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Common genetic change found in some tumors of patients who relapse after aromatase inhibitor treatment


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About one in five people diagnosed with estrogen receptor-positive (ER+) breast cancer relapse within 10 years after treatment. Researchers and health care providers do not know why this happens. This early research aims to identify a genetic change in the tumor that may cause relapse, but more studies are needed to understand why patients relapse and who is at risk. (5/3/17)


STUDY AT A GLANCE

This study is about:

A genetic change in estrogen receptor-positive (ER+) breast cancers that may affect resistance to treatment with aromatase inhibitors.

Why is this study important?

About 20% or more of patients with ER+ breast cancers who have been treated with hormonal therapies such as selective estrogen receptor modulators (SERMs) (e.g. tamoxifen) and/or aromatase inhibitors (AIs) (e.g. letrozole) relapse within 10 years, and some progress to metastatic disease. Researchers and health care providers are unsure why these patients relapse after treatment.

Study findings: 

  1. In about 22% of ER+ breast cancer patients who relapsed after treatment with aromatase inhibitors, a specific genetic change caused much higher-than-normal levels of the CYP19A1 protein, which makes estrogen. This genetic change was:
    • not commonly found in primary breast tumors, and
    • found in very few patients who received selective estrogen receptor modulators, such as tamoxifien.
  2. Researchers created cells in the laboratory that made large quantities of CYP19A1. In these cells estrogen was able to bind to estrogen receptors, which decreased response to aromatase inhibitor treatment.

What does this mean for me?

This early work study suggests some patients treated with an aromatase inhibitor develop a genetic change in their ER+ breast tumors, leading to the patient developing resistance to their treatment. While this effort suggests that more work is needed to further study aromatase inhibitor resistance, it does not change clinical practice. It is important to note that according to this study, only about 20% of patients who receive an aromatase inhibitor develop resistance. Women with ER+ breast cancer should talk with their health care providers to determine which treatment is best for them and how to monitor for signs of relapse after treatment.

Questions to ask your health care provider:

  • What treatments are available for women with estrogen receptor-positive breast cancer?
  • How long should I remain on hormonal therapy?
  • What are the side effects of the treatment?
  • What does breast cancer relapse mean?
  • How will I know if my cancer has relapsed?

IN DEPTH REVIEW OF RESEARCH

Study background:

Estrogen receptors on the surface of the breast are the treatment target for women with estrogen receptor-positive (ER+) breast cancers. Estrogen receptors are activated when they bind with the hormone estrogen, which can lead to changes that promote breast cancer growth. Therapies for ER+ breast cancer include selective estrogen receptor modulators (SERMs), such as tamoxifen, and/or aromatase inhibitors (AIs), such as letrozole. These drugs stop tumor growth by blocking estrogen from binding to estrogen receptors. However, around 20% of patients who receive these therapies relapse (meaning their cancers return) within 10 years. Researchers do not understand why this happens.

Luca Magnani and colleagues from Imperial College London and other institutions published work in Nature Genetics in January 2017 trying to further understand the way that ER+ breast cancer patients relapse after hormonal treatment.

Researchers of this study wanted to know:

Why do some ER+ breast cancer patients relapse after aromatase inhibitor treatment?    

Population(s) looked at in the study:

The breast cancer tumors the researchers studied were from patients who:

  • had HER2-negative tumors.
  • received only an aromatase inhibitor (37 patients) or only tamoxifen, a selective estrogen receptor modulator (30 patients).
  • had at least one year of follow-up.
  • had a distant metastasis after surgery and after adjuvant therapy.

Study findings: 

  1. About 22% of ER+ breast cancer patients who were treated with an aromatase inhibitor and relapsed after treatment had a specific genetic change in their tumor that abnormally multiplied the CYP19A1 gene (responsible for making estrogen). This genetic change was:
    • not commonly found in the primary breast tumor, and
    • found in very few patients who received a selective estrogen receptor modulator, such as tamoxifen.
  2. Researchers created cells in the laboratory that produced many copies of CYP19A1.  These modified cells were found to have increased estrogen binding to estrogen receptors, which ultimately led to a decreased response to aromatase inhibitor treatment. 

Limitations:

This research study had a relatively small sample size (37 tumors from patients who received aromatase inhibitors (AIs) and 30 tumors from patients who received selective estrogen receptor modulators (SERMs)).  While these findings may explain the relapse of some ER+ breast cancer patients after treatment with an aromatase inhibitor, it does not explain why nearly one in five patients relapse.  While this early work is not clinically relevant today, more work should be done to determine whether the CYP19A1 genetic change in tumors can be used as a biomarker or target for therapy. Finally, the researchers performed some of their experiments in cells grown in the laboratory—while this is a necessary early step in understanding cancer biology, cells grown in the laboratory do not always behave the same as cells in human bodies.                    

Conclusions:

This early work suggests that aromatase inhibitor therapy may change the tumor environment in patients with estrogen receptor-positive breast cancer. However, this preliminary work is not yet clinically applicable, as more work needs to be done to understand the biology of relapsing estrogen receptor-positive breast cancer. Breast cancer patients should discuss their questions about treatment or concerns about relapse with their health care providers.

Posted 5/3/17

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References

Magnani L, Frige G, Gadaleta RM, et al. “Acquired CYP19A1 amplification is an early specific mechanism of aromatase inhibitor resistance in ERα metastatic breast cancer.” Nature Genetics. Published online first on January 23, 2017.

 

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