Clinical Update - Breast Cancer
HER2 and response to paclitaxel in node-positive breast cancer
Commentary by Dr Tom Ferguson and Dr Anna Nowak
The article
Hayes DF, Thor AD, Dressler LG, et al. HER2 and response to paclitaxel in node-negative breast cancer. N Engl J Med 2007;357(15):1496-506.
Reviewers
Dr Tom Ferguson is an advanced trainee in medical oncology at Sir Charles Gairdner Hospital, Perth. Dr Anna Nowak is a medical oncologist at Sir Charles Gairdner Hospital and Senior Lecturer, University of Western Australia.
Summary
Abbreviations
Doxorubicin and Cyclosphosphamide (AC); Breast Cancer International Research Group (BCIRG); The Cancer and Leukemia Group B (CALGB); Confidence Interval (CI); Disease-Free Survival (DFS); Estrogen Receptor (ER); Fluorescence In Situ Hybridization (FISH); Fluorouracil, Epirubicin and Cyclophosphamide (FEC); Human Epidermal Growth Factor Receptor type 2 (HER2); Hazard Ratio (HR); National Surgical Adjuvant Breast and Bowel Project (NSABP); Programmes d’Actions Concertées Sein (PACS); Docetaxel, Doxorubicin and Cyclophosphamide (TAC); Docetaxel and Cyclophosphamide (TC).
Study design
This paper describes a retrospective analysis of tissue samples from a subgroup of women enrolled in a randomised trial, CALGB 9344/INT0148. The trial examined the benefit of adjuvant doxorubicin and cyclophosphamide with the addition of paclitaxel among node positive breast cancer patients. From 3121 patients in the trial, 1500 women were randomly selected to have their tissue samples examined for HER2 expression or amplification. Tissue blocks from 1322 of the 1500 women were available. Immunohistochemical analysis and fluorescence in situ hybridization (FISH) were performed on the tissue specimens to determine HER2 status. The primary end point was disease-free survival (DFS).
Findings
Among HER2 positive women, the addition of paclitaxel resulted in significant benefits for both recurrence (hazard ratio (HR) for recurrence=0.59; p=0.01) and overall survival (HR for death=0.57; p=0.01), regardless of estrogen receptor (ER) status. Paclitaxel did not improve DFS in women with HER2 negative, ER positive tumours (p=0.71), however it did appear to benefit women with HER2 negative, ER negative tumours (p=0.002).
Conclusion
The authors concluded that patients with HER2 positive breast cancer benefit from the addition of paclitaxel after adjuvant treatment with doxorubicin plus cyclophosphamide in node-positive breast cancer, regardless of estrogen receptor status. However, patients with HER2-negative, estrogen receptor-positive breast cancer did not appear to benefit from the addition of paclitaxel following adjuvant chemotherapy.
Commentary
What does this article add to existing clinical evidence in this area?
Adjuvant therapy following surgery for early breast cancer significantly improves disease free survival and overall survival. With advances in our understanding of the biology and molecular basis of breast cancer, the goal of tailoring adjuvant therapy to the individual tumour features is becoming more realistic.
This study presents evidence that the use of paclitaxel following doxorubicin and cyclophosphamide (AC) chemotherapy does not benefit women with estrogen receptor (ER) positive and HER2 negative tumours. Benefit from the addition of paclitaxel was observed in all HER2 positive patients, including those in the small group who had HER2 positive/ER positive tumours. The number of women in this group was not published; the p-value for DFS approached significance (p=0.058). Women with HER2 negative/ER negative tumours also benefited from the addition of paclitaxel. The HER2 negative/ER positive subgroup who did not benefit from paclitaxel included more than half of the total participants. This study raises the idea that this large proportion of women could avoid the inconvenience, cost and toxicity of paclitaxel treatment.
This is the first large adjuvant taxane study to report DFS according to both ER and HER2 status. The influence of hormone receptor status on benefit from the use of adjuvant paclitaxel was examined in the initial report of the CALGB 9344 trial and has also been reported in other trials studying the role of taxanes in early breast cancer. The resulting data are conflicting. If the finding from Hayes et al1 is confirmed, a consistent pattern would be expected such that the hormone receptor positive women get less benefit from taxanes than the hormone receptor negative women, since most hormone receptor positive tumours are likely to be HER2 negative. The initial report of CALGB 93442 gave a hazard ratio for recurrence 0.91 (95% CI:0.78,1.07) for hormone receptor positive patients and 0.72 (95% CI:0.59,0.86) for hormone receptor negative/unknown patients. However, the NSABP B-28 trial,3 which randomised 3060 women to AC or AC followed by paclitaxel in a very similar regimen, showed no interaction between hormone receptor status and benefit from paclitaxel; if anything, a trend was seen in the other direction. The PACS 013 and BCIRG 0014 studies both tested the use of docetaxel in the experimental arm, and demonstrated similar improvements in outcome for both hormone receptor positive and hormone receptor negative patients. Hence, the analyses reported to date from these other studies do not support the hypothesis generated by Hayes et al.1
How adequate was the methodology used in addressing the aim of the study?
This study has some methodological limitations. Being a retrospective analysis of a subset of women randomly selected from the trial, selection bias should be considered. However, almost 50% of all patients were included in this analysis, and the characteristics of the selected women were not significantly different to the entire population. Retrospective testing also has limitations as the age and storage conditions of the blocks may potentially affect HER2 testing by immunohistochemistry and FISH analysis.5 Nevertheless, three methods of testing were performed independently and the quality of results for all three assays were similar. There was a degree of discordance between the three methods of testing which is expected. The authors have not commented on variation in HER2 results according to year of sample collection.
One of the major conclusions of this study is that HER2 negative/ER positive patients do not appear to benefit from the addition of paclitaxel. This is based on a third order interaction and should be regarded as hypothesis generating and exploratory.
What are the implications of this study for clinical practice in Australia?
It is over 13 years since the CALGB 9344 trial opened. The control arm of four cycles of AC chemotherapy as adjuvant treatment for node positive breast cancer would currently be considered inappropriate for many of these patients. As well as the AC followed by paclitaxel regimen, other taxane-containing regimens such as docetaxel, doxorubicin and cyclophosphamide (TAC), fluorouracil (5FU), epirubicin and cyclophosphamide (FEC) followed by docetaxel, docetaxel and cyclophosphamide (TC), and dose-dense chemotherapy are also used. It is important not to extrapolate the results of this analysis to all taxane-containing regimens. Nevertheless, it raises some doubt about the efficacy of incorporating 3-weekly paclitaxel into an adjuvant chemotherapy regimen for women with ER positive and HER2 negative tumours. It would be premature to change clinical practice based on the results of this single study, however, these findings are potentially clinically important and require further investigation. As pointed out by Moore6 in her editorial of this paper, ‘oncologists have a responsibility to their patients to be aware of this report’. If confirmed in retrospective analyses of other studies, the addition of paclitaxel to standard anthracycline-based chemotherapy for node positive/hormone receptor positive/HER2 negative patients would need to be re-evaluated. Before we change clinical practice, these findings need to be reproduced and examined in regimens using docetaxel and weekly paclitaxel.
References
1. Hayes DF, Thor AD, Dressler LG, et al. HER2 and response to paclitaxel in node positive breast cancer. New England Journal of Medicine 2007;375:1496-506
2. Henderson IC, Berry DA, Demetri GD, et al. Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. Journal of Clinical Oncology 2003;21:976-83
3. Roche H, Fumoleau P, Spielmann M, et al. Sequential adjuvant epirubicin-based and docetaxel chemotherapy for node-positive breast cancer patients: the FNCLCC PACS 01 Trial. Journal of Clinical Oncology 2006;24:5664-71
4. Martin M, Pienkowski T, Mackey J, et al. Adjuvant docetaxel for node-positive breast cancer. New England Journal of Medicine 2005;352:2302-13
5. Risio M, De Rosa G, Sarotto I, et al. HER2 testing in gastric cancer: molecular morphology and storage time-related changes in archival samples. International Journal of Oncology. 2003;23(5):1381-7
6. Moore A. Breast-cancer therapy – Looking back to the future. New England Journal of Medicine 2007;375:1547-49
Editor: Dr Karen Luxford, General Manager, National Breast Cancer Centre.
Editorial Committee: Mr John Collins - Surgeon,
Dr Sue-Anne McLachlan - Medical Oncologist,
Dr Sue Pendlebury - Radiation Oncologist,
A/Prof Martin Stockler - Medical Oncologist, Ms Jo Keyser - Specialist Breast Nurse, Dr Sally Meade - Breast Surgeon, Dr Warwick Lee - Radiologist.
Disclaimer
Clinical Update - Breast Cancer is produced by the National Breast Cancer Centre (NBCC) and is intended to provide health professionals with timely expert commentary on new research in breast cancer. Commentaries included in Clinical Update - Breast Cancer do not replace recommendations included in NBCC clinical practice guidelines.
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