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Hot flashes from adjuvant hormone therapy (AHT) are predictive of worse breast cancer outcomes, according to a Swedish population-based study, a finding that contrasts with previous clinical trial results examining this relationship.

Patients in the study who started on drugs for hot flashes within 6 months of initiating AHT had lower disease-free survival (DFS) rates at 5 and 10 years (92.3% and 87.0%) compared with those who did not take drugs for hot flashes (95.8% and 91.0%, respectively), reported Wei He, PhD, of the Karolinska Institutet in Stockholm, and colleagues.

At a median follow-up of 6.8 years, this translated into a significantly worse DFS for the patients who started on drugs for hot flashes (adjusted HR 1.67, 95% CI 1.11-2.52), the team said in their study in the .

The AHT discontinuation rate was 48.9% for the entire study population, with 3- and 5-year discontinuation rates of 34.6% and 57.5%, respectively, for patients who needed therapy for hot flashes within 6 months of starting AHT, as compared to 27.2% and 43.3%, respectively, for those who did not.

Patients who started to use drugs for hot flashes were significantly more likely to discontinue AHT (HR 1.47, 95% CI 1.21-1.78), and those that discontinued AHT were more likely to have shorter DFS (adjusted HR 1.46, 95% CI 1.18-1.80).

"These findings again suggest that results from clinical trials cannot be readily generalized to the real-world setting," He and co-authors wrote. "Our findings also highlight that current approaches to managing therapy-related hot flashes by simply prescribing symptom-relieving drugs are insufficient. Other interventions on targeted risk groups are needed to reduce treatment discontinuation among women with severe AHT-related adverse effects to improve their breast cancer outcomes."

Of the 7,152 patients followed in the study, 3.5% started to use drugs for hot flashes (including selective serotonin reuptake inhibitors, venlafaxine, and gabapentin) within 6 months after initiating AHT, the researchers reported. Users of the drugs were more likely to be younger, premenopausal, and to be taking hormone-replacement therapy before their breast cancer diagnosis. There were no significant differences in tumor characteristics and comorbidity status between users and non-users of drugs for hot flashes.

Subgroup analyses showed that the association between use of drugs for hot flashes and treatment discontinuation was stronger among women with:

• Low income (HR 1.91, 95% CI 1.41-2.59)

• No family history of cancer among first-degree relatives (HR 1.81, 95% CI 1.39-2.35)

• No first-degree relatives who died of cancer (HR 1.71, 95% CI 1.37-2.12)

In a press release, study co-author Erwei Zeng, MSc, also with Karolinska Institutet, noted that the link between using drugs for hot flashes and discontinuing AHT was weaker among patients with a family history of cancer, suggesting the reason could be that "family members who had cancer or died of cancer had a stronger motivation to complete AHT, even if they experienced treatment-related adverse effects."

Study Rationale

While AHT -- including tamoxifen and aromatase inhibitors -- has been shown to reduce breast cancer mortality, the treatments are also associated with adverse effects, such as hot flashes, that can detrimentally affect quality of life.

He and co-authors noted that it has been hypothesized that treatment-emergent adverse events can be a marker for the efficacy of AHT. For example, an of use of tamoxifen or anastrozole for adjuvant treatment of postmenopausal breast cancer showed that the appearance of new vasomotor symptoms within the first 3 months of treatment "is a useful biomarker, suggesting a greater response to endocrine treatment compared with women without these symptoms," the ATAC researchers wrote.

By linking several Swedish registries, He and co-authors were able to identify chemotherapy-free patients with breast cancer who who initiated AHT in Stockholm from 2006 through 2019, and followed them until 2020. New use of drugs for hot flashes was defined as having at least one prescription of the drugs within 6 months after initiating AHT, but not having prescriptions in the preceding 12 months.

Patients were followed from 6 months after initiation of AHT until treatment discontinuation, local recurrence, distant metastasis, contralateral breast cancer, death, emigration, endometrial cancer, venous thromboembolism, completion of 5 years of treatment, or the end of the study period.

Study limitations, the team said, included the possibility that some use of drugs for hot flashes was due to other reasons besides treatment-related adverse events, and that a prescription refill doesn't necessarily mean the patient took the medication. "However, this misclassification would likely attenuate rather than create the observed association in our study," the researchers said.

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