Two years of adjuvant endocrine therapy in premenopausal patients with oestrogen receptor–positive breast cancer shows benefits out to 20 years, with a differential treatment benefit depending on the type of therapy and the patient’s genomic risk.
The findings come from a secondary analysis of the Stockholm trial (STO-5), which initially randomised 924 premenopausal patients with invasive operable breast cancer to two years of goserelin, tamoxifen, combined goserelin and tamoxifen, or no adjuvant endocrine therapy.
The analysis, published in the Journal of Clinical Oncology, focussed on 584 patients with oestrogen receptor–positive breast cancer.
It found significantly improved long-term distant recurrence-free interval (DRFI) from goserelin, tamoxifen, and the combination (HR 0.49; 0.57; and 0.63 respectively), compared with control.
“No significant long-term benefit from the combination of goserelin and tamoxifen was seen, compared with tamoxifen only or goserelin only,” the study said.
“Given the differences in mechanisms of action, we speculate that when tamoxifen and goserelin are given in combination, the agonistic effects of tamoxifen may counteract the oestrogen-depleting effects of goserelin.”
The study also determined a 70-gene signature risk classification on tissue samples from a subset of 463 patients.
It found genomic low-risk patients significantly benefitted from tamoxifen (HR 0.24) while genomic high-risk patients benefitted from goserelin (HR 0.24).
“Notably, in the Kaplan-Meier graphs, differences in DRFI from goserelin in genomic high-risk patients were observed early, whereas differences from tamoxifen in genomic low-risk patients were observed first after approximately 10 years,” it said.
“Compared with either therapy alone, further multivariable analyses showed no significant long-term benefit from the combination in genomic low-risk or high-risk patients.”
“However, in genomic high-risk patients, significantly increased long-term risk of distant recurrence from the addition of tamoxifen to goserelin was seen (HR, 3.36; 95% CI, 1.39 to 8.07).”
The study found genomic low-risk patients had a steady long-term risk of distant recurrence with HR slightly increasing from years 5 to 10 and then steady throughout the rest of the 20-year follow-up.
“Moreover, a long-lasting benefit from tamoxifen was observed from year 4 to year 20 compared with control with significantly estimated HRs at years 5, 10, 15, and 20 showing a reduced risk (HR, 0.23; 95% CI, 0.06 to 0.92 at year 20).”
Genomic high-risk patients had early risk of distant recurrence and early benefit from goserelin with a large increase in HR within the first five years which rapidly decreased thereafter.
“The observed effect of 2 years of goserelin might be clinically important for patients who are unable to accept or endure 5 years of therapy, given the strong but reversible side effects associated with goserelin,” the study said.
An editorial in the journal said the study had many strengths including the lengthy follow-up and banked tissue for immunohistochemistry and transcriptional profiling using contemporary techniques.
“A key finding is the heartening and enduring distant recurrence-free interval benefit of only 2 years of adjuvant endocrine therapy of any type which one hopes translated into a survival benefit without excess toxicity.”
“An unexpected but exploratory finding of this late analysis of STO-5 is the suggestion of differential response to the type of endocrine therapy depending on genomic risk assessment using a multigene assay.”
They said, if replicated, the findings would be “extremely useful to try to tailor adjuvant endocrine therapy for premenopausal women in a more precise way than through reliance on traditional clinical markers such as stage and conventional biomarkers alone.”
Further long-term follow-up was required in other studies of contemporary adjuvant therapy “which often partners ovarian function suppression with an aromatase inhibitor rather than tamoxifen.”