Abstract P4-04-12: Identification of a common genotype in patients (pts) with HER2-positive, ER-negative, inflammatory breast cancer (IBC) that was primary-refractory to trastuzumab who have had 5+ years of disease control with lapatinib therapy
Authors: O'Shaughnessy J , Levin M , Palmer G , Ross JS , Palma N , Yelensky R , Cao Y , Ramos C , Hoke G , Wang K 
Published: August 2014

Background: HER2-amplified inflammatory breast cancer (IBC) that is primary-refractory to trastuzumab has a poor prognosis. The objective of this study was to describe the genotypes of the IBC obtained from 3 pts with high grade, ER-negative, HER2+ classical IBC, primary-refractory to trastuzumab, with chest wall disease, who remain with no evidence of disease (NED) on lapatinib for 5+ years.

The 3 postmenopausal pts presented with locally advanced IBC, 2 with disease extending onto the chest wall, and the third with chest wall recurrence while on adjuvant trastuzumab. Two pts were treated with preoperative trastuzumab with multiple chemotherapy agents with no response. They were then treated with preoperative lapatinib and had a clinical partial response. They underwent salvage mastectomy showing extensive residual disease, followed by chest wall/regional radiotherapy (RT), continuing on lapatinib. The third patient received preoperative AC followed by docetaxel and had extensive residual disease at mastectomy. She underwent chest wall/regional RT and then had chest wall recurrence while on adjuvant trastuzumab. She was treated with lapatinib and resection of residual chest wall disease. All 3 pts remain NED on 1250mg lapatinib daily. The 3 pts have a strong family history of breast cancer; two have known wild type germline BRCA1/2.

Methods: Following IRB-approved informed consent, targeted next generation DNA sequencing (NGS) was performed using HiSeq-2000 (Illumina) on pts’ FFPE primary IBC at a CLIA-certified laboratory, to characterize all classes of genomic alterations across 4,604 exons of 287 cancer-related genes. Phosphoprotein analysis was performed using a proprietary Reverse Phase Protein Microarray (RPMA) platform on pts's FFPE IBC to characterize the activity of the targets of anti-HER2 therapy, and their downstream pathways.

Results: In 2 pts’ IBCs NGS identified a common genotype with amplified ERBB2, mutant p53 and PIK3CA (c.3140A&gt;G_p.H1047R), homozygous deletions of both CDKN2A and CDKN2B, and truncated BRCA2 (1 pt) or PALB2 (1 pt). The third pt's FFPE residual disease from her mastectomy did not yield sufficient DNA from invasive tumor cells for sequencing and we plan to sequence DNA from her original diagnostic core biopsy. Phosphoprotein analysis of one pt's trastuzumab-refractory, lapatinib-naive IBC showed 3+ expression of HER1 (but not pHER1 Y1068 nor pHER2 Y1248), pAkt S473, pS6 ribosomal S235-236 protein (2+), p4E-BP1 S65 and Notch1. The second pt's lapatinib-treated IBC showed 3+ overexpression of only p4E-BP1 S65.

Conclusions: Pts with a common tumor phenotype who have highly durable responses with a targeted therapy may share a common tumor genotype. Two pts’ trastuzumab-refractory HER2+ IBCs that have been very durably responsive to lapatinib share p53, PIK3CA, p16 and BRCA2-related mutations, potentially enabling the prospective identification of trastuzumab-refractory IBC pts who may benefit substantially from lapatinib.

Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-04-12.