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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
arpie
3 days ago Place Hormone blocking therapy
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Zoladex 3 monthly available but not PBS covered for women
I wanted to share something I recently learned as it might help ease the burden of regular monthly injections. I recently learned that the goserelin injections many of us have monthly are actually available in a 3 monthly dose (10.8mg). I was a really hopeful thinking this could significantly reduce the stress, time and cost that comes with needing to have an injection every 4 weeks. However, my Med Onc informed me that in Australia, the PBS doesn't subsidise the 3 monthly dose for women, although it does for men (prostate cancer). The reasoning given that there's `insufficient evidence of reliable suppression of serum oestradiol' in women. What doesn't make sense is that there is evidence suggesting otherwise. Recent research indicates that the 3 monthly dose is non-inferior to the monthly dose for pre-menopausal women with breast cancer in terms of ovarian suppression. For me, the monthly injections come with a real burden: financially - GP visits and medication add up every month time wise - frequent GP appointments and pharmacy trips take time out of the week. physically and emotionally - injection itself is painful, it's a large slow release implant into the abdominal subcutaneous tissue. The main alternative - surgical removal of the ovaries is obviously much more invasive and comes with it's own risks and long term consequences. Given that the 3 monthly option is already in use, clinically tested and could ease the burden for many of us, I would really like to see equal PBS access for women. I'm curious, has anyone else looked into this and how to go about taking action?
NWhite1
6 days ago Place Hormone blocking therapy
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A solution to the prohibitive cost of Hyaluronic Acid
Hello I have been on Letrozole since February 2026 and have awful dryness in my vagina. I have had pretty good success with remedying it using Hyalofemme [Hyaluronic Acid] which if you get compounded in Australia costs $110.00 a month ! There are very few manufacturers here in Australia and recently one started advertising a product for around $40 a month but you need a subscription [no thank you]. I have found an online chemist in the UK which will ship me Hyalofemme (6 tubes for 6 months) for $100.00 !!! Each tube lasts 30 days. It is called Expresschemist UK. I also use organic coconut oil for daily lubrication. Kind Regards
Cadence
25 days ago Place Hormone blocking therapy
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Lymphoedema Information & Events
Lymphoedema can develop after breast cancer surgery or radiotherapy treatment. If lymph nodes are removed – usually from the armpit – fluid can build up and cause swelling known as ‘lymphoedema’. Find out what causes it, ways to reduce your risk of lymphoedema, and what to do if you develop lymphoedema. Signs and symptoms of lymphoedema Reduce your risk of lymphoedema Lymphoedema treatment Compression garments for lymphoedema Coping with lymphoedema Watch Ask the Expert 'Living well with lymphoedema' - with Maree O’Connor
Mez_BCNA
27 days ago Place News and events
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Suffering with Letrozole side-effects weeks after coming off it…
I think it has been discussed a lot already.. sorry… 55 y.o stage 2 ILC with mastectomy, preventative mastectomy on other side, radiotherapy. Finished all by end June this year. But I just need some HOPE that Letrozole side effects will wear off eventually… After 5 months of taking Letrozole, and going ok, I suddenly had burning pain in my wrists, hands, knees, thighs, many tender to touch, was hobbling around plus on sore feet, not even being able to clear up the kitchen after hubby cooks.. Not able to complete a shift at work.. I tried exemestane six weeks after stopping Letrozole. But for only 2 days as my wrists burned even more. I’m now 7-8 weeks post Letrozole and trying to at least go to stretch classes three times a week, and go for walks. Still relying on regular Panadol/Nurofen, can’t clear the kitchen up in the evening or go to work. Just about collapse into bed at night to make everything stop burning. When will it ever end?!!
lfillmore
1 month ago Place Hormone blocking therapy
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Radiation, driving and fatigue
I was hoping to hear about any experiences of driving and fatigue while undergoing radiation. I've been told to be aware of fatigue. The radiation oncologist and nurses have raised concerns and eyebrows when I've told them it's a one hour drive door to door, so two hour round trip x 15 sessions. I'm also maintaining hope that I can continue working part time in an outdoors job where lately I'm doing 14k+ steps a day. Ultimately I'm going to see how it goes. I'm not going to break myself. If I get too tired then I have backup people to help with the driving (public transport isn't an option around here), reduce my activity at work or take leave, or get accommodation near the hospital for some of the sessions. I'm wondering if some people have got through radiation without fatigue? Or if fatigue has occurred has it affected driving? And how fast the fatigue appears - might you have been okay one morning and zonked in the afternoon?
Moomincorn
1 month ago Place Chemotherapy and radiotherapy
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Ovestin Cream
Hi everyone!! I accidently sent this info to myself. So have worked out how to send it to everyone else. I had a recent appointment with my oncologist which went well. He doesn't need to see me for 12 months. Got my repeat for Anastrozole. I mentioned the Ovestin cream which I have started using again since surgery. At a previous appointment he said it was okay to use as I use it just twice a week. He said he didn't say that. I'm positive he did. I've stopped using it and have gone for an over the counter product he recommended. Replens. Then in the next breath he said if that doesn't work for me go back to using the Ovestin. I felt confused. Intimacy is uncomfortable as I am dry and sore inside again. Intimacy is an important part of our relationship. Because of this I really don't want to be intimate. I would love some feed back, please.
Barbie54
1 month ago Place Side effects
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Predict - Breast Cancer app
I’ve just discovered an app called ‘Predict - Breast Cancer’. I may be late to the party on this one and you might all know about it but I’d like to know your opinions if you’ve used it and if you’ve discussed it with your oncologists. It strongly recommends that patients use this tool in consultation with their doctor. The app’s blurb says: “This tool applies to women who have had surgery for early invasive breast cancer and are deciding which other treatments to have.” ”Predict is a tool that helps show how breast cancer treatments after surgery might improve survival rates. Once details about the patient and their cancer have been entered, the tool will show how different treatments would be expected to improve survival rates up to 15 years after diagnosis. This is based on data from similar women in the past. It is important to note that these treatments have side effects which should also be considered when deciding on a treatment.” It claims: ”Development of the model was a collaborative project between the Cambridge Breast Unit, University of Cambridge Department of Oncology and the UK's Eastern Cancer Information and Registration Centre (ECRIC) (now part of the National Cancer Registration and Analysis Service) and was supported by an unrestricted educational grant from Pfizer Limited (the company had no input into the model at all). The website has been built by the Winton Centre for Risk & Evidence Communication at the University of Cambridge who are funded by a generous donation from the David and Claudia Harding Foundation and the Winton Charitable Foundation. Predict has been endorsed by the American Joint Committee on Cancer.” This is a link to the app: https://breast.v3.predict.cam/tool
SYLV1E
1 month ago Place General
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What to expect - AC after Carbo/paclitaxel/pembro
Hi fighters, I am super worried about what to expect with my first AC coming up. I'll be having my birthday gathering 3 days after it too. I've got one more paclitaxel on its own in the 12 week carboplatin , paclitaxel, pembrolizumab regimen. For triple negative. I'm mid 40s. Apart from a few short bouts of intense side effects, i feel I've been fairly fortunate. No nausea. Good appetite. Side effects: Pins and needles - then used cold gloves and socks so only mild tingles after that mostly. Headaches and some fatigue occasionally in first weeks. Constipation after carbo - dealt with easily. Hints of UTI but also dealt with swiftly and all ok. Whole body red rash week 9 followed by itchy hands and feet (skin was fine) keeping me up all night for 3 nights before getting better. Fast testing heart rate in middle weeks - very out of breath and rate skyrocketing with a little activity. I attribute my last weeks being very easy due to skipping 2 weeks due to low neutrophils and getting those booster injections nearly 2 weeks straight. Also paclitaxel dose reduce due to that horrible itch. Do we think AC won't likely be so kind to me? Am I stupid for wanting to get together with friends in my birthday? Of course no sick people allowed! I have remained social and continued to work (at schools!) so far. Please share your experiences with AC, particularly if you feel similarities with mine so far. Many thanks in advance ❤️
winter-spring
1 month ago Place General
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Letrozole and dermatitis?
Hi all - I have been on letrozole for about 10 weeks now, following a lumpectomy and radiation for hormone positive ILC. Over the last couple of weeks I have developed a terribly itchy red rash over my legs and arms. My GP is investigating the cause, but I wondered if anyone else had experienced this as a possible side-effect of letrozole? I have seen other posts about rashes being a side effect of other AIs but not so much letrozole? thanks!
JMC
2 months ago Place Hormone blocking therapy
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