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ASCO, CAP Update Guidelines for HER2 Testing in Breast Cancer Patients

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The American Society for Clinical Oncology and the College of American Pathologists have jointly issued updated guidelines in which they continued to recommend that oncologists, surgeons, and pathologists establish the HER2 status of all invasive breast cancer patients, with early stage or recurrent disease.

The guidelines suggest that in order to assess whether a breast tumor is being driven by HER2 protein overexpression or HER2 gene amplification, healthcare providers use immunohistochemistry or in situ hybridization-based tests that are either approved by the US Food and Drug Administration or are performed by a lab accredited by CAP or another body.

ASCO and CAP revised their recommendations for what healthcare providers should do when test results are equivocal. According to the guidelines, pathologists should perform reflex testing using an alternative assay and repeat testing if molecular analysis of the tumor sample is discordant with histopathological characteristics of the tumor. The group did not support retesting for all HER2 negative patients, and noted that the risk of a false-positive result "declines considerably" with proficiency testing and lab accreditation.

The latest update comes six years after ASCO and CAP issued guidelines around HER2 testing for breast cancer patients. The 2007 guidelines were focused on reducing inaccurate results, and outlined criteria for specimen handling, test concordance, and test cutoffs for positive, equivocal, and negative results. ASCO and CAP estimated at the time that 20 percent of HER2 testing may be inaccurate. Back in 2007, the groups similarly recommended HER2 testing for all invasive breast cancer patients.

In the latest guidelines, ASCO and CAP acknowledged that since 2007, new platforms for gauging HER2 status have emerged and different types of HER2 genotypic abnormalities have come to light. However, upon reviewing the available evidence on newer test platforms, the groups only endorsed HER2 amplification analysis by bright-field in situ hybridization, and found insufficient evidence to recommend mRNA assays based on microarrays or RT-PCR platforms (PGx Reporter 12/21/2011).

"The Update Committee wishes to re-emphasize that it is important that any new test methodology for the same clinical use be compared with a reference test that assays for the same analyte and for which there are high levels of evidence that use of the test leads to clinical benefit for the patient (ie, clinical utility)," ASCO and CAP wrote in the guidelines.

Also with greater use of HER2 testing, ASCO and CAP highlighted unusual HER2 abnormalities that researchers have identified, such as "aneusomy of chromosome 17, colocalization of HER2 and CEP17 signals that affect HER2 /CEP17 ratio in dual-signal in situ hybridization assays, and genomic heterogeneity." Noting the rarity of these abnormalities, ASCO and CAP reviewed the available literature and provided guidance on what these markers may mean for patient care.

Between 15 percent and 20 percent of patients with primary breast cancer have HER2-positive tumors. Establishing HER2-status for breast cancer patients helps oncologists determine whether they should be treated with drugs that interrogate the HER2/neu receptor, such as Roche/Genentech's Herceptin (trastuzumab).

Another Genentech drug, called Perjeta (pertuzumab), inhibits the HER2 receptor from binding with other HER receptors and is approved for metastatic HER2-positive breast cancer patients. A third treatment option for advanced breast cancer patients with HER2-positive tumors is Genentech's Kadcyla (trastuzumab emtansine), which is an antibody drug conjugate linking Herceptin with a cytotoxic agent. ASCO and CAP also pointed out that clinical data suggests that GlaxoSmithKline's Tykerb (lapatinib) in combination with paclitaxel doesn't offer any benefit to metastatic breast cancer patients who are HER2 negative.

In the guidelines, the groups support giving HER2-positive breast cancer patients 12 months of Herceptin, after data from two studies suggested last year that one year of treatment with the drug should remain the standard of care. One study, comparing two years of treatment to one year of treatment, showed that those receiving the drug for 12 months had statistically significant overall and disease free survival. Another trial, comparing six months of treatment to one year of treatment, was inconclusive for non-inferiority.

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