Can Letrozole Cause Hot Flashes?
Yes, letrozole commonly causes hot flashes in postmenopausal women with hormone-sensitive breast cancer—this is one of the most frequent side effects, occurring in over 20% of patients. 1
Understanding Why This Occurs
Letrozole is a potent aromatase inhibitor that suppresses estrogen levels by over 95% throughout the body, creating a profound estrogen-depleted state that triggers vasomotor symptoms. 2, 3 This mechanism of action—while critical for treating hormone-receptor positive breast cancer—directly causes the hot flashes that many patients experience.
Frequency and Clinical Context
Both tamoxifen and aromatase inhibitors (including letrozole) contribute to hot flashes and night sweats, though they have different overall side effect profiles. 4 In clinical trials:
- Hot flashes are reported as one of the most common adverse reactions (>20%) with letrozole 1
- In the ATAC trial comparing anastrozole to tamoxifen, hot flushes occurred in 35.7% of anastrozole patients versus 40.9% of tamoxifen patients 4
- In the MA.17R trial, hot flashes occurred in approximately 38% of letrozole patients versus 37% of placebo patients 4
Interestingly, the case presentation in the 2022 Journal of Clinical Oncology guidelines describes a patient who switched FROM tamoxifen TO letrozole specifically because of severe hot flashes, suggesting that individual responses vary and some patients may actually tolerate letrozole better than tamoxifen for this particular symptom. 4
Management Approach for Letrozole-Induced Hot Flashes
First-Line Non-Hormonal Options
For breast cancer patients on letrozole experiencing bothersome hot flashes, non-hormonal treatments should be prioritized since hormonal therapy is contraindicated. 5
- SNRIs (venlafaxine) and SSRIs (paroxetine 7.5mg daily) are recommended for severe hot flashes, with high-quality evidence supporting their use 6, 5
- Gabapentin 900mg/day decreases hot flash severity by 46% versus 15% with placebo 6, 5
- Avoid paroxetine in patients on tamoxifen due to CYP2D6 inhibition, but this concern does not apply to letrozole users 5
Lifestyle Modifications
- Weight loss of ≥10% body weight 6
- Smoking cessation 6
- Limited alcohol intake 6
- Cognitive behavioral therapy (CBT) to reduce perceived burden of hot flashes 6
Critical Clinical Consideration
Up to 20% of breast cancer patients discontinue their life-saving endocrine therapy due to intolerable menopausal symptoms, which directly impacts mortality. 5 Therefore, proactive management of hot flashes in patients on letrozole is not merely a quality-of-life issue—it is a mortality issue, as maintaining adherence to aromatase inhibitors is critical for reducing recurrence and improving survival. 5
When to Escalate Treatment
If hot flashes are severe enough that the patient is considering discontinuing letrozole, aggressive symptom management with the non-hormonal options listed above should be implemented immediately. 5 The goal is to make the side effects tolerable enough to maintain adherence to the cancer treatment, as the survival benefit of letrozole far outweighs the burden of hot flashes when properly managed.
Common Pitfall to Avoid
Do not assume all patients will experience hot flashes with the same severity. While hot flashes are common with letrozole, individual tolerance varies significantly—some patients may find letrozole more tolerable than tamoxifen for vasomotor symptoms, as illustrated in the clinical case. 4 Assess symptom burden individually and tailor management accordingly rather than preemptively treating all patients.