Human Epidermal Growth Factor Receptor-2 Status Research Articles

Prognostic and Predictive Significance of HER2-low Expression in Metastatic Hormone Receptor Positive Breast Cancer Patients Receiving CDK4-6 Inhibitor Therapy

Objective: This study aimed to analyze the predictive and prognostic value of HER2-low expression in hormone receptor (HR) positive human epidermal growth factor receptor-2 (HER2) negative metastatic breast cancer patients receiving cyclin-dependent kinase-4/6 inhibitor (CDK4/6i) therapy. Methods: This retrospective study included patients who received CDK4/6i plus endocrine therapy (ET). The pathological and clinical characteristics and survival times of the patients were compared and analyzed. Results: Our study included 122 patients. There were HER2-zero 88(72%) and HER2-low 34 (28%) patients. The median progression free survival (mPFS) of all patients who received CDK4/6i+ET was 21 (95% confidence interval (CI),18.5–23.5) months, while mPFS was not reached in the HER2-zero group, and mPFS in the HER2-low group was 12 (95%CI, 6.8–17.1) months (p=0.001). The mPFS was shorter in patients with primary endocrine resistance (6 vs. 21 months, p=0.001). There was a change in the HER2-low status of 26(45%) patients with recurrence compared to the first biopsy. In the HER2-zero and HER2-low groups, 22(25%) and 24(71%) patients, respectively, progressed with CDK4/6i+ET (p=0.001). Estrogen receptor (ER) levels less than and greater than 50% resulted different mPFS (6 and 21 months, respectively) (p=0.025). Median PFS differed based on CDK4/6i+ET combination, treatment line, and best treatment response (all p=0.001). In multivariate analysis, HER2 status(p=0.018), chemotherapy status(p=0.006), best response status with CDK4/6i (p=0.001) for PFS, and best response status with CDK4/6i therapy (p=0.007) for OS were significant. Conclusions: In patients with HR+HER- metastatic breast cancer receiving CDK4/6i therapy, the duration of mPFS was lower in the HER2-low group than that in the HER2-zero group. HER2-low expression is a predictive biomarker of response to CDK4/6 inhibitor therapy.

Abstract PO4-07-04: Breast Cancer HER2 Status Prediction from Hematoxylin-Eosin Stained Images Using Point Cloud Transformer

Abstract Background: Human epidermal growth factor receptor-2 (HER2) status is a key factor in determining the treatment strategy for breast cancer patients. Patients with HER2-positive status are more likely to benefit from HER2-targeted therapy, leading to improved prognosis. In current routine diagnostic practice, pathologists utilize Hematoxylin-Eosin (HE) stained tumor tissues for histopathological assessment. Subsequently, IHC assessment and/or FISH test are performed to evaluate the HER2 status. However, manual assessment results may be affected by tissue usability and observer-subjectivity. Therefore, there is a necessity to predict the HER2 status directly from HE images to minimize time and cost while ensuring enhanced consistency. Methods: We identified 608 HE diagnostic slides with HER2 status from The Cancer Genome Atlas in breast cancer (TCGA-BRCA). It contains 474 HER2-positive slides (IHC 3+, IHC 2+ and FISH positive) and 134 HER2-negative slides (IHC 0, IHC 1+, IHC 2+ and FISH negative). To analyze these slides, we first tiled the HE images into patches with a fixed size of 256 × 256 at 20 × magnification. Then the patch-level feature was derived from a self-supervised pretrained transformer. Meanwhile, artificial intelligence (AI) methods are adopted to predict HER2 status from HE images. To capture the long-distance patch relations within a slide, we represented the patches as distinct points and utilized the Point Cloud Transformer model for HER2 status prediction. Specifically, 1024 patches (points) in each slide were randomly selected and input into the Point Cloud Transformer. This process yielded a slide-level prediction result for the HER2 status. Furthermore, Graph Attention Network (GAT), Graph Sample and Aggregate Network (Graph SAGE), and hierarchical Point Cloud Network (PointNet++) were adopted to compare the effectiveness of HER2 status prediction using Point Cloud Transformer. Of note that Point Cloud Transformer incorporated attention mechanisms for point aggregation compared to PointNet++. Results: The Point Cloud Transformer was trained with 5-fold cross-validation, and the area under the curve (AUC) of the receiver operating characteristic (ROC) curve was reported. The performance of point-based models outperformed the graph-based models. And the Point Cloud Transformer achieved the highest AUC of 0.7496 among all AI models. The detailed AUC for each AI model was shown in Table 1. Conclusion: Our study revealed that the HER2 status can be predicted directly from HE images without using IHC images. Furthermore, point-based models have demonstrated the ability to capture long-distance relations among patches, surpassing graph-based models in terms of prediction performance. To further enhance performance, we adopted a better point aggregation method, such as the Point Cloud Transformer, which held promise for further improving the accuracy of predictions in the future. Table 1: AUC of HER2 status prediction from HE images in the TCGA-BRCA dataset Method GAT Graph SAGE PointNet++ Point Cloud Transformer AUC 0.6640 0.6737 0.7201 0.7496 Citation Format: Bao Li, Zhenyu Liu, Yang Du, Jie Tian. Breast Cancer HER2 Status Prediction from Hematoxylin-Eosin Stained Images Using Point Cloud Transformer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-07-04.

Human epidermal growth factor receptor-2 expression and subsequent dynamic changes in patients with ovarian cancer

Human epidermal growth factor receptor-2 (HER2)-targeting drugs are increasingly being incorporated into therapeutic paradigms for non-breast cancers, yet studies on HER2 expression in ovarian cancer (OC) are inadequate. Here, we studied the HER2 status and dynamic changes in OC by reviewing the records of patients who underwent HER2 testing at a single institution. Clinical parameters, including histology, BRCA status, and immunohistochemistry (IHC), were evaluated alongside HER2 expression, timing, and anatomical location. Among 200 patients, 28% and 6% exhibited expression scores of 2+ and 3+, respectively. HER2 3+ scores were observed in 23%, 11%, 9%, and 5% of mucinous, endometrioid, clear cell, and high-grade serous tumors, respectively, and were exclusively identified in BRCA-wildtype, mismatch repair-proficient, or PD-L1-low-expressing tumors. The TP53 mutation rate was low, whereas ARID1A, KRAS, and PIK3CA mutations were relatively more prevalent with HER2 scores of 2+ or 3+ than with 0 or 1+. Four of the five tumors with an HER2 3+ score exhibited ERBB2 amplification. Among 19 patients who underwent multiple time-lagged biopsies, 11 showed increased HER2 expression in subsequent biopsies. Patients with HER2-overexpressing OC exhibited distinct histological, IHC, and genomic profiles. HER2-targeting agents are potential options for BRCA-wildtype patients, particularly as later lines of treatment.

Real-World Data on Pathological Response and Survival Outcomes After Neoadjuvant Chemotherapy in HER2-Low Breast Cancer Patients

BackgroundData on the pathological responses and survival outcomes after neoadjuvant chemotherapy (NACT) in human epidermal growth factor receptor-2 (HER2)-low breast cancer (BC) are lacking. This study aims to investigate this topic in the real world. MethodsClinicopathological data from 819 HER2-negative BC patients who underwent NACT between 2010 and 2020 were retrospectively retrieved from the Shanghai Jiaotong University Breast Cancer Database. These patients were categorized into HER2-low and HER2-0 groups. Logistic analyses were conducted to identify predictors of complete pathological response (pCR) and breast pCR. Cox regression analyses were conducted to assess the factors associated with disease-free survival (DFS) and overall survival (OS). Kaplan-Meier (K-M) curves were generated to compare DFS and OS between HER2-low BC and HER2-0 BC. ResultsOf the 819 BC patients, 669 (81.7%) had HER2-low tumors, and 150 (18.3%) had HER2-0 tumors. HER2-low BC had a significantly higher ratio of ER ≥ 10%, PR ≥ 20%, and Ki67 ≥ 15% than HER2-0 BC. A significantly higher breast pCR rate was observed in HER2-low BC than in HER2-0 BC (13.6% and 7.3%, respectively, P = .036). Age, HER2 status (low or 0), Ki67, and surgery options were associated with breast pCR in HER2-negative BC. In HER2-low BC, the pCR rate of ER ≥ 10% BC was significantly lower than that of ER < 10% BC, but the DFS and OS of ER 10% BC were significantly higher. The K-M curve showed no significant differences in DFS or OS between HER2-low and HER2-0 BC. Cox regression revealed that ER expression and histological grade (III vs. I∼II) were significantly associated with survival in HER2-low BC. ConclusionsIn this real-world data (RWD) study, a significantly higher breast pCR rate was found in HER2-low BC than in HER2-0 BC, although there was no significant difference in survival. Moreover, ER expression had a significant prognostic impact on HER2-low BC.

HAHNet: a convolutional neural network for HER2 status classification of breast cancer

ObjectiveBreast cancer is a significant health issue for women, and human epidermal growth factor receptor-2 (HER2) plays a crucial role as a vital prognostic and predictive factor. The HER2 status is essential for formulating effective treatment plans for breast cancer. However, the assessment of HER2 status using immunohistochemistry (IHC) is time-consuming and costly. Existing computational methods for evaluating HER2 status have limitations and lack sufficient accuracy. Therefore, there is an urgent need for an improved computational method to better assess HER2 status, which holds significant importance in saving lives and alleviating the burden on pathologists.ResultsThis paper analyzes the characteristics of histological images of breast cancer and proposes a neural network model named HAHNet that combines multi-scale features with attention mechanisms for HER2 status classification. HAHNet directly classifies the HER2 status from hematoxylin and eosin (H&E) stained histological images, reducing additional costs. It achieves superior performance compared to other computational methods.ConclusionsAccording to our experimental results, the proposed HAHNet achieved high performance in classifying the HER2 status of breast cancer using only H&E stained samples. It can be applied in case classification, benefiting the work of pathologists and potentially helping more breast cancer patients.

Clinicopathological characteristics of HER2-low breast cancer: a retrospective study

Human Epidermal Growth Factor Receptor-2 (HER2)-negative breast cancers (BCs) contain HER2-low and HER2-zero ones. HER2-low breast cancer has been receiving wide-spread concerns as the marvelous effect of novel anti-HER2 antibody-drug conjugates, however, the characteristic remains unknown. Our aim was to explore the differences of clinicopathological indicators and survival outcomes between HER2-low and HER2-0 breast cancers. We retrospectively analyzed 501 invasive breast cancer patients with complete data on HER2 status from 2017 to 2021 in our single center, of whom 415 HER2 negative patients were included for subsequent analysis. Each cohort was further divided into hormone receptor (HR) positive and HR negative subgroup. Clinicopathological factors and survival outcomes were collected and compared between HER2-low BCs and HER2-0 BCs. HER2-low BCs was obviously higher in HR positive BCs, with 277 (90.5%) HER2-low HR positive patients, 29 (9.5%) HER2-low HR negative patients, 68 (62.4%) HER2-0 HR positive patients and 41 (37.6%) HER2-0 HR negative patients (P < 0.001). Significant differences between HER2-low BCs and Her2-0 BCs were observed in lymph node ratio (LNR) (mean rank, 215 vs. 188 P = 0.014), estrogen receptor (ER)expression (90.5% vs. 62.4% P < 0.001), progesterone receptor (PR) expression (84.3% vs. 56.9% P < 0.001), Ki-67 expression (46.4% vs. 61.5% P < 0.001), androgen receptor (AR) expression (68% vs. 50.5% P < 0.001), adjuvant chemotherapy (69% vs. 79.8% P = 0.03). HER2-low BCs had lower histological grade than HER2-0 BCs, with grade I–II (68.7% vs. 43.1%) and grade III (22.2% vs. 43.1%) P < 0.01. No statistical differences were detected between the two groups for DFS and DDFS. Our results demonstrated that HR and AR status was closely related to HER2-low breast cancers. Further exploration about survival prognosis of HER2-low breast cancer is badly needed.

PET/CT and SPECT/CT Imaging of HER2-Positive Breast Cancer.

HER2 (Human Epidermal Growth Factor Receptor 2)-positive breast cancer is characterized by amplification of the HER2 gene and is associated with more aggressive tumor growth, increased risk of metastasis, and poorer prognosis when compared to other subtypes of breast cancer. HER2 expression is therefore a critical tumor feature that can be used to diagnose and treat breast cancer. Moving forward, advances in HER2 in vivo imaging, involving the use of techniques such as positron emission tomography (PET) and single-photon emission computed tomography (SPECT), may allow for a greater role for HER2 status in guiding the management of breast cancer patients. This will apply both to patients who are HER2-positive and those who have limited-to-minimal immunohistochemical HER2 expression (HER2-low), with imaging ultimately helping clinicians determine the size and location of tumors. Additionally, PET and SPECT could help evaluate effectiveness of HER2-targeted therapies, such as trastuzumab or pertuzumab for HER2-positive cancers, and specially modified antibody drug conjugates (ADC), such as trastuzumab-deruxtecan, for HER2-low variants. This review will explore the current and future role of HER2 imaging in personalizing the care of patients diagnosed with breast cancer.

Efficacy of post‑mastectomy radiotherapy in patients with T1‑2N1 breast cancer aged ≤35years or with a positive HER‑2 status.

Post-mastectomy radiotherapy (PMRT) is highly recommended for patients with breast cancer with one to three positive nodes; however, there remains some controversy regarding its use. The present retrospective study aimed to explore which patients may be able to avoid PMRT and its associated side effects. A total of 728 patients with T1-2N1 breast cancer who were treated with or without PMRT were included in the present study. The results suggested that PMRT significantly decreased the locoregional recurrence rate (LRR) [hazard ratio (HR)=5.602, 95% confidence interval (CI)=3.139-9.998, P<0.01; 3-year LRR: 4 vs. 17%] and improved overall survival (OS) (HR=0.651, 95% CI=0.437-0.971, P=0.03; 3-year OS: 91 vs. 87%) for patients with T1-2N1 breast cancer. By contrast, PMRT had no significant effect on the distant metastasis (DM) rate (HR=0.691, 95% CI=0.468-1.019, P=0.06; 3-year DM: 10 vs. 15%). Further stratified analysis revealed that PMRT did not reduce the LRR and DM, or improve OS in patients aged ≤35 years or in those with a positive human epidermal growth factor receptor-2 (HER-2) status. The analysis of 438 patients treated with PMRT revealed that patients aged ≤35 years or those with a positive HER-2 status were more likely to experience local recurrence even following PMRT. Thus, the benefits of using PMRT in patients with T1-2N1 breast cancer who are aged ≤35 years or in those with a positive HER-2 status need to be carefully considered. Further studies are required to confirm whether this patient group may be exempted from PMRT.

MOUNTAINEER-03: Phase 3 study of tucatinib, trastuzumab, and modified FOLFOX6 as first line treatment in HER2+ metastatic colorectal cancer.

TPS3631 Background: The current standard of care (SOC) for the treatment of metastatic colorectal cancer (mCRC) is multi-agent chemotherapy, with or without a VEGF or EGFR inhibitor. Human epidermal growth factor receptor-2 (HER2) is a validated clinical target in breast and gastric cancers. HER2 amplification occurs in 3%–5% of patients with mCRC; the rate of HER2 amplification can increase to approximately 10% in patients with RAS/BRAF wild-type mCRC tumors. Tucatinib (TUC)—a highly selective, HER2-directed tyrosine kinase inhibitor—is approved in multiple regions for HER2-positive (HER2+) metastatic breast cancer, approved in the US for HER2+ metastatic colorectal cancer, and under investigation in gastrointestinal cancers. MOUNTAINEER (NCT03043313) evaluated the safety and efficacy of TUC and trastuzumab (Tras) in patients with treatment-refractory RAS wild-type, HER2+ mCRC. Results from the primary endpoint analysis showed clinically meaningful activity, with a confirmed objective response rate (ORR) per blinded independent central review (BICR) of 38.1% (95% confidence interval [CI] 27.7, 49.3) and median duration of response per BICR of 12.4 months (95% CI 8.5, 20.5). Results also demonstrated TUC + Tras was well tolerated, with a low discontinuation rate (5.8%) and no deaths due to adverse events. MOUNTAINEER-03 will further investigate TUC in combination with modified FOLFOX (mFOLFOX) and Tras in patients with RAS wild-type HER2+ mCRC. Methods: MOUNTAINEER-03 (NCT05253651) is a global, open-label, randomized, phase III study for first-line treatment of HER2+ and RAS wild-type mCRC. Approximately 400 patients will be randomized 1:1 to the TUC experimental arm (TUC [300 mg orally twice daily] + Tras + mFOLFOX) or the SOC arm (mFOLFOX alone or in combination with either bevacizumab or cetuximab). HER2 status is determined centrally with tissue-based HER2 immunohistochemistry and in situ hybridization assays. Eligible patients must not have received prior treatment in the metastatic setting but may have received adjuvant treatment if completed &gt; 6 months prior to enrollment. Patients must be ≥18 years old with an Eastern Cooperative Oncology Group Performance Status of ≤1 and RAS wild-type mCRC. Patients with treated stable central nervous system metastases are eligible. Randomization is stratified by primary tumor location (left-sided vs other) and liver metastases (presence/absence). The primary endpoint is progression-free survival per RECIST v1.1 assessed by BICR. Key secondary endpoints are overall survival and confirmed ORR per RECIST v1.1 assessed by BICR. Enrollment is ongoing in North America, Asia, Australia, and Europe. Clinical trial information: NCT05253651 .

HER2-low breast cancer brain metastases: Incidence and treatment implications.

2035 Background: Brain metastases (BrM) are a major cause of morbidity and mortality among women with breast cancer (BC). Central nervous system (CNS)-penetrating systemic therapies for patients with HER2-negative BrM are lacking; this is particularly problematic for patients with triple negative disease (TNBC) who have a high likelihood of developing BrM. Given CNS activity of trastuzumab deruxtecan, efficacy for patients with HER2-low BrM is of interest. Methods: A retrospective study of two cohorts of patients who underwent surgery for BC BrM at Sunnybrook Health Sciences Centre between 1999-2013 and 2008-2018 were identified. Estrogen receptor, progesterone receptor, and human epidermal growth factor receptor-2 (HER2) status were assessed based on 2018 ASCO/CAP guidelines. HER2-zero was defined as immunohistochemistry (IHC) 0; HER2-low was defined as IHC 1+ or IHC 2+ with fluorescence in situ hybridization (FISH) negative status. HER2-positive was defined as IHC 3+ or IHC 2+ with positive FISH. Clinicopathological features were recorded. We also assessed the prognostic association between extent of HER2 expression and i) brain-specific progression free survival (bsPFS), as well as ii) overall survival (OS). Results: Out of 137 patients with resected BrM, tissue for HER2 assessment was available in 74.5% (n=102) of cases. In this cohort, the median age at BrM diagnosis was 53.5 (range, 32-85). 18.6% (n=19) had leptomeningeal disease and 68.6% (n=70) had extracranial disease. 53% (n=54) of the BrM were HER2-positive; 29.4% (n=30) were HER2-low and 17.6% (n=18) had HER2-zero status. Among BrM that were triple negative based on ASCO/CAP guidelines, 14 out of 22 cases (63.6%) were re-classified as being HER2-low. 15/25 (60%) BrM that were hormone receptor positive/HER2 negative (HR+/HER2-) based on ASCO/CAP guidelines were re-classified as being HER2-low. In total, 51 patients had matched primary breast and BrM tissue available; results of HER2 status when categorized as HER2-zero, HER2-low and HER2-positive were concordant in 82.3% (n= 42/51) of cases (Cohen’s kappa 0.58, p=0.0719). In 7 cases, the primary breast tissue was HER2-zero whereas the BrM was either HER2-low (n=5) or HER2-positive (n=2). In only one case (2%), expression of HER2 was lower in the BrM (HER2-low) compared to the primary BC (HER2-positive). Median time from primary BC to the development of BrM was 35 months (IQR, 14-69) in the overall cohort; patients with HER2-zero BrM had a numerically longer time to development of BrM (45.8 months), compared to those with HER2-low (35 months) and HER2-positive (35 months) BrM (p=0.948). There was no significant association between HER2-zero, HER2-low and HER2-positive status in BrM and either bsPFS or OS. Conclusions: Among patients with surgically resected BrM, a high proportion of those with metastatic TNBC and HR+/HER2-negative disease have “HER2-low” BrM with potential to benefit from HER2-targeted therapy.

Targeting HER2 in colorectal cancer

Among the molecular subgroups of interest in metastatic colorectal cancer (mCRC), innovations are underway for tumors with overexpression of HER2 (Human Epidermal Growth Factor Receptor 2). Overexpression of the HER2 protein concerns 2 to 5% of CRC at any stage mainly located in the distal colon and rectum. Diagnosis is based on immunohistochemistry, in situ hybridization with appropriate criteria for colorectal localization, and molecular biology (NGS: next-generation sequencing). Overexpression of HER2 is a predictive factor for resistance to treatments targeting EGFR which are indicated in the case where the tumor is wild-type RAS. It seems to be associated with a poor prognosis of mCRC with a higher risk of brain metastasis. Regarding treatments targeting HER2, no randomized controlled phase III has been published to date. However, several combinations have been evaluated in phase II with clinically meaningful objective response rates: trastuzumab-deruxtecan (45%), trastuzumab-tucatinib (46%), trastuzumab-pyrotinib (45%), trastuzumab-pertuzumab (30%) ou trastuzumab-lapatinib (30%). In this literature review, we present here the current state of knowledge on the diagnostic methods of HER2 overexpression in CRC, the main clinical, molecular and prognostic characteristics, and the efficacy results of the different therapeutic combinations for the patients with HER2 overexpressed mCRC. This justifies, despite the lack of marketing authorization in France and in Europe for agents targeting HER2 in CRC, the systematic evaluation of the HER2 status, as recommended in particular by the NCCN (National Comprehensive Cancer Network).

Prognostic value of the preoperative prognostic nutritional index and systemic immuno-inflammatory index in Chinese breast cancer patients: A clinical retrospective cohort study.

It has been shown that peripheral blood inflammatory factor ratios correlate with the prognosis of various malignancies. Although indicative of prognosis in some tumors, its value for prognosis in breast cancer patients is unclear. The clinical data of breast cancer patients diagnosed with breast cancer in the Second Hospital of Jilin University from January 1, 2013, to December 31, 2017, were retrospectively analyzed. Theprognostic nutritional index(PNI) optimal cutoff values of the subjects' operating characteristic curves divided the patients into a low PNI group (≤51.05) and a high PNI group (>51.05). Correlations between breast cancer and PNI clinicopathological variables were determined by the χ2 test or Fisher exact test. Kaplan-Meier plots and log-rank tests were used to assess clinical outcomes in terms of disease-free survival (DFS). The prognostic value of PNI was analyzed by univariate and multivariate Cox proportional risk regression models. The best cutoff value for predicting DFS by pretreatment PNI was 51.05 and the Youden index when was 0.416, with a sensitivity of 71.4% and specificity of 70.2%. Univariate analysis showed that PNI ≤ 51.05, human epidermal growth factor receptor-2 (HER-2) positivity, and the number of lymph node metastases >4 were risk factors affecting DFS in invasive breast cancer (p < 0.05). Cox multifactor analysis showed that PNI and lymph node status were the most important factors affecting the prognosis of invasive breast cancer. Neutrophils-to-lymphocytes ratio and platelets-to-lymphocytes ratio were not significantly correlated with patient prognosis (p > 0.05). Preoperative peripheral blood PNI in patients with invasive breast cancer are independent risk factors affecting patients' prognosis, they are positively correlated with prognosis and can be used as indicators to assess prognosis. PNI, HER-2, and lymph node status had the best predictive efficacy with the area under the curve = 0.816 (95% confidence interval: 0.680-0.951, p < 0.001).

Comparison of breast cancer HER-2 receptor testing with immunohistochemistry and in situ hybridization.

Human epidermal growth factor receptor-2 (HER2) status can be tested with immunohistochemistry (IHC) and in situ hybridization (ISH). The 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) HER2 testing guidelines suggest initial HER2 testing using IHC and further testing IHC equivocal cases with ISH. However, many institutions perform both IHC and ISH on the same specimen. This study aims to analyze the concordance between HER2 IHC and ISH in order to evaluate the benefit of repeating HER2 testing on the same breast cancer specimens. Patients diagnosed with invasive breast cancer through BreastScreen NSW Sydney West program between January 2018 and December 2020 were identified and their HER2 IHC and HER2 ISH results on core needle biopsy (CNB) and surgical excisions (SE) were retrospectively collected. Specimens with both IHC and ISH results were then analyzed for agreement and concordance using unweighted kappa values. Equivocal IHC (2+) cases were excluded from concordance analysis. Overall, there were 240 invasive breast cancer specimens (CNB and SE) with both IHC and ISH recorded. Concordance between HER2 IHC and ISH was 100% (95% CI: 96.2-100%; κ=1.00 (P<0.001)). Of the IHC equivocal cases (n=146), 94.5% were ISH negative. There was perfect positive concordance and agreement between non-equivocal IHC and ISH results. This reinforces that IHC alone can be utilized reliably for testing HER2 status of non-equivocal cases consistent with the 2018 ASCO/CAP guidelines.

Mucinous Carcinoma of Breast: A Histopathological and Immunohistochemical Study

Introduction: Mucinous Carcinoma (MC) is a special type of breast cancer. It comprises 4% (1-7%) of all invasive breast cancer. MC is also called colloid breast cancer characterised by nests of cells floating in lakes of mucin. It is divided into two subtypes Pure Mucinous Carcinoma (PMC) and Mixed Mucinous Carcinoma (MMC). PMC classified into two main types according to its structural and cytological features type A (paucicellular) the classical variant with a large amount of extracellular mucin, and type B (hypercellular) a hypercellular variant with less mucin and often with neuroendocrine differentiation. Hormone receptors, Human Epidermal growth factor Receptor-2 (HER2) and MUC2 status play an important role in prognosis and management. Aim: To study histopathological features of MC breast and Immunohistochemical (IHC) status. Materials and Methods: A retrospective study of patients who presented with breast cancer were studied at Department of Pathology, Karnataka Institute of Medical Sciences, Hubballi, Karnataka, India. The study was analysed in June 2002 and authors included data from January 2021 to June 2022. The data included the age at diagnosis, Tumour (T), Lymph Nodes (N), and Metastases (M) (TNM) stage, presence and number of Lymph Node (LN) metastases, Oestrogen Receptor (ER), Progesterone Receptor (PR), HER2 and MUC2 status. The patients in whom the diagnosis of MC of breast was given on histopathology were only included in the study. Patients of breast cancer of other pathological types were excluded from the detailed study. Descriptive statistics like mean, tables, and charts were used with the help of Microsoft office 2007 to interpret the results. Results: A total of 245 patients reported as invasive breast cancer during 18 months of study period, out of which 12 cases diagnosed as MC were taken in study. Amongst 12 cases, eight cases were PMC and four cases were MMC. The mean age at presentation was 63.37±16.38 years (eight PMC) and 60.0±19.30 years (four MMC). A total of 11 out of 12 cases were females and only one was male case (PMC). Majority of PMC 04 (50.0%) and MMC 03 (75.0%) were observed to be in TNM Stage 2, and four of 12 cases of MC had LN metastasis with no distant metastasis. MC showed higher expression of hormone receptors and lower expression of HER2/neu and MUC2 positivity, which corroborates with other studies and concluded that, MC with such an immunohistochemistry profile was prognostically better. Conclusion: Mucinous Breast Carcinoma (MBC) is a rare type of breast cancer accounting for about 4% of all diagnosed breast cancers. These are associated with a better long-term prognosis than other breast cancers. Hormone receptors and HER2 status play an important role in prognosis and management. MUC2 also plays a major role in mediating the proliferation, apoptosis, metastases of breast cancer cells and determining the use of chemotherapy drugs.

HER2 amplification in colorectal cancer with brain metastasis: A propensity score matching study

BackgroundThe association between human epidermal growth factor receptor-2 (HER2) amplification and brain metastasis (BM) in patients having colorectal cancer (CRC) has been suggested but not yet established. This study investigated the expression patterns of HER2, its association with BM, and its prognostic value in patients having CRC. MethodsWe retrospectively identified 99 patients having metastatic CRC (mCRC) and BM (the BM cohort) and compared them with a cohort of 249 patients having mCRC and without BM (the stage IV cohort) by propensity score matching. Immunohistochemical studies of HER2 on all available paraffin-embedded tumour samples, either from the primary tumour, the metastasis (brain and/or extracranial sites) or both, were performed and analysed. HER2 fluorescent in situ hybridisation was applied when necessary. The expression of HER2 was compared and correlated with survival. ResultsHER2 amplifications were detected in 16 (18.4%) of 87 and 9 (3.6%) of 249 patients who had specimens available in the BM and stage IV cohorts, respectively (P < .001). After propensity score matching, HER2 amplification was significantly associated with BM (odds ratio: 5.38, P = .003). HER2 heterogeneity was frequently observed not only at the single tumour level but also in paired tumour samples. A marginally significant longer survival since BM was found in patients having HER2-amplified mCRC than in those without (P = .07). ConclusionsHER2 amplification was significantly associated with BM in patients having mCRC and might have prognostic value for survival since BM. Given the heterogeneity of HER2 expression, the testing of HER2 status on available tissues from both primary and metastatic tumours should be encouraged.

Clinical Characteristics and Survival Outcomes of Patients with De Novo Metastatic Breast Cancer.

Though less than 5% of patients with breast cancer present with De Novo Metastasis (dnMBC) in Western societies, this percentage may reach 30% in developing countries. In this study, we present survival outcomes of patients diagnosed with dnMBC treated at a tertiary center in a developing country. Using hospital-based database, consecutive patients with dnMBC diagnosed between 2013 and 2017 were identified. Demographic data, tumor characteristics, types of treatment, and survival data were retrospectively collected. A total of 435 patients were included; median age (range) at time of diagnosis was 51 (24-85) years. Most of the tumors expressed hormone receptors (81% Estrogen Receptor positive, 77% Progesterone Receptor positive). Human epidermal growth factor receptor-2 (HER2) overexpression was reported in 134 (30.9%) patients, while only 24 (5.5%) had Triple Negative (TN) disease. Bone, lung and liver were the most common sites of metastasis involved in 70.6%, 36.1%, and 32.0%, respectively. The median Overall Survival (OS) for all patients was 38 months, and 5-year OS was 32.6%. On univariate analysis, high tumor grade, advanced T-stage, TN-disease and metastasis to multiple sites, but not HER2 status, were associated with poor OS. On multivariate analysis, high tumor grade (Hazard Ratio =1.6, p=0.002), advanced T-stage (Hazard Ratio=1.6, p=0.003), and triple negative status (Hazard Ratio= 2.1, p=0.008) predicted poor OS. The overall survival of patients with dnMBC remains poor. Better understanding of the disease behavior and factors affecting survival is required for optimal utilization of available regimens and new drugs to hopefully improve patients' outcomes.

The Role of Serum CD26 in the Diagnosis of Gastric Cancer.

PurposeThe value of serum cluster of differentiation 26 (CD26) in gastric cancer remains unknown. We investigated serum CD26 as a non-invasive serological marker for the diagnosis of gastric cancer and its relationship with serum human epidermal growth factor receptor-2 (HER2) levels.Patients and MethodsWe enrolled 393 gastric cancer patients treated with endoscopic resection or surgery, and 90 healthy controls. HER2 positivity in tissue was evaluated by immunohistochemistry staining, and the serum CD26 and HER2 levels were measured using an enzyme-linked immunosorbent assay.ResultsSerum CD26 levels were significantly lower in gastric cancer patients than in healthy controls (582.2 ± 254.3 vs 862.7 ± 410.6 ng/mL, P<0.001). Serum CD26 levels were significantly lower in advanced gastric cancer compared to early gastric cancer (642.2 ± 333.9 vs 503.4 ± 332.7 ng/mL, P<0.001), and tended to decrease with gastric cancer progression. To diagnose gastric cancer, the optimal cut-off value of serum CD26 was 762.7 ng/mL with 75.6% sensitivity and 64.4% specificity. Serum CD26 levels were weakly correlated with serum HER2 levels (rs=0.363, P<0.001). However, no difference in serum CD26 levels was observed between tissue HER2-negative and HER2-positive gastric cancer groups (586.2 ± 362.1 vs 579.6 ± 264.8 ng/mL, P=0.898).ConclusionCD26 is a useful non-invasive serological marker for gastric cancer diagnosis; however, its levels do not correlate with HER2 status.

Treatment Strategies for Residual Disease following Neoadjuvant Chemotherapy in Patients with Early-Stage Breast Cancer.

Breast cancer continues to be the most diagnosed cancer among women worldwide. Neoadjuvant chemotherapy is the standard of care for breast cancer patients with locally advanced disease and patients with poor pathological features, such as triple-negative (TN) or human epidermal growth factor receptor-2 (HER2)-positive subtypes. Neoadjuvant therapy offers several advantages, including better surgical outcomes, early systemic treatment for micro-metastases, and accurate tumor biology and chemosensitivity assessment. Multiple studies have shown that achieving pathological complete response (pCR) following neoadjuvant chemotherapy is associated with better prognosis and better treatment outcomes; almost half of such patients may fail to achieve pCR. Tumor proliferative index, hormone receptor (HR) status, and HER2 expression are the major predictors of pCR. Strategies to improve pCR have been dependent on augmenting neoadjuvant chemotherapy with the addition of taxanes and dual anti-HER2 targeted therapy in patients with HER2-positive tumor, and more recently, immunotherapy for patients with TN disease. The clinical management of patients with residual disease following neoadjuvant chemotherapy varies and depends mostly on the level of HR expression and HER2 status. Recent data have suggested that switching trastuzumab to trastuzumab-emtansine (T-DM1) in patients with HER2-positive disease and the addition of capecitabine for patients with HER2-negative and HR-negative subtype is associated with a better outcome; both strategies are incorporated into current clinical practice guidelines. This paper reviews available and ongoing studies addressing strategies to better manage patients who continue to have residual disease following neoadjuvant chemotherapy.

Model-based inference of metastatic seeding rates in de novo metastatic breast cancer reveals the impact of secondary seeding and molecular subtype.

We present a stochastic network model of metastasis spread for de novo metastatic breast cancer, composed of tumor to metastasis (primary seeding) and metastasis to metastasis spread (secondary seeding), parameterized using the SEER (Surveillance, Epidemiology, and End Results) database. The model provides a quantification of tumor cell dissemination rates between the tumor and metastasis sites. These rates were used to estimate the probability of developing a metastasis for untreated patients. The model was validated using tenfold cross-validation. We also investigated the effect of HER2 (Human Epidermal Growth Factor Receptor 2) status, estrogen receptor (ER) status and progesterone receptor (PR) status on the probability of metastatic spread. We found that dissemination rate through secondary seeding is up to 300 times higher than through primary seeding. Hormone receptor positivity promotes seeding to the bone and reduces seeding to the lungs and primary seeding to the liver, while HER2 expression increases dissemination to the bone, lungs and primary seeding to the liver. Secondary seeding from the lungs to the liver seems to be hormone receptor-independent, while that from the lungs to the brain appears HER2-independent.

P-45 Microsatellite instability and HER2 status in radically resectable locally advanced esophago-gastric adenocarcinoma: A single-center experience

Peri-operative systemic chemotherapy significantly improved the prognosis of patients with resectable locally advanced gastric cancer (LAGC) but, despite that, relapse-related death remains a major challenge. Neoadjuvant chemotherapy (NAC) plays a crucial role and is currently recommend by international guidelines. Several biomarkers, including human epidermal growth factor receptor-2 (HER2) and mismatch repair (MMR) or microsatellite instability (MSI) are crucial for treatment decision in metastatic setting. However, currently, no biomarkers can guide the choice of NAC in clinical practice. In addition, most of available data derived from surgical specimens, harboring potential confusing factors after NAC. Our aim was to evaluate correlations between MSI and HER2 status and clinical outcomes in resectable LAGC treated with perioperative chemotherapy. We conducted a retrospective cohort study of resectable LAGC patients treated with NAC and surgery +/- adjuvant chemotherapy from 2006 to 2018, for whom endoscopic pre-NAC and surgical post-NAC samples were available. A uniform small cohort of patients receiving adjuvant chemotherapy only was added for general prognostic analyses. Clinical parameters were collected including patient and tumor characteristics. Determinations of HER2 and MMR status were carried out on endoscopic pre-NAC and surgical samples. Pathologic complete response (pCR) rate, Overall survival (OS) and event-free survival (EFS) were estimated and evaluated for association with histologic downstaging and MSI status using Cox proportional hazard models. Moreover, in dMMR cases, a custom in-house Next-Generation Sequencing (NGS) (Ion Torrent S5) panel was performed, assessing mutational status of 26 tumor-genes (EGFR, MET, ALK, RET, KRAS, NRAS, HRAS, BRAF, KIT, PDGFR α/β, GNAQ, GNA11, PIK3CA, AKT1, MAP2K1, MAP2K2, TP53, ERBB2, SMAD4, PTEN, STK11, CTNNB1, NOTCH1, POLE, ESR1). We selected 76 out 90 patients, with a median age at diagnosis of 61 years. Fifty-nine patients received NAC, while 17 were treated with adjuvant chemotherapy alone. Overall, dMMR/MSI-H counted for 8% of cases, entirely consistent between endoscopic and surgical samples. Six percent of tumors were HER2 positive on endoscopic tumor assessment and 4% on surgical samples. Tumor downstaging was observed in 52.5% of the population, with 3 pCR (5.1%), none of them in MSI-H cancers. According to MSI status and pCR, EFS and OS were better for MSI-H patients and MSS achieving pCR compared to MSS without pCR [EFS NR vs NR vs 30.0 months (95% CI 16.8 – NR.), P = .08; OS NR vs NR vs 39.6 (95% CI 27.6 – NR) P = .10]. Considering the entire population, EFS and OS were analyzed according to MSI status with a better outcome for MSI-H patients [EFS NR vs 48.0 months (95% CI 25.2 – 229.4), P = .121; OS NR vs 62.4 (95% CI 28.8 – 229.4) P < .143]. The most common alteration in MSI-H cases was TP53 mutation (4/6), other mutations detected were KRAS, SMAD4, ERBB2, BRAF, PIK3CA, RET and PTEN. Our work confirms the positive prognostic effect of MSI-H in the curative setting of LAGC, not correlated with the rate of pathologic tumor response to NAC. Prospective ad-hoc trial focused on dMMR/MSI-H and more accurate molecular profiling are strongly needed in resectable LAGC.