UPDATED GUIDELINES FOR HER2 TESTING

The new update to clinical practice guidelines for HER2 testing in breast cancer has recommendations to improve the accuracy of this testing, helping to ensure that no woman misses out on potential life-saving therapy with HER2-targeted drugs.

The update, issued jointly by the American Society of Clinical Oncology and the College of American Pathologists, waspublished online October 7 in the Journal of Clinical Oncology.

Testing for HER2 status in breast cancer and use of targetedHER2 therapy further "paves the way" for personalized therapy in oncology, lead author Antonio Wolff, MD, professor of oncology at the Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, commented in an interview withMedscape Medical News.

Breast cancer has led the way for this approach, beginning in the 1970s with testing for estrogen-receptor (ER) status and the use of endocrine therapies such as tamoxifen, and then in the late 1990s with the breakthrough findings that showed significantly improved survival in women with HER2-positive breast cancer with the first HER2-targeted therapy trastuzumab (Herceptin).

Other areas of oncology are only now catching up, with the last few years seeing progress with targeted therapies in lung cancer, which now requires testing for EGFR and ALK mutations, and also in colorectal cancer, which now requires testing for KRAS mutations.

Targeted HER2 therapy has also expanded, and there are now 3 more agents available — lapatinib (Tykerb), pertuzumab (Perjeta), and T-DM1 (Kadcyla). These agents offer dramatic benefits in breast cancer, but only for women whose tumors are positive for HER2 (about 15% to 20% of primary breast tumors).

Which is why testing for HER2 is so important, to find the women most likely to be helped by these therapies, Dr. Wolff said.

At the same time, identifying women who are not HER2-positive spares these women from undergoing treatment from which they are unlikely to benefit, avoids toxicities, and also saves costs, which can be substantial. A year of treatment with trastuzumab costs around $70,000 in the United States, and the newer drugs are even more expensive.

HER2 Testing Widely Used

The guidelines recommend that all women with invasive breast cancer (primary or recurrence) are tested for HER2 status, and across the United States this is being implemented, he said. The updated guidelines cite a published study that examined a period from 2003 to 2004 and found that 90% of women with primary invasive cancer had evidence of HER2 testing (Cancer. 2010;16:2549-2559). Dr. Wolff believes that the figure would be even higher now, with probably more than 95% of breast cancer being tested.

"I do believe that the vast majority of women in the United States are tested, but this is not the case in other parts of the world," he commented. It is particularly a problem in lower-income countries, as theHER2 therapies are expensive, he added.

The guideline outlines details of sample preparation and HER2 testing, which can be carried out by 2 different platforms — either immunohistochemistry to measure protein expression, or in situ hybridization to measure gene amplification.

"It doesn't matter which test is used, assuming it is properly developed and validated," Dr. Wolff said. "It's not a question of using the right test, it's an issue of doing the test right," he said.

In the majority of cases, testing will give a clear answer, showing either HER2-positive or HER2-negative status, but in about 5% of cases or less, the answer is equivocal. In these cases, the test should be repeated, but using the other testing platform to that used in the first case, he explained.

The guidelines states: "Delay the decision to recommend HER2-targeted therapy if the HER2 test result is equivocal. Mandatory retesting should be done on the same specimen using the alternative test if the initial HER2 test result is equivocal or on an alternative specimen."

The proportion of tests that come back with equivocal results has been greatly reduced, Dr. Wolff commented. Previously, about 5% to 10% of tests would fall into this grey area, but after improvements in standardization and tissue handling that are outlined in the updated guidelines, fewer tests now come back equivocal, he said.

However, despite the updated guidelines, a clear and definitive answer will not always be possible for a very small number of patients. The guidelines note: "In rare cases, it may be difficult to know for sure if the result is positive or negative. If additional testing on other tissue specimens is not possible, pathologists and oncologists should consider all available clinical data on the patient prior to recommending HER2-targeted therapy."

Test Results Should Fit With Clinical Picture

Dr. Wolff emphasized the importance of taking into account other test results and the whole clinical picture when looking at the HER2 results, and then asking, "Do the results make sense?"

"The results should be in keeping with the general clinical picture," he said.

"It's important to apply context," he explained. For example, if a tumor is low grade, measures of proliferation are low, and ER testing is positive, all of which might suggest a less aggressive tumor type, but if the HER2 test comes back positive, then he suggests a double-check. "I would want some reassurance from the pathologist on the test result," he said.

Dr. Wolff also suggested that it is worth retesting if the clinical course of the disease is surprising. For example, he hypothesized about a case in which other pathological features point to a low-grade tumor, and the HER2 test in the original primary tumor came back negative, but then the patient went on to develop lung and liver metastases, suggesting a different and aggressive phenotype. If possible at that point, it would be useful to biopsy a metastatic site for diagnostic confirmation and test the metastatic tumor.

Historical series have documented cases of changes in HER2 status from the primary tumor to the metastases in about 5% to 10% cases, he said. However, there is a question of whether this is really a change in the biology of the cancer, or whether there have been changes in the way the HER2 testing was carried out 5 to 10 years ago, before there was standardization, he commented.

Coauthor and cochair on the panel, Elizabeth Hammond, MD, FCAP, professor of pathology at the University of Utah School of Medicine in Salt Lake City, commented in a statement: "The number of patients with equivocal HER2 test results used to be rather large. But evidence suggests that the quality of HER2 testing is improving and the frequency of equivocal and inaccurate results is decreasing. We believe that this is at least in part due to our earlier recommendations in 2007. We hope the current guideline will resolve remaining challenges in the field, and ultimately result in better outcomes for all patients with breast cancer."

Dr. Wolff and Dr. Hammond have disclosed no relevant financial relationships. Several coauthors report having consultancy agreements with various pharmaceutical and diagnostic companies.

J Clin Oncol. Published online October 7, 2013. Abstract