Background: More than half of premenopausal women with breast cancer have tumors that are estrogen receptor (ER) positive. Despite this, there has been limited utilization of neoadjuvant endocrine therapy in that setting.

Trial Design: A Phase 2 study in premenopausal women (Age>18) with tumor size>2cm and locally advanced tumor, ER positive (Allred 6-8), HER2 negative, breast cancer who are not considered candidates for breast conservation surgery (BCS) or are borderline for BCS. Patients will be treated with a LHRH-A in combination with letrozole for a period of 4 weeks. At the end of 4 weeks, patients will undergo biopsy of the tumor for Ki67 assessment along with a serum estradiol (E2) level to confirm adequate hormone suppression.

Patients will then fall into one of 3 groups:

1. Postmenopausal (E2<10pg/ml) and Ki67≤10%

These patients will remain on letrozole for 16-18 weeks followed by definitive surgery. Patients with a PEPI-0 and continued estradiol suppression will be offered surgical oophorectomy, continued letrozole and no chemotherapy (CT).

2. Postmenopausal (E2<10pg/ml) and Ki67>10%

These patients will be designated endocrine therapy resistant and be offered neoadjuvant CT. Patients who decline neoadjuvant CT should be offered immediate surgery.

3. Premenopausal (E2≥10pg/ml)

There is a failure of the LHRH-A to fully suppress estradiol levels at one month, treatment decisions will be individualized.

Specific aims

1. To determine the pathological complete response (pCR) rate to CT in patients with a Ki67>10% at one month, despite a fully suppressed estradiol level.

2. To determine the PEPI-0 rate in patients whose estradiol is fully suppressed

at both 4 weeks and 16 weeks and whose 4 week tumor Ki67<10%.

3. In patients with a PEPI-0 tumor to determine the acceptability of management with surgical oophorectomy with continued oral letrozole and no CT.

Statistical methods:The study design was chosen assuming the expectation for the efficacy of neoadjuvant CT in premenopausal women with ER+ breast cancer is low, with a pCR rate in the range of 5%.Our hypothesis is that patients with tumors resistant to endocrine therapy will be enriched for sensitivity to CT to a level typical of patients with ER negative disease (20%). Thus, the trial was designed so that at a 0.1 significance level, there would be a 90% chance of detecting a pCR rate >20% when the true pCR rate >5%. A 90% binomial confidence interval (CI) for the true pCR rate will be constructed. We anticipate approximately 20% of patients will have a 4 week Ki67 > 10%. A sample of 235 eligible patients will be required to obtain 35 with a 4-week post treatment Ki67 value >10 % and estradiol level <10 pg/ml who are willing to switch to neoadjuvant CT.

We anticipate that 75% of patients will have a 4-week Ki67 <10% along with estradiol <10pg/ml. Based upon the sample size needed, there would be 175 patients who complete 16 weeks of neoadjuvant endocrine therapy. We estimate at least 20% of the patients with a Ki67 <10% at 4 weeks will be in the PEPI 0, Stage 0/1 group after surgery. A 90% binomial CI will be constructed for the proportion of these who choose to forego CT.

Accrual: Open June 2014. Target=235.

Citation Format: Andre Mattar, Rodrigo Goncalves, Matthew J Ellis, Roberto Hegg. A phase 2 study of neoadjuvant goserelin and letrozole for premenopausal women with estrogen receptor positive HER2 negative stage 2 and 3 breast cancer [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr OT2-1-02.