Heterogeneous Amplification of HER2 Is a Rare but Clinically Significant Event in Invasive Ductal Carcinoma.
Authors: Iurisci I. , Cottu P. , Ngo C. , Lae M. , Pierga J. , Diéras V. , Sigal-Zafrani B. , Kirova Y. , Mignot L. , Vincent-Salomon A. 
Published: December 2010

Abstract
BackgroundWe have recently shown that pT1ab HER2 positive tumors carry a poor prognosis, which may be alleviated by trastuzumab (T) based therapy (Rodrigues et al, ASCO 2009). We had also reported that heterogeneous expression of HER2 (hetHER2) may be associated with a poor outcome depending on the HER2 overexpressing subclone (Cottu et al, Ann Oncol 2007). Meanwhile, ASCO/CAP guidelines have questioned the minimum valid score for HER2 expression (Moeder et al, J Clin Oncol 2007; Wolff et al, J Clin Oncol 2007). We describe here the characteristics and outcome of a series of patients with hetHER2 disease.Patients and methodsHER2 status is routinely assessed in our institution in advanced breast cancer patients since 1999, and in early patients since 2002. Out of 1300 HER2 positive cases, we have been able to identify 12 pts with heterogeneous expression of HER2 in the primary tumor (&lt;1%). HetHER2 was defined as more than 5% and less than 59% of infiltrating cells overexpressing HER2 with an intense and complete membrane staining, and /or with a FISH ratio ≥ 2.2. Confirmation was obtained by FISH in 8 patients. Detailed pathological analysis, clinical characteristics and outcome were obtained.ResultsMedian age at diagnosis was 45 years (31-64). All pts received adequate locoregional therapy according to institutional guidelines. Pathological characteristics of the primary tumors are depicted in the table.Pathological Characteristics pT1pT2pT3Tumor Size (n)633 n/ n evaluable%ER+11/1292PR+5/1242HER2 FISH+8/1080vascular emboli5/862.5 pN0pNmi/i+pN+pN (n)624 I / lowII / intermediateIII / highGrade (Elston Ellis)255Mitotic Index327 All patients had infiltrating ductal carcinoma, two of them bearing also a ductal carcinoma in situ component. Most ER+ tumors had a faint staining, observed in less than 50% of tumor cells. In 1 pt with a node-positive tumor, the same pattern of heterogeneous overexpression of EHR2 was observed in the primary tumor and in the lymph nodes. Chemotherapy was given to 9 patients (75%), hormonal treatment to 6 pts (50%) and T was added to chemotherapy in 3 pts. With a median follow-up of 69 months (0-200), 6 pts have relapsed, none of them having received T based therapy. Median time to relapse was 46 mths (14-151). Initial sites of relapses were axillary lymph nodes (1), mediastinal lymph nodes (1), skin (1), liver (2) and ipsilateral relapse (1). No brain metastases were recorded. HER2 status was obtained in four relapses and was considered either negative (Skin), or highly overexpressed (liver) or heterogeneous (ipsilateral and axillary lymph node relapses). None of the 3 T treated pts has relapsed so far, but their follow up is still under 6 months.ConclusionsMore than half of the tumors exhibited at least 1 poor prognosis feature beyond HER2 overexpression. In the line of the recent reanalysis of the NCCTG9831 adjuvant T trial which has suggested that T may be beneficial to hetHER2 patients (Sukov et al, ASCO 2009), our data support the evidence of a poor prognosis of hetHER2 disease, which may be similar to the prognosis of the “real” HER2 3+ and amplified disease. Prospective evaluation of anti HER2 based therapy in this subset of patients is clearly warranted.
Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 6034.