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Why Do Some HER2-Positive Breast Cancers Not Respond to Herceptin?

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Herceptin (chemical name: trastuzumab) is a targeted therapy medicine used to treat HER2-positive breast cancer.

HER2-positive breast cancers make too much of the HER2 protein. The HER2 protein sits on the surface of cancer cells and receives signals that tell the cancer to grow and spread. About one out of every four breast cancers is HER2-positive. HER2-positive breast cancers tend to be more aggressive and harder to treat than HER2-negative breast cancers.

Herceptin works by attaching to the HER2 protein and blocking it from receiving growth signals. Herceptin, which is given intravenously, is approved by the U.S. Food and Drug Administration (FDA) to:

  • treat advanced-stage, HER2-positive breast cancers
  • be given to women with earlier stages of HER2-positive disease as adjuvant treatment (treatment after initial treatment, such as surgery) either alone or as part of a regimen with chemotherapy

A newer form of Herceptin, Herceptin Hylecta (chemical name: trastuzumab and hyaluronidase-oysk), can be given as an injection.

While Herceptin works very well in most cases, some HER2-positive breast cancers don’t respond as well to Herceptin, and doctors have been trying to figure out why this happens.

A study suggests that strongly estrogen-receptor-positive breast cancers with a low FISH test ratio are less likely to respond to Herceptin.

The research was published online on April 21, 2016 by JAMA Oncology. Read the abstract of “Effects of Estrogen Receptor and Human Epidermal Growth Factor Receptor-2 Levels on the Efficacy of Trastuzumab: A Secondary Analysis of the HERA Trial.”

The HER2 status of a cancer is determined by a test that measures either the level of HER2 protein in cancer cells or the number of HER2 genes in cancer cells. There are four tests for HER2 status, one of which is the FISH (Fluorescence In Situ Hybridization) test.

The FISH test measures the number of copies of the HER2 gene, as well as the HER2-to-CEP17 ratio. CEP17 stands for chromosome enumeration probe 17, which means that the cancer cells have more than one chromosome 17. Cancers that have more than one chromosome 17 are more likely to have more copies of the HER2 gene. The HER2-to-CEP17 ratio is sometimes considered a better indicator of whether a cancer is HER2-positive. The higher the ratio, the more HER2-positive a cancer is.

To do this study, the researchers looked at information from the HERA trial. The HERA trial included more than 5,000 women diagnosed with early-stage, HER2-positive breast cancer between 2001 and 2005 and found that giving Herceptin after adjuvant chemotherapy reduced the risk of recurrence (the cancer coming back) better than just chemotherapy after surgery.

This study focused on 3,652 women in the HERA trial who received either 1 or 2 years of Herceptin after surgery and chemotherapy.

For 3,037 women, the researchers had information on:

  • FISH ratio
  • estrogen receptor levels in the cancer
  • number of copies of the HER2 gene in the cancer

These women were called group one.

For 615 women, the researchers had information on:

  • transcript levels of the ESR1 and HER2 genes in the cancer

These women were called group two.

Transcription is the first step in a gene’s job of creating proteins. So knowing the transcript levels of the ESR1 and HER2 genes is similar to knowing how many copies of each gene there are in the cancer.

The ESR1 gene creates estrogen receptors in a cell. So the more copies of the gene, the more estrogen receptors a cancer cell has.

The women were followed for about 8 years.

The researchers found that breast cancers that were estrogen-receptor-negative had more copies of the HER2 gene compared to cancers that were estrogen-receptor-positive. This difference was statistically significant, which means that it was likely due to the difference in estrogen receptor status and not just because of chance.

In group one, most cancers responded well to Herceptin, except cancers that were estrogen-receptor-positive and had a low FISH ratio (from 2 to less than 5).

In group two, cancers with high levels of the ESR1 gene got less benefit from Herceptin.

The researchers said the results suggest that some strongly estrogen-receptor-positive breast cancers that are also HER2-positive may be more responsive to anti-estrogen treatments, such as tamoxifen or the aromatase inhibitors, than they are to anti-HER2 treatments, such as Herceptin.

If you’ve been diagnosed with early-stage breast cancer that is estrogen-receptor-positive and HER2-positive and are making decisions about treatments after surgery or are already being treated with Herceptin but the cancer is not responding well, you may want to talk to your doctor about this study.

Ask which tests were used to determine the HER2 status and estrogen receptor status of the cancer. You also can ask if the tests reported the number of copies of the ESR1 gene and the FISH ratio (if the FISH test was done). It may be that another medicine besides Herceptin would be more effective for you.

Together, you and your doctor can figure out the best treatment plan for your unique situation.

And stay tuned to for the latest research findings that may lead to new, better ways to prevent, diagnose, and treat breast cancer.

Editor’s Note: This article was updated with information about Herceptin Hylecta, which the FDA approved on Feb. 28, 2019.

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