Efforts to Improve HER2 Testing Continue ASCO Panelist Sees Progress

Anita T. Shaffer @Shaffer1
Published: Tuesday, Oct 11, 2011
Antonio C. Wolff, MD

Antonio C. Wolff, MD

The movement to improve the accuracy and predictive value of tumor marker testing in patients with breast cancer has resulted in a dramatic upswing in the number of accredited laboratories, as well as a continuing effort to clarify definitions that guide therapy decisions.

Antonio C. Wolff, MD, who has helped lead such efforts, reviewed several of the key controversies that have surrounded guidelines research. He is an associate professor of Oncology and a research scientist in the Breast Cancer Program at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Hospital, Baltimore, Maryland.

Wolff co-chaired the cooperative panel of the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP) that issued guidelines in 2007 for testing for the human epidermal growth factor receptor 2 (HER2) in invasive breast cancer. The marker guides decisions for trastuzumab (Herceptin) and lapatinib (Tykerb), and possibly in other therapies.

“We wanted to standardize methodology, making sure that the same test done in the same tissue with the same patient anywhere would as much as possible yield the same information,” Wolff said. “The panel never set out to change the eligibility for trastuzumab. This has been a huge source of confusion.”

Table 1. Key Points in 2011 Clinical Notice

  HER2 HER2 ER and PgR
Cold ischemic time Changed from "short" to ≤1 hour Interval ≤1 hour
Document time between tissue removal and start of fixation
Fixation time in neutral buffered formalin 6-48 hours in NBF; less fixation time permissible for needle biopsy specimens 6-72 hours in NBF for all specimens
Optimal sample for testing Resection specimens recommended Core needle biopsies recommended
Pathologist discretion in selecting sample for testing

ER indicates estrogen receptor; HER2, human epidermal growth factor receptor 2; NBF, neutral buffered formalin; PgR, progesterone receptor.

ASCO Guidelines Clinical Notice, American Society of Clinical Oncology Website. http://goo.gl/pVdGb. Updated January 13, 2011. Accessed August 22, 2011.

In 2005, researchers believed that up to approximately 20% of all HER2 testing worldwide yielded false positives. Wolff said the picture for false negatives was not as clear, with estimates ranging from 5% to 10%.

While researchers set out to compare results from local laboratories with central facilities, the issues turned on broader questions of testing protocols. “It’s not an issue of whether the test was done centrally or locally, but whether the test was done correctly,” Wolff said.

Today, there are indications that the frequency of HER2 false positives has dropped to less than 6% in the United States, Wolff said in an interview.

Meanwhile, the number of HER2- testing laboratories participating in the CAP accreditation program has risen markedly for both immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) methods. There were 1120 IHC and 316 FISH laboratories participating in the program this year, up from 125 IHC and 174 FISH facilities in 2004, according to a CAP survey. Likewise, more laboratories are becoming accredited for estrogen receptor (ER) testing, with the numbers rising from 97 in 2004 to 1200 this year.

There are about 1500 laboratories doing HER2 testing in the United States, Wolff said.

The joint guidelines panel recommended tissue-handling guidelines for HER2 testing in 2007, with a key factor being a gap between gathering of a specimen at a hospital and testing the sample in a laboratory (J Clin Oncol. 2007;25(1):118-145).

It’s not an issue of which is the right test to do—IHC or FISH— but whether you’re doing the test right. ”
–Antonio C. Wolff, MD
Although clinicians and administrators at each point were following protocols, more coordination was necessary, Wolff said. “We are all responsible,” he said. “The enemy ultimately was us.”

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