Letrozole vs Exemestane: What to Choose and for Whom

Letrozole and exemestane have comparable effectiveness in treating breast cancer, so the choice between them rarely comes down to ‘strength’. Much more important are prior treatment, tolerability, bone status and even the goal of therapy, which may be not oncological at all. The editorial team examines for whom and when doctors consider each drug.

Adjuvant therapy of breast cancer

The main area of use for both drugs is adjuvant (postoperative) endocrine therapy of hormone-receptor-positive breast cancer in postmenopausal women. The goal is to reduce the risk of recurrence over the following years. Here the doctor can choose between three strategies: an aromatase inhibitor from the start, sequential treatment with tamoxifen and an aromatase inhibitor, or extended therapy after completion of the base course.

Letrozole was studied as a drug for starting treatment. In the BIG 1-98 study (Thürlimann et al., 2005) letrozole from the start of therapy was superior to tamoxifen in disease-free survival. Exemestane is well studied in the ‘switching’ strategy: in the IES study (Coombes et al., 2004) switching to exemestane after 2–3 years of tamoxifen reduced the risk of recurrence compared with continuing tamoxifen.

Exemestane as a starting drug was compared with anastrozole in the MA.27 study (Goss et al., 2013), and the effectiveness proved comparable. So in practice both letrozole and exemestane are used both from the start and in sequential regimens; the specific strategy is determined by the oncologist taking into account the risk of recurrence and tolerability.

Premenopausal women are prescribed both drugs only together with medical or surgical suppression of ovarian function. Without this, aromatase inhibitors are not only ineffective but can also stimulate the ovaries.

Prevention and advanced cancer

For postmenopausal women with an increased risk of breast cancer, strategies of medical prevention have been developed. Exemestane was studied in the MAP.3 study (Goss et al., 2011), where it significantly reduced the incidence of invasive breast cancer compared with placebo. For letrozole there are no large prevention studies of this scale; among non-steroidal inhibitors, anastrozole was studied for prevention.

In advanced (metastatic) cancer, the absence of complete cross-resistance between the steroidal and non-steroidal inhibitors is important. If the disease progresses under letrozole or anastrozole, the oncologist may consider exemestane, often in combination with other drugs. Thus, in the BOLERO-2 study (Baselga et al., 2012) exemestane was combined with everolimus in patients after progression on non-steroidal inhibitors.

Letrozole in advanced cancer is widely used as first-line endocrine therapy, in particular in combination with modern targeted drugs. Specific combinations are constantly updated in oncology guidelines.

Another practical reason to change the drug is intolerance. If under one inhibitor joint pains are pronounced, the oncologist may try another, in particular switch from a non-steroidal to a steroidal one or vice versa, before abandoning the class altogether.

Reproductive medicine: why letrozole

Letrozole has an important non-oncological niche: ovulation induction in women with polycystic ovary syndrome. A short course of an aromatase inhibitor lowers estrogens, the pituitary responds with a rise in FSH, and a follicle matures in the ovary. In the large study by Legro et al. (2014) letrozole provided a higher live-birth rate than clomiphene.

In many countries this use of letrozole remains off-label, but it is supported by current international recommendations on PCOS. The drug is also used in fertility-preservation protocols in breast cancer patients, to reduce the rise in estrogens during ovarian stimulation.

Exemestane is practically not used in reproductive medicine. For this task a short course and quick clearance after completion are important, and there is no large evidence base for exemestane in this niche.

So, if the matter concerns infertility, the choice is practically unequivocal in favor of letrozole, but only within a reproductive specialist's protocol with ultrasound monitoring of the follicles.

Men: when aromatase inhibitors are appropriate and when not

In men, aromatase inhibitors are used off-label in certain situations: in male breast cancer (combined with suppression of gonadotropins), in some cases of infertility with a low ratio of testosterone to estradiol, and in pediatrics — in studies on delaying the closure of growth plates. A review by de Ronde and de Jong (2011) describes these scenarios in detail.

Aromatase inhibitors raise testosterone in men, but a study by Leder et al. (2004) with anastrozole in elderly men and later work showed that a reduction in estradiol can harm bone tissue. That is precisely why the Endocrine Society guidelines (2018) do not recommend aromatase inhibitors as a replacement for testosterone replacement therapy in hypogonadism.

In the sports community, aromatase inhibitors are used without prescription, often striving to ‘reduce estrogen to zero’. The editorial team emphasizes that in men this leads to joint pain, loss of bone mass, decreased libido, and worsening of the lipid profile and mood. Any such attempts without laboratory monitoring are a dangerous practice.

Contraindications and monitoring

Aromatase inhibitors are contraindicated during pregnancy and breastfeeding, and in women with active ovarian function without its suppression they are not used to treat cancer. Severe hepatic insufficiency requires a separate assessment by a doctor.

During long-term therapy it is mandatory to monitor bone mineral density using densitometry at the start and periodically thereafter, vitamin D levels, and the lipid profile. In the presence of osteopenia the doctor may prescribe drugs to protect the bones.

Joint pains, stiffness, numbness of the fingers (sometimes against a background of carpal tunnel syndrome) should be discussed with the doctor: they can often be reduced by physical activity, a change of drug or symptomatic therapy, without interrupting the cancer treatment.

• Densitometry before the start and during therapy.
• Lipid profile, liver function.
• Vitamin D and calcium — at the doctor's discretion.
• For premenopausal women — monitoring of ovarian function suppression.

Editorial conclusions

In oncology letrozole and exemestane are equivalent tools with different ‘best-studied’ niches: letrozole — the start of adjuvant therapy and first line in advanced cancer, exemestane — switching after tamoxifen, prevention in the high-risk group, and treatment after progression on non-steroidal inhibitors.

Outside oncology, letrozole has an important role in treating infertility in PCOS, whereas exemestane is practically not used in this field.

For men, neither drug is a way to treat hypogonadism, and uncontrolled suppression of estradiol causes real harm to the bones and metabolism.

We also recommend reading our articles on the mechanistic differences between letrozole and exemestane, on the comparison of raloxifene with clomiphene, and on estradiol control in men.

References

1. Breast International Group (BIG) 1-98 Collaborative Group; Thürlimann B, Keshaviah A, Coates AS, et al. A comparison of letrozole and tamoxifen in postmenopausal women with early breast cancer. N Engl J Med. 2005;353(26):2747–2757.
2. Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350(11):1081–1092.
3. Goss PE, Ingle JN, Pritchard KI, et al. Exemestane versus anastrozole in postmenopausal women with early breast cancer: NCIC CTG MA.27 — a randomized controlled phase III trial. J Clin Oncol. 2013;31(11):1398–1404.
4. Goss PE, Ingle JN, Alés-Martínez JE, et al. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364(25):2381–2391.
5. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366(6):520–529.
6. Legro RS, Brzyski RG, Diamond MP, et al. Letrozole versus clomiphene for infertility in the polycystic ovary syndrome. N Engl J Med. 2014;371(2):119–129.
7. de Ronde W, de Jong FH. Aromatase inhibitors in men: effects and therapeutic options. Reprod Biol Endocrinol. 2011;9:93.
8. Leder BZ, Rohrer JL, Rubin SD, Gallo J, Longcope C. Effects of aromatase inhibition in elderly men with low or borderline-low serum testosterone levels. J Clin Endocrinol Metab. 2004;89(3):1174–1180.