Trastuzumab therapy for the metastatic patient: does the primary match?
Authors: B. Leyland-Jones
Journal: Annals of Oncology (2002)

"They were a well-matched couple as both of them were madly in love—she with herself, and he with himself." This issue of Annals of Oncology contains a critically important article [1.Gancberg D. Di Leo A. Cardoso A. et al.Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites.Ann Oncol. 2002; 13: 1036-1043Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar] comparing HER-2 status between primary breast cancer and corresponding distant metastatic sites. Since trastuzumab is indicated for HER-2-overexpressing breast cancer patients with metastatic disease, and since one relies almost exclusively on pathological testing in the primary breast sample, the perfect matching of primary with metastatic HER-2 testing becomes crucial. The seminal work of Fidler, Folkman (and others referenced in the Gancberg article) have not only demonstrated critical biological differences between primary and metastatic tumours, but used these differences as the basis for novel antimetastatic approaches to therapy. It is therefore almost astonishing that this Gancberg paper is the first publication using a 'moderate' number of breast cancer patients to compare HER-2 status of primary breast tumours exclusively to their distant metastases. For those readers less familiar with the trastuzumab story, I will briefly review the background in order to emphasize the importance of this work. The first issue of this journal was published in January 1990 (the year that I moved to McGill University). In that issue, Gianni Bonadonna wrote an elegant retrospective detailing the significant progress that had been attained in basic and translational aspects of oncology research during the past 30 years [2.Bonadonna G. Does chemotherapy fulfill its expectations in cancer treatment?.Ann Oncol. 1990; 1: 11-21Abstract Full Text PDF PubMed Scopus (10) Google Scholar], with the promise that the 1990s would be a decade in which the fruits of this labour would materialize in the clinic. For the breast cancer oncologist, trastuzumab represents a paradigm shift (to use Dennis Slamon's phrase) which beautifully demonstrates this translation. Trastuzumab is the first clinical application in breast cancer of the oncogenic work of the 1970s and 80s that won Varmus and Bishop their Nobel Prize and of the hybridoma technology of Kohler and Millstein that achieved another Nobel. Apart from becoming the first monoclonal antibody with an oncogenic target to reach the clinic, trastuzumab also became the first targeted breast therapy to rely upon a pathological screening test (although many will argue appropriately that tamoxifen represents the first example). The pathological testing of HER-2 by fluorecence in situ hybridization (FISH) and immunohistochemistry (IHC) as an indicator for trastuzumab treatment has filled hundreds of research papers in recent years. The specific pathological requirement for trastuzumab therapy varies worldwide. The most common dictum is that IHC 3+ patients should be treated and that those patients with IHC 2+ over-expression need verification of positivity by FISH to merit trastuzumab therapy. In some parts of the world, especially Europe, IHC 3+ is the only approved standard. In the USA, FISH is rapidly moving towards becoming the standard testing vehicle. Nevertheless, the recent figures released from both the NSABP and Inter-Group Herceptin Adjuvant Breast Cancer studies revealing discrepancies between IHC and FISH and between peripheral and central laboratory testing raise tremendous concern [3.Tubbs R. Making the call on HER-2 testing methods. CAP Today. Northfield, IL: College of American.Pathologists. 2002; Google Scholar, 4.Paik S. Bryant J. Tan-Chiu E. et al.Real-world performance of HER2 testing—National Surgical Adjuvant Breast and Bowel Project experience.J Natl Cancer Inst. 2002; 94: 852-854Crossref PubMed Scopus (442) Google Scholar]. The Gancberg article in this issue also refers to this problem. Gancberg et al. show the utilization of strong staining (3+) with HercepTest as the sole indicator of HER-2 positivity to be very stringent and that it underestimates the number of samples with HER-2 gene amplification [1.Gancberg D. Di Leo A. Cardoso A. et al.Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites.Ann Oncol. 2002; 13: 1036-1043Abstract Full Text Full Text PDF PubMed Scopus (283) Google Scholar]. At a time when gene amplification by FISH is increasingly accepted as the 'gold standard' (but, in contrast, 3+ HercepTest positivity is the most frequently used indicator test), this underestimation is of grave concern. They report that their laboratory has adopted an IHC protocol using the monoclonal antibody CB‐11 with antigen retrieval for their initial screening which allows them to decrease the rate of false-negatives. They subsequently confirm all positive results with FISH, thereby reducing the rate of false-positives. I believe that my breast medical oncology and pathology colleagues responsible for trastuzumab prescriptions will find this HercepTest stringency result and the Larsimont laboratory protocol of considerable interest. As for the main thrust of the Gancberg paper, this is the first report to examine 107 patients comparing the primary breast tumour with at least one distant metastatic lesion. Of the five previous studies comparing HER-2 status in breast primary tumours and distant metastases, the Niehans' paper [5.Niehans G.A. Singleton T.P. Dykoski et al. Stability of HER-2/neu expression over time and at multiple sites.J Natl Cancer Inst. 1993; 85: 1230-1235Crossref PubMed Scopus (152) Google Scholar] examined 30 patients, the Tanner paper [6.Tanner M. Järvinen P, Isola J. Amplification of HER-2/neu and topoisomerase II-α in primary metastatic breast cancer.Cancer Res. 2001; 61: 5345-5348PubMed Google Scholar] 46 and the Edgerton [7.Edgerton S.E. Merhel D. Moore D.H. et al.HER-2/neu/erbB-2 status by immunohistochemistry and FISH: clonality and progression with recurrence and metastases.Breast Cancer Res Treat. 2000; 64: 55Google Scholar] 93 (although the reporting was preliminary), the Shimizu [8.Shimizu C. Fukutomi T. Tsuda H. et al.c-erbB-2 protein overexpression and p53 immunoreaction in primary and recurrent breast cancer tissues.J Surg Oncol. 2000; 73: 17-20Crossref PubMed Scopus (91) Google Scholar] examined seven and the Masood [9.Masood S. Bui M.M. Assessment of Her-2/neu overexpression in primary breast cancers and their metastatic lesions: an immunohistochemical study.Ann Clin Lab Sci. 2000; 30: 259-265PubMed Google Scholar] 11 patients. Gancberg and colleagues found similar levels of amplification (25 and 24%) and overexpression (13 and 19%) of HER-2 in primary and metastatic samples, respectively. They found a 6% discordance in HercepTest and a 7% discordance by FISH. Although the FISH discordance was mixed (two cases amplified in the primary tumour but not in the metastasis; three samples amplified in the metastasis but not in the primary), all 6% HercepTest discordant cases showed greater overexpression in metastatic rather than primary source. The authors debate whether these discrepancies reflect enhanced tumour aggressiveness in the metastatic rather than the primary site or whether such discrepancy represents protein degradation in the primary samples collected years before the current analysis. They conclude that protein degradation is the most likely source of this discordance, which reminds us all of the precariousness of relying upon primary samples obtained many years ago. If indeed protein degradation is the reason for this discordance, we must be grateful for the relatively low figure of 6%! The authors also looked at discordance between multiple distant metastatic sites belonging to the same patient. In17 cases, only three of 16 (19%) were discordant by FISH and three of 17 (18%) were discordant by IHC. The authors concluded that the study did not support the routine testing of metastases to confirm HER-2 positivity when detected in the primary tumour, but add the caveat "particularly if results obtained by FISH are available". For the patient in which the primary tumour sample has been collected many years before and in whom one obtains a negative IHC result, they suggest either additional FISH testing on the primary tumour sample or attempting to biopsy a metastatic site (if the latter is easily accessible). The other five publications correlating HER-2 status in breast primary tumours and distant metastases support these conclusions but are limited by patient size, technical and informational aspects. The Niehans paper relied upon autopsy samples … again an issue that jeopardizes IHC interpretation. The Shimizu, Masood and Tanner papers are all extremely limited by patient numbers and the Edgerton paper lacks substantial detail. Hence, the Denis Larsimont laboratory publication in this issue becomes the critical reference paper in this field to date. For practicing breast medical oncologists around the world, the message emanating from this paper … the apparent lack of necessity to universally biopsy the patient's metastatic lesion is very good news. However, the article continues to raise our concerns with regard to both the HercepTest as the definitive IHC approach and also the inadequacy of primary breast tumours collected many years before for IHC testing. At a time when the majority of the world, in my experience, rely upon IHC and HercepTest for prescribing trastuzumab, this is not the best news we could hear!