Study: Early research on a drug to prevent breast cancer


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Women with a BRCA1 mutation

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Many researchers are interested in non-surgical options to reduce the higher-than-average risk of developing breast cancer in BRCA mutation carriers. This research study identified a type of drug, called a “RANK ligand inhibitor,” that may prevent breast cancer. Among mice that were genetically engineered to have no BRCA1 genes, those that were given the drug developed tumors less frequently than those that did not. While this is an exciting early study for BRCA mutation carriers, more work and human clinical trials need to be done before this can be used as a prevention therapy in humans. (7/12/16)

Update added 11/24/19: The RANK ligand inhibitor, denosumab is currently being studied as a possible breast and ovarian cancer preventive agent in human clinical trials.

Contents

At a glance                    Questions to ask your doctor
Findings     In-depth            
Guidelines Limitations
Clinical trials       Resources and references


STUDY AT A GLANCE

This study is about:

Whether inhibiting a potential new target (RANK ligand) can help prevent breast cancer in BRCA1 mutation carriers.

Why is this study important?

Women who carry a BRCA1 mutation have an approximately 65% risk of developing breast cancer by the time they are 70 years old, and they often develop more aggressive tumors at an earlier age than women who do not have mutations. To lower their breast cancer risk, BRCA1 carriers can opt to undergo prophylactic mastectomy or take risk-reducing medications such as tamoxifen or raloxifene.  However, no current medication reduces breast cancer risk as much as surgery.

Study findings: 

  1. Mice that were genetically engineered to have no BRCA1 genes and were given a drug known as a RANK ligand inhibitor developed fewer breast tumors compared to mice that were not given the drug.

What does this mean for me?

This interesting early work suggests drugs that inhibit RANK ligand might prevent breast cancer in BRCA1 carriers. However, more work needs to be done before inhibiting RANK ligand becomes an established method of prevention—drugs that work well in mice don’t necessarily work well for humans. Mice can be used to model a human disease, but differences between the species means that drugs that work in one do not always work in the other.

Some media outlets called the RANK ligand inhibitor drug the ‘holy grail’ of breast cancer prevention for BRCA1 mutation carriers. But these headlines are misleading and inaccurate because this study was only done in mice and cells grown in the lab. Clinical trials need to determine whether this drug works for humans. BRCA1 mutation carriers should talk to their health care providers to determine which method of breast cancer risk reduction they are most comfortable with.

Expert Guidelines

The National Comprehensive Cancer Network (NCCN) is a panel of top cancer experts who create national guidelines detection, prevention and treatment of cancer. NCCN publishes guidelines for people at high risk for breast cancer due to an inherited mutation. The guidelines for women with a BRCA1 or BRCA2 mutation include:

Breast cancer screening

  • Learning to be aware of changes in breasts beginning at age 18
  • Clinical breast exam every 6-12 months beginning at age 25
  • Annual breast MRI with contrast (or mammogram if MRI is unavailable) beginning at age 25 
  • Annual breast MRI with contrast and mammogram at ages 30-75
  • Consider 3D mammography if available
  • Screening after age 75 should be considered on an individual basis
  • Consider participation in an imaging or screening clinical trial

Breast cancer risk reduction

  • Discussion of risk-reducing mastectomy
  • Consider medication to reduce breast cancer risk​

Questions To Ask Your Health Care Provider

  • I am a BRCA1 mutation carrier. What can I do to lower my breast cancer risk?
  • I am a BRCA mutation carrier who has not had cancer. Are there clinical trials looking at new ways to prevent cancer, and do I qualify for them?
  • Are there currently drugs available to lower the risk of breast cancer in BRCA mutation carriers?

Open Clinical Trials

Study looking at RANKL inhibitor for breast cancer prevention:

  • NCT04067726: RANKL Inhibition and Mammographic Breast Density. Data supporting a role for RANKL signaling in mammographic density and breast cancer development has begun to emerge, but clinical trial data providing definitive evidence that would allow the adoption of RANKL inhibition in primary breast cancer prevention are not yet available. The hypothesis is that RANKL inhibition with denosumab will decrease mammographic density in high-risk premenopausal women with dense breasts.    

Additional studies for breast cancer prevention in high-risk women:

Study looking at RANKL inhibitor for ovarian cancer prevention: 

 

IN DEPTH REVIEW OF RESEARCH

Study background:

BRCA1 mutation carriers are predisposed to developing breast cancer that is more aggressive and occurs earlier than breast cancer in the general population. Women with BRCA1 mutations are counseled to undergo one or more risk management strategies, such increased screening, which does not prevent cancer but can catch it at an earlier stage; risk-reducing medication; and/or risk-reducing surgeries.  While these strategies have helped many women reduce their risk of cancer, there is still a need for better nonsurgical means of cancer prevention in BRCA mutation carriers.

Researchers of this current study explored the use of a type of drug known as a RANK ligand inhibitor for breast cancer prevention in BRCA1 mutation carriers. Emma Nolan and her colleagues at the Walter and Eliza Hall Institute of Medical Research and other institutions published research in Nature Medicine that explores what happens when RANK ligand is inhibited.   

Researchers of this study wanted to know:

Can inhibiting RANK ligand be used as a method for breast cancer prevention in BRCA1 mutation carriers?

Population(s) looked at in the study:

This research used a number of different laboratory models of breast cancer.

  • For some of the experiments, the researchers used breast tissue from 33 premenopausal women undergoing breast reduction surgery (used as the ‘wild type’ control) and 24 BRCA1 mutation carriers undergoing prophylactic mastectomies (Study Findings #3 and #4).
  • They also used human breast tumors from the Amgen Tissue Bank cohort in one of their experiments (Study Findings #1 and 2).
  • For the remainder of the experiments (Study Finding #5), researchers used mice that were genetically engineered to have no BRCA1 genes in their breast tissue (these mice have been shown to develop breast cancers that are similar to human breast cancer).  Note that differs from humans, who have one defective and one healthy BRCA1 gene.

Study findings: 

  1. RANK ligand, the target of the drug in this study, is found in much higher levels in BRCA1-mutated tumors compared to tumors with normal BRCA1.
  2. RANK ligand was not found in significantly higher levels in BRCA2-mutated breast tumors.
  3. Breast tissue cells from BRCA1 patients that had the RANK ligand formed tumors more easily in the laboratory than cells from the same BRCA1 patients that did not have the RANK ligand.
  4. BRCA1-mutated cells that had the RANK ligand were more sensitive to DNA damage than BRCA1-mutated cells that did not have the RANK ligand.
  5. Mice that were genetically engineered to have no BRCA1 genes and were given the RANK ligand inhibiting drug developed fewer breast tumors compared to the control mice, which were also BRCA1 mutated but were not given the inhibitor.
    • 11 of 17 mice given the RANK ligand inhibitor did not develop tumors by the researchers’ chosen end date for the experiment.

Limitations:

While the results are interesting, this is primarily a mouse study with some data in human cells to back it up. More work needs to be done to translate these findings to the clinic, particularly clinical trials to show that the drug is safe for long-term use and effective in preventing breast cancer. Additionally, the mice used in the experiment with the RANK ligand inhibitor were genetically engineered to have no BRCA1 genes. This is different than humans with BRCA1 mutations, who start off with one good copy of BRCA1 (out of the two that they inherited from their parents).  

Conclusions:

The results of this study suggest that inhibiting RANK ligand may help prevent breast cancer in mice with BRCA1 mutations. More work needs to be done before this can be used as a breast cancer prevention therapy in BRCA1 mutation carriers.  FORCE agrees with the Health News Review critique that media reports using the term “holy grail” to describe this early study were misleading. However, this is still an important first step towards developing a new option for BRCA1 mutations carriers who wish to delay or avoid risk-reducing surgery.  

For now, women who are interested in new risk-reducing measures that do not involve surgery should talk to their heath care provider about participating in clinical trials for breast cancer prevention in high-risk women or use our hereditary cancer research database to find clinical research studies that are enrolling people affected by hereditary cancer.

Posted 7/12/15

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