Goserelin, a gonadotropin-releasing hormone agonist, is administered along with tamoxifen for ovarian ablation in pre- or perimenopausal women with BC. Goserelin suppresses the release of follicle-stimulating hormone and luteinizing hormone from the pituitary, resulting in reduced estradiol production and secretion. However, the benefit of the coadministration of goserelin and tamoxifen has been called into question by studies such as the ZIPP (Zoladex in Premenopausal Patients) subset trial, leaving many unanswered questions.

A recently published, secondary analysis of 20 years of data from the Stockholm Trial (STO-5, 1990-1997) helps address this issue. STO-5 enrolled 924 premenopausal women diagnosed with invasive BC between May 1990 and January 1997. Patients were randomized into four treatment arms: 2 years of goserelin (3.6 mg SC once every 28 days) monotherapy, 2 years of tamoxifen (40 mg orally once daily) monotherapy, 2 years of combination therapy with goserelin and tamoxifen, or no adjuvant endocrine therapy (control group). The authors acknowledge that having an untreated control group would not be feasible or ethical today, but when this trial started the benefit of endocrine therapy (ET) had not been firmly established. Patients were further stratified into three groups based on lymph node (LN) involvement (0, 1-3, or >4 positive LNs). Those patients with positive LNs were treated with cyclophosphamide, methotrexate, and fluorouracil; locoregional radiotherapy was added to those with >4 positive LNs.

Of the 924 premenopausal women studied, 584 had estrogen receptor-positive (ER+) BC. In 2019-2021, 586 tumors underwent a 70-gene signature quality check to classify the primary tumor as either low or high genomic risk. Of these 586 tumors, 463 were ER+. Among these 463 ER+ BCs, 305 were in genomic low-risk patients and 158 were in genomic high-risk patients. High genomic risk is generally associated with larger tumor size, higher grade, HER2-positive status, and poorer prognosis.

Data from the 584 ER+ patients were assessed for long-term ET benefit by trial arm. Characteristics of this population included a median age of 47 years and mostly grade II disease (63%), positive progesterone receptor status (91%), negative HER2 status (88%), and low Ki-67 scores (70%). Long-term (i.e., 20 year) distant recurrence-free interval (DRFI) was significantly improved in the treatment groups compared with the control group as evidenced by statistically significant reduced hazard ratios (HRs) for goserelin (HR = 0.49; 95% CI, 0.32-0.75), tamoxifen (HR = 0.57; 95% CI, 0.38-0.87), and combination therapy compared with controls (HR = 0.63; 95% CI, 0.42-0.94).

Long-term ET benefit was assessed for the 463 ER+ patients who underwent genomic risk stratification. Investigators found that long-term DRFI was not significantly improved by tamoxifen in the genomic low-risk group compared with controls. On the other hand, significant improvement was seen in long-term DRFI with goserelin in genomic high-risk patients. However, there was no significant long-term benefit with combination therapy in either genomic low- or high-risk patients. Concerningly, significantly increased risk of distant recurrences was observed in genomic high-risk, but not low-risk, patients when combination therapy was administered (HR = 3.36; 95% CI, 1.39-8.07).

While genomic low-risk patients had a steady long-term risk of distant recurrence throughout the 20-year period, tamoxifen therapy reduced this risk by 77% (HR = 0.23; 95% CI, 0.06-0.92) at year 20. For genomic high-risk patients, goserelin reduced risk of distant recurrence by 74% (HR = 0.26; 95% CI 0.11-0.61) at year 5.

Pharmacists can use this genomic-based, long-term outcome data—which showed lack of benefit from combination therapy with goserelin and tamoxifen—to help optimize the BC treatment regimen for their premenopausal patients.

The content contained in this article is for informational purposes only. The content is not intended to be a substitute for professional advice. Reliance on any information provided in this article is solely at your own risk.

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