The state of HER-2 status

Abstract

This editorial comments on the manuscript reported by Bergqvist et al. [1.Bergqvist J. Ohd J. Smeds J. et al.Quantitative real-time PCR analysis and microarray-based RNA expression of HER2 in relation to outcome.Ann Oncol. 2007; 18: 845-850Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar] who have investigated real-time PCR (RT-PCR) and microarray-based RNA expression (RNA-EP) as alternative strategies to immunohistochemistry (IHC) and in situ hybridization (ISH) for HER-2 testing in breast cancer patients. Bergqvist et al. [1.Bergqvist J. Ohd J. Smeds J. et al.Quantitative real-time PCR analysis and microarray-based RNA expression of HER2 in relation to outcome.Ann Oncol. 2007; 18: 845-850Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar] have compared the performance of ‘standard’ and ‘new’ HER-2 testing tools in a series of ∼250 primary breast tumors. Moreover, they have correlated clinical outcomes (relapse-free, breast cancer-related, and overall survival) with HER-2 scores evaluated by the investigated techniques. Bergqvist et al. [1.Bergqvist J. Ohd J. Smeds J. et al.Quantitative real-time PCR analysis and microarray-based RNA expression of HER2 in relation to outcome.Ann Oncol. 2007; 18: 845-850Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar] have to be congratulated for the significant amount of work that has been done and for exhaustively reporting the results of their study. This editorial will attempt to address two definite questions related to HER-2 testing: (i) in which clinical situation HER-2 testing results are of capital importance for patient's management? (ii) are new HER-2 testing technologies required to better assist clinicians in the decision-making process? There are four different clinical scenarios in which HER-2 testing results have or might have a role in the clinical management of breast cancer patients. The identification of patient candidates for anti-HER-2 therapies either in the early or in the metastatic setting is by far the most relevant information provided by HER-2 testing of breast cancer samples. Large phase III trials have unequivocally proved the efficacy of anti-HER-2 agents such as trastuzumab and lapatinib in patients carrying HER-2-positive tumors [2.Slamon D.J. Leyland-Jones B. Shak S. et al.Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2.N Engl J Med. 2001; 344: 783-792Crossref PubMed Scopus (9405) Google Scholar, 3.Piccart-Gebhart M.J. Procter M. Leyland-Jones B. et al.Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer.N Engl J Med. 2005; 353: 1659-1672Crossref PubMed Scopus (4221) Google Scholar, 4.Romond E.H. Perez E.A. Bryant J. et al.Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer.N Engl J Med. 2005; 353: 1673-1684Crossref PubMed Scopus (4543) Google Scholar, 5.Joensuu H. Kellokumpu-Lehtinen P.L. Bono P. et al.Adjuvant docetaxel or vinorelbine with or without trastuzumab for breast cancer.N Engl J Med. 2006; 354: 809-820Crossref PubMed Scopus (1271) Google Scholar, 6.Slamon D. Eiermann W. Robert N. et al.Phase III randomized trial comparing doxorubicin and cyclophosphamide followed by docetaxel with doxorubicin and cyclophosphamide followed by docetaxel and trastuzumab with docetaxel, carboplatin and trastuzumab in HER2 positive early breast cancer patients: BCIRG 006 study.Breast Cancer Res Treat. 2005; 94 (Abstr 1): S5Google Scholar, 7.Geyer C.E. Forster J. Lindquist D. et al.Lapatinib plus capecitabine for HER2-positive advanced breast cancer.N Engl J Med. 2006; 355: 2733-2743Crossref PubMed Scopus (2828) Google Scholar]. An emerging clinical situation in which HER-2 testing results can provide the clinician with meaningful information is represented by early breast cancer patients carrying hormone receptor and HER-2-positive tumors. In this setting, adjuvant hormonotherapy alone, either with antiestrogens or aromatase inhibitors, might not be the most appropriate treatment option. Preclinical and retrospective clinical studies indicate that these tumors might not be entirely sensitive to hormonal agents [8.Osborne C.K. Bardou V. Hopp T.A. et al.Role of the estrogen receptor coactivator AIB1 (SRC-3) and HER-2/neu in tamoxifen resistance in breast cancer.J Natl Cancer Inst. 2003; 95: 353-361Crossref PubMed Scopus (702) Google Scholar, 9.Dowsett M. Allred D.C. Relationship between quantitative ER and PgR expression and HER2 status with recurrence in the ATAC trial.Breast Cancer Res Treat. 2006; 100 (Abstr 48): S21Google Scholar]. In particular, early results from the trans-anastrazole or tamoxifen alone or in combination (TransATAC) study indicate that in the adjuvant setting HER-2 and hormone receptor-positive breast cancer tends to be less sensitive to both tamoxifen and aromatase inhibitors than HER-2-negative and hormone receptor-positive disease. The magnitude of anastrozole's superiority over tamoxifen seems to be independent of the primary tumor HER-2 status [9.Dowsett M. Allred D.C. Relationship between quantitative ER and PgR expression and HER2 status with recurrence in the ATAC trial.Breast Cancer Res Treat. 2006; 100 (Abstr 48): S21Google Scholar]. Of note, this recent finding contrasts the main conclusions from two previously reported neo-adjuvant studies indicating an increased superiority of aromatase inhibitors over tamoxifen in the presence of HER-2 and hormone receptor-positive disease [10.Ellis M.J. Coop A. Singh B. et al.Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial.J Clin Oncol. 2001; 19: 3808-3816Crossref PubMed Scopus (1027) Google Scholar, 11.Smith I.E. Dowsett M. Ebbs S.R. et al.Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial.J Clin Oncol. 2005; 23: 5108-5116Crossref PubMed Scopus (635) Google Scholar]. Of note, the two neo-adjuvant studies correlated HER-2 status with objective response rates to neo-adjuvant hormonotherapy [10.Ellis M.J. Coop A. Singh B. et al.Letrozole is more effective neoadjuvant endocrine therapy than tamoxifen for ErbB-1- and/or ErbB-2-positive, estrogen receptor-positive primary breast cancer: evidence from a phase III randomized trial.J Clin Oncol. 2001; 19: 3808-3816Crossref PubMed Scopus (1027) Google Scholar, 11.Smith I.E. Dowsett M. Ebbs S.R. et al.Neoadjuvant treatment of postmenopausal breast cancer with anastrozole, tamoxifen, or both in combination: the Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) multicenter double-blind randomized trial.J Clin Oncol. 2005; 23: 5108-5116Crossref PubMed Scopus (635) Google Scholar], while in the TransATAC study, disease-free survival was the main clinical outcome correlated with the primary tumor HER-2 status [9.Dowsett M. Allred D.C. Relationship between quantitative ER and PgR expression and HER2 status with recurrence in the ATAC trial.Breast Cancer Res Treat. 2006; 100 (Abstr 48): S21Google Scholar]. This difference between TransATAC and the two neo-adjuvant studies might explain the apparent discordance. Based on these data, a few courses of adjuvant chemotherapy preceding the start of hormonotherapy might be appropriate in hormone receptor and HER-2-positive early breast cancer, particularly, if in the presence of other factors, indicating increased sensitivity to chemotherapy such as hyperproliferation [12.Colozza M. Azambuja E. Cardoso F. et al.Proliferative markers as prognostic and predictive tools in early breast cancer: where are we now?.Ann Oncol. 2005; 16: 1723-1739Abstract Full Text Full Text PDF PubMed Scopus (243) Google Scholar, 13.Urruticoechea A. Smith I.E. Dowsett M. Proliferation marker Ki-67 in early breast cancer.J Clin Oncol. 2005; 23: 7212-7220Crossref PubMed Scopus (634) Google Scholar]. The two other clinical scenarios in which HER-2 testing results could assist the clinician in the decision-making process are in my opinion more controversial. HER-2 positivity has repeatedly been indicated as an adverse prognostic factor in early breast cancer patients [14.Ross J.S. Fletcher J.A. Linette G.P. et al.The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy.Oncologist. 2003; 8: 307-325Crossref PubMed Scopus (529) Google Scholar]. A pure prognostic factor indicates prognosis at any time during the patient's follow-up, while HER-2 positivity seems to be a good predictor of early recurrence (i.e. within 2–3 years from breast cancer surgery) [15.Schroeter C.A. De Potter C.R. Rathsmann K. et al.c-erbB-2 positive breast tumours behave more aggressively in the first years after diagnosis.Br J Cancer. 1992; 66: 728-734Crossref PubMed Scopus (29) Google Scholar]. There is no substantial evidence that HER-2-positive patients who are disease free 5 years after breast cancer surgery are still at an increased risk of relapse when compared with HER-2-negative patients [14.Ross J.S. Fletcher J.A. Linette G.P. et al.The Her-2/neu gene and protein in breast cancer 2003: biomarker and target of therapy.Oncologist. 2003; 8: 307-325Crossref PubMed Scopus (529) Google Scholar]. Conversely, largely accepted prognostic factors such as nodal status and tumor size can provide a prognostic characterization at any time during the patient's follow-up [16.Saphner T. Tormey D.C. Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy.J Clin Oncol. 1996; 14: 2738-2746Crossref PubMed Scopus (725) Google Scholar]. HER-2 and hormonal receptors tend to define different breast cancer subclasses, each with a peculiar risk of disease relapse over time and with different degrees of sensitivity to hormonal and cytotoxic agents [15.Schroeter C.A. De Potter C.R. Rathsmann K. et al.c-erbB-2 positive breast tumours behave more aggressively in the first years after diagnosis.Br J Cancer. 1992; 66: 728-734Crossref PubMed Scopus (29) Google Scholar, 16.Saphner T. Tormey D.C. Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy.J Clin Oncol. 1996; 14: 2738-2746Crossref PubMed Scopus (725) Google Scholar, 17.Berry D.A. Cirrincione C. Henderson I.C. et al.Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer.JAMA. 2006; 295: 1658-1667Crossref PubMed Scopus (625) Google Scholar, 18.Goldhirsch A. Glick J.H. Gelber R.D. et al.Meeting highlights: international expert consensus on the primary therapy of early breast cancer 2005.Ann Oncol. 2005; 16: 1569-1583Abstract Full Text Full Text PDF PubMed Scopus (942) Google Scholar, 19.Paik S. Tang G. Shak S. et al.Gene expression and benefit of chemotherapy in women with node-negative, estrogen receptor-positive breast cancer.J Clin Oncol. 2006; 24: 3726-3734Crossref PubMed Scopus (2138) Google Scholar]. Markers such as hormone receptors and HER-2 contribute to define the individual tumor's biological profile and provide guidance on the treatment type to be used (i.e. hormonal therapy, cytotoxics, biotherapies, combination treatment). Pure prognostic factors such as tumor size and nodal status should not play a role in the selection of the treatment type, while they should indicate the ‘level of intensity’ of a given treatment type selected on the basis of the individual tumor's biological profile. Nevertheless, it has to be recognized that the clinician can be faced with controversial situations (i.e. biologically aggressive tumors with extremely favorable prognostic markers or, vice versa, biologically ‘differentiated’ tumors associated with adverse prognostic factors). The last controversial area in which HER-2 testing could provide the clinician with clinically meaningful data is the use of anthracycline-based adjuvant therapy in HER-2-positive breast cancer patients. Despite the fact that different retrospective studies have indicated that only HER-2-positive breast cancer patients derive substantial benefit from anthracycline-based adjuvant therapies [20.Yamauchi H. Stearns V. Hayes D.F. When is a tumor marker ready for prime time? A case study of c-erbB-2 as a predictive factor in breast cancer.J Clin Oncol. 2001; 19: 2334-2356Crossref PubMed Scopus (278) Google Scholar], a growing set of data are indicating that HER-2 could only be a surrogate marker of anthracycline's sensitivity because of the topoisomerase II alpha gene amplification observed in approximately one-third of HER-2 amplified tumors and rarely reported in HER-2 nonamplified breast cancer [21.Di Leo A. Isola J. Topoisomerase II alpha as a marker predicting the efficacy of anthracyclines in breast cancer: are we at the end of the beginning?.Clin Breast Cancer. 2003; 4: 179-186Abstract Full Text PDF PubMed Google Scholar]. In addition, data on topoisomerase II α protein seem to indicate that protein overexpression predicts increased sensitivity to anthracyclines [22.Di Leo A. Larsimont D. Gancberg D. et al.HER-2 and topo-isomerase II alpha as predictive markers in a population of node-positive breast cancer patients randomly treated with adjuvant CMF or epirubicin plus cyclophosphamide.Ann Oncol. 2001; 12: 1081-1089Abstract Full Text PDF PubMed Scopus (108) Google Scholar, 23.Durbecq V. Paesmans M. Cardoso F. et al.Topoisomerase-II alpha expression as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel.Mol Cancer Ther. 2004; 3: 1207-1214Crossref PubMed Google Scholar, 24.O'Malley F.P. Chia S. Tu D. et al.Topoisomerase II alpha protein overexpression has predictive utility in a randomized trial comparing CMF to CEF in premenopausal women with node positive breast cancer (NCIC CTG MA.5).Breast Cancer Res Treat. 2006; 100 (Abstr 38): s18Google Scholar] and that protein overexpression is reported in HER-2-positive as well as in HER-2-negative tumors independently of the topoisomerase II α gene status [25.Durbecq V. Desmedt C. Paesmans M. et al.Correlation between topoisomerase II alpha gene amplification and protein expression in HER-2 amplified breast cancer.Int J Oncol. 2004; 25: 1473-1479PubMed Google Scholar, 26.Mueller R.E. Parkes R.K. Andrulis I. et al.Amplification of the TOP2A gene does not predict high levels of topoisomerase II alpha protein in human breast tumor samples.Genes Chromosomes Cancer. 2004; 39: 288-297Crossref PubMed Scopus (102) Google Scholar, 27.Callagy G. Pharoah P. Chin S.F. et al.Identification and validation of prognostic markers in breast cancer with the complementary use of array-CGH and tissue microarrays.J Pathol. 2005; 205: 388-396Crossref PubMed Scopus (126) Google Scholar]. These data have certainly contributed to the reconsideration of HER-2's role as a predictive marker of anthracyclines activity in breast cancer patients. The second question that the present editorial attempts to address is whether or not new HER-2 testing technologies are needed. The answer to this question is ‘definitely yes’, assuming that the new test provides the clinician with more relevant information than standard tests. The identification of HER-2-positive tumors is certainly crucial in order to identify patient candidates for anti-HER-2 therapies. The new HER-2 test should be more reliable than the currently available tests to carefully select patients eligible for anti-HER-2 therapies. Figure 1 reports the design of an ‘ideal’ study validating a new HER-2 testing technology in patients receiving anti-HER-2 therapies. If the use of the new test ameliorates the selection criteria for anti-HER-2 treatments and leads to an improvement in the clinical activity of anti-HER-2 compounds, then the new test has fulfilled the main requirement and it can become a standard. The study by Bergqvist et al. [1.Bergqvist J. Ohd J. Smeds J. et al.Quantitative real-time PCR analysis and microarray-based RNA expression of HER2 in relation to outcome.Ann Oncol. 2007; 18: 845-850Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar] discussed in the present editorial cannot evaluate the performance of RT-PCR and RNA-EP in terms of predicting the response to anti-HER-2 therapies because patients from this study were not treated with anti-HER-2 compounds. The indication that HER-2-positive patients by RT-PCR and RNA-EP might have a worse long-term prognosis than HER-2-positive patients by standard tests does not seem to be a strong enough evidence to consider the new tests as an upcoming standard [1.Bergqvist J. Ohd J. Smeds J. et al.Quantitative real-time PCR analysis and microarray-based RNA expression of HER2 in relation to outcome.Ann Oncol. 2007; 18: 845-850Abstract Full Text Full Text PDF PubMed Scopus (33) Google Scholar]. In fact, the present study indicates, as previously discussed in this editorial, that most if not all of the adverse prognostic significance associated with HER-2 positivity is due to the increased risk of early relapses. Five-year hazard ratios for relapse-free survival were 2.2 and 2.4 and 10-year hazard ratios went down to 1.9 and 1.8 when HER-2 positivity was confirmed by RT-PCR and RNA-EP, respectively. This indicates that if hazard ratios by time periods would have been calculated, hazard ratios for the time period ‘5–10 years’ would have likely lost most of their clinical and statistical significance. Moreover, as the authors point out, RT-PCR and RNA-EP are certainly less widespread and feasible techniques than IHC and ISH. This is relevant for a diagnostic test that is nowadays routinely carried out in a large number of pathology departments worldwide. In summary, it is felt that new HER-2 tests might be helpful in providing the clinician with relevant information, in particular, for a more accurate use of anti-HER-2 compounds. The available evidence does not support the use of RT-PCR and RNA-EP as alternative or complementary tests to currently available HER-2 diagnostic tools. There are other important issues related to the HER-2 testing field. Among these, improvement in HER-2 scores reproducibility between different laboratories is a high priority, as recently highlighted by an American Society of Clinical Oncology/College of American Pathologists panel [28.Wolff A.C. Hammond M.E. Schwartz J.N. et al.American Society of Clinical Oncology/College of American Pathologists guideline recommendations for human epidermal growth factor receptor 2 testing in breast cancer.J Clin Oncol. 2007; 25: 118-145Crossref PubMed Scopus (3044) Google Scholar]. Reproducibility studies indicate that ∼20% of HER-2 assays carried out at the treatment site's pathology department are incorrect when the same specimen is reevaluated in a high-volume central laboratory [29.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, 30.Perez E.A. Suman V.J. Davidson N.E. et al.HER2 testing by local, central, and reference laboratories in specimens from the North Central Cancer Treatment Group N9831 intergroup adjuvant trial.J Clin Oncol. 2006; 24: 3032-3038Crossref PubMed Scopus (411) Google Scholar, 31.Persons D.L. Tubbs R.R. Cooley L.D. et al.HER-2 fluorescence in situ hybridization: results from the survey program of the College of American Pathologists.Arch Pathol Lab Med. 2006; 130: 325-331PubMed Google Scholar, 32.Roche P.C. Suman V.J. Jenkins R.B. et al.Concordance between local and central laboratory HER2 testing in the breast intergroup trial N9831.J Natl Cancer Inst. 2002; 94: 855-857Crossref PubMed Scopus (358) Google Scholar]. There are additional research themes. The identification of molecular markers complementing HER-2 scores with the aim to better define the profile of anti-HER-2 compound sensitive tumors is certainly a relevant research area. Different events seem to play a role in the onset of clinical resistance to anti-HER-2 compounds. Among these, activation of the insulin-like growth factor-1 pathway, phosphate and tensin homolog deficiency, phosphoinositide 3-kinase gene mutations, compensatory signaling from other HER family members, and polymorphism of the Fc receptor have been indicated as potential markers of resistance [33.Nahta R. Esteva F.J. HER2 therapy: molecular mechanisms of trastuzumab resistance.Breast Cancer Res. 2006; 8: 215Crossref PubMed Scopus (345) Google Scholar]. Ongoing clinical studies will likely clarify the role of these markers in predicting the likelihood of response of HER-2-positive tumors to anti-HER-2 therapies. An additional theme currently under investigation is the clinical significance of chromosome 17 polysomy in relationship to the activity of anti-HER-2 therapies. It has been reported that most of the IHC HER-2-positive (3+) and FISH-negative tumors carry chromosome 17 polysomy [34.Ma Y. Lespagnard L. Durbecq V. et al.Polysomy 17 in HER-2/neu status elaboration in breast cancer: effect on daily practice.Clin Cancer Res. 2005; 11: 4393-4399Crossref PubMed Scopus (103) Google Scholar]. Large phase III clinical trials that have established anti-HER-2 therapies as a new standard in HER-2-positive breast cancer might help to define the predictive value of chromosome 17 polysomy as far as the clinical activity of anti-HER-2 compounds is concerned. These studies might reveal that tumors carrying high levels of HER-2 protein in the absence of gene amplification might also derive some benefit from HER-2 targeting therapies. In conclusion, after many years of research focusing on HER-2 and its significance in breast cancer biology, clinical behavior, and medical treatment, and despite substantial progress that has been done in this field, we have to agree that the HER-2 research area is still evolving and that it will likely continue to impact on our current view of breast cancer biology and treatment.