Correlation of Ki-67 with tumor fraction in metastatic HR-positive invasive lobular and no special type breast cancer.

e13014 Background: Invasive lobular carcinoma (ILC) is characterized by loss of E-cadherin, resulting in an infiltrative, discohesive growth pattern that complicates the monitoring of metastatic ILC (mILC). A pooled analysis of the SUCCESS trials showed that ILC patients tend to exhibit lower Ki-67 grade compared to no special type (NST) breast cancer although survival is comparable. This in part may be due to the heterogenous nature of ILC versus delayed detection. Circulating tumor DNA (ctDNA) analysis using liquid biopsy genomic sequencing provides a minimally invasive approach for disease monitoring. This study evaluated the relationship between tumor fraction (TFx) and Ki-67 index to potentially establish the added value for clinical utility in TFx-based ctDNA monitoring in metastatic breast cancer (mBC). Methods: From January 2016 – December 2025, 321 patients with mBC treated at UPMC Hillman Cancer Center underwent longitudinal liquid biopsy testing at times of clinical progression. Hormone receptor–positive (HR+) mILC and mNST cases with serial blood draws were selected, including 112 samples from 31 patients with mILC and 363 samples from 32 patients with mNST. Cell-free DNA underwent low-pass whole-genome sequencing with a mean coverage 0.21x. TFx was estimated using the ichorCNA algorithm. Ki-67 values at initial diagnosis and during clinical progression when available were collected. Treatment lines and clinical outcomes were abstracted from medical records. Results: Most samples were collected during first- to fourth-line metastatic therapy. TFx ranged from 0–65.12% (mean, 11.6%) in ILC and 0–67.43% (median, 12.97%) in NST, with no significant difference between HR+ mILC and mNST (p = 0.76). Baseline Ki-67 levels were available for 24 patients with ILC (range, 2–90%; mean, 26.3%) and 27 patients with NST (range, 0–80%; mean, 38.1%) and did not differ significantly between groups (p = 0.057), with a trend toward lower Ki-67 in mILC. Mean longitudinal TFx correlated with baseline Ki-67 in mNST (r = 0.403, p = 0.037) but not in mILC (r = 0.188, p = 0.390). Decreasing TFx was associated with radiographic response, whereas increasing TFx was observed with treatment resistance. Conclusions: Mean longitudinal TFx correlated with Ki-67 index in mNST but not in mILC although there was a trend towards significantly different Ki-67 levels between groups. A larger cohort is needed to establish this correlation. Nevertheless, TFx dynamics reflected disease progression in both mILC and mNST, suggesting the clinical value of earlier ctDNA monitoring, particularly in mILC where Ki-67 index may inadequately reflect prognosis and underscores the need for further genetic characterization of both subtypes.