Relationship Between Hypoxia and Endocrine Response in Human Breast Cancer

Sponsor

Fudan University (Other)

Overall Status

Unknown status

CT.gov ID

NCT01814449

Collaborator

(none)

130

Enrollment

Location

Duration (Months)

Patients Per Site Per Month

Study Details

Study Description

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

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer Hypoxia	Other: 18FMISO PET/CT scan Drug: Letrozole

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 Design

Study Type:

Observational [Patient Registry]

Anticipated Enrollment :

130 participants

Observational Model:

Case-Control

Time Perspective:

Prospective

Official Title:

Department of Breast Surgery And Department of Nuclear Medicine, Fudan University Shanghai Cancer Center,

Study Start Date :

Mar 1, 2012

Anticipated Primary Completion Date :

Feb 1, 2014

Anticipated Study Completion Date :

May 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Hypoxic Group 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.	Other: 18FMISO PET/CT scan The baseline 18F-FMISO PET/CT scans were scheduled before initiation of endocrine therapy. All patients were injected intravenously with 370 MBq of 18F-FMISO and PET/CT static emission scans were conducted at 4 hours after injection. Drug: Letrozole Patients were assigned to primary endocrine therapy with letrozole 2.5mg daily for at least 4 months.
Non-Hypoxic Group Lower 18FMISO uptake (TBR<1.2)in primary breast cancer by 18FMISO PET/CT scan.Primary endocrine therapy letrozole was given to the patients.	Other: 18FMISO PET/CT scan The baseline 18F-FMISO PET/CT scans were scheduled before initiation of endocrine therapy. All patients were injected intravenously with 370 MBq of 18F-FMISO and PET/CT static emission scans were conducted at 4 hours after injection. Drug: Letrozole Patients were assigned to primary endocrine therapy with letrozole 2.5mg daily for at least 4 months.

Arm

Intervention/Treatment

Hypoxic Group

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.

Other: 18FMISO PET/CT scan

The baseline 18F-FMISO PET/CT scans were scheduled before initiation of endocrine therapy. All patients were injected intravenously with 370 MBq of 18F-FMISO and PET/CT static emission scans were conducted at 4 hours after injection.

Drug: Letrozole

Patients were assigned to primary endocrine therapy with letrozole 2.5mg daily for at least 4 months.

Non-Hypoxic Group

Lower 18FMISO uptake (TBR<1.2)in primary breast cancer by 18FMISO PET/CT scan.Primary endocrine therapy letrozole was given to the patients.

Other: 18FMISO PET/CT scan

Drug: Letrozole

Patients were assigned to primary endocrine therapy with letrozole 2.5mg daily for at least 4 months.

Outcome Measures

Primary Outcome Measures

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

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

Other Outcome Measures

Disease free survival [5 years]
An early recurrence of the disease during adjuvant endocrine therapy was also regarded as a resistance to endocrine therapy

Eligibility Criteria

Criteria

Ages Eligible for Study:

60 Years to 90 Years

Sexes Eligible for Study:

Female

Accepts Healthy Volunteers:

Inclusion Criteria:

Postmenopausal female
With primary invasive ER positive breast cancer pathologically approved by core needle biopsy
The target lesion must be measurable and maximum diameter should be over 2cm.
Require and accept Endocrine therapy
Never treated with endocrine therapy before
Patients must have an ECOG performance status of 0 to 2
Leucocyte count must be ≥ 3.010^9/L and platelet count must be ≥ 4010^9/L; AST/SGOT or ALT/AGPT must be < 2 times the ULN; serum creatinine must be < 2 times the ULN

Exclusion Criteria:

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