Proliferation Index in “HER2 Low” Metastatic Breast Cancer

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Abstract Introduction/Objective There is considerable genetic heterogeneity between primary and metastatic breast cancer. The new classification of the "HER2-low" category includes tumors characterized by a low level of HER2 expression (immunohistochemistry (IHC) score 1+ or 2+ without in situ hybridization (ISH) amplification), in addition to the known HER2 negative (HER2-0) and HER2+ (amplified) cases. The Ki67 proliferation index (PI) can predict breast cancer prognosis. Proliferation changes in metastatic breast cancer and in different HER2 categories are not well delineated in clinical cohorts. In this study, we delineate proliferation characteristics of primary and metastatic breast cancer in association with HER2 status. Methods/Case Report We retrospectively reviewed the biological data from 98 metastatic breast cancer specimens for 90 patients from 2018-2021 (see Table 1). As part of the clinical workup, 72 metastatic cancer specimens had PI/Ki67, estrogen receptor (ER), and progesterone receptor (PR) testing by (IHC). HER2 was tested by IHC and reflexed ISH. We identified the overall frequency of breast cancer patients with different HER2 subtypes and compared the PI between primary and metastatic breast cancer within different HER2 categories. Results (if a Case Study enter NA) The median age at primary breast diagnosis was 51 (IQR; 42 – 58), and the median for metastatic cancer was 64 (IQR;57-70). Average PI/Ki67 was lower in metastatic cancers than in primary breast cancer samples, 38% and 46%, respectively (t-test, p < .001, two-tailed). Most metastatic and primary tumors were HR-positive, 24 (56%) and 16 (64%). The triple-negative subtype HR-HER2- has the highest PI/Ki67 in primary and metastatic tumors. Among the metastatic specimens, we found “HER2 low” expression in 45 (62.5%); 19 (26.4%) were HER2-positive, and 8 (6.3%) were HER2-0. 85% of traditionally HER2-negative samples were “HER2 low”. There were no statistically significant differences between the Ki67 proliferation index of “HER2 low”, HER2+, and HER2-0 patients (ANOVA, p= 0.488). Five patients (7%) showed different HER2 expressions between primary and metastatic cancer. Conclusion The average PI in our cohort is lower in metastatic breast cancers compared to primary breast cancers. This is an unexpected finding considering the pathophysiology of the metastatic cascade. Including "HER2 low" criteria increases the number of patients with metastatic breast cancer potentially eligible for HER2 targeted treatment from 26.4% (HER2+ / amplified) to over 60% (HER2 1+/2+ not amplified).