HER2-low breast cancer and response to neoadjuvant chemotherapy:a population-based cohort study

About half of breast cancers (BC) without amplification of the human epidermal growth factor receptor 2 (HER2) have a low HER2 protein expression level (HER2-low). The clinical impact of HER2-low and the response to neoadjuvant chemotherapy (NAC) is unclear. This study aimed to assess the association between HER2-low BC and pathological response to NAC. Data from the Dutch Pathology Registry were collected for 11,988 BC patients treated with NAC between 2014 and 2022. HER2-low BC was defined as an immunohistochemical score of 1+ or 2+ and a negative molecular reflex test. We compared clinicopathological features of HER2-0 versus HER2-low BC and assessed the correlation between HER2 status and the pathological complete response (pCR) rate after NAC, including overall survival. Among hormone receptor (HR)-positive tumours, 67% (n=4,619) were HER2-low, compared to 47% (n=1,167) in the HR-negative group. Around 32% (n=207) of patients had a discordant HER2 status between the pre-NAC biopsy and the corresponding post-NAC resection, within which 87% (n=165) changed from HER2-0 to HER2-low or vice versa. The pCR rate was significantly lower in HER2-low BC compared to HER2-0 BC within the HR-positive group (4% versus 5%; p=0.022). However, the absolute difference was limited, so the clinical relevance is questionable. In HR-negative cases, the difference in pCR was not significant (32% versus 34%; p=0.266). No significant difference in overall survival was observed between HER2-low and HER2-0 tumours, regardless of hormone receptor status. The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has improved survival outcomes of patients with HER2-low metastatic BC. The finding that one-third of the patients in this study had a discordant HER2 status between the pre-NAC biopsy and the post-NAC resection specimen could impact clinical decision-making should T-DXd be used in early BC treatment.</p

HER2-low breast cancer and response to neoadjuvant chemotherapy:a population-based cohort study

About half of breast cancers (BC) without amplification of the human epidermal growth factor receptor 2 (HER2) have a low HER2 protein expression level (HER2-low). The clinical impact of HER2-low and the response to neoadjuvant chemotherapy (NAC) is unclear. This study aimed to assess the association between HER2-low BC and pathological response to NAC. Data from the Dutch Pathology Registry were collected for 11,988 BC patients treated with NAC between 2014 and 2022. HER2-low BC was defined as an immunohistochemical score of 1+ or 2+ and a negative molecular reflex test. We compared clinicopathological features of HER2-0 versus HER2-low BC and assessed the correlation between HER2 status and the pathological complete response (pCR) rate after NAC, including overall survival. Among hormone receptor (HR)-positive tumours, 67% (n=4,619) were HER2-low, compared to 47% (n=1,167) in the HR-negative group. Around 32% (n=207) of patients had a discordant HER2 status between the pre-NAC biopsy and the corresponding post-NAC resection, within which 87% (n=165) changed from HER2-0 to HER2-low or vice versa. The pCR rate was significantly lower in HER2-low BC compared to HER2-0 BC within the HR-positive group (4% versus 5%; p=0.022). However, the absolute difference was limited, so the clinical relevance is questionable. In HR-negative cases, the difference in pCR was not significant (32% versus 34%; p=0.266). No significant difference in overall survival was observed between HER2-low and HER2-0 tumours, regardless of hormone receptor status. The antibody-drug conjugate trastuzumab deruxtecan (T-DXd) has improved survival outcomes of patients with HER2-low metastatic BC. The finding that one-third of the patients in this study had a discordant HER2 status between the pre-NAC biopsy and the post-NAC resection specimen could impact clinical decision-making should T-DXd be used in early BC treatment.</p

Histological interpretation of differentiated vulvar intraepithelial neoplasia (dVIN) remains challenging-observations from a bi-national ring-study

Differentiated vulvar intraepithelial neoplasia (dVIN) is a premalignant lesion that is known to progress rapidly to invasive carcinoma. Accurate histological diagnosis is therefore crucial to allow appropriate treatment. To identify reliable diagnostic features, we evaluated the inter-observer agreement in the histological assessment of dVIN, among a bi-national, multi-institutional group of pathologists. Two investigators from Erasmus MC selected 36 hematoxylin-eosin-stained glass slides of dVIN and no-dysplasia, and prepared a list of 15 histological features of dVIN. Nine participating pathologists (i) diagnosed each slide as dVIN or no-dysplasia, (ii) indicated which features they used for the diagnosis, and (iii) rated these features in terms of their diagnostic usefulness. Diagnoses rendered by > 50% participants were taken as the consensus (gold standard). p53-immunohistochemistry (IHC) was performed for all cases, and the expression patterns were correlated with the consensus diagnoses. Kappa statistics were computed to measure inter-observer agreements, and concordance of the p53-IHC patterns with the consensus diagnoses. For the diagnosis of dVIN, overall agreement was moderate (= 0.42), and pair-wise agreements ranged from slight (= 0.10) to substantial (= 0.73). Based on the levels of agreement and ratings of usefulness, the most helpful diagnostic features were parakeratosis, cobblestone appearance, chromatin abnormality, angulated nuclei, atypia discernable under x 100, and altered cellular alignment. p53-IHC patterns showed substantial concordance (= 0.67) with the consensus diagnoses. Histological interpretation of dVIN remains challenging with suboptimal inter-observer agreement. We identified the histological features that may facilitate the diagnosis of dVIN. For cases with a histological suspicion of dVIN, consensus-based pathological evaluation may improve the reliability of the diagnosis

Interobserver Agreement of PD-L1/SP142 Immunohistochemistry and Tumor-Infiltrating Lymphocytes (TILs) in Distant Metastases of Triple-Negative Breast Cancer: A Proof-of-Concept Study. A Report on Behalf of the International Immuno-Oncology Biomarker Working Group

Patients with advanced triple-negative breast cancer (TNBC) benefit from treatment with atezolizumab, provided that the tumor contains 651% of PD-L1/SP142-positive immune cells. Numbers of tumor-infiltrating lymphocytes (TILs) vary strongly according to the anatomic localization of TNBC metastases. We investigated inter-pathologist agreement in the assessment of PD-L1/SP142 immunohistochemistry and TILs. Ten pathologists evaluated PD-L1/SP142 expression in a proficiency test comprising 28 primary TNBCs, as well as PD-L1/SP142 expression and levels of TILs in 49 distant TNBC metastases with various localizations. Interobserver agreement for PD-L1 status (positive versus negative) was high in the proficiency test: the corresponding scores as percentages showed good agreement with the consensus diagnosis. In TNBC metastases, there was substantial variability in PD-L1 status at the individual patient level. For one in five patients, the chance of treatment was essentially random, with half of the pathologists designating them as positive and half negative. Assessment of PD-L1/SP142 and TILs as percentages in TNBC metastases showed poor and moderate agreement, respectively. Additional training for metastatic TNBC is required to enhance interobserver agreement. Such training, focusing on metastatic specimens, seems worthwhile, since the same pathologists obtained high percentages of concordance (ranging from 93% to 100%) on the PD-L1 status of primary TNBCs

Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group.

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University.Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance.Funder: The Canadian Cancer SocietyFunder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring

Report on computational assessment of Tumor Infiltrating Lymphocytes from the International Immuno-Oncology Biomarker Working Group

Funder: U.S. Department of Health & Human Services | NIH | National Cancer Institute (NCI)Funder: National Center for Research Resources under award number 1 C06 RR12463-01, VA Merit Review Award IBX004121A from the United States Department of Veterans Affairs Biomedical Laboratory Research and Development Service, the DOD Prostate Cancer Idea Development Award (W81XWH-15-1-0558), the DOD Lung Cancer Investigator-Initiated Translational Research Award (W81XWH-18-1-0440), the DOD Peer Reviewed Cancer Research Program (W81XWH-16-1-0329), the Ohio Third Frontier Technology Validation Fund, the Wallace H. Coulter Foundation Program in the Department of Biomedical Engineering and the Clinical and Translational Science Award Program (CTSA) at Case Western Reserve University.Funder: Susan G Komen Foundation (CCR CCR18547966) and a Young Investigator Grant from the Breast Cancer Alliance.Funder: The Canadian Cancer SocietyFunder: Breast Cancer Research Foundation (BCRF), Grant No. 17-194Abstract: Assessment of tumor-infiltrating lymphocytes (TILs) is increasingly recognized as an integral part of the prognostic workflow in triple-negative (TNBC) and HER2-positive breast cancer, as well as many other solid tumors. This recognition has come about thanks to standardized visual reporting guidelines, which helped to reduce inter-reader variability. Now, there are ripe opportunities to employ computational methods that extract spatio-morphologic predictive features, enabling computer-aided diagnostics. We detail the benefits of computational TILs assessment, the readiness of TILs scoring for computational assessment, and outline considerations for overcoming key barriers to clinical translation in this arena. Specifically, we discuss: 1. ensuring computational workflows closely capture visual guidelines and standards; 2. challenges and thoughts standards for assessment of algorithms including training, preanalytical, analytical, and clinical validation; 3. perspectives on how to realize the potential of machine learning models and to overcome the perceptual and practical limits of visual scoring

Pitfalls in assessing stromal tumor infiltrating lymphocytes (sTILs) in breast cancer

Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are important prognostic and predictive biomarkers in triple-negative (TNBC) and HER2-positive breast cancer. Incorporating sTILs into clinical practice necessitates reproducible assessment. Previously developed standardized scoring guidelines have been widely embraced by the clinical and research communities. We evaluated sources of variability in sTIL assessment by pathologists in three previous sTIL ring studies. We identify common challenges and evaluate impact of discrepancies on outcome estimates in early TNBC using a newly-developed prognostic tool. Discordant sTIL assessment is driven by heterogeneity in lymphocyte distribution. Additional factors include: technical slide-related issues; scoring outside the tumor boundary; tumors with minimal assessable stroma; including lymphocytes associated with other structures; and including other inflammatory cells. Small variations in sTIL assessment modestly alter risk estimation in early TNBC but have the potential to affect treatment selection if cutpoints are employed. Scoring and averaging multiple areas, as well as use of reference images, improve consistency of sTIL evaluation. Moreover, to assist in avoiding the pitfalls identified in this analysis, we developed an educational resource available at www.tilsinbreastcancer.org/pitfalls

Application of a risk-management framework for integration of stromal tumor-infiltrating lymphocytes in clinical trials

Funder: Breast Cancer Research Foundation (BCRF); doi: https://doi.org/10.13039/100001006Abstract: Stromal tumor-infiltrating lymphocytes (sTILs) are a potential predictive biomarker for immunotherapy response in metastatic triple-negative breast cancer (TNBC). To incorporate sTILs into clinical trials and diagnostics, reliable assessment is essential. In this review, we propose a new concept, namely the implementation of a risk-management framework that enables the use of sTILs as a stratification factor in clinical trials. We present the design of a biomarker risk-mitigation workflow that can be applied to any biomarker incorporation in clinical trials. We demonstrate the implementation of this concept using sTILs as an integral biomarker in a single-center phase II immunotherapy trial for metastatic TNBC (TONIC trial, NCT02499367), using this workflow to mitigate risks of suboptimal inclusion of sTILs in this specific trial. In this review, we demonstrate that a web-based scoring platform can mitigate potential risk factors when including sTILs in clinical trials, and we argue that this framework can be applied for any future biomarker-driven clinical trial setting

HER2 protein overexpression in non-amplified ductal carcinoma in situ: quality issue or transcription mechanisms gone awry?

we read with interest the recent report by Hui et al. entitled 'Discordant HER2 immunohistochemical expression and gene amplification in ductal carcinoma in situ - evaluating HER2 in synchronous in situ and invasive carcinoma'.1 This study compares HER2 immunohistochemistry (IHC) and chromogenic in situ hybridization (CISH) between admixed synchronous in situ and invasive carcinomas exhibiting an equivocal 2+ HER2 IHC score in the invasive component. This article is protected by copyright. All rights reserved.status: publishe