using changes in circulating tumor cells to predict cause of herceptin resistance and

[Lani]

alter treatment (eg by adding EGFR inhibitor)


The role of EGFR amplification in trastuzumab resistance: A correlative analysis of TBCRC003.


Sub-category:
HER2+

Category:
Breast Cancer - HER2/ER

Meeting:
2011 ASCO Annual Meeting

Abstract No:
528

Citation:
J Clin Oncol 29: 2011 (suppl; abstr 528)


Attend this session at the
ASCO Annual Meeting!
Session: Breast Cancer - HER2/ER

Type: Poster Discussion Session

Time: Tuesday June 7, 8:00 AM to 12:00 PM

Location: McCormick Place E450a

Discussion Time: Tuesday June 7, 11:30 AM to 12:30 PM

Location: McCormick Place Arie Crown Theater

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Author(s): I. E. Krop, L. Flores, J. S. Najita, I. A. Mayer, T. J. Hobday, C. I. Falkson, C. L. Arteaga, A. C. Wolff, E. C. Dees, M. F. Rimawi, R. Nanda, K. Josephs, N. U. Lin, E. P. Winer, Translational Breast Cancer Research Consortium; Dana-Farber Cancer Institute, Boston, MA; Vanderbilt-Ingram Cancer Center, Nashville, TN; Mayo Clinic, Rochester, MN; University of Alabama at Birmingham, Birmingham, AL; The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University, Baltimore, MD; University of North Carolina Lineberger Comprehensive Cancer Center, Chapel Hill, NC; Baylor College of Medicine, Houston, TX; The University of Chicago, Chicago, IL


Abstract Disclosures


Abstract:

Background: To identify mechanisms of resistance to trastuzumab (T), we developed and characterized T-resistant HER2+ breast cancer (BC) cell lines; these lines acquired EGFR amplification and were sensitive to both lapatinib (L) and gefitinib. To validate this finding, we prospectively assessed EGFR copy number in circulating tumor cells (CTC) from patients (pts) on TBCRC003, a multicenter clinical trial of L and T. Methods: Pts with measurable, HER2+ metastatic BC (MBC) were eligible. Cohort 1: No prior T, L, or chemotherapy (CT) for MBC, and > 1 yr from adjuvant T, if received. Cohort 2: 1-2 prior lines of CT for MBC, including T, or relapse within 1 yr of adjuvant T. Pts received L 1,000 mg QD + T (2 mg/kg weekly or 6 mg/kg Q3W). CTC were collected using a modification of the CellSearch Profile Kit (Veridex) at baseline, 4wk, and progression. CTC were analyzed by FISH for EGFR and CEP7 and amplification was defined as EGFR/CEP7≥2. Results: EGFR amplification was present in CTC at baseline in 11/39 (28%) patients in cohort 2 (pts with prior T), but in only 2/34 (6%) of patients in cohort 1 (no prior T for MBC) (p=0.015). In cohort 2, 1/10 (10%) patients who went on to have progressive disease as best response had EGFR amplification in their CTC at baseline, while 6/18 (33%) patients with stable disease and 4/11 (36%) with partial responses had EGFR amplification. Conclusions: These data, which demonstrate the feasibility of using CTC collection as a means of evaluating resistance mechanisms in patients on clinical trials, support the hypothesis that EGFR amplification is selected for by treatment with T and can mediate resistance to this agent. The observed trend toward improved outcome in pts with EGFR amplified CTC when treated with a regimen containing L (which inhibits both EGFR and HER2) is consistent with a functional role for this amplification. Our recent observation that EGFR amplification develops in 26% of residual HER2+ cancers after preoperative treatment with T+CT (Krop et al, ASCO 2010) further supports this hypothesis. These results provide the rationale for a trial of an EGFR inhibitor specifically in pts with HER2+ MBC and EGFR amplified CTC. Additional CTC data from this study will be presented at the conference