Abstract P4-15-07: HER2 positive (HER2/CEP17 ratio≥2.0) invasive mammary carcinomas with average &lt;4.0 HER2 and &lt;2.0 CEP17 signals/cell: Clinicopathologic features, correlation with HER2 immunohistochemistry and response to neoadjuvant chemotherapy
Authors: Livasy Chad A , Limentani Kimberly , Calhoun Benjamin C , Limentani Steven 
Published: May 2015

Background: ASCO/CAP guidelines for the determination of HER2 amplification have recently been revised in an attempt to clarify which patients will benefit from HER2 directed therapy. Patients with HER2/CEP17 ratios ≥2.0 were eligible for the first generation trials of adjuvant trastuzumab regardless of the average number of HER2 signals/cell. Array CGH and FISH studies have since demonstrated the presence of complex segmental aneusomy of chromosome 17 in a subset of breast tumors. These focal copy number gains and losses can skew the HER2/CEP17 ratio and result in discordant results with HER2 immunohistochemistry (IHC). There is limited data on the clinicopathologic features, HER2 protein expression and response to therapy for tumors showing a HER2/CEP17 ratio ≥2.0 and average &lt;4.0 HER2 signals/cell.

Methods: All cases with HER2/CEP17 ratio ≥2.0 and average &lt;4 HER2 signals/cell were identified from our database from 2009-2013. HER2 IHC was performed and scored on all identified cases. Tumor grade, histologic subtype, hormone receptor status and menopausal status were recorded. For patients receiving neoadjuvant chemotherapy, response was measured using residual cancer burden (RCB) class and yAJCC pathologic stage.

Results: 70 (1.5%) of 4659 FISH cases met criteria for inclusion in the study. 22 (31%) of the 70 patients were premenopausal. All tumors were ductal (no special type) with the following features features: low-grade 14%, intermediate-grade 40%, high-grade 45%, estrogen receptor positive 79% and progesterone receptor positive 65%. HER2 protein evaluation demonstrated 52 (74%) negative (0-1+), 16 (23%) equivocal (2+) and 2 (3%) positive (3+) results. Most tumors (83%) showed 1+ or 2+ staining. 12 patients received neoadjuvant chemotherapy (see table). Six of these patients did not receive trastuzumab as part of their therapy due to congestive heart failure (n=1) or uncertainty about the patient's HER2 status (n=5).

Neoadjuvant chemotherapy patient summaryPatient # (regimen)RatioHER2 copy#CEP17 copy#HER2 IHCER/PRyAJCCRCB classPatient 1 (AC+TH)2.23.91.81++/+ypT0 N0(i+)1Patient 2 (TCH)2.23.81.71++/-ypT0 N00Patient 3 (TCH)2.23.81.72++/+ypTis N00Patient 4 (AC+TH)2.33.01.30+/+ypT2 N2a2Patient 5 (TCH)2.23.71.71+-/-ypT1c N01Patient 6 (TCH)2.23.91.82+-/-ypTis N00Patient 7 (TC)*2.03.41.70-/-ypT0 N00Patient 8 (AC+T)2.23.61.71++/-ypT1c N02Patient 9 (TC)2.13.91.91+-/-ypT0 N00Patient 10 (AC)2.53.41.41++/+ypT1b N1a2Patient 11 (TAC)2.43.61.52+-/-ypT3 N1mi2Patient 12 (AC)2.03.31.61+-/-ypT1c N1a2*Congestive heart failure

Conclusions: HER2 FISH positive invasive mammary carcinomas with a HER2/CEP17 ratio ≥2.0 and average &lt;4.0 HER2 signals/cell are rare (1.5% in this study) and frequently show 1+ or 2+ staining by IHC. Treatment decisions for these patients were impacted by the uncertainty of HER2 status under the previous guidelines. In this small data set, these tumors demonstrated a good response to neoadjuvant trastuzumab-based chemotherapy and further support the recent modifications of ASCO/CAP guidelines to determine HER2 amplification.

Citation Format: Chad A Livasy, Kimberly Limentani, Benjamin C Calhoun, Steven Limentani. HER2 positive (HER2/CEP17 ratio≥2.0) invasive mammary carcinomas with average &lt;4.0 HER2 and &lt;2.0 CEP17 signals/cell: Clinicopathologic features, correlation with HER2 immunohistochemistry and response to neoadjuvant chemotherapy [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P4-15-07.