EDITORIAL

"Build Quality in"—HER2 Testing in the Real World

Jo Anne Zujewski

Affiliation of author: J. Zujewski, National Cancer Institute, Bethesda, MD.

Correspondence to: Jo Anne Zujewski, M.D., National Cancer Institute, Center for Cancer Research, National Institutes of Health, Medicine Branch, 10 Center Dr., Bldg. 10, Rm. 12N/226, Bethesda, MD 20892 (e-mail: zujewski{at}nih.gov).

As I was preparing this editorial I read a very interesting article titled "Being Misread: A Lesson in Vigilance" by Clare Crawford-Mason (1). This poignant story describes how the author made a sound medical decision to avoid a hysterectomy using the principles established by the late quality guru, W. Edwards Deming (2). The question she asked herself based on Deming's teachings was, "Would you really make a decision about something as important as this with a single data point—just one reading of one slide?" This is the issue at hand today, with the publication of two extremely important papers on testing for HER2 (3,4).

HER2 is a very interesting molecule. HER2 overexpression occurs in 20%–30% of breast cancer cases (5). Overexpression of HER2, resulting from amplification of the Her2-neu gene, is associated with poor clinical outcome in women with lymph node-positive breast cancer (5,6). The prognostic significance of HER2 in lymph node-negative breast cancer is less certain (610). HER2 has been proposed as a predictive marker for response to adjuvant chemotherapy (11,12), although this has not been proven in prospective, randomized, controlled clinical trials (13). Some authors have suggested that HER2 is a predictor for resistance to endocrine therapy, also an unresolved issue at this time (1416).

HER2, a 185-kDa transmembrane receptor with partial homology to the epidermal growth factor receptor, has intrinsic tyrosine kinase activity (17). This molecule is an attractive target for cancer therapeutics. Trastuzumab, an HER2-directed monoclonal antibody, has demonstrated clinical benefit both as a single agent (18) and in combination with chemotherapy (19). Clinical trials have demonstrated that overexpression of HER2 in tumor tissue predicts for a response to trastuzumab. There are multiple methods for examining HER2 in tumor tissue, including assessing gene amplification via Southern hybridization, dot–blot hybridization, or fluorescence in situ hybridization (FISH); assessing gene expression via northern hybridization or expression microarrays; or assessing protein levels via western immunoblot or immunohistochemistry techniques. The difficulties of dealing with frozen tissue in the real world of clinical medicine have made testing of HER2 on formalin-fixed tissues a necessity. Methods suitable for use in fixed tissues include immunohistochemistry (protein expression) or FISH (gene amplification). Previous studies have demonstrated that subjects whose tumors have 3+ (by immunohistochemistry) HER2 overexpression have a marked improvement in clinical response when compared with subjects whose tumors have 2+ overexpression (20). Gene amplification of HER2 by FISH also predicts for clinical benefit from trastuzumab therapy in metastatic disease (20). Data such as these led the cooperative groups to identify subjects for randomized clinical trials using trastuzumab in early-stage breast cancer to include protein overexpression of HER2 (3+ by immunohistochemistry) or gene amplification by FISH analysis.

Recognizing both the importance of accurately detecting HER2 overexpression in evaluating the worth of trastuzumab in the adjuvant setting and the imprecise science of clinical laboratory testing, the National Surgical Adjuvant Breast and Bowel Project (NSABP) and the Breast Intergroup Trial both required central laboratories to test for HER2. The decision to "build quality in" (2) by requiring more than one data point was wise. Incorrect classification of HER2 status in individuals in this context could lead to underpowered statistics and erroneous conclusions. In the study by Roche et al. (4), 26% of the tests that were found positive in the community could not be confirmed in central laboratory testing. The results by Paik et al. (3) were similar; 18% of the tests that were found positive in the community could not be confirmed in central laboratory testing. Both groups, appropriately, have elected to modify eligibility criteria requiring central laboratory testing to confirm HER2 status in these important studies. Because all subjects referred were found by local laboratories to be HER2-positive, these studies provide information on the rate of false positives. The rate of false negatives, also an important question, could not be ascertained in these trials.

This brings me back to W. Edwards Deming and the importance of quality. HER2 testing is just one facet of a complex and interrelated health care system. Quality in health care in general, and in the testing of molecular targets in particular, means recognizing the limits of a single test and examining the system we use to obtain information and continually improving it, so that we can make sound clinical research and medical decisions. Paik et al. (3) attempt to understand the reasons for the false testing results, and clues may be found in the volume of laboratory tests performed or the ability to confirm test results using a second methodology. The increased costs for added 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. The avoidance of costs on a human level is even harder to measure, but includes a lower risk of side effects in individuals receiving therapy from which they are not likely to benefit, less confusion on the part of our patients who need to know if a particular therapy is of potential benefit when making personal health-care decisions, and avoiding the loss of public trust that can occur with the dissemination of conflicting medical information. Although there are costs associated with building quality checks into the system, the alternative could be even more costly to both society and individuals. As we move into the era of molecular targets, the importance of accurately assessing the target cannot be overemphasized. The publication of the papers by Paik et al. (3) and Roche et al. (4) are important steps in establishing the process by which we can assure quality in clinical research and in translating those findings into clinical care.

REFERENCES

1 Crawford-Mason C. Being misread: a lesson in vigilance. The Washington Post 2002 Apr 23; page HE01.

2 Deming WE. The W. Edwards Deming Institute. [Accessed: 04/29/2002.] Available from: http://www.deming.org/index.html.

3 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.[Abstract/Free Full Text]

4 Roche PC, Suman VJ, Jenkins RB, Davidson NE, Martino S, Kaufman PA, et al. Concordance between local and central laboratory HER-2 testing in the breast intergroup trial N9831. J Natl Cancer Inst 2002;94:855–7.[Abstract/Free Full Text]

5 Slamon DJ, Clark GM, Wong SG, Levin WJ, Ullrich A, McGuire WL. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science 1987;235:177–82.[Medline]

6 Toikkanen S, Helin H, Isola J, Joensuu H. Prognostic significance of HER-2 oncoprotein expression in breast cancer: a 30-year follow-up. J Clin Oncol 1992;10:1044–8.[Abstract]

7 Paik S, Hazan R, Fisher ER, Sass RE, Fisher B, Redmond C, et al. Pathologic findings from the National Surgical Adjuvant Breast and Bowel Project: prognostic significance of erbB-2 protein overexpression in primary breast cancer. J Clin Oncol 1990;8:103–12.[Abstract]

8 Andrulis IL, Bull SB, Blackstein ME, Sutherland D, Mak C, Sidlofsky S, et al. neu/erbB-2 amplification identifies a poor-prognosis group of women with node-negative breast cancer. Toronto Breast Cancer Study Group. J Clin Oncol 1998;16:1340–9.[Abstract]

9 Allred DC, Clark GM, Tandon AK, Molina R, Tormey DC, Osborne CK, et al. HER-2/neu in node-negative breast cancer: prognostic significance of overexpression influenced by the presence of in situ carcinoma. J Clin Oncol 1992;10:599–605.[Abstract]

10 Gusterson BA, Gelber RD, Goldhirsch A, Price KN, Save-Soderborgh J, Anbazhagan R, et al. Prognostic importance of c-erbB-2 expression in breast cancer. International (Ludwig) Breast Cancer Study Group. J Clin Oncol 1992;10:1049–56.[Abstract]

11 Thor AD, Berry DA, Budman DR, Muss HB, Kute T, Henderson IC, et al. erbB-2, p53, and efficacy of adjuvant therapy in lymph node-positive breast cancer. J Natl Cancer Inst 1998;90:1346–60.[Abstract/Free Full Text]

12 Paik S, Bryant J, Park C, Fisher B, Tan-Chiu E, Hyams D, et al. erbB-2 and response to doxorubicin in patients with axillary lymph node-positive, hormone receptor-negative breast cancer. J Natl Cancer Inst 1998;90:1361–70.[Abstract/Free Full Text]

13 Clark GM. Should selection of adjuvant chemotherapy for patients with breast cancer be based on erbB-2 status? J Natl Cancer Inst 1998;90:1320–1.[Free Full Text]

14 Elledge RM, Green S, Ciocca D, Pugh R, Allred DC, Clark GM, et al. HER-2 expression and response to tamoxifen in estrogen receptor-positive breast cancer: a Southwest Oncology Group Study. Clin Cancer Res 1998;4:7–12.[Abstract]

15 Carlomagno C, Perrone F, Gallo C, De Laurentiis M, Lauria R, Morabito A, et al. c-erb B2 overexpression decreases the benefit of adjuvant tamoxifen in early-stage breast cancer without axillary lymph node metastases. J Clin Oncol 1996;14:2702–8.[Abstract]

16 Sjogren S, Inganas M, Lindgren A, Holmberg L, Bergh J. Prognostic and predictive value of c-erbB-2 overexpression in primary breast cancer, alone and in combination with other prognostic markers. J Clin Oncol 1998;16:462–9.[Abstract]

17 Coussens L, Yang-Feng TL, Liao YC, Chen E, Gray A, McGrath J, et al. Tyrosine kinase receptor with extensive homology to EGF receptor shares chromosomal location with neu oncogene. Science 1985;230:1132–9.[Medline]

18 Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, et al. Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 1999;17:2639–48.[Abstract/Free Full Text]

19 Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 2001;344:783–92.[Abstract/Free Full Text]

20 Vogel CL, Cobleigh MA, Tripathy D, Gutheil JC, Harris LN, Fehrenbacher L, et al. Efficacy and safety of trastuzumab as a single agent in first-line treatment of HER2-overexpressing metastatic breast cancer. J Clin Oncol 2002;20:719–26.[Abstract/Free Full Text]


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