70-Gene Risk Signature May Determine Long Term Benefit of Endocrine Therapy in Premenopausal Breast Cancer Patients

SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. Approximately 284,200 new cases of breast cancer will be diagnosed in 2021 and about 44,130 individuals will die of the disease, largely due to metastatic recurrence. Approximately 75% of patients with breast cancer are Hormone Receptor positive (Estrogen Receptor/Progesterone Receptor positive) and this is a predictor of response to endocrine therapy. In premenopausal woman, the ovary is the main source of estrogen production, whereas in postmenopausal women, the primary source of estrogen is the Aromatase enzyme mediated conversion of androstenedione and testosterone to estrone and estradiol in extragonadal/peripheral tissues.

ZOLADEX® (Goserelin) is a potent synthetic analogue of Luteinizing Hormone-Releasing Hormone (LHRH), also known as a Gonadotropin Releasing Hormone (GnRH) agonist analogue. It stimulates the production of the sex hormones Testosterone and Estrogen in a non-pulsatile (non-physiological) manner, resulting in the disruption of the endogenous hormonal feedback systems, and down-regulation of Testosterone and Estrogen production. Given that premenopausal patients with breast cancer have their disease diagnosed earlier in life, they are at an increased risk of fatal disease during their lifetime. The long term benefit of endocrine therapy, including ovarian suppression, has not been studied in this patient population.

Zipp-trial (STO-5) in one of three well defined randomized, controlled, clinical studies of adjuvant endocrine therapy, conducted between 1990 and 1997 by the Stockholm Breast Cancer Study Group. This trial included premenopausal patients with invasive breast cancer treated with a modified radical mastectomy or breast conserving surgery and axillary lymph node dissection or biopsy. Patients undergoing breast conserving surgery also received adjuvant radiotherapy to the breast (50 Gy over 5 weeks). Patients were included in study irrespective of ER status. All patients with node positive disease electively received adjuvant cytotoxic chemotherapy and those with four or more lymph node metastases received radiotherapy as well.

The Stockholm part of the Zoladex In Premenopausal Patients (ZIPP-trial, STO-5) included 924 patients and the purpose of this analysis was to examine the long-term 20-year benefit of ZOLADEX® and Tamoxifen, stratified by the molecular 70-gene risk prediction signature in this patient population. Patients were stratified by lymph node status and divided into 3 groups: patients with lymph node-negative status, those with 1-3 positive lymph nodes who had received chemotherapy, and those with 4 or more positive lymph nodes who received chemotherapy and locoregional radiotherapy. All of these patients were included in a 2X2 factorial randomization to receive ZOLADEX® 3.6 mg Subcutaneously every 28 days (N=230), Tamoxifen 40 mg orally daily (N=231), ZOLADEX® plus Tamoxifen (N=230), or no endocrine therapy (N = 233), for 2 years. Node-positive patients received adjuvant chemotherapy in addition to endocrine therapy. The median age was 46 years.

The researchers identified clinically relevant breast cancer markers by immunohistochemistry in 729 patients, of whom 610 patients had Hormone Receptor-positive tumors. Molecular risk classification data were available in 465 patients and the 70-gene signature classified patients into groups with either Low risk (N=306) or High risk of disease recurrence (N=159). Of the 610 patients with Hormone Receptor-positive tumors, 160 received ZOLADEX®, 142 received Tamoxifen, 156 received the combination, and 152 received no endocrine therapy (control group).

The researchers noted that the 20-year risk for distant recurrence was significantly reduced in the patients who received ZOLADEX®, Tamoxifen or both, compared with those who did not receive endocrine therapy. The respective Hazard Ratios (HRs) were 0.48, 0.59, and 0.67 after adjusting for prior therapy and tumor characteristics. Stratification by the 70-gene signature demonstrated that Low risk patients derived a significant benefit from Tamoxifen therapy (HR=0.38), whereas ZOLADEX® plus Tamoxifen provided less benefit to these patients ((HR=0.80 and 0.72, respectively). In contrast, patients at High risk had significant benefit from ZOLADEX® therapy (HR=0.22), whereas less benefit was observed with Tamoxifen or ZOLADEX® plus Tamoxifen (HR=0.69 and 0.64, respectively).

The authors concluded that long term endocrine therapy benefit in premenopausal patients is influenced by molecular risk classification, with significant benefit from ZOLADEX® noted in High risk patients, whereas Low risk patients benefit from Tamoxifen.

LBA1 – 20-year benefit of endocrine therapy in premenopausal breast cancer patients by the 70-gene risk signature. Johansson A, Dar H, Van ‘T Veer L, et al. DOI:https://doi.org/10.1016/j.annonc.2021.03.210