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BackgroundTo identify predictive markers for responders in lapatinib-treated patients and to demonstrate molecular changes during lapatinib treatment via cell-free genomics.Patients and methodsWe 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. A parallel biomarker study was conducted by simultaneously performing immunohistochemistry and next-generation sequencing (NGS) with tumor and blood samples.ResultsComplete response was confirmed in 7/32 patients (21.8%), 2 of whom received radical surgery with pathologic-confirmed complete response. Fifteen partial responses (46.8%) were observed, resulting in a 68.6% overall response rate. 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+ 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 with 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.ConclusionsThe 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.

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chromosomes 7q, 1q and and losses of chromosome 14q. The degree of discrepancy of genomic alterations across biopsy regions was positively correlated with spatial distances across biopsy regions. Tumour subclone growth was found to be predominantly spatially contiguous, with subclone dispersal a rare event found only in one case, which notably was associated with metastasis.Conclusions: Spatial dynamics is strongly associated with genomic alterations and plays an important role in tumour evolution.Clinical trial identification: NCT03226886.

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Patient-reported outcomes (PROs) from IMvigor130: A global, randomised, partially blinded phase III study of atezolizumab (atezo) + platinum-based chemotherapy (PBC) vs placebo (PBO) + PBC in previously untreated locally advanced or metastatic urothelial carcinoma (mUC)

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