Phase 2 Study of Lovastatin as Breast Cancer Chemoprevention

A Phase 2 Trial of Lovastatin for Modification of Abnormal Breast Duct Cytology and Risk-Associated Biomarkers in Women at High Inherited Risk of Breast Cancer

The study evaluates if a 6-month course of oral lovastatin at 80 mg/day would decrease abnormal breast duct cytology in women with a high inherited breast cancer risk.

Study Overview

• Status: Terminated
• Conditions: Breast Cancer
• Intervention / Treatment: Drug: Lovastatin

Detailed Description

The study evaluates if a 6-month course of oral lovastatin at 80 mg/day (as 40 mg twice-a-day) would decrease abnormal breast duct cytology in women with a high inherited breast cancer risk. Breast duct cytology was assessed as hyperplasia or hyperplasia with atypia, as measured by random periareolar fine needle aspiration (rpFNA), of breast duct cells.

A stratified analysis of this objective will be performed according to BRCA mutation status (absence or presence of an inherited deleterious BRCA1 or BRCA2 mutation).

Additional objectives of the study are to:

• Assess change in mammographic density, which is known to associate with breast cancer risk, before and after treatment with lovastatin
• Asess incidence of breast cancers and new high-risk breast lesions, including atypical hyperplasia, ductal or lobular carcinoma in situ, or radial scar.

• Assess change in other breast cancer risk-associated biomarkers in rpFNA specimens, including:

  • Ki-67 (a marker of cell proliferation)
  • Estrogen receptor (ER)
  • Progesterone receptor (PR)
  • HER/2-neu over-expression
  • Susceptibility to DNA damage

• Study Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Stanford, California, United States, 94305
      • Stanford University Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

INCLUSION CRITERIA

• Female

• Increased inherited risk of breast cancer, as defined by:

  • Known deleterious mutation in BRCA1, BRCA2, or other high-risk mutation
  • Family history conveying at least a 2-fold increase in breast cancer risk
• ECOG performance status 0
• Normal organ and marrow function, including complete blood count and comprehensive metabolic panel within normal institutional limits
• Subject agreement to limit alcoholic beverage consumption to three alcoholic drinks per week.

EXCLUSION CRITERIA

• Prior history of invasive breast cancer less than 2 years previously (EXCEPTION: stage III or lower breast cancer > 2 years ago)
• Current or history of other cancers (EXCEPTION: non-melanoma skin cancer, or stage III or cancer without evidence of recurrence for 5 years
• Initial mammogram, breast MRI, or clinical breast examination prompts recommendation for biopsy by study investigators.
• Evidence of malignant cytology on initial rpFNA.
• Use of other investigational agents.
• Use of tamoxifen or selective estrogen response modifiers (SERMS), including raloxifene, within the last 2 years.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to lovastatin.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection; symptomatic congestive heart failure; unstable angina pectoris; cardiac arrhythmia; or psychiatric illness/social situations that would limit compliance with study requirements.
• Currently receiving lovastatin and cyclosporine, gemfibrozil, erythromycin, fibrates or niacin, (unless discontinued for study participation)
• No evidence of active liver disease, nor elevation of serum transaminases (prior history of liver disease, if not currently active, is not an exclusion)
• No evidence of myopathy or myositis, including symptoms of generalized muscle aches or weakness, muscle tenderness, or elevation in creatine phosphokinase.
• Lactating (breastfeeding)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Lovastatin 80 mg/day; Lovastatin 80 mg/day as 40 mg orally twice daily, for 6 months.	Drug: Lovastatin; Lovastatin 80 mg/day as 40 mg orally twice daily. Lovastatin is approved by FDA as a cholesterol-lowering agent.; Other Names: Mevacor; Altoprev; Advicor (as a combination with niacin); Altocor; Statosan (Atos Pharma)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in the Incidence of Abnormal Breast Duct Cytology After Treatment With Lovastatin 80 mg/Day	Assessed on that basis of pre- and post-treatment evaluation with RPFNA (random periareolar fine needle aspiration). All subjects received a prescription for lovastatin 80 mg/day, to be taken as 40 mg twice-a-day. Cytology was qualitatively and quantitatively, using the Masood semiquantitative scale to assign a number to each specimen, with higher numbers indicating increasing degrees of abnormality, as follows: 06-10 Non-proliferative breast disease (NPBD) 11-14 Proliferative breast disease without atypia (PBD-A) 15-18 Proliferative breast disease with atypia (PBD+A) 19-24 Carcinoma in situ and invasive cancer (CIS/IC) If no cells could be obtained after multiple RPFNA attempts, the classification was acellular. Change from NPBD to PBD-A was considered Unfavorable. Change from NPBD to Acellular was considered Equivocal. Change from PBD-A to NPBD was considered Favorable.	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Mammographic Density Before and After Treatment With Lovastatin 80 mg/Day	Bilateral mammography was performed at study entry (before lovastatin therapy) and at study conclusion (after lovastatin therapy) . Mammograms were assessed for a decline in mean breast density, using the American College of Radiology Breast Imaging Reporting and Data System (BI-RAD) composition system for mammographic density assessment. Category 0 Need additional imaging evaluation; Negative; Benign; Probably benign; Suspicious abnormality; Highly suggestive of malignancy; Known biopsy-proven malignancy	6 months
Change in Total Cholesterol After Treatment With Lovastatin 80 mg/Day		6 months
Change in Low Density Lipoprotein (LDL) After Treatment With Lovastatin 80 mg/Day		6 months

Collaborators and Investigators

• Sponsor: Stanford University
• Investigators: Principal Investigator: James Ford, MD, Stanford University

Publications and helpful links

General Publications

• Vinayak S, Schwartz EJ, Jensen K, Lipson J, Alli E, McPherson L, Fernandez AM, Sharma VB, Staton A, Mills MA, Schackmann EA, Telli ML, Kardashian A, Ford JM, Kurian AW. A clinical trial of lovastatin for modification of biomarkers associated with breast cancer risk. Breast Cancer Res Treat. 2013 Nov;142(2):389-98. doi: 10.1007/s10549-013-2739-z. Epub 2013 Oct 29.

Study record dates

Study Major Dates

• Study Start: November 1, 2005
• Primary Completion (Actual): May 1, 2010
• Study Completion (Actual): December 1, 2010

Study Registration Dates

• First Submitted: January 31, 2006
• First Submitted That Met QC Criteria: January 31, 2006
• First Posted (Estimate): February 2, 2006

Study Record Updates

• Last Update Posted (Actual): March 9, 2017
• Last Update Submitted That Met QC Criteria: January 19, 2017
• Last Verified: January 1, 2017

More Information

Terms related to this study

• Keywords: duct cytology
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms; Neoplasms by Site; Breast Diseases; Breast Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites; Anticholesteremic Agents; Hypolipidemic Agents; Lipid Regulating Agents; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lovastatin; L 647318; Dihydromevinolin
• Other Study ID Numbers: IRB-13732; BRSNSTU0010 (Other Identifier: OnCore); 95505 (Other Identifier: Stanford University Alternate IRB Approval Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO