Purpose The accuracy of predictive and prognostic biomarker assessment in breast cancer is paramount since these guide therapy decisions. The aim was to investigate the concordance of biomarkers and immunohistochemical (IHC)-based surrogate tumor subtypes between core needle biopsies (CNB) and consecutive paired breast cancer surgical resections. Methods This retrospective study comprised two cohorts of patients with primary breast cancer diagnosed between 2016 and 2017: one treated with primary surgery ( n = 526) and one with neoadjuvant chemotherapy (NAC) ( n = 216). The agreement between preoperative CNB and paired tumor specimens regarding the assessment of biomarkers and surrogate tumor subtypes was evaluated in both cohorts. Results In the primary surgery cohort, the concordance rates and kappa values for estrogen receptor (ER), progesterone receptor (PR) and Ki67 were 98.6% ( κ = 0.917), 89.3% ( κ = 0.725) and 78.8% ( κ = 0.529), respectively. Importantly, human epidermal growth factor receptor 2 (HER2) IHC assessment showed only moderate agreement ( κ = 0.462). HER2 status combining IHC and in situ hybridization was discordant in 3.6% of cases, potentially impacting on indications for HER2-targeted therapy. The concordance rate for IHC-based surrogate tumor subtypes was only 73.2–78.3%. Generally lower concordance rates for ER, PR and HER2 were observed in the NAC cohort. Here, HER2 status was discordant in 7.4%. Conclusions The agreement of HER2 and Ki67 between CNB and paired surgical specimen in primary breast cancer is insufficient. Limited agreement of surrogate tumor subtypes indicates a significant clinical value of biomarker re-testing on surgical specimens.

We compared estrogen receptor (ER), progesterone receptor (PR), human epidermal growth-factor receptor 2 (HER2), Ki67, and grade scores among the pathology departments in Sweden. We investigated how ER and HER2 positivity rates affect the distribution of endocrine and HER2-targeted treatments among oncology departments. All breast cancer patients diagnosed between 2013 and 2018 in Sweden were identified in the National Quality Register for Breast Cancer. Cases with data on ER, PR, HER2, Ki67, grade, and treatment were selected (43,261 cases from 29 departments following the guidelines for biomarker testing). The ER positivity rates ranged from 84.2% to 97.6% with 6/29 labs out of the overall confidence intervals (CIs), while PR rates varied between 64.8% and 86.6% with 7/29 labs out of the CIs. HER2 positivity rates ranged from 9.4% to 16.3%, with 3/29 labs out of the overall CIs. Median Ki67 varied between 15% and 30%, where 19/29 labs showed significant intra-laboratory variability. The proportion of grade-II cases varied between 42.9% and 57.1%, and 13/29 labs were outside of the CI. Adjusting for patient characteristics, the proportion of endocrine and anti-HER2 treatments followed the rate of ER and HER2 positivity, illustrating the clinical effect of inter- and intra-laboratory variability. There was limited variability among departments in ER, PR, and HER2 testing. However, even a few outlier pathology labs affected endocrine and HER2-targeted treatment rates in a clinically relevant proportion, suggesting the need for improvement. High variability was found in grading and Ki67 assessment, illustrating the need for the adoption of new technologies in practice.

Regulation of hairy and enhancer of split homologue-1 (HES-1) by estradiol and all-trans retinoic acid affects proliferation of human breast cancer cells. Here, we identify and characterize cis-regulatory elements involved in HES-1 regulation. In the distal 5 0 promoter of the HES-1 gene, we found a retinoic acid response element and in the distal 3 0 region, an estrogen receptor a(ER)a binding site. The ERa binding site, composed of an estrogen response element (ERE) and an ERE half-site, is important for both ERa binding and transcriptional regulation.Chromatin immunoprecipitation assays revealed that ERa is recruited to the ERE and associates with the HES-1 promoter. We also show recruitment of nuclear receptor co-regulators to the ERE in response to estradiol, followed by a decrease in histone acetylation and RNA polymerase II docking in the HES-1 promoter region. Our findings are consistent with a novel type of repressive estrogen response element in the distal 3 0 region of the HES-1 gene.

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Background: Around 15% of all breast cancers are HER2+, a subtype that prior to HER2-targeted therapy was associated with a poor prognosis. With advances in treatment the survival has dramatically improved, and previous studies suggest that the level of HER2 copies are predictive of the effect of anti-HER2 therapies. However, some patients progress despite HER2-targeted therapy and routine HER2 testing is hampered by inaccuracy to discriminate patients with therapy-resistant disease. Furthermore, tumor-infiltrating lymphocytes (TILs) in the tumor stroma shows prognostic value not only in triple negative but also in HER2+ breast cancer. However, the clinical utility in the adjuvant setting for HER2+ disease needs further validation. The aim of this study was to investigate the prognostic significance of HER2/CEP17 ratio, HER2 copy numbers and TILs among early breast cancer patients treated with HER2-targeted therapy. Materials and methods: A retrospective study cohort comprising a total of 584 patients with HER2+ early breast cancer, all treated with the monoclonal antibody trastuzumab targeting HER2 during 2006-2014 in the Stockholm Region, Sweden, was identified and HER2 re-testing (silver in situ hybridization and immunohistochemistry (IHC)) was performed on 474 whole tissue sections prior to neoadjuvant (18.1%) or adjuvant therapy. Stromal TILs were manually assessed on all hematoxylin-eosin stained slides. Registry-based information on patient- and tumor characteristics including treatment were completed from medical records with a median follow-up of 8.0 years. Results: Among the 474 analyzed tumors, 11.4% were HER2 IHC score 2+ and 86.7% were 3+. In addition, 61.6% were ER+ and the median TIL score was 15%. The median HER2 copy number was 9.8 signals/cell and only 12.9% had <6.0 average HER2 signals/cell and 2.5% had a HER2/CEP17 ratio <2.0. Survival analysis showed no significant association between HER2 IHC score (recurrence: p=0.58; breast cancer specific death: p=0.69), HER2 signals (p=0.77; p=0.73), HER2/CEP17 ratio (p=0.73; p=0.85), ER status (p=0.55; p=0.11), PR status (p=0.97; p=0.46), Ki67 (p=0.14; p=0.77) or tumor grade (p=0.71; p=0.16) with risk of recurrence or breast cancer specific death. The hazard ratio (HR) for recurrence did not significantly differ by HER2 signals/cell (HR 1.12, CI 0.53-2.37, p=0.77) or ER status (HR 1.18, CI 0.68-2.05, p=0.55). Tumors with low TILs were independently associated with recurrence (cutoff <40%: HR 4.5, CI 1.4-14.9, p=0.012) and breast cancer specific survival (cutoff <30%: HR 3.5, CI 1.2-10.1, p=0.02). Among the 56 recurrences (11.8%), 37.5% had ER- primary tumors and 82.4% of the 34 HER2-analyzed recurrent tumors remained HER2+. Conclusions: This study demonstrates that routine clinicopathological data, including HER2 status, is insufficient to predict breast cancer recurrence among patients treated with HER2-targeted therapy. Neither HER2 levels, HER2/CEP17 ratio or ER status correlated to risk of recurrence. Importantly, TILs showed robust prognostic potential in trastuzumab-treated patients. Our results emphasize the need for detailed molecular analyses to understand the biology behind resistance to HER2-targeted therapy and to further tailor therapy for HER2+ breast cancer patients. Citation Format: Stephanie Robertson, Caroline Rönnlund, Irma Fredriksson, Theodoros Foukakis, Johan Hartman. Tumor-infiltrating lymphocytes but not HER2 copy number or ratio show prognostic value in trastuzumab-treated HER2-positive breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-02-03.