Annals of Oncology Advance Access originally published online on February 13, 2008
Annals of Oncology 2008 19(3):595-597; doi:10.1093/annonc/mdn021
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letters to the editor |
Intratumoral heterogeneity of HER2/neu expression and its consequences for the management of advanced breast cancer
HER2/neu oncogene overexpression has become a paramount prognostic and predictive marker in invasive breast carcinoma [1]. Its expression is usually highly homogeneous in malignant tissue [2]. Some cases of intratumoral heterogeneity have, however, been reported [3] (Figure 1). The impact of this heterogeneity on the natural history of breast cancer and its consequences on clinical management are unknown. We report here three clinical cases illustrating the complexity of this topic.
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Case 1: A 58-year-old woman presented with node-negative, high-grade, hormone receptor (HR)-negative, invasive breast ductal carcinoma. HER2 overexpression was observed in only 30% of invasive tumor cells, with faint staining. She underwent breast-conserving surgery, radiotherapy and anthracycline-based chemotherapy. Two years later, she presented with liver metastases. Liver biopsy confirmed metastases from breast carcinoma. HER2 staining was moderately present in 95%–100% of tumor cells (Figure 2). FISH analysis showed HER2 gene amplification with eight spots per nucleus. Complete remission, as defined by RECIST criteria, was obtained with a capecitabine–trastuzumab combination.
Case 2: A 50-year-old woman presented with homolateral axillary relapse of invasive ductal breast carcinoma. The same heterogeneous pattern of HER2 expression was observed in the primary tumor and axillary lymph node (Figure 1B). The patient was included in a clinical trial with docetaxel, trastuzumab and lapatinib and achieved a complete response. After 8 months of trastuzumab–lapatinib maintenance therapy, a new axillary relapse occurred. Biopsy demonstrated no overexpression of HER2.
Case 3: A 55-year-old woman presented with node-positive, HR-positive, invasive breast ductal carcinoma treated by mastectomy, adjuvant adriamycin–cyclophosphamide-based chemotherapy, radiation therapy and tamoxifen for 5 years. Initial HER2 status was unknown. At the age of 65, she presented with a chest wall relapse and bone metastases. Biopsy confirmed an HR-positive invasive relapse associated with HER2 overexpression on immunohistochemistry (IHC). Treatment with docetaxel and trastuzumab allowed a major bone and local response. Surgical resection of the chest wall showed residual HR-positive invasive carcinoma, but without HER2 overexpression.
We report three clinical cases raising the issues of intratumoral heterogeneity of HER2 expression, the natural history of this particular subset of tumors and consequently their management at both early and advanced stages. HER2 status is usually not modified by therapy [4]. In a consecutive series of >600 HER2-positive breast cancers treated at Institut Curie, 
5% exhibited intratumoral heterogeneity of HER2 overexpression, as shown by both IHC, according to French validated methods [5] and FISH (Figure 1). None of these three patients received trastuzumab in the adjuvant setting. These cases show that HER2 status in metastases may be similar to that of the primary tumor (i.e. heterogeneous, case 3) or different. In case 2, liver metastases exhibited FISH-confirmed HER2 gene amplification, when HER2 status was deemed heterogeneous in the primary tumor. We postulate that such cases may represent the proof that specific cell subclones may evolve separately. HER2-positive cells may account for metastatic progression. If this is the case, biopsies should be carried out on metastases from primary tumors with heterogeneous HER2 expression. Cases 1 and 3 also demonstrate that HER2 status may apparently ‘change’ during HER2-targeted therapy. The first hypothesis to explain this effect is mainly a selection of one preferential subclone in the residual tumor harboring a different HER2 status than the majority of the cells in the primary tumor. Although the intimate pharmacodynamic mechanisms of trastuzumab and lapatinib have not been fully elucidated, complete eradication of HER2-positive cells is a possible hypothesis [6]. Consequently, this provides a new rationale concerning the duration of HER2-targeted therapy, which is currently being challenged by the French PHARE clinical trial [7, 8] (http://www.e-cancer.fr/Les-Essais-cliniques/Essai-PHARE/op_1-it_779-la_1-ve_1.html). This issue also raises the problem of the determination of surrogate markers of the efficacy of anti-HER2 therapy, particularly in the adjuvant setting, or after complete remission from HER2-positive metastatic disease, as the heterogeneity of HER2 status in breast carcinoma opens a challenging field of research.
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1 Department of Medical Oncology
2 Department of Pathology, Institut Curie, 26 rue d'Ulm, 75005 Paris, France
* (E-mail: paul.cottu{at}curie.net)
Acknowledgements
Conflict of interest: The authors declare no conflict of interest.
References
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2. Gancberg D, Di Leo A, Cardoso F, et al. Comparison of HER-2 status between primary breast cancer and corresponding distant metastatic sites. Ann Oncol (2002) 13:1036–1043.
3. Hanna W, Nofech-Mozes S, Kahn HJ. Intratumoral heterogeneity of HER2/neu in breast cancer—a rare event. Breast J (2007) 13:122–129.[CrossRef][Web of Science][Medline]
4. Vincent-Salomon A, Jouve M, Genin P, et al. HER2 status in patients with breast carcinoma is not modified selectively by preoperative chemotherapy and is stable during the metastatic process. Cancer (2002) 94:2169–2173.[CrossRef][Web of Science][Medline]
5. Vincent-Salomon A, MacGrogan G, Couturier J, et al. Calibration of immunohistochemistry for assessment of HER2 in breast cancer: results of the French multicentre GEFPICS study. Histopathology (2003) 42:337–347.[CrossRef][Web of Science][Medline]
6. Kunitomo K, Inoue S, Ichihara F, et al. A case of metastatic breast cancer with outgrowth of HER2-negative cells after eradication of HER2-positive cells by humanized anti-HER2 monoclonal antibody (trastuzumab) combined with docetaxel. Hum Pathol (2004) 35:379–381.[CrossRef][Web of Science][Medline]
7. National Cancer Institute (France) NIH: Clinical Trials: Trastuzumab for 6 Months or 1 Year in Treating Women with Nonmetastatic Breast Cancer That Can Be Removed by Surgery. http://clinicaltrials.gov/show/NCT00381901 (25 January 2008, date last accessed).
8. Hillner BE, Smith TJ. Do the large benefits justify the large costs of adjuvant breast cancer trastuzumab? J Clin Oncol (2007) 25:611–613.
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