Dynamic HER2-low status among patients with triple negative breast cancer (TNBC): The impact of repeat biopsies

1005 Background: Trastuzumab deruxtecan (T-DXd) is FDA-approved for HER2-low, but not HER2-0 metastatic triple negative (TNBC) and hormone positive breast cancer. Therefore, identifying HER2-low status is of great clinical importance. Prior studies have shown HER2-low status in TNBC is dynamic, but the correlation between the number of successive biopsies (Bxs) conducted and the likelihood of a HER2-low result is unknown. Methods: Patients (pts) were identified from an institutional database including all pts with TNBC treated in a single large academic center between 2017-2022. Only pts with TNBC at diagnosis were included. Bxs without known HER2 status were excluded. Pathological, clinical, and demographic data were extracted. HER2-low was defined as HER2 IHC 1+, or 2+ with non-amplified ISH. The type of Bx was categorized as core Bx, surgical Bx, or metastatic Bx based on the timing and method of Bx acquisition. For the early-metastatic matched analysis, the core Bx was considered the early Bx, unless the core Bx was missing and then the surgical bx was used instead. For cases with several metastatic Bxs the first metastatic Bx was used. Results: 529 consecutive pts with TNBC at diagnosis were included. The proportion of pts with HER2-low result increased as the number of successive Bxs increased (60%, 74%, 83%, 87% and 100% when 1 (192 pts), 2 (235 pts), 3 (52 pts), 4 (38 pts), and 5-9 (12 pts) Bxs were conducted, respectively). In women without a prior HER2-low result, about one third converted to HER2-low with each successive additional biopsy (e.g. 322/529 at 1 st biopsy, 44/131 on 2 nd biopsy, 8/25 at 3 rd biopsy, 3/8 at 4 th biopsy). HER2 status distribution did not significantly vary between the different types of Bx (58%, 63%, and 54% of pts had a HER2-low result in their core, surgical or metastatic Bx, respectively; p=0.2). Among 246 women with matched core-surgical biopsies, one quarter changed their HER2 status (55% from low to 0, 44% from 0 to low, and 1% from low to 3+). Core-surgical HER2 status conversion rates did not differ between women who had neoadjuvant therapy with residual disease and women who had surgery as their primary intervention. Among women with both matched early-metastatic (70 pts) or two matched metastatic Bxs (39 pts), nearly half (44%) converted their HER2 status (68%, 26% and 6% or 35%, 59% and 6% were converted from low to 0, 0 to low and low to 3+ in the matched early-metastatic or the two matched metastatic Bxs, respectively). Conclusions: Our findings show that HER2 status is dynamic in pts with TNBC and support the idea that HER2-low is a spectrum, not a specific entity. We further report the novel finding that for pts with TNBC without a prior HER2-low result, repeat Bxs at progression can increase the chance of obtaining a HER2-low result and provide clinically impactful information. Whether the dynamic HER2 result represents underlying biology or analytic variation remains to be determined.