European Journal of Cancer (2014) 50, 1038– 1039
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Letter to the Editor
Reply to letter by Ieni et al. Gaetano Aurilio a,⇑, Franco Nole` a, Giuseppe Viale b,c, Giancarlo Pruneri b,c a
Department of Medical Oncology, European Institute of Oncology, Milan, Italy Department of Pathology, European Institute of Oncology, Milan, Italy c University of Milan, School of Medicine, Italy b
To the Editor, We would like to thank Ieni et al. for their letter regarding our article. [1]. The detection of Her-2 amplification and/or overexpression in breast carcinoma is a crucial step for identifying patients who may benefit from the steadily broadening anti-Her-2 drugs armory, including Trastuzumab, Pertuzumab, the antibody-drug conjugate Trastuzumab emtansine (TDM-1) and Tyrosine kinase inhibitors (TKIs). Her-2 aberration may be ascertained in up to 20% of breast carcinomas: although usually ubiquitous throughout the tumour, it has been repeatedly reported that Her-2 amplification and/or overexpression may be found in a minority of the tumour component (tumour heterogeneity) in up to a third of Her-2-positive breast cancers. Her-2 aberration may be lost or gained along the clinical course of the disease: in a recent meta-analysis, we found that Her-2 status in primary tumours and loco-regional or distant metastases may change from positive to negative and vice versa in 13% and 5% of the patients, respectively, accounting for a pooled discordance rate of 8% [1]. Likewise, Ieni et al. report on a series of 148 breast cancer patients evaluated by immunohistochemistry (IHC) and fluorescent in situ hybridisation (FISH) with a 4.8% pooled discordance rate in Her-2 status between primary tumour and matched lymph nodes. Tumours are complex living systems subjected to a selective ⇑ Corresponding author: Tel.: +39 3483655278.
E-mail address: [email protected] (G. Aurilio). 0959-8049/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2014.01.015
pressure prompting clonal selection: it is therefore conceivable that Her-2 status in the metastatic deposits may be converted from positive to negative under anti-Her-2 therapy, or from negative to positive for the outgrowth of Her-2 positive small clones overlooked in the primary tumour. This view has nevertheless been challenged by the observation that Her-2 testing is associated with an inter- and intra-laboratory discordance rate approaching 15%, prompting some authors to claim that the Her-2 status switching may be the consequence of technical and/or interpretative inconsistencies rather than a true biological issue, at least in a fraction of the cases. This dilemma may be solved only by applying stringent criteria to the pre-analytical and analytical phases of tissue handling and to the interpretation of the results. Paradoxically, one of the most critical issues remains the definition of ‘Her-2 positivity’, whose modification over time has generated confusion within the clinical community. As a matter of fact, following the positive results of the pivotal clinical trials [2,3], only patients whose tumours overexpressed Her-2 by IHC in more than 10% invasive tumour cells, or showed Her-2 gene amplification (4 or more copies of the gene/cell, or a ratio P2 between the gene copy number and the chromosome 17 centromere) have been originally considered as candidate to trastuzumab treatment according to the regulatory agencies worldwide. In 2007, the American Society of Clinical Oncology (ASCO)/ College of American Pathologists (CAP) raised the threshold for a positive IHC to >30% overexpressing
G. Aurilio et al. / European Journal of Cancer 50 (2014) 1038–1039
tumour cells and for a positive ISH to a ratio of P2.2 or a gene copy number of >6/cell, in order to increase the concordance rate between the two assays [4]. Nevertheless, these guidelines were misinterpreted as defining new thresholds for eligibility of the patients to the therapy, thus potentially disallowing a fraction of Her-2 positive patients from receiving a targeted therapy. These and other controversial issues have been recently addressed by the updated ASCO/CAP recommendations, which definitely confirm that Her-2 positivity is defined according to the thresholds of >10% for IHC and P6.0 signals per cell or Her-2/CEP17 ratio of P2 for ISH, and provide detailed technical guidelines for the pre-analytical and analytical phases and results interpretation [5]. Furthermore, ASCO/CAP acknowledge the occurrence of discrepancy in Her-2 status between primary tumour and a local or distant recurrence in the setting of multiple metastatic sites and, although underlining that it is not possible to discriminate between a true biological change, tumour heterogeneity or technical flaws, suggest to retest Her-2 whenever feasible. Along this line, it is worth of note that Ieni et al. evaluated Her-2 overexpression and amplification by applying heterogeneous thresholds, i.e. at least 30% of immunoreactive cells by IHC and a Her-2/CEP17 ratio >2 by FISH. These technical issues notwithstanding, the authors report a pooled discordant rate slightly lower than that of most published study and our meta-analysis. Their findings are worth of note, especially since obtained by comparing synchronous primary tumours and lymph node metastases in a series of untreated locally advanced breast cancer patients, therefore implying that the switch in Her-2 status may occur in a relatively early phase of tumour development. As a consequence, the data of Ieni et al. suggest that it might be of clinical utility to test Her-2 also in the metastatic lymph nodes of patients with poorly differentiated tumours that are Her-2 negative in the primary site. Taking into account the pivotal role of Her-2 aberration in dictating the prognosis and the response to different targeted therapies of breast cancer
1039
patients, its multiple testing at diagnosis or upon the clinical course of the disease is likely to become a rule in the future: ASCO/CAP suggest to perform a new Her-2 test in surgical specimens for all the patients whose Her-2 status is defined as negative in core needle biopsies if they contain only a small amount of invasive tumour or if tumour grade is low in the biopsy and higher in the surgical specimen. Despite the financial implications, diagnostic delay and health disparities possibly associated with multiple testing, evaluating Her-2 status at diagnosis and in loco-regional or distant metastasis are of paramount clinical utility, especially in view of the availability of new targeted compounds and different therapeutic schedules, which are likely to further improve survival of truly Her-2-positive breast cancer patients. Conflict of interest statement None declared. References [1] Aurilio G, Disalvatore D, Pruneri G, et al. A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. Eur J Cancer 2014;50(2):277–89. [2] Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353(16):1659–72. [3] Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353(16):1673–84. [4] Wolff AC, Hammond ME, Schwartz JN, 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(1):118–45. [5] Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 2013;31(31):3997–4013.
Available at www.sciencedirect.com
ScienceDirect journal homepage: www.ejcancer.com
Letter to the Editor
Reply to letter by Ieni et al. Gaetano Aurilio a,⇑, Franco Nole` a, Giuseppe Viale b,c, Giancarlo Pruneri b,c a
Department of Medical Oncology, European Institute of Oncology, Milan, Italy Department of Pathology, European Institute of Oncology, Milan, Italy c University of Milan, School of Medicine, Italy b
To the Editor, We would like to thank Ieni et al. for their letter regarding our article. [1]. The detection of Her-2 amplification and/or overexpression in breast carcinoma is a crucial step for identifying patients who may benefit from the steadily broadening anti-Her-2 drugs armory, including Trastuzumab, Pertuzumab, the antibody-drug conjugate Trastuzumab emtansine (TDM-1) and Tyrosine kinase inhibitors (TKIs). Her-2 aberration may be ascertained in up to 20% of breast carcinomas: although usually ubiquitous throughout the tumour, it has been repeatedly reported that Her-2 amplification and/or overexpression may be found in a minority of the tumour component (tumour heterogeneity) in up to a third of Her-2-positive breast cancers. Her-2 aberration may be lost or gained along the clinical course of the disease: in a recent meta-analysis, we found that Her-2 status in primary tumours and loco-regional or distant metastases may change from positive to negative and vice versa in 13% and 5% of the patients, respectively, accounting for a pooled discordance rate of 8% [1]. Likewise, Ieni et al. report on a series of 148 breast cancer patients evaluated by immunohistochemistry (IHC) and fluorescent in situ hybridisation (FISH) with a 4.8% pooled discordance rate in Her-2 status between primary tumour and matched lymph nodes. Tumours are complex living systems subjected to a selective ⇑ Corresponding author: Tel.: +39 3483655278.
E-mail address: [email protected] (G. Aurilio). 0959-8049/$ - see front matter Ó 2014 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.ejca.2014.01.015
pressure prompting clonal selection: it is therefore conceivable that Her-2 status in the metastatic deposits may be converted from positive to negative under anti-Her-2 therapy, or from negative to positive for the outgrowth of Her-2 positive small clones overlooked in the primary tumour. This view has nevertheless been challenged by the observation that Her-2 testing is associated with an inter- and intra-laboratory discordance rate approaching 15%, prompting some authors to claim that the Her-2 status switching may be the consequence of technical and/or interpretative inconsistencies rather than a true biological issue, at least in a fraction of the cases. This dilemma may be solved only by applying stringent criteria to the pre-analytical and analytical phases of tissue handling and to the interpretation of the results. Paradoxically, one of the most critical issues remains the definition of ‘Her-2 positivity’, whose modification over time has generated confusion within the clinical community. As a matter of fact, following the positive results of the pivotal clinical trials [2,3], only patients whose tumours overexpressed Her-2 by IHC in more than 10% invasive tumour cells, or showed Her-2 gene amplification (4 or more copies of the gene/cell, or a ratio P2 between the gene copy number and the chromosome 17 centromere) have been originally considered as candidate to trastuzumab treatment according to the regulatory agencies worldwide. In 2007, the American Society of Clinical Oncology (ASCO)/ College of American Pathologists (CAP) raised the threshold for a positive IHC to >30% overexpressing
G. Aurilio et al. / European Journal of Cancer 50 (2014) 1038–1039
tumour cells and for a positive ISH to a ratio of P2.2 or a gene copy number of >6/cell, in order to increase the concordance rate between the two assays [4]. Nevertheless, these guidelines were misinterpreted as defining new thresholds for eligibility of the patients to the therapy, thus potentially disallowing a fraction of Her-2 positive patients from receiving a targeted therapy. These and other controversial issues have been recently addressed by the updated ASCO/CAP recommendations, which definitely confirm that Her-2 positivity is defined according to the thresholds of >10% for IHC and P6.0 signals per cell or Her-2/CEP17 ratio of P2 for ISH, and provide detailed technical guidelines for the pre-analytical and analytical phases and results interpretation [5]. Furthermore, ASCO/CAP acknowledge the occurrence of discrepancy in Her-2 status between primary tumour and a local or distant recurrence in the setting of multiple metastatic sites and, although underlining that it is not possible to discriminate between a true biological change, tumour heterogeneity or technical flaws, suggest to retest Her-2 whenever feasible. Along this line, it is worth of note that Ieni et al. evaluated Her-2 overexpression and amplification by applying heterogeneous thresholds, i.e. at least 30% of immunoreactive cells by IHC and a Her-2/CEP17 ratio >2 by FISH. These technical issues notwithstanding, the authors report a pooled discordant rate slightly lower than that of most published study and our meta-analysis. Their findings are worth of note, especially since obtained by comparing synchronous primary tumours and lymph node metastases in a series of untreated locally advanced breast cancer patients, therefore implying that the switch in Her-2 status may occur in a relatively early phase of tumour development. As a consequence, the data of Ieni et al. suggest that it might be of clinical utility to test Her-2 also in the metastatic lymph nodes of patients with poorly differentiated tumours that are Her-2 negative in the primary site. Taking into account the pivotal role of Her-2 aberration in dictating the prognosis and the response to different targeted therapies of breast cancer
1039
patients, its multiple testing at diagnosis or upon the clinical course of the disease is likely to become a rule in the future: ASCO/CAP suggest to perform a new Her-2 test in surgical specimens for all the patients whose Her-2 status is defined as negative in core needle biopsies if they contain only a small amount of invasive tumour or if tumour grade is low in the biopsy and higher in the surgical specimen. Despite the financial implications, diagnostic delay and health disparities possibly associated with multiple testing, evaluating Her-2 status at diagnosis and in loco-regional or distant metastasis are of paramount clinical utility, especially in view of the availability of new targeted compounds and different therapeutic schedules, which are likely to further improve survival of truly Her-2-positive breast cancer patients. Conflict of interest statement None declared. References [1] Aurilio G, Disalvatore D, Pruneri G, et al. A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. Eur J Cancer 2014;50(2):277–89. [2] Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer. N Engl J Med 2005;353(16):1659–72. [3] Romond EH, Perez EA, Bryant J, et al. Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 2005;353(16):1673–84. [4] Wolff AC, Hammond ME, Schwartz JN, 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(1):118–45. [5] Wolff AC, Hammond ME, Hicks DG, et al. Recommendations for human epidermal growth factor receptor 2 testing in breast cancer: American Society of Clinical Oncology/College of American Pathologists clinical practice guideline update. J Clin Oncol 2013;31(31):3997–4013.
