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Background. Endocrine resistant metastatic disease develops in ~20-25% of hormone-receptor positive (HR+) breast cancer (BC) patients despite endocrine therapy (ET) use. Upregulation of HER family receptor tyrosine kinases (RTKs) represent escape mechanisms in response to ET in some HR+ tumors. Short-term neoadjuvant ET (NET) offers the opportunity to identify early endocrine escape mechanisms initiated in individual tumors. Methods. This was a single arm, interventional phase II clinical trial evaluating 4 weeks (+/-1 week) of NET in patients with early-stage HR+/HER2-negative (HER2-) BC. The primary objective was to assess NET-induced changes in HER1-4 proteins by immunohistochemistry (IHC) score. Protein upregulation was defined as an increase of ≥1 in IHC score following NET. Results. Thirty-seven patients with cT1-T3, cN0, HR+/HER2- BC were enrolled. In 35 patients with evaluable tumor HER protein after NET, HER2 was upregulated in 48.6% (17/35; p=0.025), with HER2-positive status (IHC 3+ or FISH-amplified) detected in three patients at surgery, who were recommended adjuvant trastuzumab-based therapy. Downregulation of HER3 and/or HER4 protein was detected in 54.2% of tumors, whereas HER1 protein remained low and unchanged in all cases. While no significant volumetric reduction was detected radiographically after short-term NET, significant reduction in tumor proliferation rates were observed. No significant associations were identified between any clinicopathologic covariates and changes in HER1-4 protein expression on multivariable analysis. Conclusion. Short-term NET frequently and preferentially upregulates HER2 over other HER-family RTKs in early-stage HR+/HER2- BC and may be a promising strategy to identify tumors that utilize HER2 as an early endocrine escape pathway. Trial registration number: NCT03219476 Date of registration for prospectively registered trials: July 17, 2017

We report a unique case of a post-menopausal female who presented with a lesion on the areola. A biopsy of the lesion demonstrated a pagetoid intraepithelial neoplasm suggesting a differential diagnosis of mammary Paget disease and pagetoid Bowen disease. Excision of the lesion confirmed the diagnosis of mammary Paget disease with typical histological appearance. This case is extremely rare since both keratin 7 and ERBB2 were negative, and there was no evidence of underlying in situ or invasive carcinoma.

The HercepTest was approved 20 + years ago as the companion diagnostic test for trastuzumab in HER2 amplified/overexpressing breast cancers. Subsequent HER2 immunohistochemistry (IHC) assays followed, including the now most common Ventana 4B5 assay. While this IHC assay has become the clinical standard, its reliability, reproducibility, and accuracy have largely been approved and accepted based on concordance between small numbers of pathologists without validation in a real-world setting. In this study, we evaluate the concordance and inter-rater reliability of scoring HER2 IHC in 170 breast cancer biopsies by 18 breast cancer-specialized pathologists from 15 institutions. We used the ONEST (Observers Needed to Evaluate Subjective Tests) method to determine the plateau of concordance and the minimum number of pathologists needed to estimate inter-rater agreement values for large numbers of raters, as seen in the real-world setting. We report substantial discordance within the intermediate categories (