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Journal of Clinical Oncology, Vol 26, No 10 (April 1), 2008: pp. 1769-1771 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.15.6893
In ReplyEndocrine Cancer Group, Edinburgh Cancer Research Centre, Western General Hospital, Edinburgh, United Kingdom
University of Nottingham, Molecular Medical Sciences, Department of Histopathology, Nottingham City Hospital, Nottingham, United Kingdom
Department of Medicine, Breast Unit, Royal Marsden Hospital, London, United Kingdom
Department of Pathology, Western Infirmary, Glasgow, United Kingdom
Department of Oncology, Western General Hospital, Lothian University Hospitals Trust, Edinburgh, United Kingdom
Department of Medicine, Breast Unit, Royal Marsden Hospital, London, United Kingdom
ICR-CTSU Section of Clinical Trials, The Institute of Cancer Research, Sutton, Surrey, United Kingdom
Consultant Clinical Oncologist, Velindre NHS Trust, Cardiff, United Kingdom
Consultant Medical Oncologist, Guys & St Thomas Hospital NHS Trust, London, United Kingdom Thank you for the opportunity to respond to the letter by Neven et al regarding our recent article.1 Our original observation,2 presented at the June 2005 American Society of Clinical Oncology meeting, contemporaneously with reports by Huang et al,3,4 showed that in estrogen receptor (ER)–positive tumors, histologic type, grade, and progesterone receptor status but not nodal status was associated with increasing frequency of human epidermal growth factor receptor 2 (HER-2) positivity. Simultaneously for ER-negative patients, we observed an association with nodal status but not grade. At that time we suggested a significant interaction between HER-2 and ER in determining disease spread or differentiation in breast cancer.5 These observations were based on samples from both the United Kingdom Taxotere as Adjuvant Chemotherapy (TACT) and United Kingdom Tamoxifen versus Exemestane Adjuvant Multicenter (TEAM) trials analyzed within Bartlett's laboratory. The analyses were subsequently extended to the entire TACT patient cohort,1 for whom a high quality of HER-2 testing has been achieved.6 Data on the TEAM trial cohort will be analyzed separately. Confirmation of an interaction between HER-2 and increasing grade in ER-positive breast cancer by Neven et al adds to the evidence that this is a significant and potentially clinically important interaction. We apologize if we appeared to overlook this finding and the related finding on age and HER-2 status in ER-positive and ER-negative disease.3,4 Nonetheless, the key observation in our 2005 and 2007 data was the apparent switch in HER-2 interactions with key pathologic features, stage, and grade in ER-positive and ER-negative disease. This apparent switching of HER-2 function based on ER status required both the observation relating to grade and that relating to nodal status. The supporting analysis in the letter from Neven et al confirms this interaction. Concerning the qualitative interaction between age and expression of HER-2 and steroid receptors, Neven et al state, "Considering patients under the age of 40 years, we described that the age-related decline in HER-2–positive breast cancers was restricted to the ER-positive and especially the ER-positive progesterone-receptor–positive subset." The observations made by Huang and ourselves differ as follows: We observed that in ER-positive but not ER-negative disease, increased HER-2 positivity was associated with early-onset (age < 40 years) breast cancer (Fig 1C in Bartlett et al1). In contrast, Huang et al3 observed that in an ER-positive population, the impact of age on increased risk of HER-2 positivity was restricted to patients younger than 46 years. Both groups have added linked observations on the interaction among age, hormone receptors, and HER-2 status, which improve our understanding of these factors. Neven et al suggest in their report that the nature of the TACT trial population, which is confined to early breast cancers eligible for adjuvant chemotherapy, may bias our findings. In confirming these findings in sequential patient cohort from a single hospital, they provide valuable supporting evidence for our hypothesis-generating study. There remain key differences between the TACT trial population1 and the Neven et al population (Table 1). In the Neven et al series the frequency of ER negativity is much lower than observed in comparable series elsewhere.4,7 The frequencies of HER-2–positive and node-positive patients in the Neven series are lower than currently predicted for single-center consecutive series. Thus, whereas the TACT trial population represents higher-risk patients, the Neven et al series appears biased toward lower-risk patients than would normally be expected in a symptomatic breast clinic practice, suggesting the possible inclusion of a significant proportion of screen-detected cancers. The importance of this observation is that the interactions between HER-2 and ER we observed seem to hold across a wide range of classical risk groups. However, the inclusion of large numbers of low-risk patients introduces the possibility of type II errors in the Neven et al series. There are few (n = 55) grade 1/2 ER-negative cancers in the Neven et al series and only 13.7% of all patients have more than three positive nodes, and more than 60% of patients are node negative. This may explain the one difference between the data reported by Neven et al and our data. Neven et al suggested in ER-positive cancers a significant association between nodal status and HER-2 status is still observed, particularly in grade 3 cancers (from 4.2 to 3.4% for grade 2 and from 16.2% to 23.8% for grade 3 cancers, odds ratios of 0.80 and 1.61 respectively). Although we observed an increase in HER-2 positivity with node positivity in ER-positive breast cancers (from 12.2% to 16.3% for grade 2 and from 25.1% to 30.7% for grade 3 cancers; odds ratio, 1.40 and 1.32, respectively, Table 31), the increase was smaller than the effect observed by Neven in grade 3 disease. Furthermore, it was neither statistically significant nor as marked as that observed for ER-negative disease in our trial (24.4% to 49.6% for grade 2 and 20.8% to 44.6% for grade 3 disease; odds ratio, 3.05 and 3.06, respectively). In our earlier report2 including TACT patients and lower-risk patients from the TEAM trial, no significant interaction with nodal status was observed in ER-positive patients. HER-2 positivity in the TEAM trial population in this analysis was 16.2%, closer to the range observed by Neven. Therefore, we failed to observe a statistical association between nodal status and HER-2 positivity in two patient groups (TACT, TEAM). Although, the possibility remains that such an interaction exists, it is clearly at a lower level than that observed in ER-negative patients. Additional analysis of the TEAM trial pathology study, which is scheduled to include 5000 ER-positive patients with centrally evaluated ER and HER-2 will address this question in detail.
It is also of note that few of the ER-positive low-grade (grade 1) cancers in the Neven et al series were HER-2 positive. Such data have been used by others to exclude HER-2 testing in ER-positive low-grade cancers. Conversely, in our study, which reflects the population eligible for adjuvant chemotherapy and thus adjuvant trastuzumab, no pathologic criteria could be used to select patients who could be excluded from HER-2 testing. Between 4% and 5% grade 1, ER-positive tumors were HER-2 positive and therefore eligible for trastuzumab. We continue to believe that all tumors, regardless of their pathologic risk factors, should be considered for HER-2 testing. We recently reported the differences between ER-positive and ER-negative disease and HER-2 status with respect to age, grade, and nodal status.1,2 By confirming our analyses, Neven et al have added supporting evidence for this hypothesis. It remains to be seen if functional, and thus potentially treatable via drugs, pathways incorporating ER signaling can be identified to explain these effects. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: None Consultant or Advisory Role: John M.S. Bartlett, Dako, Denmark (C), Roche (C), Abbott Vysis (C), Pfizer (C); Ian O. Ellis, Dako (C); Mitch Dowsett, Pfizer (C), Roche (C); David A. Cameron, Sanofi-aventis (C), Pfizer (C), Roche (C); Paul O. Ellis, Sanofi-aventis (C), Pfizer (C) Stock Ownership: None Honoraria: John M.S. Bartlett, Pfizer, Roche, Dako; David A. Cameron, Sanofi-aventis, Pfizer, Roche; Judith M. Bliss, Pfizer; Paul Ellis, Sanofi-aventis Research Funding: John M.S. Bartlett, Roche; Ian O. Ellis, Roche; Mitch Dowsett, Roche; Clare Peckitt, Pfizer, Roche, Sanofi-aventis; Judith M. Bliss, Pfizer, Roche, Sanofi-aventis Expert Testimony: None Other Remuneration: Judith M. Bliss, Pfizer
ACKNOWLEDGMENTS The TACT Trial is jointly funded by Cancer Research UK and educational grants from Sanofi-Aventis, Roche and Pharmacia Upjohn. Storage, construction of microarrays and tissue HER-2 testing was funded by an educational grant from Roche. REFERENCES
1. Bartlett, JMS, Ellis, IO, Dowsett, M, et al: Human epidermal growth factor receptor 2 status correlates with lymph node involvement in patients with estrogen receptor (ER) negative, but with grade in those with ER-positive early-stage breast cancer suitable for cytotoxic chemotherapy. J Clin Oncol 25:4423-4430, 2007 2. Bartlett, J, Mallon, EA, Forsyth, A, et al: HER-2 (in the TACT and TEAM trials) differentially affects invasive potential in ER-ve and ER+ve breast cancers. J Clin Oncol 23:850s, 2005 (suppl; abstr 9557)[CrossRef] 3. Huang HJ, Neven P, Drijkoningen M, et al: Association between tumour characteristics and HER-2/neu by immunohistochemistry in 1362 women with primary operable breast cancer. J Clin Path 58:611-616, 2005 4. Huang HJ, Neven P, Drijkoningen M, et al: Association between HER-2/neu and the progesterone receptor in oestrogen-dependent breast cancer is age-related. Breast Cancer Res Treat 91:81-87, 2005[CrossRef][Medline] 5. Johnston SRD, Johnson L, Dowsett M, et al: HER-2 status in primary breast cancer patients treated in the UK TACT trial - relationship with tumour size, grade, nodal involvement and ER status. Breast Cancer Res Treat 82:512, 2003 6. Dowsett M, Bartlett J, Ellis IO, et al: Correlation between immunohistochemistry (HercepTest) and fluorescence in situ hybridization (FISH) for HER-2 in 426 breast carcinomas from 37 centres. J Pathol 199:418-423, 2003[CrossRef][Medline] 7. Barnes DM, Millis RR, Gillett CE, et al: The interaction of oestrogen receptor status and pathological features with adjuvant treatment in relation to survival in patients with operable breast cancer: A retrospective study of 2660 patients. Endocr Relat Cancer 11:85-96, 2004[Abstract]
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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