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FRAGRANCE Trial(Femara Reanalysed Through Genomics for Response Assessment, Calibration and Empowerment)

Phase 2
Open (Enrolling)
Breast Cancer

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Trial Information

FRAGRANCE Trial(Femara Reanalysed Through Genomics for Response Assessment, Calibration and Empowerment)

The aromatase inhibitors are drugs already approved for the treatment of breast cancer in
the adjuvant and metastatic setting, and have demonstrated a superiority when compared to
other hormone therapy agents as tamoxifen. FRAGRANCE is a trial of neoadjuvant hormone
therapy activated in September 2004 at the Jules Bordet Institute. The main objective of
this study is to find a genetic signature of de novo resistance to letrozole The standard
dose of letrozol, 2,5 mg/day, is given orally during 4 months previous to the definitive
breast surgery. The advantages of the neoadjuvant setting are a) the possibility to directly
evaluate the response to therapy, which is of great value to decide adjuvant treatment; b)
the increase chance of performing breast conserving surgery; c) and, because a tumor sample
is obtained before and after treatment, the identification of predictive markers of response
or resistance to treatment, including a genetic signature, obtained using the microarray
technology. Eligible patients are women with early hormonal receptor positive breast cancer,
with any contra-indication or refusal to the administration of chemotherapy The side effects
of letrozole are already well known, and include more commonly hot flashes, nausea and
vomiting, headache, arthralgia/myalgia, fatigue, and oedema. After surgery, adjuvant
treatment will be done according to the standard practice of the Institute, considering the
possibility of continuing letrozole for a total of at least 5 years, if a satisfactory
response is achieved The first part of this trial will include 49 patients.

This trial will soon become a multicenter, multinational trial of 160 patients.

Inclusion Criteria

Inclusion criteria :

1. Female gender

2. Post-menopausal(no age limit) defined as:

1. Radiation-induced menopause or surgical bilateral oophorectomy, or

2. Women with an intact uterus and

i. > 55 years of age or ii. without menses for the last 5 years or iii. £ 55 years of
age and has not had menses for at least the last 12 months (but has had menses in the
last 5 years) and has postmenopausal levels of FSH c. Women without an intact uterus
and i. > 55 years of age or ii. £ 55 years of age and has postmenopausal levels of

3. Contraindications for the use of neoadjuvant/adjuvant chemotherapy, refusal by the
patient to receive chemotherapy or if the investigator believes the patient is a
suitable candidate for this protocol.

4. WHO performance status < 1

5. Histologically-confirmed ductal or lobular operable adenocarcinoma of the breast
(stage I, II and III)

6. Confirmed absence of liver, lung and bone metastases.

7. Primary tumor of at least 2 cm, measured clinically and/or radiologically

8. Multifocal invasive tumors are not eligible, unless a biopsy showing ER positivity
can be obtained from each tumor lesion.

9. ER-positive and/or PgR-positive tumors, defined according to immunohistochemistry
(i.e. > 10% of positive cells after immunostaining), if woman younger 70 years;
ER-positive or PgR-positive tumors if woman older than 70 years.

10. Fixed and frozen samples from the primary tumor, obtained before treatment, must be
available for evaluation of biological markers (cDNA microarrays, EGFR, HER-2,
intra-tumoral aromatase).

11. No concurrent second malignancy, including contralateral breast cancer (exceptions
are: adequately treated basal cell carcinoma of the skin and in situ carcinoma of the
cervix). Any prior second malignancy must be in remission for ³ 5 years.

12. No other serious illness or medical condition including:

- History of documented congestive heart failure; angina pectoris requiring
antianginal medication; evidence of recent (< 6 months) transmural infarction on
ECG; poorly controlled hypertension (e.g. systolic >180 mm Hg or diastolic
greater than 100 mm Hg); clinically significant valvular heart disease; or
high-risk uncontrolled arrhythmias.

- Chronic lung disease

- History of significant neurological or psychiatric disorders that would prohibit
the understanding and giving of informed consent, including psychotic disorders,
mental retardation, and dementia.

- Active concurrent infection

13. No concurrent or previous anti-cancer treatment is allowed

14. Adequate organ function as defined by:

- Neutrophils ³ 1.5 x 109/L

- Platelets ³ 100 x 109/L

- Bilirubin £ 1.5x upper limit of normal (ULN)

- Transaminases £ 2.5x ULN

- Creatinine £ 1.5x ULN

15. Normal left ventricular ejection fraction by echocardiography or MUGA scan [for
combination studies only]

16. Absence of any psychological, familial, sociological or geographical condition
potentially hampering compliance with the study protocol and follow-up schedule;
those conditions should be discussed with the patient before registration in the

17. Before patient registration/randomization, informed consent must be given according
to ICH/EU GCP, and national/local regulations.

Exclusion crieria :

Non specified

Type of Study:


Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

Response Rate Pathologic complete response rate

Outcome Time Frame:

at the end of the study

Safety Issue:


Principal Investigator

Christos Sotiriou, MD, PhD

Investigator Role:

Study Chair

Investigator Affiliation:

Jules Bordet Institute


Belgium: Ministry of Social Affairs, Public Health and the Environment

Study ID:




Start Date:

November 2004

Completion Date:

December 2013

Related Keywords:

  • Breast Cancer
  • neoadjuvant treatment
  • Breast Neoplasms