Letrozole explained - a good read

LETROZOLE AND THE HALF WHO STOP TOO SOON

In one large study of 8,769 women prescribed hormone tablets after breast cancer, only 49 percent took them for the full planned time at the right schedule.

Women who stopped early had a higher risk of death in that study.

This post explains one of those tablets, letrozole, so that the years of treatment make sense.

WHAT LETROZOLE IS

Letrozole is a small 2.5 mg tablet taken once a day. Doctors use it for hormone receptor positive breast cancer in women after menopause. It is used after surgery to lower the chance of the cancer coming back, after five years of tamoxifen for extra protection, and in advanced cancer to keep the disease under control.

WHERE ESTROGEN COMES FROM AFTER MENOPAUSE

After menopause the ovaries make very little estrogen. Yet estrogen does not disappear. An enzyme called aromatase keeps making it in tissues around the body, and even inside the breast tumour itself. It does this by converting hormones from the adrenal glands into estrone and estradiol.

Some breast cancers use that estrogen as fuel to grow.

HOW LETROZOLE CUTS THE FUEL

Letrozole binds tightly to the iron centre of the aromatase enzyme and jams it. Picture a factory with one central machine that turns raw material into estrogen. Letrozole jams that machine.

Within two to three days, estrogen levels in the blood fall by 75 to 95 percent. In one small study, letrozole blocked more than 99 percent of the body's estrogen production in every woman tested.

The tablet is also precise. It leaves the stress hormone cortisol, the salt balancing hormone aldosterone and thyroid function essentially untouched.

WHY IT IS FOR WOMEN AFTER MENOPAUSE

In women whose ovaries are still active, cutting estrogen would be expected to make the brain push the ovaries even harder. For that reason, guidelines only use drugs like letrozole before menopause together with treatment that switches off the ovaries.

WHAT THE BIG TRIALS FOUND

In the BIG 1-98 trial of over 8,000 women, letrozole lowered the risk of the cancer returning compared with tamoxifen, and lowered the risk of it spreading to distant organs by 27 percent.

When researchers pooled data from nearly 32,000 women, five years of an aromatase inhibitor cut the risk of dying from breast cancer over ten years by about 40 percent compared with no hormone tablet at all.

Letrozole lowers risk. It does not guarantee anything, and it is not described as a cure. For a woman at medium or high risk after menopause, it sits at the centre of the plan. Exercise, diet and supplements support that plan. They never replace the tablet.

HOW THE BODY HANDLES IT

Letrozole is fully absorbed whether taken with food or not. It lasts about two days in the blood and takes two to six weeks to reach steady levels. The liver clears it mainly through an enzyme called CYP2A6.

Genes matter at this step.

Letrozole levels can vary more than tenfold between women on the same dose, partly because of CYP2A6 gene differences.

Slow metabolisers in one study cleared the drug 46 percent more slowly. This does not change dosing today, and no guideline uses genetic testing for letrozole doses yet.

THE SIDE EFFECTS, NAMED PLAINLY

The same estrogen that feeds the cancer also protects bones, joints and cholesterol. Removing it brings predictable costs.

In BIG 1-98, raised cholesterol appeared in 52 percent of women on letrozole. Hot flushes affected about a third. Joint pain affected about a quarter, and nearly half in another trial. Fractures occurred in 14.7 percent over about eight years of follow up, compared with 11.4 percent on tamoxifen.

Fatigue, dizziness and sleepiness are also listed. Rare but serious reactions include severe allergy, severe skin reactions and liver inflammation.

Letrozole must not be taken in pregnancy. Women who could become pregnant need a pregnancy test first and contraception during treatment and for at least three weeks after.

WHAT HELPS WITH SIDE EFFECTS

@ Exercise has the best evidence. In a year long trial, women who did 150 minutes of aerobic exercise a week plus strength training twice a week cut their worst joint pain by about 29 percent.

@ Acupuncture gave a small extra improvement over sham acupuncture in another trial.

@ Bone protection works. In a trial of 3,420 women on these tablets, an injection called denosumab halved the rate of first fractures.

@ Some medicines used for joint pain or hot flushes are antidepressants. Those are decisions for the prescriber, who weighs their own risks.

WHAT TO BE CAREFUL WITH

UK guidelines advise against soy isoflavone, red clover, black cohosh and vitamin E supplements for hot flushes in women with breast cancer.

In mice, high dose genistein from soy reversed letrozole's effect on tumours. That is animal evidence only, but it supports caution with concentrated supplements.

Hormone replacement therapy is normally stopped at diagnosis. Tamoxifen taken at the same time lowers letrozole levels by about 38 percent. Always show your pharmacist every supplement and medicine you take.

THE QUIET RISK OF STOPPING

Letrozole does not need tapering. The risk is stopping too soon. In the study mentioned at the start, stopping early was linked to a 26 percent higher risk of death, and taking tablets irregularly was linked to a 49 percent higher risk.

Another study used blood levels and found that 28 percent of women were not taking letrozole regularly, while only 3 percent said so.

If side effects are hard, say so. Your team can treat the side effect or review the plan. Never stop or change the dose on your own.

FIVE QUESTIONS TO TAKE TO YOUR NEXT CLINIC VISIT

#1 - How long is letrozole planned for in my case, and will extending it be considered.

#2 - Have I had a baseline bone density scan, and do I need bone protection.

#3 - How and when will my cholesterol be checked.

#4 - What can we do if joint pain or hot flushes become hard to live with.

#5 - Which supplements and other medicines are safe alongside letrozole.

Share it with someone who takes letrozole, or tell us in the comments which question you most want answered.

WHEN TO GET HELP FAST

Get emergency help for swelling of the face, lips or throat, trouble breathing, or blistering or peeling skin.

Contact your care team quickly for yellow skin or eyes, dark urine, chest pain, sudden breathlessness, a swollen painful leg, a fracture after a small fall, a sudden tendon injury, persistent low mood, possible pregnancy, a new lump, or any warning sign in your care plan.

=====

Prepared by Edward Paul Mshani, BPharm

=====

Disclaimer

This content is for educational purposes only and does not constitute medical advice, diagnosis or treatment. Do not stop, start or modify any prescribed medication or supplement regimen without consulting a qualified healthcare professional. Individual clinical decisions require personalised medical assessment.

=====

Sources

-----

Tier 1, human clinical trials and meta analyses

-----

Breast International Group (BIG) 1-98 Collaborative Group; Thürlimann B, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005 Dec 29;353(26):2747-57. doi: 10.1056/NEJMoa052258. Erratum in: N Engl J Med. 2006 May 18;354(20):2200. Wardly, Andrew [corrected to Wardley, Andrew ]. PMID: 16382061.

Early Breast Cancer Trialists' Collaborative Group (EBCTCG). Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials. Lancet. 2015 Oct 3;386(10001):1341-1352. doi: 10.1016/S0140-6736(15)61074-1. Epub 2015 Jul 23. PMID: 26211827.

Goss PE, 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 Nov 6;349(19):1793-802. doi: 10.1056/NEJMoa032312. Epub 2003 Oct 9. PMID: 14551341.

Goss PE, et al. Extending Aromatase-Inhibitor Adjuvant Therapy to 10 Years. N Engl J Med. 2016 Jul 21;375(3):209-19. doi: 10.1056/NEJMoa1604700. Epub 2016 Jun 5. PMID: 27264120; PMCID: PMC5024713.

Finn RS, Martin M, Rugo HS, Jones S, Im SA, Gelmon K, Harbeck N, Lipatov ON, Walshe JM, Moulder S, Gauthier E, Lu DR, Randolph S, Diéras V, Slamon DJ. Palbociclib and Letrozole in Advanced Breast Cancer. N Engl J Med. 2016 Nov 17;375(20):1925-1936. doi: 10.1056/NEJMoa1607303. PMID: 27959613.

Hortobagyi GN, et al. Ribociclib as First-Line Therapy for HR-Positive, Advanced Breast Cancer. N Engl J Med. 2016 Nov 3;375(18):1738-1748. doi: 10.1056/NEJMoa1609709. Epub 2016 Oct 7. Erratum in: N Engl J Med. 2018 Dec 27;379(26):2582. doi: 10.1056/NEJMx180043. PMID: 27717303.

Geisler J, Haynes B, Anker G, Dowsett M, Lønning PE. 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 Feb 1;20(3):751-7. doi: 10.1200/JCO.2002.20.3.751. PMID: 11821457.

Legro RS, et al; NICHD Reproductive Medicine Network. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014 Jul 10;371(2):119-29. doi: 10.1056/NEJMoa1313517. Erratum in: N Engl J Med. 2014 Oct 9;317(15):1465. PMID: 25006718; PMCID: PMC4175743.

Gnant M, et al; Austrian Breast and Colorectal Cancer Study Group. Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial. Lancet. 2015 Aug 1;386(9992):433-43. doi: 10.1016/S0140-6736(15)60995-3. Epub 2015 May 31. PMID: 26040499.

Hershman DL, et al. Effect of Acupuncture vs Sham Acupuncture or Waitlist Control on Joint Pain Related to Aromatase Inhibitors Among Women With Early-Stage Breast Cancer: A Randomized Clinical Trial. JAMA. 2018 Jul 10;320(2):167-176. doi: 10.1001/jama.2018.8907. PMID: 29998338; PMCID: PMC6583520.

Henry NL, et al. Randomized, Multicenter, Placebo-Controlled Clinical Trial of Duloxetine Versus Placebo for Aromatase Inhibitor-Associated Arthralgias in Early-Stage Breast Cancer: SWOG S1202. J Clin Oncol. 2018 Feb 1;36(4):326-332. doi: 10.1200/JCO.2017.74.6651. Epub 2017 Nov 14. PMID: 29136387; PMCID: PMC5805479.

Irwin ML, et al. Randomized exercise trial of aromatase inhibitor-induced arthralgia in breast cancer survivors. J Clin Oncol. 2015 Apr 1;33(10):1104-11. doi: 10.1200/JCO.2014.57.1547. Epub 2014 Dec 1. PMID: 25452437; PMCID: PMC4372849.

-----

Tier 2, observational and longitudinal

-----

Hershman DL, Kushi LH, Shao T, Buono D, Kershenbaum A, Tsai WY, Fehrenbacher L, Gomez SL, Miles S, Neugut AI. Early discontinuation and nonadherence to adjuvant hormonal therapy in a cohort of 8,769 early-stage breast cancer patients. J Clin Oncol. 2010 Sep 20;28(27):4120-8. doi: 10.1200/JCO.2009.25.9655. Epub 2010 Jun 28. PMID: 20585090; PMCID: PMC2953970.

Hershman DL, Shao T, Kushi LH, Buono D, Tsai WY, Fehrenbacher L, Kwan M, Gomez SL, Neugut AI. Early discontinuation and non-adherence to adjuvant hormonal therapy are associated with increased mortality in women with breast cancer. Breast Cancer Res Treat. 2011 Apr;126(2):529-37. doi: 10.1007/s10549-010-1132-4. Epub 2010 Aug 28. PMID: 20803066; PMCID: PMC3462663.

Desta Z, Kreutz Y, Nguyen AT, Li L, Skaar T, Kamdem LK, Henry NL, Hayes DF, Storniolo AM, Stearns V, Hoffmann E, Tyndale RF, Flockhart DA. Plasma letrozole concentrations in postmenopausal women with breast cancer are associated with CYP2A6 genetic variants, body mass index, and age. Clin Pharmacol Ther. 2011 Nov;90(5):693-700. doi: 10.1038/clpt.2011.174. Epub 2011 Oct 5. PMID: 21975350; PMCID: PMC3667657.

Borrie AE, et al. Letrozole concentration is associated with CYP2A6 variation but not with arthralgia in patients with breast cancer. Breast Cancer Res Treat. 2018 Nov;172(2):371-379. doi: 10.1007/s10549-018-4910-z. Epub 2018 Aug 9. PMID: 30094551.

Hertz DL, Douglas JA, Kidwell KM, Gersch CL, Desta Z, Storniolo AM, Stearns V, Skaar TC, Hayes DF, Henry NL, Rae JM. Genome-wide association study of letrozole plasma concentrations identifies non-exonic variants that may affect CYP2A6 metabolic activity. Pharmacogenet Genomics. 2021 Jul 1;31(5):116-123. doi: 10.1097/FPC.0000000000000429. PMID: 34096894; PMCID: PMC8185249.

Puszkiel A, et al. Identification of non-adherence to adjuvant letrozole using a population pharmacokinetics approach in hormone receptor-positive breast cancer patients. Eur J Pharm Sci. 2024 Aug 1;199:106809. doi: 10.1016/j,ejps.2024.106809. Epub 2024 May 22. PMID: 38788907.

Ibrahim EM, Al-Homaidh A. Physical activity and survival after breast cancer diagnosis: meta-analysis of published studies. Med Oncol. 2011 Sep;28(3):753-65. doi: 10.1007/s12032-010-9536-x. Epub 2010 Apr 22. PMID: 20411366.

-----

Tier 3, mechanistic and preclinical

-----

Ju YH, Doerge DR, Woodling KA, Hartman JA, Kwak J, Helferich WG. Dietary genistein negates the inhibitory effect of letrozole on the growth of aromatase-expressing estrogen-dependent human breast cancer cells (MCF-7Ca) in vivo. Carcinogenesis. 2008 Nov;29(11):2162-8. doi: 10.1093/carcin/bgn161. Epub 2008 Jul 16. PMID: 18632754; PMCID: PMC2722859.

Jeselsohn R, Buchwalter G, De Angelis C, Brown M, Schiff R. ESR1 mutations—a mechanism for acquired endocrine resistance in breast cancer. Nat Rev Clin Oncol. 2015 Oct;12(10):573-83. doi: 10.1038/nrclinonc.2015.117. Epub 2015 Jun 30. PMID: 26122181; PMCID: PMC4911210.

-----

Reference spine, regulatory and guideline

-----

Novartis, FEMARA (letrozole) US Prescribing Information, revised 12/2024, DailyMed setid 82b77d74-085f-45ac-a7dd-1f5c038bf406

National Institute for Health and Care Excellence, Early and locally advanced breast cancer, NG101

LiverTox, Letrozole, NCBI Bookshelf NBK548381