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Two years of adjuvant endocrine therapy for premenopausal breast cancer protected against metastatic recurrence for 20 years, a new analysis of a randomized trial showed.

Premenopausal women who received goserelin, tamoxifen, or the combination had a 37%-51% reduction in the risk of distant recurrence versus no adjuvant endocrine therapy after 20 years of follow-up. The benefit varied by tumor genomic profile, as genomically low-risk patients benefited from tamoxifen whereas high-risk patients benefited from goserelin.

Adding tamoxifen to goserelin significantly increased the risk of recurrence in high-risk patients, reported Annelie Johansson, PhD, of the Karolinska Institute and University Hospital in Stockholm, and colleagues, in the . The findings offer reassurance to patients who do not complete the recommended 5 years of adjuvant endocrine therapy for hormone-receptor positive breast cancer.

"For patients unable to endure 5 years of endocrine therapy, the significant benefit from 2 years of treatment, as seen in this study, could be helpful for both patients and clinicians," the authors concluded. "However, further studies are needed to understand the optimal treatment duration. Moreover, no long-term benefit from combined goserelin-tamoxifen therapy over single-treatment was observed in the ."

The findings are both heartening and intriguing, wrote Nancy Davidson, MD, of the University of Washington and Fred Hutchinson Cancer Center in Seattle, in an . Heartening because of the long-term protection against distant recurrence with just 2 years and adjuvant endocrine therapy and intriguing because of the apparent differential response by genomic risk.

"These [genomic risk] findings should be viewed as hypothesis generating given the small numbers of patients, retrospective nature of the analysis, and the use of a nonstandard dose of tamoxifen according to today's practice," she stated.

Moreover, no previous trials of adjuvant endocrine therapy have shown an adverse interaction between tamoxifen and ovarian function suppression (OFS).

"Nonetheless, findings of differential efficacy as demonstrated by Johansson et al, if replicated in other datasets, would be extremely useful to try to tailor adjuvant endocrine therapy for premenopausal women," Davidson continued.

The trial began before the now-common practice of pairing OFS with an aromatase inhibitor, introducing an element of uncertainty to the STO-5 results, she added.

The STO-5 trial involved 924 premenopausal Swedish women enrolled in the much larger of adjuvant goserelin for early-stage breast cancer. STO-5 investigators randomized patients to 2 years of adjuvant goserelin, tamoxifen, a combination of the two drugs, or no adjuvant therapy.

In 2020, investigators retrospectively performed primary tumor immunohistochemistry (n=731) and gene expression profiling (n=586). They used a 70-gene signature to identify genomically low- and high-risk patients.

The STO-5 population included 584 women with hormone receptor-positive breast cancer. They had a median age of 47 at enrollment. The subgroup included 305 genomically low-risk patients and 158 high-risk patients.

After a minimum follow-up of 20 years in all patients, patients allocated to any of the three arms of endocrine therapy had a significantly reduced risk of distant metastasis versus the patients who received no adjuvant endocrine therapy:

• Goserelin: HR 0.49 (95% CI 0.32-0.75)
• Tamoxifen: HR 0.57 (95% CI 0.38-0.87)
• Combination: HR 0.63 (95% CI 0.42-0.94)

The analysis showed a statistically significant goserelin-tamoxifen interaction (P=0.016). Low-risk patients had a 76% reduction in the HR when treated with tamoxifen (95% CI 0.10-0.60), and high-risk patients had an identical benefit with single-agent goserelin (95% CI 0.10-0.54). In contrast, the combination of the endocrine agents more than tripled the risk of distant recurrence as compared with no adjuvant therapy (HR 3.36, 95% CI 1.39-8.07). The goserelin-tamoxifen interaction achieved statistical significance in high-risk patients (P=0.006) but not low-risk patients (P=0.080).

Further analysis showed that genomically low-risk patients had a steady risk of distant recurrence, increasing slightly between years 5 and 10 and then remaining stable to year 20. As compared with the control arm, adjuvant tamoxifen provided long-lasting benefit from years 4 through 20.

On the other hand, genomically high-risk patients had an early risk and obtained early benefit from goserelin. The risk of distant relapse increased substantially during the first 5 years, followed by a rapid decline. The distant relapse-free interval improved significantly with goserelin during the first 8 years of follow-up, as compared with the control arm.

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