Impact of genomic alterations on lapatinib treatment outcome and cell-free genomic landscape during HER2 therapy in HER2-positive gastric cancer patients.

Kim ST1, Banks KC2, Pectasides E3, Kim SY1, Kim K1, Lanman RB2, Talasaz A2, An J4, Choi MG4, Lee JH4, Sohn TS4, Bae JM4, Kim S4, Park SH1, Park JO1, Park YS1, Lim HY1, Kim NKD5, Park W5, Lee H6, Bass AJ3, Kim K7, Kang WK1, Lee J1.

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Abstract

BACKGROUND:

To identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics.

PATIENTS AND METHODS:

We prospectively evaluated the efficacy of combining lapatinib with capecitabine and oxaliplatin as first line neoadjuvant therapy in patients with previously untreated, HER2-overexpressing advanced gastric cancer (AGC). A parallel biomarker study was conducted by simultaneously performing immunohistochemistry (IHC) and next-generation sequencing with tumor and blood samples.

RESULTS:

Complete response (CR) was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed CR. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. Next-generation sequencing (NGS) of the 16 tumor specimens demonstrated that the most common co-occurring copy number alteration was CCNE1 amplification, which was present in 40% of HER2-positive tumors. The relationship between CCNE1 amplification and lack of response to HER2 targeted therapy trended toward statistical significance (66.7% of non-responders versus 22.2% of responders harbored CCNE1 amplification; p = 0.08). Patients with high level ERBB2 amplification by NGS were more likely to respond to therapy, compared to patients with low level ERBB2 amplification (p = 0.02). Analysis of cfDNA showed that detectable ERBB2 copy number amplification in plasma was predictive to the response (100%, response rate) and changes in plasma-detected genomic alterations were associated with lapatinib sensitivity and/or resistance. The follow-up cfDNA genomics at disease progression demonstrated that there are emergences of other genomic aberrations such as MYC, EGFR, FGFR2 and MET amplifications.

CONCLUSIONS:

The present study showed that HER2+ GC patients respond differently according to concomitant genomic aberrations beyond ERBB2, high ERBB2 amplification by NGS or cfDNA can be a positive predictor for patient selection, and tumor genomic alterations change significantly during targeted agent therapy.