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A Phase II Non-randomized, Parallel Group Study of Goserelin or Leuprorelin Plus Letrozole in Premenopausal Patients Versus Letrozole Alone in Postmenopausal Patients With Metastatic Breast Cancer

Phase 2
18 Years
Not Enrolling
Metastatic Breast Cancer

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Trial Information

A Phase II Non-randomized, Parallel Group Study of Goserelin or Leuprorelin Plus Letrozole in Premenopausal Patients Versus Letrozole Alone in Postmenopausal Patients With Metastatic Breast Cancer

The sites of estrogen synthesis are the ovaries of premenopausal women and extragonadal
sites such as fat, muscle, and skin, normal breast stromal cell and breast tumor tissue.
After ovarian failure, estrogen is synthesized in peripheral tissues such as fat and muscles
and this peripheral aromatization in postmenopausal women is almost completely inhibited by
single-agent administration of the third generation inhibitor (anastrozole, letrozole and
exemestane etc). In contrast, there is a barrier to using aromatase inhibitors as
monotherapy in premenopausal women. First, high level of androstenedione competes initially
with the inhibitors as substrate for the enzyme complex. Second, suppression of estrogen
results in a reflex increase in gonadotrophin levels, provoking an ovarian hyperstimulation
syndrome, which causes a steep increase of aromatase in the ovary and in turn overcomes the
blockade by inhibitor.

The rationale of combination therapy regimen of a gonadotropins-releasing hormone (GnRH)
agonist such as goserelin plus aromatase inhibitor in premenopausal patient is that, having
effectively rendered the patients postmenopausal with the use of goserelin, the peripheral
E2 production can be inhibited by aromatase inhibitor. Goserelin alone has been shown to
produce castrate level of estradiol (E2) and response rates similar to oophorectomy in
premenopausal women.

Selective aromatase inhibitors including letrozole have now become the standard second-line
endocrine therapy, after the failure of tamoxifen in postmenopausal women with advanced
breast cancer. Aromatase inhibitor is now challenged as first-line endocrine therapy for
hormone-sensitive breast cancer.

Ovarian expression of aromatase is regulated by gonadotropins, LH and FSH. Theoretically,
the combination of a GnRH analogue and an aromatase inhibitor can induce a complete estrogen
blockade in premenopausal breast cancer patients. Although combination of goserelin and
tamoxifen is an established therapeutic option in premenopausal patients with breast cancer,
from the results of earlier studies comparing tamoxifen and aromatase inhibitors as first
line therapy in postmenopausal patients with advanced breast cancer, it can be hypothesized
that letrozole may accomplish better clinical results than tamoxifen as a first line
hormonal therapy in patients with metastatic breast cancer who become menopause by GnRH
agonist as first line hormonal therapy.

Developing this combination therapy would be particularly useful since more than 50% of
breast cancers are developed in less than 50 years old women in Korea. Therefore, we are
going to evaluate the clinical and endocrine results of first-line goserelin plus letrozole
in premenopausal patients with metastatic breast cancer with first-line letrozole alone in
postmenopausal patients.

Recently, CYP19 single nucleotide polymorphism (SNP) in tumor tissue was shown to be
associated with the efficacy of aromatase inhibitor. In a study, when 67 postmenopausal
patients with hormone receptor positive metastatic breast cancer were treated with
letrozole, median TTP was significantly longer in patients with the rs4646 variant of
intratumoral CYP19, a SNP in 3'-UTR, compared with normal CYP19 (17.2 months versus 6.4
months; P=0.02). This result suggests the importance of both the local aromatase activity
and the tumor specific genetic alterations in the efficacy of aromatase inhibitors.

Up to recently, tumor-specific genetic markers have been assessed primarily in tumor
biopsies. However, in advanced stage patients, tumor tissues are often unavailable, since
surgery is not always performed or in some cases even the biopsy samples cannot be obtained,
which limits the use of tumor tissue for genetic assessment. The detection of tumor specific
genetic alterations in cancer patients at distant sites from the tumor, such as in blood,
would provide a useful predictor for the efficacy to treatment. Some of the tumor genetic
alterations have been observed in extracellular circulating DNA in blood samples of breast
cancer patients, including alterations in microsatellites, LOH, TP53 gene mutations and so

Inclusion Criteria:

1. Histologically or cytologically diagnosed stage IV or recurrent breast cancer
patients according to American Joint Committee on Cancer (AJCC)

2. Positive estrogen receptor or progesterone receptor (>grade 3/7 by modified Allred
IHC score)

3. Females at least 18 years of age and under 75 years

4. Prior chemotherapy for adjuvant setting or metastatic disease is allowed if the
number of chemotherapy is ≤ 3.

5. Prior adjuvant antiestrogen therapy is allowed, provided that had not been received
within 3 weeks before the entry of the study

6. Prior adjuvant aromatase inhibitor therapy is allowed if the agent had not been given
within one year of the entry.

7. Prior radiation therapy is allowed as long as the irradiated area is not the only
source of measurable disease.

8. No other forms of cancer therapy, such as radiation, immunotherapy for at least 3
weeks before the enrollment in the study.

9. Performance status of 0, 1 and 2 on the ECOG criteria.

10. Clinically measurable disease, defined as unidimensionally measurable lesions with
clearly defined margins on x-ray, CT scan, MRI or physical examination. Lesions
serving as measurable disease must be at least 1 cm by 1 cm, as defined by x-ray, CT
scan, MRI, or physical examination.

11. Bone only or pleural fluid only disease is included as long as evaluation for
clinical benefit is possible.

12. Estimated life expectancy of at least 12 weeks.

13. Compliant patient who can be followed-up adequately.

14. Adequate hematologic (WBC count 3,000/mm3, platelet count 100,000/mm3), hepatic
(bilirubin level 1.8 mg/dL, AST, ALT 2.0xULN, albumin 2.5 g/dL), and renal
(creatinine concentration 1.5 mg/dL) function.

15. Informed consent from patient or patient's relative.

16. Childbearing women should use non-hormonal contraceptive method.

Exclusion Criteria:

1. Previous chemotherapy more than 3 including adjuvant therapy.

2. Second primary malignancy (except in situ carcinoma of the cervix or adequately
treated basal cell carcinoma of the skin or prior malignancy treated more than 5
years ago without recurrence).

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

To evaluate the response rates and clinical benefits of letrozole + goserelin in premenopausal patients versus letrozole alone in postmenopausal patients with metastatic breast cancer as first line hormonal therapy

Outcome Time Frame:

4 years

Safety Issue:


Principal Investigator

Jungsil Ro, MD,PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

National Cancer Center, Korea


South Korea: Institutional Review Board

Study ID:




Start Date:

October 2005

Completion Date:

August 2010

Related Keywords:

  • Metastatic Breast Cancer
  • Breast Neoplasms