Originally published as JCO Early Release 10.1200/JCO.2009.22.8361 on July 20 2009

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Pritchard, K. I. PubMed PubMed Citation Articles by Pritchard, K. I. Related Articles Related Article Social Bookmarking                            What's this?

Are HER2 and TOP2A Useful As Prognostic or Predictive Biomarkers for Anthracycline-Based Adjuvant Chemotherapy for Breast Cancer?

Sunnybrook Odette Cancer Centre and the University of Toronto, Toronto, Ontario, Canada

There is an old maxim that says one should first tell the audience what you are going to tell them, then tell it to them, and then tell them what you have told them. In that vein, I shall begin by saying that the answer to the question in the title of this editorial is no. The reasons are that published data to support the use of human epidermal growth factor receptor 2 (HER2) or topoisomerase (DNA) II alpha 170kDa (TOP2A) as targets are currently contradictory—more so than a year ago—and thatTOP2A measurement is not a standardized technique that is widely available in North American or European pathology laboratories.

Going back 10 years or more, a number of investigators published prospectively designed retrospective explorations of the role of HER2 as a predictive factor for differential response of adjuvant therapy of breast cancer with anthracycline-containing compared with non–anthracycline-containing regimens.^1–4 Although these studies were limited by tissue availability (60% to 95% of cases had tissue available) and by power within individual trials which were originally sized to answer clinical comparisons (but not predictive substudies), results initially seemed consistent. Several of these trials suggested that HER2 protein overexpression or gene amplification was associated with a significantly greater response to anthracycline- containing therapy.^2,4 Indeed, meta-analyses based on all published studies^5–7 concluded that although many of these substudies did not meet individual significance^1,3 that meta-analysis technique supported those studies that did^2,4 in suggesting that HER2 status was a significantly predictive factor for better response to anthracycline-containing than to non–anthracycline-containing chemotherapy.

Paradoxically, however, a large randomized British trial of adjuvant therapy for breast cancer which showed superiority overall for the anthracycline-containing versus a non–anthracycline-containing⁸ regimen was mined to examine the role of HER2 with opposite results.⁹ As part of an ongoing project to carry out an individual patient meta-analysis on this subject,¹⁰ we became aware of these contradictory results before they were published, and explored together all possible technical and methodologic reasons for this discrepancy. No explanation could be found for this contradiction, but it did become clear that at least one other published paper supporting the predictive value of TOP2A in this setting¹¹ also contained data which suggested that HER2 was not predictive in a trial very similar to one which clearly suggested that it did.⁴

TOP2A was explored by several of the same clinical trialists who mined their data with regard to the predictive rate of HER2 in trials of anthracycline-containing versus non–anthracycline-containing therapy^11–13 and in these studies, it seemed also clear and consistent that TOP2A gene amplification was predictive for a benefit of anthracycline-containing versus non–anthracycline-containing therapy. Indeed, this was thought to explain the association of HER2 with this predictive value since TOP2A and HER2 are closely located on chromosome 17 and TOP2A is a known target of the anthracyclines, whereas an association between HER2 amplification and anthracycline response has no obvious direct explanation. However, the same British trial that showed an opposite association with HER2 also failed to confirm the positive value of TOP2A.⁹

To further complicate these contradictions, some trials showed a very clear correlation between the predictive results of HER2 and TOP2A alterations (amplification/deletion)^4,12 while others suggest positive predictive value for TOP2A alterations but not for HER2 amplification.^11,13 Furthermore, while Slamon and Press¹³ reported that only in tumors with HER2 amplification will TOP2A alterations be seen, other studies do not show such a consistent association.^4,12 The relevance of TOP2A deletion versus amplification is also not clear due to inconsistent results. These differences may relate in part to technical measurement issues.

Interest in the role of HER2 and TOP2A as prognostic and particularly as predictive factors for the use of anthracycline-containing versus non–anthracycline-containing therapy continues apace. The article published by Tubbs et al¹⁴ in this issue of Journal of Clinical Oncology adds information to the body of knowledge concerning the prognostic value of these biomarkers in women treated with anthracycline-containing regimens. But the authors themselves make clear that these data cannot add to any knowledge concerning the predictive value of either of these markers because of the underlying design of the study in which this question was explored. As the senior author of this article has so clearly outlined for us in previous articles,^15,16 while prognostic factors identify patients whose tumors are associated with differing outcomes, predictive factors are those which can identify different outcomes in association with particular therapies. Predictive factors for a given therapy, anthracyclines in this case, can only be identified in trials in which patients are randomly assigned to at least one arm which does and one arm which does not contain the therapy of interest. The trial in which the current explorations have been undertaken, the Southwest Oncology Group S9313/Intergroup 0137 is one in which each treatment arm contained a differing dose regimen of the same two drugs, doxorubicin and cyclophosphamide. Thus, the predictive information we need most in this area cannot be augmented from any analyses of this particular trial.

Nonetheless, this study provides confirmatory data concerning a number of issues. First, this large correlative trial confirms that HER2 amplification was present in approximately 20% of patients. Furthermore, at least in univariate analysis HER2 served as a prognostic marker in this population of women treated with an anthracycline as has been reported by others. This prognostic effect while confirmed in multivariate analysis only for women with tumors having HER2/chromosome enumeration probe (CEP) 17 ratios of 4.0 is still consistent with other data. Furthermore, the mixed predictive and prognostic effects of HER2 and of TOP2A may result in women in whom TOP2A and HER2 amplification may confer a worse prognosis if not treated or if not treated with anthracyclines, but a better result from treatment with anthracyclines. This demonstrates why one cannot separate prognostic and predictive effects in a trial in which the therapy of interest is given to all patients. Similarly the authors explore the question of chromosome 17 copy number as a prognostic/predictive factor as reported by others¹⁷ but are also unable to clarify this matter in the current study setting. These authors also confirm a reported incidence of TOP2A alteration of approximately 9%, of which about half are deletions and half alterations. This matches very well with the rates of HER2 and TOP2A alterations seen in other studies.^11,12 In addition, they confirm previous reports in which virtually all patients with TOP2A alterations also have HER2 amplification.¹³ Thus, Tubbs et al's article,¹⁴ although mainly confirming and strengthening already reported data, also stresses the importance of mining biomarker data from both completed and ongoing trials. This type of exploratory study will however be most useful in trials which compare the agent of interest to a regimen that does not contain that agent, to validate the role of HER2, TOP2A, and other biomarkers in predicting responses to anthracyclines, taxanes, and a variety of other therapies.

It is crucial that the exploration of these questions of tissue collected from previously completed randomized trials with their mature outcome data be prioritized. Many studies which will never be repeated may contain in their data/tumor repositories answers to these important questions. In the meantime, however, it remains unclear that HER2 and/or TOP2A amplification/alteration are ready for routine clinical use in selecting anthracycline-containing chemotherapy. Further data will be required to confirm these or other biomarkers¹⁷ for this routine use. Moreover, technical measurement issues remain problematic. Although Tubbs et al¹⁴ adds some consistency to these data, different articles still report differing associations between HER2 amplification and TOP2A alteration and the proportion of TOP2A amplifications and deletions differ.^11–13 Clearly accurate and reproducible measurements remain crucial. Quality assurance will become even more important if and as these measures are moved into routine clinical use. It is clear that widely used quality assurance standards for estrogen receptor, progesterone receptor, and HER2 measurements are still lacking and that these issues must be better controlled as we consider introducing more such measurements into clinical practice.

AUTHOR'S DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

The author(s) indicated no potential conflicts of interest.

REFERENCES

1. Paik S, Bryant J, Park C, et al: ErbB-2 and response to doxorubicin in patients with axillary lymph node positive, hormone receptor negative breast cancer. J Natl Cancer Inst 90:1361–1370, 1998.[Abstract/Free Full Text]

2. Paik S, Bryant J, Tan-Chiu E, et al: HER2 and choice of adjuvant chemotherapy for invasive breast cancer: National Surgical Adjuvant Breast and Bowel Project Protocol B-15. J Nat C Inst 92:1991–1998, 2000.[CrossRef]

3. Di Leo A, Chan S, Paesmans M, et al: HER2/neu as a predictive marker in a population of advanced breast cancer patients randomly treated either with single-agent doxorubicin or single-agent docetaxel. Br Cancer Res Treat 86:197–206, 2005.

4. Pritchard KI, Shepherd LE, O'Malley FP, et al: HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354:2103–2111, 2006.[Abstract/Free Full Text]

5. Dhesy-Thind B, Pritchard K, Messersmith H, et al: HER2/ neu in systemic therapy for women with breast cancer: A systematic review. Breast Cancer Res Treat 109:209–229, 2008.[CrossRef][Medline]

6. Gennari A, Sormani MP, Pronzato P, et al: HER2 status and efficacy of adjuvant anthracyclines in early breast cancer: A pooled analysis of randomized trials. J Natl Cancer Inst 100:14–20, 2008.[Abstract/Free Full Text]

7. De Laurentiis M, Arpino G, Massarelli E, et al: A meta-analysis on the interaction between HER-2 expression and response to endocrine treatment in advanced breast cancer. Clinical Cancer Res 11:4741–4748, 2005.[Abstract/Free Full Text]

8. Poole CJ, Earl H, Hiller L, et al: Epirubicin and cyclophosphamide, methotrexate, and fluourouracil as adjuvant therapy for early breast cancer. N Engl J Med 355:1851–1862, 2006.[Abstract/Free Full Text]

9. Bartlett JMS, Munro A, Cameron DA, et al: Type I receptor tyrosine kinase profiles identify patients with enhanced benefit from anthracyclines in the BR9601 adjuvant breast cancer chemotherapy trial. J Clin Oncol 26:5027–5035, 2008.[Abstract/Free Full Text]

10. Di Leo A, Isola J, Piette F, et al: A meta-analysis of phase III trials evaluating the predictive value of HER2 and topoisomerase II alpha in early breast cancer patients treated with CMF or anthracycline-based adjuvant therapy. Br Cancer Res Treat 107:214; 2008 abstr 705.

11. Knoop AS, Knudsen H, Balslev E, et al: Retrospective analysis of topoisomerase IIa amplifications and deletions as predictive markers in primary breast cancer patients randomly assigned to cyclophosphamide, methotrexate, and fluorouracil or cyclophosphamide, epirubicin and fluorouracil: Danish Breast Cancer Cooperative Group. J Clin Oncol 23:7483–7490, 2005.[Abstract/Free Full Text]

12. O'Malley F, Chia S, Tu D, et al: Topoisomerase II alpha and responsiveness of breast cancer to adjuvant chemotherapy. J Natl Cancer Inst 101:644–650, 2009.[Abstract/Free Full Text]

13. Slamon DJ, Mackey J, Crown J, et al: Role of anthracycline-based therapy in the adjuvant treatment of breast cancer: Efficacy analyses determined by molecular subtypes of the disease. Br Cancer Res Treat 106:112; 2007 abstr 13.

14. Tubbs R, Barlow W, Budd T, et al: Outcome of early stage breast cancer patients treated with doxorubicin-based adjuvant chemotherapy as a function of HER2 and TOP2A status. J Clin Oncol 27:3881–3886, 2009.[Abstract/Free Full Text]

15. Hayes DF: Prognostic and predictive factors for breast cancer: Translating technology to oncology. J Clin Oncol 23:1596–1597, 2005.[Free Full Text]

16. Hayes DF: Prognostic and predictive factors revisited. The Breast 14:493–499, 2005.[CrossRef][Medline]

17. Bartlett JMS, Munro A, Dunn J, et al: Chromosome 17 polysomy (CH17) as a predictor of anthracycline response: Emerging evidence from the UK NEAT adjuvant breast cancer trial. Br Cancer Res Treat 107:103; 2008 abstr 45.[CrossRef][Medline]

CiteULike    Complore    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this?

Related Article

• Outcome of Patients With Early-Stage Breast Cancer Treated With Doxorubicin-Based Adjuvant Chemotherapy As a Function of HER2 and TOP2A Status
  Raymond Tubbs, William E. Barlow, G. Thomas Budd, Eric Swain, Peggy Porter, Allen Gown, I-Ten Yeh, George Sledge, Charles Shapiro, James Ingle, Charles Haskell, Kathy S. Albain, Robert Livingston, and Daniel F. Hayes
  JCO 2009 27: 3881-3886 [Abstract] [Full Text]

This article has been cited by other articles:

				K. I. Pritchard, F. O'malley, L. Shepherd, M. N. Levine, D. Tu, V. Bramwell, I. Andrulis, and S. Chia Response J Natl Cancer Inst, November 5, 2009; (2009) djp403v1. [Full Text] [PDF]

				Can Anthracycline Response Be Predicted from HER2 and TOP2A Status of Breast Tumors? Journal Watch Oncology and Hematology, October 6, 2009; 2009(1006): 2 - 2. [Full Text]

				K. I. Pritchard Commentary: Anthracyclines in Early-Stage Breast Cancer: Is It the End of an Era? Oncologist, October 1, 2009; 14(10): 959 - 962. [Full Text] [PDF]

This Article Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Google Scholar Articles by Pritchard, K. I. PubMed PubMed Citation Articles by Pritchard, K. I. Related Articles Related Article Social Bookmarking                            What's this?