Predictors of Surgical Margin Following Breast-Conserving Surgery: A Large Population-Based Cohort Study

Background: The purpose of this retrospective, population-based, cohort study was to identify patient and tumor characteristics that are associated with a high risk of tumor-positive margins after breast-conserving surgery (BCS) to optimize preoperative counseling. Methods: All patients with invasive breast cancer (IBC) reported according to the synoptic reporting module in the Dutch Pathology Registry between 2009 and 2015 were included (n = 42.048 cases). Data extraction included age, type of surgery, several tumor characteristics, and resection margin status according to the Dutch indications for re-excision (free, focally positive, or more than focally positive). Univariate and multivariate tests were used to determine the association between clinicopathological features and margin status, restricted to patients with BCS. Results: Of 42,048 cases, a total of 25,315 cases (60.2 %) with IBC underwent BCS. Of these patients, 2578 patients (10.2 %) had focally positive resection margins and 1665 (6.6 %) had more than focally positive resection margins. By univariate analysis, the following features were significantly associated with involved margins: age 2 cm, intermediate- and high-grade, positive ER status, positive Her2 status, angio-invasion, and the presence/extent of a ductal carcinoma in situ (DCIS) component. In multivariate logistic regression, the variables with the strongest association with involved margins (OR > 2) were multifocality, lobular subtype, large tumor size, and the presence of DCIS. Conclusions: Several clinicopathologic features are associated with involved resection margins after BCS for IBC. Assessment of these features preoperatively could be used to optimize preoperative counseling

Expression of hypoxia-induced proteins in ductal carcinoma in situ and invasive cancer of the male breast

AIMS: The aim of this study was to determine the role of hypoxia in male breast carcinogenesis by evaluating the expression of the hypoxia-related proteins, hypoxia-inducible factor-1α (HIF-1α), carbonic anhydrase IX (CAIX) and glucose transporter-1 (Glut-1), in ductal carcinoma in situ (DCIS) of the male breast in relation to invasive cancer (IC). METHODS: Tumour tissue blocks of 18 cases of pure DCIS, 58 DCIS cases adjacent to IC (DCIS-AIC) and the 58 IC cases were stained by immunohistochemistry for HIF-1α, CAIX and Glut-1, and expression frequencies and patterns (diffuse and/or perinecrotic) were noted. RESULTS: HIF-1α overexpression was observed in 61.1% (11/18) of pure DCIS, in 37.9% (22/58) of DCIS-AIC and in 36.2% (21/58) of IC cases (not significant (n.s.)). CAIX overexpression was observed in 16.7% (3/18) of pure DCIS, in 37.9% (22/58) of DCIS-AIC and in 24.1% (14/58) of IC cases (n.s.). Glut-1 overexpression was observed in 61.1% (11/18) of pure DCIS, in 75.9% (44/58) of DCIS-AIC and in 62.1% (36/58) of IC cases (n.s.). Expression of hypoxia-related proteins was seen around necrosis in a little over one-third of DCIS cases, and often coincided with expression in adjacent IC when present. All these observations indicate that the hypoxia response is already at its maximum in the preinvasive DCIS stage. CONCLUSIONS: In conclusion, male DCIS frequently shows activated hypoxia response, comparable to male IC. This indicates that the activated hypoxia response previously seen in male IC is not a late bystander but likely a genuine carcinogenetic event

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

Selecting patients with HER2-low Breast Cancer: getting out of the tangle

The promising effect of antibody–drug conjugates on breast cancer with low expression of HER2 (HER2-low) raises many questions regarding the optimal selection of patients for this treatment. A key question is whether HER2 immunohistochemistry, an assay optimised to detect HER2 amplification, is reliable enough to assess HER2 protein levels to select patients with HER2-low breast cancer in daily pathology practices worldwide. Moreover, whether this assessment can be performed with sufficient reproducibility between pathologists in daily practices is debatable. Herein, we address the historical track record of the CAP-ASCO HER2 Guidelines, the reported limited reproducibility by pathologists of HER2 immunohistochemistry in the non-amplified cases, and the performance variation of different antibodies. Based on this summary, we propose solutions to improve the robustness to enable reliable identification of patients with HER2-low breast cancer

HER2-low and tumor infiltrating lymphocytes in triple-negative breast cancer:Are they connected?

Most patients with triple-negative breast cancer (TNBC) are not candidates for targeted therapy, leaving chemotherapy as the primary treatment option. Recently, immunotherapy has demonstrated promising results in TNBC, due to its immunogenicity. In addition, a novel antibody–drug conjugate, namely, trastuzumab-deruxtecan, has shown effectiveness in TNBC patients with low-HER2 expression (HER2-low). These novel treatment options raise the question about the potential association between the density of stromal tumor-infiltrating lymphocytes (sTILs) and the level of HER2 expression. We aimed to evaluate the association between the level of HER2 expression (HER2-low versus HER2-0) and density of sTILs in TNBC patients, and how they impact the response to neoadjuvant chemotherapy (NAC). This was a retrospective multicenter study including all TNBC patients diagnosed between 2018 and 2022. Central pathology review included sTILs percentages and level of HER2 expression. Tumors were reclassified as either HER2-0 (HER2 IHC 0) or HER2-low (IHC 1 + or 2 + with negative reflex test). Various clinicopathologic characteristics, including sTILs density, and response to NAC were compared between HER2-0 and HER2-low cases. In total, 753 TNBC patients were included in this study, of which 292 patients received NAC. Interobserver agreement between the original pathology report and central review was moderate (77% had the same IHC status after reclassification in either HER2-0 or HER2-low; k = 0.45). HER2-low TNBC represented about one third (36%) of the tumors. No significant difference in sTILs density or complete pathologic response rate was found between HER2-0 and HER2-low cases (p = 0.476 and p = 0.339, respectively). The density of sTILs (≥ 10% sTILs vs. &lt; 10%) was independently associated with achieving a pCR (p = 0.011). In conclusion, no significant association was found between HER2-low status and density of sTILs nor response to NAC. Nonetheless, sTILs could be an independent biomarker for predicting NAC response in TNBC patients.</p

HER2-low and tumor infiltrating lymphocytes in triple-negative breast cancer:Are they connected?

Most patients with triple-negative breast cancer (TNBC) are not candidates for targeted therapy, leaving chemotherapy as the primary treatment option. Recently, immunotherapy has demonstrated promising results in TNBC, due to its immunogenicity. In addition, a novel antibody–drug conjugate, namely, trastuzumab-deruxtecan, has shown effectiveness in TNBC patients with low-HER2 expression (HER2-low). These novel treatment options raise the question about the potential association between the density of stromal tumor-infiltrating lymphocytes (sTILs) and the level of HER2 expression. We aimed to evaluate the association between the level of HER2 expression (HER2-low versus HER2-0) and density of sTILs in TNBC patients, and how they impact the response to neoadjuvant chemotherapy (NAC). This was a retrospective multicenter study including all TNBC patients diagnosed between 2018 and 2022. Central pathology review included sTILs percentages and level of HER2 expression. Tumors were reclassified as either HER2-0 (HER2 IHC 0) or HER2-low (IHC 1 + or 2 + with negative reflex test). Various clinicopathologic characteristics, including sTILs density, and response to NAC were compared between HER2-0 and HER2-low cases. In total, 753 TNBC patients were included in this study, of which 292 patients received NAC. Interobserver agreement between the original pathology report and central review was moderate (77% had the same IHC status after reclassification in either HER2-0 or HER2-low; k = 0.45). HER2-low TNBC represented about one third (36%) of the tumors. No significant difference in sTILs density or complete pathologic response rate was found between HER2-0 and HER2-low cases (p = 0.476 and p = 0.339, respectively). The density of sTILs (≥ 10% sTILs vs. &lt; 10%) was independently associated with achieving a pCR (p = 0.011). In conclusion, no significant association was found between HER2-low status and density of sTILs nor response to NAC. Nonetheless, sTILs could be an independent biomarker for predicting NAC response in TNBC patients.</p

Proteomic characterization of microdissected breast tissue environment provides a protein-level overview of malignant transformation

Both healthy and cancerous breast tissue is heterogeneous, which is a bottleneck for proteomics‐based biomarker analysis, as it obscures the cellular origin of a measured protein. We therefore aimed at obtaining a protein‐level interpretation of malignant transformation through global proteome analysis of a variety of laser capture microdissected cells originating from benign and malignant breast tissues. We compared proteomic differences between these tissues, both from cells of epithelial origin and the stromal environment, and performed string analysis. Differences in protein abundances corresponded with several hallmarks of cancer, including loss of cell adhesion, transformation to a migratory phenotype, and enhanced energy metabolism. Furthermore, despite enriching for (tumor) epithelial cells, many changes to the extracellular matrix were detected in microdissected cells of epithelial origin. The stromal compartment was heterogeneous and richer in the number of fibroblast and immune cells in malignant sections, compared to benign tissue sections. Furthermore, stroma could be clearly divided into reactive and nonreactive based on extracellular matrix disassembly proteins. We conclude that proteomics analysis of both microdissected epithelium and stroma gives an additional layer of information and more detailed insight into malignant transformation