Relationship Between Hypoxia and Endocrine Response in Human Breast Cancer

• Conditions: Hypoxia; Breast Cancer
• Interventions: Other: 18FMISO PET/CT scan; Drug: Letrozole

• Registration Number: NCT01814449
• Lead Sponsor: Fudan University

Brief Summary

The aim of our current study was to analyze whether 18F-labeled Fluoromisonidazole (1-(2-nitro-1-imidazolyl)- 2-hydroxy-3-fluoropropane \[18F-FMISO\]) PET/CT and expression of HIF-1-alpha could predict response of primary endocrine therapy in ER-positive breast cancer

Detailed Description

Approximately 30% of ER-positive breast cancer will unfortunately display primary resistance to hormonal therapy, and some may develop acquired resistance to the therapy after initial treatment. Hypoxia is a normal phenomenon in solid tumors that arises, in part, from uncontrolled proliferation and immature blood vessels. Previous studies have demonstrated hypoxia significantly reduced both the growth-promoting effects of estradiol (E2) and the growth-inhibitory effects of an antiestrogen on ER-positive breast cancer cell lines. A recent study comparing neoadjuvant letrozole with letrozole plus metronomic cyclophosphamide found that increased levels of HIF-1a were significantly associated with resistance to treatment. Taken together, these data indicate that hypoxia might be associated with endocrine resistance in breast cancer.

With PET/CT, radiolabeled hypoxia-avid compounds can be applied to evaluate oxygenation status in experimental or human tumors. 18F-labeled fluoromisonidazole (1-\[2-nitro- 1-imidazolyl\]-2-hydroxy-3-fluoropropane \[18F-FMISO\]) PET/CT is the most widely used one in the clinic. Studies have demonstrated an excellent correlation between the 18F-FMISO uptake and oxygenation status of several cancers including breast cancer.

The major aim of our study was to analyze uptake of 18FFMISO as well as the IHC expression of HIF-1-alpha in ER-positive breast cancers, and to predict the clinical, pathological and biological response of primary endocrine therapy.

Study Timeline

• Study Start: 2012-03
• Status Verified: 2013-03
• Study First Submitted: 2013-03-16
• Study First Submitted QC: 2013-03-19
• Last Update Submitted: 2013-03-19
• Study First Posted: 2013-03-20
• Last Update Posted: 2013-03-20
• Primary Completion: 2014-02
• Study Completion: 2014-05

Recruitment & Eligibility

• Status: UNKNOWN
• Sex: Female
• Target Recruitment: 130

Inclusion Criteria

1. Postmenopausal female
2. With primary invasive ER positive breast cancer pathologically approved by core needle biopsy
3. The target lesion must be measurable and maximum diameter should be over 2cm.
4. Require and accept Endocrine therapy
5. Never treated with endocrine therapy before
6. Patients must have an ECOG performance status of 0 to 2
7. Leucocyte count must be ≥ 3.0*10^9/L and platelet count must be ≥ 40*10^9/L; AST/SGOT or ALT/AGPT must be < 2 times the ULN; serum creatinine must be < 2 times the ULN

Exclusion Criteria

1. Patients with brain and liver metastasis
2. Previous history of severe heart dysfunction (above Class III), infection, osteoporosis, bone related event or disease in endocrine system
3. Combination of other anticancer therapy, with the exception of biphosphonate

Study & Design

• Study Type: OBSERVATIONAL
• Study Design: Not specified

Arm && Interventions

Group	Intervention	Description
Hypoxic Group	18FMISO PET/CT scan	Higher 18FMISO uptake (Target to background Ratio, TBR\>1.2) in Primary breast cancer by 18FMISO PET/CT scan.Primary endocrine therapy Letrozole was given to the patients.
Non-Hypoxic Group	18FMISO PET/CT scan	Lower 18FMISO uptake (TBR\<1.2)in primary breast cancer by 18FMISO PET/CT scan.Primary endocrine therapy letrozole was given to the patients.
Hypoxic Group	Letrozole	Higher 18FMISO uptake (Target to background Ratio, TBR\>1.2) in Primary breast cancer by 18FMISO PET/CT scan.Primary endocrine therapy Letrozole was given to the patients.
Non-Hypoxic Group	Letrozole	Lower 18FMISO uptake (TBR\<1.2)in primary breast cancer by 18FMISO PET/CT scan.Primary endocrine therapy letrozole was given to the patients.

Primary Outcome Measures

Name	Time	Method
Clinical Objective Response	4 months	Tumor response was evaluated according to the criteria of the World Health Organization. Clinical tumor progression (PD) was defined as an increase of at least 25% in tumor size; stable disease (SD) as an increase of less than 25% or a reduction of less than 50%; partial response (cPR) as a tumor shrinkage greater than 50%; and complete response (cCR) as the complete disappearance of all clinical signs of disease.

Secondary Outcome Measures

Name	Time	Method
Pathological Response	4 months	Including pathological complete response (pCR or Grade 5),pathological partial response (pPR or Grade 3-4) and pathological non-response (NR or Grade 1-2).
Depression of Ki67 score	3 months	A biological response of Ki67 depression was tested on a second core needly biopsy on the primary site of the breast cancer after 3 months of primary endocrine therapy. Ki67\>=15% was regarded as a biological resistance to primary endocrine therapy

Trial Locations

Locations (1)

Cancer Hospital/ Institute, Fudan University; 🇨🇳 Shanghai, Shanghai, China