Drug/Small Molecule:
letrozole

PharmGKB contains no dosing guidelines for this drug/small molecule. To report known genotype-based dosing guidelines, or if you are interested in developing guidelines, click here.

PharmGKB gathers information regarding PGx on FDA drug labels from the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels", and from FDA-approved FDA and EMA-approved (European Medicines Agency) EMA labels brought to our attention. Excerpts from the label and downloadable highlighted label PDFs are manually curated by PharmGKB.

Please note that some drugs may have been removed from or added to the FDA's "Table of Pharmacogenomic Biomarkers in Drug Labels" without our knowledge. We periodically check the table for additions to this table and update PharmGKB accordingly.

There is currently no such list for European drug labels - we are working with the EMA to establish a list of European Public Assessment Reports (EPAR)s that contain PGx information. We are constructing this list by initially searching for drugs for which we have PGx-containing FDA drug labels - of these 44 EMA EPARs were identified and are being curated for pgx information.

We welcome any information regarding drug labels containing PGx information approved by the FDA, EMA or other Medicine Agencies around the world - please contact feedback.


last updated 10/25/2013

FDA Label for letrozole and ESR1, PGR

This label is on the FDA Biomarker List
Genetic testing required

Summary

Letrozole (Femara) is indicated for the adjuvant treatment of postmenopausal women with hormone receptor positive early breast cancer. It is also indicated as a first-line treatment for advanced breast cancer in postmenopausal women with hormone receptor positive or unknown tumors, or for extended adjuvant treatment of post-menopausal women with early breast cancer who have received prior standard adjuvant tamoxifen therapy.

Annotation

Excerpt from the FDA-approved letrozole (Femara) drug label:

Femara is an aromatase inhibitor indicated for adjuvant treatment of postmenopausal women with homone receptor positive early breast cancer...Extended adjuvant treatment of postmenopausal women with early breast cancer who have received prior standard adjuvant tamoxifen therapy...First and second-line treatment of postmenopausal women with hormone receptor positive or unknown advanced breast cancer

For the complete drug label text with sections containing pharmacogenetic information highlighted, see the letrozole drug label.

*Disclaimer: The contents of this page have not been endorsed by the FDA and are the sole responsibility of PharmGKB.

Full label available at DailyMed

Genes and/or phenotypes found in this label

  • Breast Neoplasms
    • Indications & usage section, Contraindications section, Adverse reactions section
    • source: PHONT
  • CYP2A6
    • Clinical pharmacology section, metabolism/PK
    • source: FDA Label
  • CYP2C19
    • Clinical pharmacology section
    • source: FDA Label
  • CYP3A4
    • Clinical pharmacology section, metabolism/PK
    • source: FDA Label

PharmGKB contains no Clinical Variants that meet the highest level of criteria.

To see more Clinical Variants with lower levels of criteria, click the button at the bottom of the page.

Disclaimer: The PharmGKB's clinical annotations reflect expert consensus based on clinical evidence and peer-reviewed literature available at the time they are written and are intended only to assist clinicians in decision-making and to identify questions for further research. New evidence may have emerged since the time an annotation was submitted to the PharmGKB. The annotations are limited in scope and are not applicable to interventions or diseases that are not specifically identified.

The annotations do not account for individual variations among patients, and cannot be considered inclusive of all proper methods of care or exclusive of other treatments. It remains the responsibility of the health-care provider to determine the best course of treatment for a patient. Adherence to any guideline is voluntary, with the ultimate determination regarding its application to be made solely by the clinician and the patient. PharmGKB assumes no responsibility for any injury or damage to persons or property arising out of or related to any use of the PharmGKB clinical annotations, or for any errors or omissions.

? = Mouse-over for quick help

This is a non-comprehensive list of genetic tests with pharmacogenetics relevance, typically submitted by the manufacturer and manually curated by PharmGKB. The information listed is provided for educational purposes only and does not constitute an endorsement of any listed test or manufacturer.

A more complete listing of genetic tests is found at the Genetic Testing Registry (GTR).

PGx Test Variants Assayed Gene?

The table below contains information about pharmacogenomic variants on PharmGKB. Please follow the link in the "Variant" column for more information about a particular variant. Each link in the "Variant" column leads to the corresponding PharmGKB Variant Page. The Variant Page contains summary data, including PharmGKB manually curated information about variant-drug pairs based on individual PubMed publications. The PMIDs for these PubMed publications can be found on the Variant Page.

The tags in the first column of the table indicate what type of information can be found on the corresponding Variant Page.

Links in the "Gene" column lead to PharmGKB Gene Pages.

Gene ? Variant?
(138)
Alternate Names / Tag SNPs ? Drugs ? Alleles ?
(+ chr strand)
Function ? Amino Acid?
Translation
No VIP available No VIP available VA CYP2A6 *1A N/A N/A N/A
VIP No VIP available VA CYP2A6 *2 N/A N/A N/A
No VIP available No VIP available VA CYP2A6 *4A N/A N/A N/A
No VIP available No VIP available VA CYP2A6 *4E N/A N/A N/A
VIP No VIP available VA CYP2A6 *7 N/A N/A N/A
VIP No VIP available VA CYP2A6 *9A N/A N/A N/A
VIP No VIP available VA CYP2A6 *12A N/A N/A N/A
No VIP available No VIP available VA CYP2A6 *17 N/A N/A N/A
VIP No VIP available VA CYP2A6 *1B1 N/A N/A N/A
No VIP available No VIP available VA CYP2A6 *20 N/A N/A N/A
No VIP available No VIP available VA CYP2A6 *23 N/A N/A N/A
No VIP available No VIP available VA CYP2A6 *26 N/A N/A N/A
No VIP available No VIP available VA CYP2A6 *35A N/A N/A N/A
No VIP available No Clinical Annotations available VA
rs10148269 45736924A>G, 536-1295T>C, 64736924A>G, 73345T>C
A > G
Intronic
No VIP available No Clinical Annotations available VA
rs11224556 100899613A>G, 105932T>C, 4462029A>G
A > G
Not Available
No VIP available No Clinical Annotations available VA
rs1152580 115275A>C, 1407-347A>C, 1407-662A>C, 380312T>G, 45694994T>G, 64694994T>G
T > G
Intronic
No VIP available No Clinical Annotations available VA
rs12435857 1091+419C>T, 45723525G>A, 64723525G>A, 86744C>T
G > A
Intronic
No VIP available No Clinical Annotations available VA
rs1256031 45746179G>A, 535+520C>T, 64090C>T, 64746179G>A, ESR2:rs1256031
G > A
Intronic
No VIP available No Clinical Annotations available VA
rs1256061 106676C>A, 1226-1725C>A, 45703593G>T, 64703593G>T
G > T
Intronic
No VIP available No Clinical Annotations available VA
rs1256064 109530T>C, 1406+949T>C, 1407-698T>C, 45700739A>G, 64700739A>G
A > G
Intronic
No VIP available No Clinical Annotations available VA
rs1256120 -476T>C, 45805001A>G, 5268T>C, 64805001A>G
A > G
Not Available
No VIP available No Clinical Annotations available VA
rs17179740 -90-6958C>T, -91+4000C>T, 45756751G>A, 53518C>T, 64756751G>A
G > A
Intronic
No VIP available No Clinical Annotations available VA
rs1801132 152265522G>C, 258892C>C, 56434979G>C, 975C>C, ESR1: 975C>G, ESR1:C325G, Pro325=, Pro325Pro
G > C
Not Available
No VIP available No Clinical Annotations available VA
rs1952586 -90-9626A>G, -91+1332A>G, 45759419T>C, 50850A>G, 64759419T>C
T > C
Intronic
No VIP available No Clinical Annotations available VA
rs2077647 122447T>C, 152129077T>C, 30T>C, 56298534T>C, ESR1:S10S, ESR1:T29C, ESR1:T30C, ESR1:rs2077647, Ser10=
T > C
Synonymous
Ser10Ser
No VIP available No Clinical Annotations available VA
rs2228480 152420095G>A, 1782G>A, 413465G>A, 56589552G>A, ESR1:1782G>A, ESR1:BtgI, ESR1:G2014A, ESR1:G594A, ESR1:rs2228480, T594T, Thr594=
G > A
Synonymous
Thr594Thr
No VIP available CA VA
rs2234693 152163335T>C, 156705T>C, 453-397T>C, 56332792T>C, ESR1:PvuII, ESR1:c.454-397T>C, ESR1:rs2234693
T > C
Intronic
No VIP available No Clinical Annotations available VA
rs3020314 1096+5029C>T, 152270672C>T, 264042C>T, 56440129C>T
C > T
Intronic
No VIP available No Clinical Annotations available VA
rs3020445 -91+15972T>C, 21625T>C, 45788644A>G, 64788644A>G
A > G
Intronic
No VIP available No Clinical Annotations available VA
rs3740751 *8248C>T, 100901599G>A, 103946C>T, 10613C>T, 10881C>T, 10998C>T, 4464015G>A
G > A
Not Available
No VIP available No Clinical Annotations available VA
rs3798577 *1029T>C, 152421130T>C, 414500T>C, 56590587T>C, ESR1:rs3798577
T > C
3' UTR
No VIP available CA VA
rs4646 *161T>G, 132952T>G, 22293401A>C, 51502844A>C
A > C
3' UTR
No VIP available No Clinical Annotations available VA
rs471767 *4550C>T, 100248C>T, 100905297G>A, 4467713G>A, 6915C>T, 7183C>T, 7300C>T
G > A
Not Available
No VIP available No Clinical Annotations available VA
rs4986938 *39G>A, 110453G>A, 1406+1872G>A, 45699816C>T, 64699816C>T, ESR2-02, ESR2:1730A>G, ESR2:rs4986938
C > T
Not Available
No VIP available No Clinical Annotations available VA
rs537681 100988034C>T, 1297+8704G>A, 17511G>A, 1789+8704G>A, 4550450C>T, 7+8704G>A
C > T
Intronic
No VIP available No Clinical Annotations available VA
rs555653 100969545A>G, 1298-6938T>C, 1789+27193T>C, 1790-6938T>C, 36000T>C, 4531961A>G, 8-6938T>C
A > G
Intronic
No VIP available No Clinical Annotations available VA
rs561610 *6853A>G, 100902994T>C, 102551A>G, 4465410T>C, 9218A>G, 9486A>G, 9603A>G
T > C
Not Available
No VIP available No Clinical Annotations available VA
rs572943 100955618G>A, 124+6873C>T, 1414+6873C>T, 1790-22135C>T, 1906+6873C>T, 4518034G>A, 49927C>T
G > A
Intronic
No VIP available No Clinical Annotations available VA
rs6493497 -182C>T, -291C>T, 22421392G>A, 4961C>T, 51630835G>A
G > A
5' Flanking
No VIP available No Clinical Annotations available VA
rs7176005 -626G>A, -735G>A, 22421836C>T, 4517G>A, 51631279C>T
C > T
5' Flanking
No VIP available No Clinical Annotations available VA
rs8017441 1225+470T>C, 45715794A>G, 64715794A>G, 94475T>C
A > G
Intronic
No VIP available CA VA
rs9340799 152163381A>G, 156751A>G, 453-351A>G, 56332838A>G, ESR1:XbaI, ESR1:c.454-351A>G, ESR1:rs9340799
A > G
Intronic
No VIP available No Clinical Annotations available VA
rs944459 *497G>A, 110911G>A, 1406+2330G>A, 45699358C>T, 64699358C>T
C > T
3' Flanking
Alleles, Functions, and Amino Acid Translations are all sourced from dbSNP 138
2D structure from PubChem
provided by PubChem

Overview

Generic Names
  • Letrozol
  • letrozole
Trade Names
  • Femara
Brand Mixture Names

PharmGKB Accession Id:
PA450196

Description

Letrozole (INN, trade name Femara®) is an oral non-steroidal aromatase inhibitor that has been introduced for the adjuvant treatment of hormonally-responsive breast cancer

Estrogens are produced by the conversion of androgens through the activity of the aromatase enzyme. Letrozole blocks production of estrogens in this way by competitive, reversible binding to the heme of its cytochrome P450 unit. The action is specific, and letrozole does not reduce production of mineralo- or corticosteroids. In contrast, the antiestrogenic action of tamoxifen, the major medical therapy prior to the arrival of aromatase inhibitors, is due to its interfering with the estrogen receptor, rather than inhibiting estrogen production.
Letrozole is approved by the United States Food and Drug Administration (FDA) for the treatment of local or metastatic breast cancer that is hormone receptor positive or has an unknown receptor status in postmenopausal women. Side effects include signs and symptoms of hypoestrogenism. There is concern that long term use may lead to osteoporosis, which is why prescriptions of Letrozole are often accompanied by prescriptions of osteoporosis-fighting medication such as Fosamax.
Letrozole has shown to reduce estrogen levels by 98 percent while raising testosterone levels. The anti-estrogen action of letrozole is preferred by athletes and bodybuilders for use during a steroid cycle to reduce bloating due to excess water retention and prevent the formation of gynecomastia related breast tissue that is a side effect of some anabolic steroids. Usage above 2.5 mg/day is known to potentially temporarily kill sex drive. Above 5mg/day for extended periods may cause kidney problems.

Letrozole has also been shown to delay the fusing of the growth plates in adolescents. This may boost the effectiveness of growth hormone, and thus Letrozole is used to treat adolescents and children with short stature.

Source: Drug Bank

Indication

For the extended adjuvant treatment of early breast cancer in postmenopausal women who have received 5 years of adjuvant tamoxifen therapy. Also for first-line treatment of postmenopausal women with hormone receptor positive or hormone receptor unknown locally advanced or metastatic breast cancer. Also indicated for the treatment of advanced breast cancer in postmenopausal women with disease progression following antiestrogen therapy.

Source: Drug Bank

Other Vocabularies

Information pulled from DrugBank has not been reviewed by PharmGKB.

Pharmacology, Interactions, and Contraindications

Mechanism of Action

Letrozole is a nonsteroidal competitive inhibitor of the aromatase enzyme system; it inhibits the conversion of androgens to estrogens. In adult nontumor- and tumorbearing female animals, letrozole is as effective as ovariectomy in reducing uterine weight, elevating serum Leuteinizing hormone (LH), and causing the regression of estrogen-dependent tumors. In contrast to ovariectomy, treatment with letrozole does not lead to an increase in serum (folicile stimulating hormone (FSH). Letrozole selectively inhibits gonadal steroidogenesis but has no significant effect on adrenal mineralocorticoid or glucocorticoid synthesis.

Source: Drug Bank

Pharmacology

Letrozole is an aromatase inhibitor used in the treatment of breast cancer. Aromatase inhibitors work by inhibiting the action of the enzyme aromatase, which converts androgens into estrogens by a process called aromatization. As breast tissue is stimulated by estrogens, decreasing their production is a way of suppressing recurrence of the breast tumor tissue.

Source: Drug Bank

Food Interaction

Take without regard to meals. Food slows absorption without decreasing the quantity absorbed.

Source: Drug Bank

Absorption, Distribution, Metabolism, Elimination & Toxicity

Biotransformation

Primarily hepatic via CYP3A4 and CYP2A6. Letrozole inhibits the aromatase enzyme by competitively binding to the heme of the cytochrome P450 subunit of the enzyme, resulting in a reduction of estrogen biosynthesis in all tissues. It is metabolized slowly to an inactive metabolite whose glucuronide conjugate is excreted renally, representing the major clearance pathway.

Source: Drug Bank

Absorption

Rapidly and completely absorbed. Absorption is not affected by food.

Source: Drug Bank

Half-Life

2 days

Source: Drug Bank

Chemical Properties

Chemical Formula

C17H11N5

Source: Drug Bank

Isomeric SMILES

c1cc(ccc1C#N)C(c2ccc(cc2)C#N)n3cncn3

Source: OpenEye

Canonical SMILES

N#CC1=CC=C(C=C1)C(N1C=NC=N1)C1=CC=C(C=C1)C#N

Source: Drug Bank

Average Molecular Weight

285.3027

Source: Drug Bank

Monoisotopic Molecular Weight

285.101445377

Source: Drug Bank

PharmGKB Curated Pathways

Pathways created internally by PharmGKB based primarily on literature evidence.

  1. Aromatase Inhibitor Pathway (Breast Cell), Pharmacodynamics
    Summary of pathways of estrogens and antiestrogens.

External Pathways

Links to non-PharmGKB pathways.

PharmGKB contains no links to external pathways for this drug. To report a pathway, click here.

Genes that are associated with this drug in PharmGKB's database based on (1) variant annotations, (2) literature review, (3) pathways or (4) information automatically retrieved from DrugBank, depending on the "evidence" and "source" listed below.

Curated Information ?

Drug Targets

Gene Description
CYP19A1 (source: Drug Bank)
ERBB2 (source: Drug Bank)
ESR1 (source: Drug Bank)
No related drugs are available.

Curated Information ?

Relationships from National Drug File - Reference Terminology (NDF-RT)

May Treat
Contraindicated With

Publications related to letrozole: 20

No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Aromatase inhibitor-induced modulation of breast density: clinical and genetic effects. British journal of cancer. 2013. Henry N L, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Challenges in pharmacogenetics. European journal of clinical pharmacology. 2013. Cascorbi Ingolf, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Genetic associations with toxicity-related discontinuation of aromatase inhibitor therapy for breast cancer. Breast cancer research and treatment. 2013. Henry N Lynn, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
Indications of clinical and genetic predictors for aromatase inhibitors related musculoskeletal adverse events in Chinese Han women with breast cancer. PloS one. 2013. Wang Jingxuan, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Reduced methadone clearance during aromatase inhibition. Journal of clinical psychopharmacology. 2012. Lu Wenjie Jessie, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available VIP No VIP available
PharmGKB summary: very important pharmacogene information for cytochrome P-450, family 2, subfamily A, polypeptide 6. Pharmacogenetics and genomics. 2012. McDonagh Ellen M, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Predictors of aromatase inhibitor discontinuation as a result of treatment-emergent symptoms in early-stage breast cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology. 2012. Henry N Lynn, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Comparison of Changes in the Lipid Profile of Postmenopausal Women With Early Stage Breast Cancer Treated With Exemestane or Letrozole. Journal of clinical pharmacology. 2011. Bell Lauren Nicole, et al. PubMed
Plasma Letrozole Concentrations in Postmenopausal Women With Breast Cancer Are Associated With CYP2A6 Genetic Variants, Body Mass Index, and Age. Clinical pharmacology and therapeutics. 2011. Desta Z, et al. PubMed
Population pharmacokinetic analysis of letrozole in Japanese postmenopausal women. European journal of clinical pharmacology. 2011. Tanii Hiromi, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Tamoxifen metabolites as active inhibitors of aromatase in the treatment of breast cancer. Breast cancer research and treatment. 2011. Lu Wenjie Jessie, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Sequential changes in gene expression profiles in breast cancers during treatment with the aromatase inhibitor, letrozole. The pharmacogenomics journal. 2010. Miller W R, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Inflammatory cytokines and aromatase inhibitor-associated musculoskeletal syndrome: a case-control study. British journal of cancer. 2010. Henry N L, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available VA No VIP available No VIP available
Functional genetic polymorphisms in the aromatase gene CYP19 vary the response of breast cancer patients to neoadjuvant therapy with aromatase inhibitors. Cancer research. 2010. Wang Liewei, et al. PubMed
Deactivation of anti-cancer drug letrozole to a carbinol metabolite by polymorphic cytochrome P450 2A6 in human liver microsomes. Xenobiotica; the fate of foreign compounds in biological systems. 2009. Murai K, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Inhibition of drug metabolizing cytochrome P450s by the aromatase inhibitor drug letrozole and its major oxidative metabolite 4,4'-methanol-bisbenzonitrile in vitro. Cancer chemotherapy and pharmacology. 2009. Jeong Seongwook, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Antiestrogen pathway (aromatase inhibitor). Pharmacogenetics and genomics. 2009. Desta Zeruesenay, et al. PubMed
No Dosing Guideline available No Drug Label available CA VA No VIP available No VIP available
A single-nucleotide polymorphism in the aromatase gene is associated with the efficacy of the aromatase inhibitor letrozole in advanced breast carcinoma. Clinical cancer research : an official journal of the American Association for Cancer Research. 2008. Colomer Ramon, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Changes in breast cancer transcriptional profiles after treatment with the aromatase inhibitor, letrozole. Pharmacogenetics and genomics. 2007. Miller William R, et al. PubMed
No Dosing Guideline available No Drug Label available No Clinical Annotation available No Variant Annotation available No VIP available No VIP available
Impact of tamoxifen on the pharmacokinetics and endocrine effects of the aromatase inhibitor letrozole in postmenopausal women with breast cancer. Clinical cancer research : an official journal of the American Association for Cancer Research. 1999. Dowsett M, et al. PubMed

LinkOuts

Web Resource:
Wikipedia
DrugBank:
DB01006
ChEBI:
6413
KEGG Compound:
C08163
KEGG Drug:
D00964
PubChem Compound:
3902
PubChem Substance:
10363
46504610
Drugs Product Database (DPD):
2231384
BindingDB:
13061
ChemSpider:
3765
Therapeutic Targets Database:
DAP000626
FDA Drug Label at DailyMed:
82b77d74-085f-45ac-a7dd-1f5c038bf406

Clinical Trials

These are trials that mention letrozole and are related to either pharmacogenetics or pharmacogenomics.

Common Searches

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Sources for PharmGKB drug information: DrugBank, Open Eye Scientific Software.