- Email: [email protected]
Prediction of cancer outcome with microarrays
Correspondence
patients should be considered for endocrine therapy alone.3,4 We respectfully request a re-evaluation of the data set on the basis of reassessment of endocrine responsiveness, and are willing to blindly review all pathological and clinical data to illustrate how the St Gallen recommendations ought to be used. Looking for gene signatures for treatment responsiveness rather than for prognosis should be the aim of this expensive yet promising research. We declare that we have no conflict of interest.
*Aron Goldhirsch, Richard D Gelber, Giuseppe Viale, Marco Colleoni, Alan S Coates [email protected] Division of Medical Oncology, Department of Medicine (AG, MC), Department of Pathology and Laboratory Medicine (GV), and European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA (RDG); and University of Sydney, Sydney, New South Wales, Australia (ASC) 1
2
3
4
Wang Y, Klijn JGN, Zhang Y, et al. Geneexpression profiles to predict distant metastases of lymph-node-negative primary breast cancer. Lancet 2005; 365: 671–79. Harvey JM, Clark GM, Osborne CK, et al. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999; 17: 1474–81. International Breast Cancer Study Group (IBCSG). Endocrine responsiveness and tailoring adjuvant therapy for postmenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst 2002; 94: 1054–65. International Breast Cancer Study Group (IBCSG). Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst 2003; 95: 1833–46.
Authors’ reply Andrew Lee is correct that our patients came from 25 different hospitals. The pathological information on the patients was based on the original pathology reports. We did not do a central pathological review of the tumours for logistical reasons and because frozen tissues are not suitable for grading. Our patients included cases collected from 1980 to 1995. Although many of the patients from the early years were not assessed with today’s histological 1686
grading methods, most pathologists described the tumours as well differentiated, moderately differentiated, or poorly differentiated. As indicated in one of Lee’s references,1 the extensive studies on histological grading (also using a score with three categories) were done in the 1990s. Vascular invasion, which is not yet included in the consensus guidelines, was not consistently mentioned in all pathology reports. Histological grade and the 76-gene signature had a significant prognostic value in the univariate analysis, indicating that they are correlated with clinical outcome. However, the 76-gene signature was the only significant factor in the multivariate analysis, suggesting that the gene signature covered the prognostic value of histological grade. Contrary to Aron Goldhirsch and colleagues’ suggestion, the poor prognosis group did not contain a disproportionately high number of patients with tumours that lacked oestrogen and progesterone receptors. The poor prognostic group contained 24% (27/112) oestrogen-receptor-negative patients, the good prognosis group 25% (15/59). These numbers will be even lower if 1% positive tumour cells is used as a threshold instead of the applied common criteria. From many trials and from the Early Breast Cancer Trialists’ Collaborative Group overview,2 we have learned that the highest annual recurrence rates occur during the first years of follow-up; the same is true for oestrogen-receptor-positive tumours treated with tamoxifen.3 As such, oestrogen-receptor-positive tumours can also be aggressive, and our gene signature also identifies these patients. An early dip in the survival curves of the patients with an unfavourable gene signature is therefore not surprising and cannot solely be explained by the presence of a high number of pure oestrogen-receptor-negative or progesterone-receptor-negative tumours. About 90% of our patients, also with a favourable gene signature, belong to
the average risk group according to the St Gallen 2003 criteria,4 and therefore deserve systemic endocrine treatment or chemotherapy. Thus our gene signature could spare a substantial number of patients from systemic therapy. With respect to sparing patients from chemotherapy specifically, this question is more difficult to answer. Several studies have shown major differences in the application of adjuvant chemotherapy between centres and countries within Europe and between Europe and the USA. This lack of consensus is reflected by the fact that several single and combined endocrine and chemotherapeutic options are accepted in this average risk group. We appreciate Goldhirsch and colleagues’ offer to re-evaluate our data to assess the endocrine responsiveness of the patients. We agree that looking for gene signatures for treatment responsiveness is important,5 but the identification of very low-risk patients who do not need intensive or long-term systemic treatment remains relevant too. YW and DA are employed by a health-care company that is in the business of commercialising diagnostic products. JGMK and JAF have no conflict of interest.
Jan G M Klijn, Yixin Wang, David Atkins, *John A Foekens [email protected] Department of Medical Oncology, Erasmus Medical Center, Rotterdam, Netherlands (JGMK); Veridex LLC, San Diego, CA, USA (YW); Veridex LLC, Raritan, NJ, USA (DA); and Department of Medical Oncology, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, Netherlands (JAF) 1
2
3
4
5
Elston CW, Ellis IO. Pathological prognostic factors in breast cancer, I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991; 19: 403–10. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of randomised trials. Lancet 1998; 351: 1451–67. Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 1996; 14: 2738–46. Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thürlimann B, Senn HJ. Meeting highlights: Updated International Expert Consensus on the Primary Therapy of Early Breast Cancer. J Clin Oncol 2003; 21: 3357–65. Jansen MPHM, Foekens JA, van Staveren IL, et al. Molecular classification of tamoxifenresistant breast carcinomas by gene expression profiling. J Clin Oncol 2005; 23: 732–40.
www.thelancet.com Vol 365 May 14, 2005
patients should be considered for endocrine therapy alone.3,4 We respectfully request a re-evaluation of the data set on the basis of reassessment of endocrine responsiveness, and are willing to blindly review all pathological and clinical data to illustrate how the St Gallen recommendations ought to be used. Looking for gene signatures for treatment responsiveness rather than for prognosis should be the aim of this expensive yet promising research. We declare that we have no conflict of interest.
*Aron Goldhirsch, Richard D Gelber, Giuseppe Viale, Marco Colleoni, Alan S Coates [email protected] Division of Medical Oncology, Department of Medicine (AG, MC), Department of Pathology and Laboratory Medicine (GV), and European Institute of Oncology, Via Ripamonti 435, 20141 Milan, Italy; Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA, USA (RDG); and University of Sydney, Sydney, New South Wales, Australia (ASC) 1
2
3
4
Wang Y, Klijn JGN, Zhang Y, et al. Geneexpression profiles to predict distant metastases of lymph-node-negative primary breast cancer. Lancet 2005; 365: 671–79. Harvey JM, Clark GM, Osborne CK, et al. Estrogen receptor status by immunohistochemistry is superior to the ligand-binding assay for predicting response to adjuvant endocrine therapy in breast cancer. J Clin Oncol 1999; 17: 1474–81. International Breast Cancer Study Group (IBCSG). Endocrine responsiveness and tailoring adjuvant therapy for postmenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst 2002; 94: 1054–65. International Breast Cancer Study Group (IBCSG). Adjuvant chemotherapy followed by goserelin versus either modality alone for premenopausal lymph node-negative breast cancer: a randomized trial. J Natl Cancer Inst 2003; 95: 1833–46.
Authors’ reply Andrew Lee is correct that our patients came from 25 different hospitals. The pathological information on the patients was based on the original pathology reports. We did not do a central pathological review of the tumours for logistical reasons and because frozen tissues are not suitable for grading. Our patients included cases collected from 1980 to 1995. Although many of the patients from the early years were not assessed with today’s histological 1686
grading methods, most pathologists described the tumours as well differentiated, moderately differentiated, or poorly differentiated. As indicated in one of Lee’s references,1 the extensive studies on histological grading (also using a score with three categories) were done in the 1990s. Vascular invasion, which is not yet included in the consensus guidelines, was not consistently mentioned in all pathology reports. Histological grade and the 76-gene signature had a significant prognostic value in the univariate analysis, indicating that they are correlated with clinical outcome. However, the 76-gene signature was the only significant factor in the multivariate analysis, suggesting that the gene signature covered the prognostic value of histological grade. Contrary to Aron Goldhirsch and colleagues’ suggestion, the poor prognosis group did not contain a disproportionately high number of patients with tumours that lacked oestrogen and progesterone receptors. The poor prognostic group contained 24% (27/112) oestrogen-receptor-negative patients, the good prognosis group 25% (15/59). These numbers will be even lower if 1% positive tumour cells is used as a threshold instead of the applied common criteria. From many trials and from the Early Breast Cancer Trialists’ Collaborative Group overview,2 we have learned that the highest annual recurrence rates occur during the first years of follow-up; the same is true for oestrogen-receptor-positive tumours treated with tamoxifen.3 As such, oestrogen-receptor-positive tumours can also be aggressive, and our gene signature also identifies these patients. An early dip in the survival curves of the patients with an unfavourable gene signature is therefore not surprising and cannot solely be explained by the presence of a high number of pure oestrogen-receptor-negative or progesterone-receptor-negative tumours. About 90% of our patients, also with a favourable gene signature, belong to
the average risk group according to the St Gallen 2003 criteria,4 and therefore deserve systemic endocrine treatment or chemotherapy. Thus our gene signature could spare a substantial number of patients from systemic therapy. With respect to sparing patients from chemotherapy specifically, this question is more difficult to answer. Several studies have shown major differences in the application of adjuvant chemotherapy between centres and countries within Europe and between Europe and the USA. This lack of consensus is reflected by the fact that several single and combined endocrine and chemotherapeutic options are accepted in this average risk group. We appreciate Goldhirsch and colleagues’ offer to re-evaluate our data to assess the endocrine responsiveness of the patients. We agree that looking for gene signatures for treatment responsiveness is important,5 but the identification of very low-risk patients who do not need intensive or long-term systemic treatment remains relevant too. YW and DA are employed by a health-care company that is in the business of commercialising diagnostic products. JGMK and JAF have no conflict of interest.
Jan G M Klijn, Yixin Wang, David Atkins, *John A Foekens [email protected] Department of Medical Oncology, Erasmus Medical Center, Rotterdam, Netherlands (JGMK); Veridex LLC, San Diego, CA, USA (YW); Veridex LLC, Raritan, NJ, USA (DA); and Department of Medical Oncology, Erasmus Medical Center, Dr Molewaterplein 50, 3015 GE Rotterdam, Netherlands (JAF) 1
2
3
4
5
Elston CW, Ellis IO. Pathological prognostic factors in breast cancer, I. The value of histological grade in breast cancer: experience from a large study with long-term follow-up. Histopathology 1991; 19: 403–10. Early Breast Cancer Trialists’ Collaborative Group. Tamoxifen for early breast cancer: an overview of randomised trials. Lancet 1998; 351: 1451–67. Saphner T, Tormey DC, Gray R. Annual hazard rates of recurrence for breast cancer after primary therapy. J Clin Oncol 1996; 14: 2738–46. Goldhirsch A, Wood WC, Gelber RD, Coates AS, Thürlimann B, Senn HJ. Meeting highlights: Updated International Expert Consensus on the Primary Therapy of Early Breast Cancer. J Clin Oncol 2003; 21: 3357–65. Jansen MPHM, Foekens JA, van Staveren IL, et al. Molecular classification of tamoxifenresistant breast carcinomas by gene expression profiling. J Clin Oncol 2005; 23: 732–40.
www.thelancet.com Vol 365 May 14, 2005