Studies call for quality assurance in selecting candidates for herceptin trials

June 04, 2002

Two new studies suggest that local laboratories are not as accurate as central testing facilities at identifying women who are most likely to benefit from receiving trastuzumab (Herceptin) as adjuvant therapy for breast cancer. The findings appear in the June 5 issue of the Journal of the National Cancer Institute.

Past studies have suggested that trastuzumab may benefit breast cancer patients whose tumors overexpress, or produce too much, of the HER2 protein--a condition that occurs in 20% to 30% of breast cancer patients. Trastuzumab is a monoclonal antibody that works by targeting the HER2 protein.

To maximize the drug's benefits, participation in trials of trastuzumab have been limited to women who, based on laboratory tests, overexpress HER2 or have an amplified HER2/neu gene, which can also lead to HER2 overexpression. To determine trial eligibility, laboratories use several testing methods, including immunohistochemical analyses such as the FDA-approved DAKO HercepTest (which measures HER2 protein overexpression) and fluorescence in situ hybridization (which measures HER2/neu gene amplification).

In one study, Patrick C. Roche, Ph.D., of the Mayo Clinic and Mayo Foundation in Rochester, Minn., and Edith A. Perez, M.D., of the Mayo Clinic in Jacksonville, Fla., and their coworkers compared results from assays done by local laboratories of 119 patients enrolled in a collaborative trial of the North Central Cancer Treatment Group and the Mayo Clinic with assays performed by a central laboratory.

The authors found that only 74% of the positive local laboratory test results could be confirmed by central testing to have HER2 overexpression and only 66% had confirmed HER2 gene amplification. Of nine tumors reported to have HER2 gene amplification by local testing, only six (67%) could be confirmed by central testing.

"The overall performance of HER2 testing by local laboratories in this initial sample of 119 patients was disappointing, with unacceptably high levels of discordance with central testing [by experienced investigators]," the authors conclude, adding that as many as 26% of the patients already enrolled based on local laboratory test results may not be the best candidates to determine whether anti-HER2 monoclonal antibody therapy is advantageous as an adjuvant to chemotherapy.

In the second study, Soonmyung Paik, M.D., of the National Surgical Adjuvant Breast and Bowel Project (NSABP), and coworkers compared HER2 assay results from 104 patients who entered a clinical trial coordinated by the NSABP based on positive results from HER2 assays conducted by local laboratories.

The authors found that results of 18% of the assays done by local testing facilities could not be reproduced by a central testing facility, meaning that these people may not be the best candidates for evaluating trastuzumab. The authors also found that there was more agreement between large-volume laboratories and central testing facilities than smaller laboratories. "Given the cost and potential cardiotoxicity of Herceptin, it is reasonable to recommend that HER2 testing be done at large-volume reference laboratories," the authors note.

Since the studies, both trials have modified their eligibility criteria to require central laboratory testing to confirm HER2 status in patients being considered for the trial.

In an accompanying editorial, Jo Anne Zujewski, M.D., of the National Cancer Institute, notes that the increased costs of adding quality measures at the local level should translate to lower costs at a societal level.

"Accurate measurement of HER2 in individual patients means smaller sample size for clinical trials, fewer inconclusive or erroneous clinical trial results, and avoidance of costs associated with administering therapies to patients unlikely to benefit," writes Zujewski. "As we move into the era of molecular targets, the importance of accurately assessing the target cannot be overemphasized."
Contact: Erik Kaldor, Mayo Clinic, (904) 953-2299; fax: (904) 953-2487,

Lori Garvey, National Surgical Adjuvant Breast and Bowel Project, (412) 330-4621; fax: (412) 330-4645,

Editorial: NCI Office of Communications, (301) 496-6641; fax: (301) 496-0846,

Roche PC, Suman VJ, Jenkins RB, Davidson NE, Martino S, Kaufman PA, et al. Concordance between local and central laboratory HER2 testing in the Breast Intergroup Trial N9831. J Natl Cancer Inst 2002;94:855-7.

Paik S, Bryant J, Tan-Chiu E, Romond E, Hiller W, Park K, et al. Real-world performance of HER2 testing--National Surgical Adjuvant breast and bowel project experience. J Natl Cancer Inst 2002;94:852-4.

Editorial: Zujewski JA. "Build quality in"--HER2 testing in the Real World. J Natl Cancer Inst 2002;94:788-9.

Attribution to the Journal of the National Cancer Institute is requested in all news coverage.

Journal of the National Cancer Institute

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