Serial circulating tumor DNA (ctDNA) monitoring in early-stage, HR+/HER2-, invasive lobular carcinoma (ILC) of the breast and impact on clinical outcomes.

581 Background: ILC accounts for ~10-15% of breast cancer (BC) cases in the US with difficult-to-diagnose patterns of metastasis. Loss of E-cadherin ( CDH1 ) is the pathogenomic feature of ILC. Tumor-informed ctDNA assays detect molecular residual disease in patients who completed definitive therapy for early-stage BC. However, little is known about the ctDNA dynamics and its prognostic relevance in ILC specifically. Here, we assessed actionable genomic alterations and correlated ctDNA dynamics with clinical outcomes in patients with HR+/HER2- ILC. Methods: We utilized Natera's proprietary real-world database linked to commercially available claims data and commercial ctDNA testing via a clinically validated, personalized, tumor-informed mPCR-NGS ctDNA assay (Signatera, Natera, Inc.) to identify patients with early-stage, HR+/HER2- ILC. Tumors with CDH1 truncated alterations from tumor whole exome sequencing were categorized as ILC. HR+/HER2- tumors were categorized using treatment regimens from insurance claim codes. Targetable alterations in PIK3CA , AKT , PTEN , BRCA1 , BRCA2 , ESR1 , NF1, and ERBB2 were assessed. ctDNA positivity rates and distant recurrence-free survival (DRFS) were evaluated using longitudinal ctDNA status (ctDNA + or -). The timing of ctDNA+ after primary BC surgery was divided into two categories: <2 years (y) and >2y. Results: 430 patients with early-stage HR+/HER2- ILC and ctDNA testing were identified. The most common targetable alterations co-mutated with CDH1 were in PIK3CA (54.4%), AKT1 (5.1%), NF1 (4.9%), and ERBB2 (4.6%). The first ctDNA test was performed on 258 (59.3%) and 172 (39.5%) patients within or after 2y surgery, respectively. Of 430 patients, 88 (20.2%) had >1 ctDNA+ test. A ctDNA+ result was reported in 31/258 (12%) and in 57/172 (33.1%) patients with testing within or after 2y surgery, respectively. Longitudinal ctDNA+ was associated with DRFS based on distant secondary malignant neoplasm claim codes. Among patients with a ctDNA- test within 2y, only 2.83% (6/212) presented a DRFS event compared to 48% (12/25) of ctDNA-+ cases (Odds ratio 31, p-value=1.42E-9). In patients with a ctDNA- test after 2y, only 2.06% (2/95) presented a DRFS event compared to 37.5% (9/24) of ctDNA+ cases (Odds ratio 27, p-value=4.92E-6). Conclusions: To our knowledge, this is the first large-scale analysis of the landscape of targetable genomic alterations and matching longitudinal ctDNA and outcomes in patients with early-stage, HR+/HER2- ILC. We find that PIK3CA is most frequently co-mutated with CDH1 , and a comparison with the CDH1 wildtype cohort will be presented. These data provide insights into the ability of ctDNA to detect recurrence earlier, including sites associated with challenges in the interpretation of imaging results in the early-stage ILC setting.