Consider Second Opinion if HER2 Test Is Negative

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A study suggests that HER2 test results may not be interpreted correctly, even at expert labs. Doctors may need to consider ordering another HER2 test if the pathology report says a breast cancer is HER2-negative. These results were presented at the 2010 San Antonio Breast Cancer Symposium (SABCS).

HER2-positive breast cancers have too many copies of the HER2/neu gene, which 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.

Herceptin (chemical name: trastuzumab) and Tykerb (chemical name: lapatinib) are targeted therapies that are used to treat HER2-positive breast cancer. These targeted therapies work by attaching to the HER2 protein and blocking it from receiving growth signals. Herceptin and Tykerb usually don't work on HER2-negative cancers.

Herceptin is approved by the U.S. Food and Drug Administration (FDA) to treat advanced-stage, HER2-positive breast cancers and to lower the risk of recurrence of early-stage, HER2-positive breast cancer with a high risk of recurrence. Herceptin is given intravenously.

Tykerb is approved by the FDA to be used in combination with the chemotherapy medicine Xeloda (chemical name: capecitabine) to treat HER2-positive, metastatic breast cancer that has stopped responding to certain chemotherapy medicines and Herceptin. Tykerb also is approved to be used in combination with the hormonal therapy Femara (chemical name: letrozole) to treat postmenopausal women diagnosed with hormone-receptor-positive, HER2-positive, advanced-stage breast cancer. Tykerb is a pill taken by mouth.

There are two tests used to figure out a breast cancer's HER2 status. The IHC (ImmunoHistoChemistry) test measures the HER2 receptor protein. The FISH (Fluorescence In Situ Hybridization) test counts copies of the HER2 gene.

In this study, 389 breast cancer tissue samples were each tested for HER2 status at three expert cancer labs (also called central labs). The HER2 test results were reviewed and approved by the pathologists at each lab. The researchers then looked at whether the three labs had different HER2 status results for a tissue sample to see how accurate the test results were.

Even though the three central labs are considered expert labs, 8% of the HER2 test results -- no matter if IHC or FISH was used -- were wrong after the results were reevaluated.

HER2 test results are not always absolutely positive or absolutely negative. Labs have different rules for classifying positive and negative HER2 status. Each pathologist also may use slightly different criteria to decide whether the results are positive or negative.

In spite of these different criteria for classifying HER2 test results, when conflicting test results were reviewed by small groups of pathologists in face-to-face meetings, 96% to 97% of the time they ultimately agreed on the HER2 status of the tissue sample.

In up to 10% of the tissue samples tested, the pathologists found that tissue from one area of a breast cancer was HER2-positive while tissue from another area of the same breast cancer was HER2-negative.

Even though FISH HER2 testing is considered more accurate than IHC testing, the researchers found that the two tests usually gave the same results (called high concordance). The FISH test is not as widely available as the IHC test. Still, since FISH is considered more accurate, many smaller labs will do the IHC test first and order the FISH test (which is often done at a central lab) only if the IHC results aren't strongly HER2-positive or HER2-negative.

Small, local labs classified 103 tissue samples as HER2-positive. When the same samples were evaluated at the central labs with both IHC and FISH testing, the cancer was shown to be HER2-negative.

Inaccurate HER2 test results may cause women diagnosed with breast cancer to not get the best care possible. If all or part of a breast cancer is HER2-positive but test results classify it as HER2-negative, doctors aren't likely to recommend Herceptin or Tykerb treatment -- even though the woman could potentially benefit from those medicines. If a breast cancer is HER2-negative but test results classify it as HER2-positive, doctors may recommend Herceptin or Tykerb treatment -- even though the woman is unlikely to get any benefits and is exposed to the medicines' risks.

Based on the results of this study, the researchers suggest:

  • HER2 test results be reviewed by more than one pathologist when the results are borderline
  • multiple areas of a tissue sample be tested; this study showed that in up to 10% of cases some areas of the cancer sample may be HER2-positive while other areas are HER2-negative
  • ordering repeat testing for cancers that are initially classified as HER2-negative to ensure that all women get the best care possible

No matter what type of breast cancer you've been diagnosed with, you might want to talk to your doctor about this study. It's worth asking your doctor about how confident he or she is in the lab that did the HER2 testing on your tissue samples and if additional HER2 testing might make sense for your unique situation.

You can learn more about HER2 and other breast cancer tests in the Pathology Report pages.

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