Tracking genomic evolution in ERBB2 -altered biliary tract cancer through longitudinal tumor profiling.

4137 Background: HER2, encoded by ERBB2 (HER2), is overexpressed and clinically actionable in a subset of patients with biliary tract cancers (BTC). Zanidatamab and trastuzumab deruxtecan are now approved for patients with HER2 overexpressed tumors, though all patients ultimately progress on treatment and acquired resistance mechanisms are poorly defined. We aimed to characterize the genomic evolution in patients with ERBB2 altered advanced BTC via serial tumor and cfDNA sampling during systemic therapy. Methods: Patients with ERBB2 altered BTC were extracted of Memorial Sloan Kettering Cancer Center (MSK)’s prospectively maintained institutional genomic profiling protocol (NCT01775072). Eligibility required ≥2 molecular profiles obtained during systemic therapy. Tumor sequencing was performed using MSK-IMPACT (tissue-based NGS) and/or MSK-ACCESS (ctDNA NGS). Paired samples could include tissue and/or ctDNA. Clinical data were annotated, and longitudinal molecular profiles were analysed to assess temporal changes in ERBB2 status. Results: Among 1628 patients with BTC in the institutional database, 122 (7.5%) had ERBB2 altered tumors. Of these, 26 patients had ≥2 molecular samples available for longitudinal analysis. Five were excluded due to incomplete clinical and/or molecular data, leaving 21 eligible patients Median age at diagnosis, 63 years (range 38–76), gallbladder cancer (n = 12, 57%), intrahepatic cholangiocarcinoma (n = 6, 29%), and extrahepatic cholangiocarcinoma (n = 3, 14%). At baseline, ERBB2 alteration patterns included ERBB2 amplification in 15 patients (71.4%), single nucleotide variants (SNV) in 2 patients (9.5%), and concurrent amplification and SNVs in 3 patients (14.3%). The most common co-occurring alterations involved TP53 (67%), SMAD4 (19%), CDKN2A (19%), and SMAD4 (19%). Over the course of systemic treatment Median number of treatment lines, 3.5 (range 1-6), 71% patients received HER2 directed therapy (n = 15) at any line, loss of ERBB2 amplification at last available molecular sampling was observed in 7 patients (46%) and gain in 1 patient. Longitudinal profiling also demonstrated acquisition of additional alterations in receptor tyrosine kinase (RTK) pathways, including MAPK genes in 19% patients and MET alterations in 4.7%. Among the 15 patients who received HER2-directed therapy, MAPK alterations were observed in 4 (25%) and MET alterations in 1 (6%) at progression. Conclusions: ERBB2 alterations in BTC evolve over time with frequent loss of amplification and emergence of RTK pathway alterations during systemic therapy. Acknowledging limitations of small sample size as well utilization of both cfDNA and tumor profiling, these findings highlight the genomic heterogeneity of ERBB2 altered BTC and support the potential value of longitudinal profiling to better understand mechanisms of resistance and help inform treatment sequencing.