Relationship Between Hypoxia and Endocrine Response in Human Breast Cancer

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

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

Study Overview

• Status: Unknown
• Conditions: Hypoxia; Breast Cancer
• Intervention / Treatment: 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 Type: Observational
• Enrollment (Anticipated): 130

Contacts and Locations

Study Locations

• China
  • Shanghai
    • Shanghai, Shanghai, China, 200032
      • Recruiting
      • Cancer Hospital/ Institute, Fudan University
      • Contact: Zhimin Shao, M.D.; Phone Number: 8808 862164175590; Email: zhimingshao@yahoo.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 60 years to 90 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Probability Sample

Study Population

Postmenopausal women who had ER-a-positive breast cancer at stages II-IV and had never received prior endocrine therapy were considered eligible for this study.

Description

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 Plan

How is the study designed?

Design Details

• Observational Models: Case-Control
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Clinical Objective Response	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.	4 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pathological Response	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).	4 months
Depression of Ki67 score	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	3 months

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Disease free survival	An early recurrence of the disease during adjuvant endocrine therapy was also regarded as a resistance to endocrine therapy	5 years

Collaborators and Investigators

• Sponsor: Fudan University
• Investigators: Principal Investigator: Guangyu Liu, M.D., Cancer Hospital/Institute,Fudan University

Study record dates

Study Major Dates

• Study Start: March 1, 2012
• Primary Completion (Anticipated): February 1, 2014
• Study Completion (Anticipated): May 1, 2014

Study Registration Dates

• First Submitted: March 16, 2013
• First Submitted That Met QC Criteria: March 19, 2013
• First Posted (Estimate): March 20, 2013

Study Record Updates

• Last Update Posted (Estimate): March 20, 2013
• Last Update Submitted That Met QC Criteria: March 19, 2013
• Last Verified: March 1, 2013

More Information

Terms related to this study

• Keywords: Breast cancer; Hypoxia; Treatment resistance; Endocrine therapy; Hypoxia related gene
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Signs and Symptoms, Respiratory; Breast Neoplasms; Hypoxia; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Hormones, Hormone Substitutes, and Hormone Antagonists; Hormone Antagonists; Aromatase Inhibitors; Steroid Synthesis Inhibitors; Estrogen Antagonists; Letrozole
• Other Study ID Numbers: 20120224.1.1