acetate. J Clin Oncol. 1998; 16:453-61. http://www.ncbi.nlm.nih.gov/pubmed/9469328?dopt=AbstractPlus

8. Gershanovich M, Chaudri HA, Campos D et al. Letrozole, a new oral aromatase inhibitor: randomised trial comparing 2.5 mg daily, 0.5 mg daily and aminoglutethimide in postmenopausal women with advanced breast cancer. Letrozole International Trial Group (AR/BC3). Ann Oncol. 1998; 9:639-45. http://www.ncbi.nlm.nih.gov/pubmed/9681078?dopt=AbstractPlus

9. Breast cancer. From: PDQ. Physician data query (database). Bethesda, MD: National Cancer Institute; 2011 Nov 21.

10. Anon. Toremifene and letrozole for advanced breast cancer. Med Lett Drugs Ther. 1998; 40:43-5. http://www.ncbi.nlm.nih.gov/pubmed/9580744?dopt=AbstractPlus

11. Bisagni G, Scaglione F et al. Letrozole, a new non-steroidal aromatase inhibitor in treating postmenopausal patients with advanced breast cancer. A pilot study. Ann Oncol. 1996; 7:99-102.

12. Bhatnagar AS, Hausler A, Schieweck K et al. Highly selective inhibition of estrogen biosynthesis by CGS 20267, a new non-steroidal aromatase inhibitor. J Steroid Biochem Mol Biol. 1990; 37:1021-7. http://www.ncbi.nlm.nih.gov/pubmed/2149502?dopt=AbstractPlus

13. Ibrahim NK, Budar AU. Aromatase inhibitors: current status. Am J Clin Oncol. 1995; 18:407-17. http://www.ncbi.nlm.nih.gov/pubmed/7572758?dopt=AbstractPlus

14. Novartis, East Hanover, NJ: Personal communication.

15. Smith IE. Pivotal trials of letrozole: a new aromatase inhibitor. Oncology. 1998; 12(Suppl 5):41-4. http://www.ncbi.nlm.nih.gov/pubmed/9556791?dopt=AbstractPlus

16. Food and Drug Administration. Labeling and prescription drug advertising; content and format for labeling for human prescription drugs. 21 CFR Parts 201 and 202. Final Rule. [Docket No. 75N-0066] Fed Regist. 1979; 44:37434-67.

17. Department of Health and Human Services, Food and Drug Administration. Subpart B—Labeling requirements for prescription drugs and/or insulin. (21 CFR Ch. 1 (4-1-87 Ed.)). 1987:18-24.

18. Anon. Drugs of choice for cancer. Treat Guidel Med Lett. 2003; 1:41-52. http://www.ncbi.nlm.nih.gov/pubmed/15529105?dopt=AbstractPlus

19. Food and Drug Administration. Center for Drug Evaluation and Research: Application number 020726: Medical Reviews. From FDA web site. http://www.accessdata.fda.gov/drugsatfda_docs/nda/97/020726_femara_toc.cfm

20. Mouridsen H, Gershanovich M, Sun Y et al. Superior efficacy of letrozole versus tamoxifen as first-line therapy for postmenopausal women with advanced breast cancer: results of a phase III study of the International Letrozole Breast Cancer Group. J Clin Oncol. 2001; 19:2596-606. http://www.ncbi.nlm.nih.gov/pubmed/11352951?dopt=AbstractPlus

21. Mouridsen H, Gershanovich M, Sun Y et al. Phase III study of letrozole versus tamoxifen as first-line therapy of advanced breast cancer in postmenopausal women: analysis of survival and update of efficacy from the International Letrozole Breast Cancer Group. J Clin Oncol. 2003; 21:2101-9. http://www.ncbi.nlm.nih.gov/pubmed/12775735?dopt=AbstractPlus

22. Buzdar A, Douma J, Davidson N et al. Phase III, multicenter, double-blind, randomized study of letrozole, an aromatase inhibitor, for advanced breast cancer versus megestrol acetate. J Clin Oncol. 2001; 19:3357-66. http://www.ncbi.nlm.nih.gov/pubmed/11454883?dopt=AbstractPlus

23. Dowsett M, Pfister C, Johnston SR et al. Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer. Clin Cancer Res. 1999; 5:2338-43. http://www.ncbi.nlm.nih.gov/pubmed/10499602?dopt=AbstractPlus

24. Ingle JN, Suman VJ, Johnson PA et al. Evaluation of tamoxifen plus letrozole with assessment of pharmacokinetic interaction in postmenopausal women with metastatic breast cancer. Clin Cancer Res. 1999; 5:1642-9. http://www.ncbi.nlm.nih.gov/pubmed/10430063?dopt=AbstractPlus

25. Goss PE, Ingle JN, Martino S et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003; 349: 1793-802. http://www.ncbi.nlm.nih.gov/pubmed/14551341?dopt=AbstractPlus

26. Winer EP, Hudis C, Burstein HJ et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for women with hormone receptor-positive breast cancer: status report 2002. J Clin Oncol. 2002; 20:3317-27. http://www.ncbi.nlm.nih.gov/pubmed/12149306?dopt=AbstractPlus

27. Bryant J, Wolmark N. Letrozole after tamoxifen for breast cancer;—what is the price of success? N Engl J Med. 2003; 349:1855-7. Editorial.

28. Burstein HJ. Beyond tamoxifen—extending endocrine treatment for early-stage breast cancer. N Engl J Med. 2003; 349:1857-9. http://www.ncbi.nlm.nih.gov/pubmed/14551340?dopt=AbstractPlus

29. Hilner BE, Ingle JN, Chelbowski RT et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol. 2003; 21:4042-57. http://www.ncbi.nlm.nih.gov/pubmed/12963702?dopt=AbstractPlus

30. Mackey JR, Joy AA. Letrozole in second-line therapy of advanced breast cancer: more questions than answers. J Clin Oncol. 2001; 19:4353-4. http://www.ncbi.nlm.nih.gov/pubmed/11731524?dopt=AbstractPlus

31. Buzdar AU, Chaudri HA, Trunet PF. Letrozole: which dose to be used? J Clin Oncol. 2000; 18:1802-3. Letter.

32. Simpson D, Curran MP, Perry CM. Letrozole: a review of its use in postmenopausal women with breast cancer. Drugs. 2004; 641:1213-30.

33. Geisler J, Haynes B, Anker G et al. Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol. 2002; 20:751-7. http://www.ncbi.nlm.nih.gov/pubmed/11821457?dopt=AbstractPlus

34. Rose C, Vtoraya O, Pluzanska A et al. An open randomised trial of second-line endocrine therapy in advanced breast cancer: comparison of the aromatase inhibitors letrozole and anastrozole. Eur J Cancer. 2003; 39:2318-27. http://www.ncbi.nlm.nih.gov/pubmed/14556923?dopt=AbstractPlus

35. Twombly R. Critics question price of success in halted clinical trial of aromatase inhibitor letrozole. J Natl Cancer Inst. 2003; 95:1738-9. http://www.ncbi.nlm.nih.gov/pubmed/14652229?dopt=AbstractPlus

36. Sperone P, Gorzegno G, Berruti A et al. Reversible pancytopenia caused by oral letrozole assumption in a patient with recurrent breast cancer. J Clin Oncol. 2002; 20:3747-8. http://www.ncbi.nlm.nih.gov/pubmed/12202678?dopt=AbstractPlus

37. Reviewers’ comments (personal observations).

38. Gilardi J, Fox K (Novartis). Femara gains U.S. FDA approval as only post-tamoxifen treatment for early breast cancer. Basel, Switzerland; 2004 Oct 29. Press release.

39. BIG 1-98 Collaborative Group, Mouridsen H, Giobbie-Hurder A et al. Letrozole therapy alone or in sequence with tamoxifen in women with breast cancer. N Engl J Med. 2009; 361:766-76. http://www.ncbi.nlm.nih.gov/pubmed/19692688?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2921823&blobtype=pdf

40. Breast International Group (BIG) 1-98 Collaborative Group, Thürlimann B, Keshaviah A et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005; 353:2747-57. http://www.ncbi.nlm.nih.gov/pubmed/16382061?dopt=AbstractPlus

41. Burstein HJ, Prestrud AA, Seidenfeld J et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol. 2010; 28:3784-96. http://www.ncbi.nlm.nih.gov/pubmed/20625130?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=5569672&blobtype=pdf

42. Wasan KM, Goss PE, Pritchard PH et al. The influence of letrozole on serum lipid concentrations in postmenopausal women with primary breast cancer who have completed 5 years of adjuvant tamoxifen (NCIC CTG MA.17L). Ann Oncol. 2005; 16:707-15. http://www.ncbi.nlm.nih.gov/pubmed/15817595?dopt=AbstractPlus

43. Perez EA, Josse RG, Pritchard KI et al. Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: a companion study to NCIC CTG MA.17. J Clin Oncol. 2006; 24:3629-35. http://www.ncbi.nlm.nih.gov/pubmed/16822845?dopt=AbstractPlus

44. Johnston S, Pippen J, Pivot X et al. Lapatinib combined with letrozole versus letrozole and placebo as first-line therapy for postmenopausal hormone receptor-positive metastatic breast cancer. J Clin Oncol. 2009; 27:5538-46. http://www.ncbi.nlm.nih.gov/pubmed/19786658?dopt=AbstractPlus

48. Rabaglio M, Sun Z, Price KN et al. Bone fractures among postmenopausal patients with endocrine-responsive early breast cancer treated with 5 years of letrozole or tamoxifen in the BIG 1-98 trial. Ann Oncol. 2009; 20:1489-98. http://www.ncbi.nlm.nih.gov/pubmed/19474112?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=2731016&blobtype=pdf

49. GlaxoSmithKline. Tykerb (lapatinib) prescribing information. Research Triangle Park, NC; 2022 Mar. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=eee37f88-ec6a-4c30-b8aa-e2c71f93088c

50. Ingle JN, Tu D, Pater JL et al. Intent-to-treat analysis of the placebo-controlled trial of letrozole for extended adjuvant therapy in early breast cancer: NCIC CTG MA.17. Ann Oncol. 2008; 19:877-82. http://www.ncbi.nlm.nih.gov/pubmed/18332043?dopt=AbstractPlus

51. Letrozole in treating women with primary breast cancer who have received 5 years of aromatase inhibitor therapy. Clinical Trials (PDQ) (database). Bethesda, MD: National Cancer Institute; 2012 Apr 25. http://www.cancer.gov/clinicaltrials/search/view?cdrid=614819&version=HealthProfessional

52. Regan MM, Neven P, Giobbie-Hurder A et al. Assessment of letrozole and tamoxifen alone and in sequence for postmenopausal women with steroid hormone receptor-positive breast cancer: the BIG 1-98 randomised clinical trial at 8•1 years median follow-up. Lancet Oncol. 2011; 12:1101-8. http://www.ncbi.nlm.nih.gov/pubmed/22018631?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3235950&blobtype=pdf

53. Schwartzberg LS, Schwarzberg LS, Franco SX et al. Lapatinib plus letrozole as first-line therapy for HER-2+ hormone receptor-positive metastatic breast cancer. Oncologist. 2010; 15:122-9. http://www.ncbi.nlm.nih.gov/pubmed/20156908?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=3227947&blobtype=pdf

70. Hadji P, Aapro MS, Body JJ et al. Management of aromatase inhibitor-associated bone loss in postmenopausal women with breast cancer: practical guidance for prevention and treatment. Ann Oncol. 2011; 22:2546-55. http://www.ncbi.nlm.nih.gov/pubmed/21415233?dopt=AbstractPlus

71. Reid DM, Doughty J, Eastell R et al. Guidance for the management of breast cancer treatment-induced bone loss: a consensus position statement from a UK Expert Group. Cancer Treat Rev. 2008; 34 Suppl 1:S3-18. http://www.ncbi.nlm.nih.gov/pubmed/18515009?dopt=AbstractPlus

72. Aapro M, Abrahamsson PA, Body JJ et al. Guidance on the use of bisphosphonates in solid tumours: recommendations of an international expert panel. Ann Oncol. 2008; 19:420-32. http://www.ncbi.nlm.nih.gov/pubmed/17906299?dopt=AbstractPlus

73. Body JJ, Bergmann P, Boonen S et al. Management of cancer treatment-induced bone loss in early breast and prostate cancer -- a consensus paper of the Belgian Bone Club. Osteoporos Int. 2007; 18:1439-50. http://www.ncbi.nlm.nih.gov/pubmed/17690930?dopt=AbstractPlus

74. Novartis Pharmaceuticals. Kisqali (ribociclib succinate) tablets prescribing information. East Hanover, NJ; 2017 Mar.

75. Hortobagyi GN, Stemmer SM, Burris HA et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med. 2016; 375:1738-1748. http://www.ncbi.nlm.nih.gov/pubmed/27717303?dopt=AbstractPlus

76. Novartis Pharmaceuticals. Kisqali Femara Co-Pack (ribociclib succinate copackaged with letrozole) tablets prescribing information. East Hanover, NJ; 2021 Dec. https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=aa5e4446-19cd-4235-a382-5b48bf6c3b2f

77. Hadji P, Aapro MS, Body JJ et al. Management of Aromatase Inhibitor-Associated Bone Loss (AIBL) in postmenopausal women with hormone sensitive breast cancer: Joint position statement of the IOF, CABS, ECTS, IEG, ESCEO IMS, and SIOG. J Bone Oncol. 2017; 7:1-12. http://www.ncbi.nlm.nih.gov/pubmed/28413771?dopt=AbstractPlus

78. Hortobagyi GN, Stemmer SM, Burris HA, et al. Overall Survival with Ribociclib plus Letrozole in Advanced Breast Cancer. N Engl J Med. 2022;386(10):942-950.

79. Gnant M, Mlineritsch B, Schippinger W, et al. Endocrine therapy plus zoledronic acid in premenopausal breast cancer. N Engl J Med. 2009;360(7):679-691.

80. Campone M, De Laurentiis M, Zamagni C, et al. Ribociclib plus letrozole in male patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer: subgroup analysis of the phase IIIb CompLEEment-1 trial. Breast Cancer Res Treat. 2022;193(1):95-103.

81. Hortobagyi GN, Stemmer SM, Burris HA, et al. Updated results from MONALEESA-2, a phase III trial of first-line ribociclib plus letrozole versus placebo plus letrozole in hormone receptor-positive, HER2-negative advanced breast cancer. Ann Oncol. 2018;29(7):1541-1547.

82. Ruhstaller T, Giobbie-Hurder A, Colleoni M, et al. Adjuvant Letrozole and Tamoxifen Alone or Sequentially for Postmenopausal Women With Hormone Receptor-Positive Breast Cancer: Long-Term Follow-Up of the BIG 1-98 Trial. J Clin Oncol. 2019;37(2):105-114.

84. Rose C, Vtoraya O, Pluzanska A, et al. An open randomised trial of second-line endocrine therapy in advanced breast cancer: comparison of the aromatase inhibitors letrozole and anastrozole. Eur J Cancer. 2003; 39:2318-27. http://www.ncbi.nlm.nih.gov/pubmed/14556923?dopt=AbstractPlus

85. De Laurentiis M, Borstnar S, Campone M, et al. Full population results from the core phase of CompLEEment-1, a phase 3b study of ribociclib plus letrozole as first-line therapy for advanced breast cancer in an expanded population. Breast Cancer Res Treat. 2021;189(3):689-699.

222. Institute for Safe Medication Practices. List of confused drug names. 2019 Feb 28. Accessed 2022 May 13. https://www.ismp.org/recommendations/confused-drug-names-list

4000. Burstein HJ, Somerfield MR, Barton DL, et al. Endocrine treatment and targeted therapy for hormone receptor-positive, human epidermal growth factor receptor 2-negative metastatic breast cancer: ASCO guideline update. J Clin Oncol. 2021;39(35):3959-3977.

10010. Francis PA, Regan MM, Fleming GF et al. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2015; 372:436-46. http://www.ncbi.nlm.nih.gov/pubmed/25495490?dopt=AbstractPlus

10011. Pagani O, Regan MM, Walley BA et al. Adjuvant exemestane with ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014; 371:107-18. http://www.ncbi.nlm.nih.gov/pubmed/24881463?dopt=AbstractPlus

10012. Francis PA, Pagani O, Fleming GF et al. Tailoring Adjuvant Endocrine Therapy for Premenopausal Breast Cancer. N Engl J Med. 2018; 379:122-137. http://www.ncbi.nlm.nih.gov/pubmed/29863451?dopt=AbstractPlus

10013. Tevaarwerk AJ, Wang M, Zhao F et al. Phase III comparison of tamoxifen versus tamoxifen plus ovarian function suppression in premenopausal women with node-negative, hormone receptor-positive breast cancer (E-3193, INT-0142): a trial of the Eastern Cooperative Oncology Group. J Clin Oncol. 2014; 32:3948-58. http://www.ncbi.nlm.nih.gov/pubmed/25349302?dopt=AbstractPlus

10016. Pan K, Bosserman LD, Chlebowski RT. Ovarian Suppression in Adjuvant Endocrine Therapy for Premenopausal Breast Cancer. J Clin Oncol. 2019; 37:858-861. http://www.ncbi.nlm.nih.gov/pubmed/30742565?dopt=AbstractPlus

10017. Burstein HJ, Lacchetti C, Anderson H et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: American Society of Clinical Oncology Clinical Practice Guideline Update on Ovarian Suppression. J Clin Oncol. 2016; 34:1689-701. http://www.ncbi.nlm.nih.gov/pubmed/26884586?dopt=AbstractPlus

10019. Burstein HJ, Lacchetti C, Anderson H et al. Adjuvant Endocrine Therapy for Women With Hormone Receptor-Positive Breast Cancer: ASCO Clinical Practice Guideline Focused Update. J Clin Oncol. 2019; 37:423-438. http://www.ncbi.nlm.nih.gov/pubmed/30452337?dopt=AbstractPlus

10020. Dowsett M, Lønning PE, Davidson NE. Incomplete Estrogen Suppression With Gonadotropin-Releasing Hormone Agonists May Reduce Clinical Efficacy in Premenopausal Women With Early Breast Cancer. J Clin Oncol. 2016; 34:1580-3. http://www.ncbi.nlm.nih.gov/pubmed/26729430?dopt=AbstractPlus

10023. Gnant M, Mlineritsch B, Stoeger H et al. Adjuvant endocrine therapy plus zoledronic acid in premenopausal women with early-stage breast cancer: 62-month follow-up from the ABCSG-12 randomised trial. Lancet Oncol. 2011; 12:631-41. http://www.ncbi.nlm.nih.gov/pubmed/21641868?dopt=AbstractPlus

10024. Gnant M, Mlineritsch B, Stoeger H et al. Zoledronic acid combined with adjuvant endocrine therapy of tamoxifen versus anastrozol plus ovarian function suppression in premenopausal early breast cancer: final analysis of the Austrian Breast and Colorectal Cancer Study Group Trial 12. Ann Oncol. 2015; 26:313-20. http://www.ncbi.nlm.nih.gov/pubmed/25403582?dopt=AbstractPlus

10025. Bellet M, Gray KP, Francis PA et al. Twelve-Month Estrogen Levels in Premenopausal Women With Hormone Receptor-Positive Breast Cancer Receiving Adjuvant Triptorelin Plus Exemestane or Tamoxifen in the Suppression of Ovarian Function Trial (SOFT): The SOFT-EST Substudy. J Clin Oncol. 2016; 34:1584-93. http://www.ncbi.nlm.nih.gov/pubmed/26729437?dopt=AbstractPlus

10026. Perrone F, De Laurentiis M, De Placido S et al. Adjuvant zoledronic acid and letrozole plus ovarian function suppression in premenopausal breast cancer: HOBOE phase 3 randomised trial. Eur J Cancer. 2019; 118:178-186. http://www.ncbi.nlm.nih.gov/pubmed/31164265?dopt=AbstractPlus

10027. Chlebowski RT, Pan K, Col NF. Ovarian suppression in combination endocrine adjuvant therapy in premenopausal women with early breast cancer. Breast Cancer Res Treat. 2017; 161:185-190. http://www.ncbi.nlm.nih.gov/pubmed/27785653?dopt=AbstractPlus

10028. AHFS final determination of medical acceptance: Off-label use of endocrine therapy in combination with ovarian suppression for the adjuvant treatment of early-stage hormone receptor-positive breast cancer in premenopausal women. Published January 4, 2021.

10029. Smith I, Yardley D, Burris H, et al. Comparative Efficacy and Safety of Adjuvant Letrozole Versus Anastrozole in Postmenopausal Patients With Hormone Receptor-Positive, Node-Positive Early Breast Cancer: Final Results of the Randomized Phase III Femara Versus Anastrozole Clinical Evaluation (FACE) Trial. J Clin Oncol. 2017;35(10):1041-1048. doi:

10053. DePlacido S, Gallo C, DeLaurentis M, et al. Adjuvant anastrozole versus exemestane versus letrozole, upfront or after 2 years of tamoxifen, in endocrine-sensitive breast cancer (FATA-GIM3): a randomised, phase 3 trial. Lancet Oncol. 2018;19;474-485.

10056. Hassett MJ, Somerfield MR, Baker ER, et al. Management of Male Breast Cancer: ASCO Guideline. J Clin Oncol. 2020;38(16):1849-1863.

10075. Burstein HJ, Prestrud AA, Seidenfeld J et al. American Society of Clinical Oncology clinical practice guideline: update on adjuvant endocrine therapy for women with hormone receptor-positive breast cancer. J Clin Oncol. 2010; 28:3784-96. http://www.ncbi.nlm.nih.gov/pubmed/20625130?dopt=AbstractPlus http://www.pubmedcentral.nih.gov/picrender.fcgi?tool=pmcentrez&artid=5569672&blobtype=pdf

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