HER2-positive Status Research Articles

Elevated expression of FREM1 in breast cancer indicates favorable prognosis and high‐level immune infiltration status

Breast cancer (BC) poses one of the major threats to female's health worldwide. Immune infiltration in BC is a key representative of the tumor microenvironment and has been proven highly relevant for prognosis. The role of the FREM1 (FRAS1‐Related Extracellular Matrix 1) gene in carcinoma has not studied, moreover, the underlying mechanism remains largely unknown. This study aims to investigate the expression profile and potential action of FREM1 on BC progression. We applied series of bioinformatic methods as well as immunohistochemistry (IHC) and immunofluorescence (IF) to analyze FREM1 expression profile, its relationship with clinicopathological characteristics, impact on clinical outcomes, relevant functions, correlation with immune infiltration in BC. The results demonstrated that FREM1 had a dramatically reduced expression in BC tissues, possessed an inverse correlation with stage, age, and metastasis, and exhibited a higher level in invasive lobular breast carcinoma than in ductal one. Furthermore, decreased FREM1 expression was often associated with estrogen receptor (ER)/progesterone receptor (PR) negative and triple negative breast carcinoma (TNBC) status while human epidermal growth factor 2 (Her‐2) positive status, and considerably correlated with a worse overall survival (OS) and recurrence‐free survival (RFS). Meanwhile, the univariate/multivariate Cox model revealed that low‐FREM1 expression can be an independent prognostic factor for BC. Additionally, FREM1 was mainly involved in the cell metabolism and immune cells infiltration. Moreover, IHC and IF demonstrated a positive correlation of its expression with the immune infiltrating levels of CD4+, CD8+ T cells, and CD86+ M1 macrophages while a negative correlation with CD68+ pan‐macrophages and CD163+ M2 macrophages. These findings suggest that FREM1 can be a potential biomarker for evaluating the immune infiltrating status, and the BC prognosis.

Details of human epidermal growth factor receptor 2 status in 454 cases of biliary tract cancer

Human epidermal growth factor receptor 2 (HER2)-targeted therapy has improved clinical outcomes in patients with HER2-positive breast and gastric cancers, although ineffective or recurrent cases are present. One reason for this is the heterogeneity of HER2 expression in cancer cells. The aim of this study was to investigate the clinicopathological characteristics and HER2 status of patients with biliary tract cancers (BTCs). We examined HER2 protein expression by immunohistochemistry, HER2 gene amplification by fluorescence in situ hybridization, and both HER2 protein and gene levels simultaneously by gene-protein assay. Samples were collected from 454 patients who underwent surgical resection for BTCs (110 intrahepatic cholangiocarcinomas [ICC], 67 perihilar extrahepatic cholangiocarcinomas [ECC-Bp], 119 distal extrahepatic cholangiocarcinomas [ECC-Bd], 80 gallbladder carcinomas [GBC], and 79 ampullary carcinomas [AVC]). HER2 status was assessed according to the guidelines for HER2 testing in gastroesophageal adenocarcinoma. HER2-positive status was detected in 14.5% of BTCs (3.7% of ICC, 3.0% of ECC-Bp, 18.5% of ECC-Bd, 31.3% of GBC, and 16.4% of AVC). Furthermore, HER2-positivity tended to correlate with low histological grade, tumor histology, and macroscopic features in certain tumors. HER2 heterogeneity was common and highly frequent (83%) in BTC cases. Reduced HER2 protein expression in the deeper invasive areas with simultaneous dedifferentiation was frequently observed in HER2-positive cancer cells. The findings of this study suggest that a large subgroup of HER2-positive BTC cases can be considered for HER2-targeted therapy. Moreover, the HER2 status in BTCs should be determined carefully using a sensitive approach toward larger cancer tissues.

Evaluation of (PARP-1) Expression in Gastric Carcinoma by Immunohistochemistry and Quantitative Real-Time PCR and its Relation to HER2 Status

Abstract Background: PARP-1 overexpression has been identified in several malignancies. Few studies have handled the expres-sion of PARP-1 protein in gastric carcinoma and its associations with outcome. Aim of Study: This study aimed at exploring the signifi-cance of PARP-1 expression in gastric adenocarcinoma and correlation with HER2 status. Subjects and Methods: Quantitative expression of PARP-1 proteins was assayed by Immunohistochemistry in 40 cases of gastric adenocarcinoma. PARP-1 mRNA was moreover evaluated by Quantitative Real-Time Polymerase Chain Re-action. Results: The level of expression of mRNA expression level was significantly increased in 25 of 40 (62.5%) of gastric adenocarcinoma tissues compared with the corresponding adjacent non cancer tissues (p < 0.001). Positive expression of PARP-1 protein was detected in 23/40 (57.5%) of gastric adenocarcinoma. PARP-1 expression in cancer tissues was significantly higher than adjacent non-cancerous tissue (p < 0.001). The aberrant high expression of PARP-1 showed significant correlation with depth of invasion (p < 0.001), advanced stage (p < 0.001), nodal (p < 0.05) and distant metas-tasis (p < 0.001). Positive correlation was detected between PARP-1 and positive HER2 status (p < 0.001). Conclusion: PARP-1 level is up regulated significantly in gastric adenocarcinoma tissue. PARP-1 is positively corre-lated with positive HER2 status and poor prognostic factors. PARP-1 might be potential prognostic marker for gastric adenocarcinoma.

Lower response to trastuzumab emtansine in metastatic breast cancer patients with human epidermal growth factor receptor 2 immunohistochemistry score of 2 and fluorescence in situ hybridization positive compared with immunohistochemistry score of 3: a retrospective study.

Tumor human epidermal growth factor receptor 2 (HER2) status is defined by either protein expression using immunohistochemistry (IHC) or gene amplification using fluorescence in situ hybridization (FISH). Approximately 20% of HER2-positive breast cancer is HER2 IHC 2+/FISH-positive. Unlike trastuzumab, it has not been studied whether the response to trastuzumab emtansine (T-DM1) differs according to HER2-positive status. We retrospectively identified and reviewed medical records of all patients with HER2-positive advanced breast cancer (ABC) who received T-DM1 in our hospital from October 2013 to December 2016. We compared the objective response rate (ORR) and progression-free survival (PFS) between patients in the HER2 IHC 3+ group and those in the HER2 IHC 2+/FISH-positive group. A total of 39 patients (IHC 3+: n = 32; IHC 2+/FISH-positive: n = 7) were analyzed. Nineteen (48.7%), 13 (33.3%), and 29 (74.4%) patients had received at least one prior chemotherapy, more than three lines of chemotherapy, and prior pertuzumab for ABC, respectively. ORR was significantly higher in the IHC 3+ group than in the IHC 2+/FISH-positive group (53.3% vs. 0%, P = 0.024). Median PFS was 7.9 months in the IHC 3+ group versus 3.9 months in the IHC 2+/FISH-positive group (hazard ratio 0.68; 95% confidence interval 0.28-1.69, P = 0.408). Among the HER2-positive ABC patients treated with T-DM1, ORR was significantly worse in HER2 IHC 2+/FISH-positive than in HER2 IHC 3+ patients. Median PFS tended to be shorter in patients with HER2 IHC 2+/FISH-positive.

Abstract 5440: Understanding the biology of high-risk ductal carcinoma in situ (DCIS) through genomics and the tumor immune microenvironment: The DEFENSE study

Abstract Introduction: Ductal carcinoma in situ (DCIS) of the breast is a premalignant lesion representing a spectrum of biology and risk. While many patients with DCIS undergo surgical resection with no survival benefit given the indolent nature of their disease, others do possess biologically aggressive DCIS that has the potential to evolve into invasive cancer if left untreated. Yet even among those patients with biologically aggressive DCIS, their risk of dying from metastatic breast cancer is only 3.3% compared to 30-40% among patients with biologically aggressive invasive cancer.1 We are interested in identifying molecular and tumor immune microenvironment factors that allow DCIS to develop high-risk features without ever becoming invasive breast cancer. Methods: We are conducting a retrospective pilot study (DEFENSE) of 10 patients with invasive high-risk breast cancer enrolled on the I-SPY2 trial matched based upon age and tumor molecular profile to 10 patients with high-risk DCIS, defined as having at least two of the following characteristics: large (&amp;gt;5cm), high-grade, hormone receptor-negative status and/or HER2-positive status. Tumors obtained from each of these patients will be divided into 22 sequential sections with regions of pathologic interest identified prior to undergoing whole exome DNA sequencing, SMART-3SEQ RNA sequencing, multiplex immunohistochemistry (mIHC) using three immune panels, and stromal profiling. Each profiling modality will be performed by a different institution included in the NIH Molecular Characterization of Screen-Detected Lesions (MCL) consortium. This pilot study will inform our decision to expand our study to a full-scale review of 200 patients (100 DCIS, 100 invasive cancer) among our institutions. Results: We have thus far demonstrated the feasibility of our pilot study with 10 blocks in total sent to and received by each institution. Whole exome DNA sequencing, SMART-3SEQ, mIHC, and stromal profiling work has begun and will be available for presentation, and we plan to make pathology, clinical and genomic data available through the MCL's collaborative partnership with the NASA Jet Propulsion Lab (JPL) cloud-based platform. Conclusions: We have successfully shown that a multi-institution collaborative can effectively share pathologic data and conduct data analyses using a variety of tumor profiling modalities. We anticipate that our data will allow us to differentiate the underlying biology of high-risk DCIS from invasive breast cancer, identifying mechanistic opportunities for future intervention.

Oncologic Outcomes of Sentinel Lymph Node Surgery After Neoadjuvant Chemotherapy for Node-Positive Breast Cancer

Sentinel lymph node (SLN) surgery after neoadjuvant chemotherapy (NAC) has been well studied. However, outcomes data addressing the oncologic safety of this technique are sparse. This study aimed to evaluate use of SLN surgery versus axillary lymph node dissection (ALND) for clinically node-positive patients treated with NAC and to report outcomes. The study identified patients at the authors' institution with biopsy proven clinically node-positive (cN1-cN3) breast cancer undergoing axillary surgery after NAC from 2009 to 2019. Practice patterns and outcomes were evaluated. Of 602 patients, 52.3% underwent SLN surgery. Use of SLN surgery increased significantly over time, reaching 75.3% during 2015-2019. For 52.5% of the patients who had an SLN identified, ALND was not used. Use of ALND (± SLN surgery) decreased from 100% in 2009 to 57.2% in 2015-2019. The nodal positivityrate of patients who proceeded directly to ALND was 64.5% (185/287), increasing significantly over time. Factorssignificantly associated with performing SLN surgery on multivariable analysiswere lower presentingclinical T category, lower presenting clinical N category(cN1 vs cN2-3) and HER2-positive status. During the median 34-month follow-up period, 17 regional recurrences were observed (16/443 with ALND; 1/159 with SLN surgery alone), for a 2-year freedom-from-regional-recurrence rate of 99.1% among the SLN surgery patients and 96.4% among the ALND patients (p = 0.10). For cN1-3 breast cancer treated with NAC, SLN surgery has been incorporated into clinical practice at the authors' institution. In this study, selection for SLN surgery was based on clinical factors and tumor biology. More than half of the patients who were selected for SLN surgerywere spared ALND, with a low nodal failure rate and no recurrence-free survival disadvantage at 2years.

Radiomics Signatures Based on Multiparametric MRI for the Preoperative Prediction of the HER2 Status of Patients with Breast Cancer

The aim of our study was to preoperatively predict the human epidermal growth factor receptor 2 (HER2) status of patients with breast cancer using radiomics signatures based on single-parametric and multiparametric magnetic resonance imaging (MRI). Three hundred six patients with invasive ductal carcinoma of no special type (IDC-NST) were retrospectively enrolled. Quantitative imaging features were extracted from fat-suppressed T2-weighted and dynamic contrast-enhanced T1 weighted (DCE-T1) preoperative MRI. Then, three radiomics signatures based on fat-suppressed T2-weighted images, DCE-T1 images and their combination were developed using a support vector machine (SVM) to predict the HER2-positive vs HER2-negative status of patients with breast cancer. The area under the curve (AUC), accuracy, sensitivity, and specificity were calculated to assess the predictive performances of the signatures. Twenty-eight quantitative radiomics features, namely, 14 texture features, 4 first-order features, 9 wavelet features, and 1 shape feature, were used to construct radiomics signatures. The performance of the radiomics signatures for distinguishing HER2-positive from HER2-negative breast cancer based on fat-suppressed T2-weighted images, DCE-T1 images, and their combination had an AUC of 0.74 (95% confidence interval [CI], 0.700 to 0.770), 0.71 (0.673 to 0.738), and 0.86 (0.832 to 0.882) in the primary cohort and 0.70 (0.666 to 0.744), 0.68 (0.650 to 0.726), and 0.81 (0.776 to 0.837) in the validation cohort, respectively. Radiomics signatures based on multiparametric MRI represent a potential and efficient alternative tool to evaluate the HER2 status in patients with breast cancer.

The financial impact of a breast cancer detected within and outside of screening: lessons from the Australian Lifepool cohort

ObjectiveTo determine the government and out‐of‐pocket community costs (out‐of‐hospital medical services and prescription medicines) associated with screen‐detected and community‐detected cancers (i.e. cancers detected outside of Australia's organised screening program [BreastScreen]). MethodsWe analyse administrative data on government‐subsidised medical services and prescription medicines for 568 Victorian women diagnosed with breast cancer or ductal carcinoma in situ (DCIS). Using multivariable regression analysis, we estimate the government and out‐of‐pocket community costs incurred in the three years after diagnosis for screen‐detected cancers and community‐detected cancers. Additionally, we estimate the government costs associated with diagnosis within and outside of BreastScreen. ResultsAverage government costs for breast cancer diagnosis were similar within and outside of BreastScreen [$808 (lower limit 676; upper limit 940) vs $837 (95%CI 671; 1,003) respectively]; however, women with community‐detected cancers incurred an additional $254 (95%CI 175; 332) out‐of‐pocket. Controlling for differences in known cancer characteristics, compared to screen‐detected cancers, community‐detected breast cancers were associated with an additional $2,622 (95%CI 644; 4,776) in government expenditure in the three years following diagnosis. Adverse cancer characteristics that were more prevalent in community‐detected cancers (high grade, lymph node involvement, HER2 positive receptor status) were associated with increased government and out‐of‐pocket costs. ConclusionsCommunity‐detected breast cancers were associated with increased government and out‐of‐pocket costs. Implications for public healthThese costs should be considered when evaluating current and alternative breast cancer screening strategies.

Factors associated with low chemotherapy dosing in high risk breast cancer.

e15520 Background: Chemotherapy dose is often reduced or delayed due to adverse effects. However, a low relative dose intensity (RDI) is associated with reduced disease control and survival. There is little data among patients receiving modern breast cancer regimens regarding the risk of low RDI, or factors associated with it. Methods: We used an institutional registry at a large multidisciplinary cancer center to identify subjects with incident invasive, non-metastatic breast cancer diagnosed between 2009-2018. We focused on a subset of high-risk patients for whom chemotherapy is clearly recommended by guidelines: triple negative (estrogen receptor, progesterone receptor and HER2 negative) or HER2-positive subtypes, and either positive lymph node metastases or tumor size &gt; 1.0 cm. We obtained administration dates and doses for the following agents: doxorubicin, cyclophosphamide, paclitaxel, docetaxel, and carboplatin. Our primary outcome was RDI &lt; 85% of guideline-recommended doses of at least one of these agents. Other outcomes included dose of each agent (first cycle dose &lt; 85% or total dose &lt; 85) and timing (delay ≥7 days or early discontinuation). Variables used for analyses included BMI ≥25, race, HER2 status, age ≥55 years, marital status, stage, and Charlson co-morbidity score. Results: More than half of our cohort of high risk breast cancer patients experienced a low RDI of at least one chemotherapy agent. Out of the 237 patients who met our inclusion criteria, 60% had a low RDI, 10% received a low first cycle dose, 38% received a low total dose, and 46% experienced either a dose delay or discontinued treatment. Using logistic regression analyses, we found that being overweight (CI: 1.01-3.54; p = 0.046) and stage 3 breast cancer (CI:1.05-5.96; p = 0.038) were associated with increased odds of having a low RDI. Low total dose was associated with being overweight (p = 0.0181), unmarried (p = 0.0278), and stage 3 (p = 0.0201). HER2-positive status was also associated with a low first cycle dose (p = 0.001) and dose delays or discontinuation (p = 0.0002). Conclusions: Having a BMI ≥25, higher-stage, or being unmarried, which may serve as a proxy for low social support, are factors that may help identify patients who will have guideline-recommended chemotherapy doses reduced.

Next-generation sequencing (NGS) identifies a new breast cancer subtype with HER2 low-amplification status as a candidate for targeted therapy.

553 Background: HER2 expression or amplification qualify patients to receive targeted therapeutics against HER2; however, traditional methods of quantifying HER2 amplification using fluorescence in situ hybridization (FISH) do not include a reliable definition for low level amplification. With the promising response rate of patients with low HER2 amplified-metastatic breast cancer to subsequent-line trastuzumab deruxtecan (DS-8201a) therapy, there is a need to improve the existing criteria to accurately identify patients with low HER2. In our study, we investigate whether HER2 amplification quantified by NGS could provide a method to stratify patients into subgroups. Methods: A total of 774 patients diagnosed with breast cancer from Guangdong Provincial People's Hospital (GDPH) who underwent targeted NGS using 520 or 33 cancer-related genes and had their HER2 status evaluated with either FISH or IHC were included in this study. HER2 status were defined as per 2018 ASCO/ACP guidelines. Results: Our results demonstrate that NGS could quantify HER2 amplification with high sensitivity and specificity, with area under the curve of 0.990 [95%CI: 0.982-0.999]. The receiver operating curve indicated an optimal cut-off of 2.62 copy number (CN) for identifying IHC/FISH HER2-negative status with 97.8% specificity. Meanwhile, the cut-off of ≥ 3.62 CN identified patients with IHC/FISH HER2-positive status with 99.8% specificity. Among the 774 patients, 65.8% (n = 509) had HER2 CN of ≤ 2.62 and were classified as HER2 non-amplified, while 25.8% (n = 199) had HER2 CN of ≥ 3.62, classified as HER2-amplified. The remaining 66 patients (8.5%) had HER2 CN between 2.62 and 3.62, and were the patients with heterogeneous IHC/FISH results, classified using NGS as HER2 low-amplified. Patients with low-amplified (49.0% vs. 38.8%, P &lt; 0.001) and amplified (50.3% vs. 38.8%, P &lt; 0.001) HER2 had significantly more number of copy number amplifications in other gene, including CDK12, RARA, and SPOP (P &lt; 0.001, P &lt; 0.001) than patients with HER2 non-amplified, indicating distinct mutation profile. Conclusions: Our results demonstrate that NGS could provide a more accurate stratification of patients based on their HER2 amplification levels. Patients with low levels of HER2 amplification has a distinct mutation profile, suggesting that NGS could serve as a robust tool to identify patients with HER2 amplification, whether high or low, who could benefit treatment with targeted agents designed against heterogeneous HER2 expression.

Changing HER2-status of the primary gastric tumor after neoadjuvant trastuzumab-based therapy.

e16529 Background: Aproximetly 16 % of patients with metastatic gastric cancer (GC) have HER2+ tumors. With localized stages, the detection rate of HER2+ is known to be lower. Addition of trastuzumab (T) to chemotherapy (CT) improved survival in metastatic, HER2+ GC. Unlike the metastatic disease, Her-2 did not represent an independent prognostic biomarker for early stages during exploratory analysis of MAGIC trial. The aim of the study was to compare human epidermal growth factor receptor 2 (HER2) expression before and after trastuzumab-based chemotherapy in patients with locally advanced HER2-positive gastric cancer, to evaluate the contribution of trastuzumab to the effectiveness of neoadjuvant treatment in this rare patient population. Methods: We assessed HER2 expression using immunohistochemistry in pre-treatment biopsied specimens and post-treatment resected specimens obtained from 10 patients with locally advanced HER2-positive (3+) gastric cancer receiving trastuzumab-based neoadjuvant chemotherapy: 8 men (80%) and 2 women (20%), from 30 to 80 years old, the median age was 63,5 years. Included 7 patients with resectable adenocarcinoma of the stomach and 3 patients with adenocarcinoma of the esophageal-gastric junction. All patients received neoadjuvant therapy with trastuzumab (100%) + chemotherapy: FLOT (2 patients), FOLFOX (7 patients), XELOX (1 patient). All patients underwent R0 gastrectomy. Tumor regression grading (TRG) after treatment were determined according to Mandard system. Results: Two patients showed a complete pathomorphological response of the tumor (20%,TRG1), therefore, the determination of postoperative HER2 status was not possible. Two patients (20%) maintained the HER2-positive status and six patients (60%) had a change in HER2 expression from positive to negative. Three patients had a (y)pT3 and 5 had a (y)pN+ tumor. Basing on histological changes the tumor regression TRG3 ( &lt; 10% residual tumor cells) was observed in 5 patients (50%). TRG 4-5(preponderance of tumor cells/tumors without changes of regression) observed in 3 patients (30%). The follow-up period is too short for disease-free survival or overall survival to be assessed. Conclusions: HER2 expression can change after trastuzumab-based chemotherapy in patients with locally advanced HER2-positive gastric cancer. Continuous monitoring of HER2 expression after neoadjuvant treatments may be utilized to determine whether the continued use of trastuzumab is advisable.

High incidence invasive breast cancer is associated with Her2/neu(+)/ER(+)/PR(+) and high grade ductal carcinoma in young age patients of Northeast India

BackgroundBreast cancer prognosis depends on age, histologic type, grade and lymph node metastasis. Treatment protocol is surgery, chemotherapy and radiotherapy followed by adjuvant therapy. Adjuvant therapy is determined by expression of Estrogen Receptor (ER), Progesterone Receptor (PR) and Human Epidermal Receptor (Her2/neu) on the cancer cells. The study aims to evaluate the ER, PR and Her-2/neu expression in invasive breast carcinomas by Immunohistochemistry (IHC) and to compare the pattern of expression with clinicopathological parameters like patient's age, histological type, grade and lymph node metastasis. MethodsThis is a retrospective study of newly diagnosed 182 female who have undergone modified radical mastectomy with axillary clearance for invasive breast cancer. Typing and grading of tumour was done on haematoxylin and eosin stained sections. IHC was done to evaluate expression of ER, PR and Her2/neu. Statistical analysis was done by chi-square and Z-test. ResultsThe age of patients ranged from 23 to 85 years. The most common type of tumour is Infiltrating ductal carcinoma grade 2 (50.8%), followed by grade 1 (39%). ER, PR and Her2/neu expression was found in 52%, 46% and 43% cases, respectively. Hormonal receptor positivity and Her2/neu overexpression was observed more in younger age group. Lymph node metastasis is more common in younger age group and higher grade tumour. ConclusionIn this study, young age group women are more prone to Breast Cancer and the IDC is significant. The hormonal receptors as well as Her2 positive status reveals that a well-designed therapeutic strategy will confer recovery of the patients.

Factors Affecting Pathological Complete Response After Neoadjuvant Chemotherapy in Operable Primary Breast Cancer.

To investigate factors influencing pathological response to neoadjuvant chemotherapy (NAC) in operable primary breast cancer. Descriptive study. Breast Center, Shunyi District Health Care Hospital for Women and Children of Beijing, Beijing 101300, P.R. China, from January 2009 to December 2017. Two hundred and sixty-one operable primary invasive breast cancer patients treated with NAC were included in this observational study. Pathological complete response (pCR) was defined as no residual invasive disease in either the breast or the axillary lymph nodes, with non-invasive breast residuals permitted (ypT0/is ypN0). Factors affecting pCR were subjected to univariate and multivariate analysis. Seventy-six patients (29.1%) achieved pCR after NAC. Tumor size, histological grade, status of estrogen receptor (ER) and progesterone receptor (PgR), expression of human epidermal growth factor receptor 2 (HER2) and Ki67, axillary lymph node status, and chemotherapy regimen were all significantly associated with pCR in univariate analysis (all p<0.05). In multivariate analysis, high histological grade, negative HR status and lymph nodes, positive HER2 status, and taxane-based regimens were independent predictive factors of pCR. Patients with HER2-positive tumors were more sensitive to NAC regimen including trastuzumab. In this study, breast cancer patients with high histological grade, negative HR status and lymph nodes, positive HER2 status, as well as taxane-based regimens were significantly associated with achieving pCR with NAC. Key Words: Breast neoplasms, Neoadjuvant therapy, Surgery, Pathology.

Abstract P6-08-21: Prevalence of HER2 positivity in germline BRCA 1/2-associated breast cancers (gBRCA1/2-BC)

Abstract Purpose: To define the prevalence of HER2 positive breast cancer (HER2+ BC) in women with gBRCA1/2-BC and to determine whether there are significant differences in the prevalence of HER2 positivity in BRCA1 mutation carriers compared to BRCA2 mutation carriers. Background: It is estimated that 5-10% of patients with breast cancer have a BRCA1 or BRCA2 mutation. Two poly ADP ribose polymerase inhibitors (PARPi) have been approved for metastatic HER2-negative gBRCA1/2-BC, as trials excluded those with HER2+ BC and gBRCA1/2 mutations. Most often, breast tumors in BRCA1 carriers lack the estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 receptor or gene amplification (HER2). BRCA2 tumors have similar rates of ER positivity as sporadic controls, but are less likely to be HER2+. The prevalence of HER2 positivity among BRCA1 and BRCA2 mutation carriers has been variably reported in the literature. The prevalence of HER2 positivity has generally been reported as lower among BRCA1 carriers than BRCA2 carriers. The prevalence of HER2 positivity in BRCA1 carriers and BRCA2 carriers has ranged from 0-10% and 0-13% respectively. The true prevalence of HER2+ breast cancer in gBRCA1/2-BC remains poorly defined. Methods: In this study, we assessed the prevalence of HER2 positivity among a cohort of 137 BRCA1 and BRCA2 mutation carriers who consented for participation in a single institution risk assessment program registry between 2009 and 2019. To be eligible for this study, participants had to have a documented diagnosis of invasive breast cancer and be a confirmed BRCA1 or BRCA2 mutation carrier. Participants with all stages of invasive breast cancer were included. Fisher’s exact tests and univariate logistic regression were used to analyze differences between BRCA1 and BRCA2 mutation carriers. Results: 69 BRCA1 mutation carriers and 68 BRCA2 carriers were included in the study. Only 38 BRCA1 mutation carriers and 41 BRCA2 mutation carriers had complete HER2 data and were included in this analysis for prevalence. 12.6 % (10/79) of the study participants had HER2+ invasive breast cancer; 3 of these participants were BRCA1 carriers and 7 were BRCA2 carriers. The prevalence of HER2 positivity in BRCA1 carriers was 7.9%. The prevalence of HER2 positivity among BRCA2 carriers was 17.0% (7/41). In this small sample, the prevalence of HER2 positivity in BRCA 2 mutation carriers was numerically higher than that in BRCA1 mutation carriers, although this difference was not statistically significant (p= 0.3145). Conclusion: In this analysis, the rates of HER2 positivity among BRCA1 mutation carriers are consistent with the range of rates previously reported (0-10%). However, the rates of HER2 positivity in BRCA2 mutation carriers (17.0%) are higher than those previously reported (0-13%). This study included participants who received breast cancer treatment at our institution where their HER2 status was verified with a pathology report, but also participants who received their breast cancer treatment at outside institutions. In the latter, HER2 status most often was obtained by verbal self-reporting. It is possible that this led to over-reporting of positive HER2 status in either BRCA1 or BRCA2 mutation carriers. Thus, estimates of HER2 positivity might be slightly overestimated. Despite some variation in HER2 positivity rates among BRCA1 and BRCA2 mutation carriers, this study demonstrates that HER2 positive breast cancers may not be as rare in gBRCA1/2-BC as previously reported in initial studies (0-3% in either BRCA1 or BRCA2 carriers). Given that BRCA1/2 mutation carriers could potentially derive therapeutic benefit from drugs, such as PARPi, it is important that future studies include gBRCA1/2-BC with HER2 positive breast cancer. Citation Format: Kristen Whitaker, Elias Obeid, Lori Goldstein, Mary Daly. Prevalence of HER2 positivity in germline BRCA 1/2-associated breast cancers (gBRCA1/2-BC) [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-21.

The prognostic value of HER2 status and efficacy of anti-HER2 therapy in patients with HR-positive mucinous breast cancer: a nationwide study from the Korean Breast Cancer Society.

The effect of human epidermal growth factor receptor 2 (HER2) status on mucinous carcinoma (MC) of the breast is unknown due to the rarity of HER2-positive cases. We evaluated the prognostic value of HER2 status and the efficacy of anti-HER2 therapy in patients with hormone receptor (HR)-positive MC. From the data of 154,661 patients recorded in the Korean Breast Cancer Registry between January 1990 and August 2016, 3076 (2.0%) were diagnosed with MC. Overall survival (OS) according to HER2 status and anti-HER2 therapy was analyzed using Kaplan-Meier estimates. Multivariate analysis was performed using the Cox proportional hazards model to estimate the adjusted hazards ratio (HR) for clinicopathologic factors. A total of 2716 HR-positive MC patients were enrolled and followed up for a median 100.1months. Of these, 2094 (77.1%) were HER2-negative and 228 (8.4%) were HER2-positive. HR-positive, HER2-positive MC patients had more advanced pathologic tumor stages (T3 or T4) (p = 0.001), more axillary lymph node involvement (p < 0.001), higher nuclear grade (p < 0.001), and more lymphovascular invasion (p = 0.012) than HER2-negative patients. Subgroup analysis of HR-positive, node-positive MC showed that HER2-positive MC was an independent prognostic factor for OS (HR = 2.657; 95% CI, 1.665-4.241; p < 0.001). HR-positive, node-positive, and HER2-negative MC had significantly longer OS than HER2-positive MBC (p = 0.017). The node-positive subgroup that received anti-HER2 therapy had increased OS, although not significantly (p = 0.224). Our nationwide database study revealed that HER2-positive status was associated with worse prognosis in HR-positive and node-positive MC. Anti-HER2 therapy might be beneficial in HR-positive, node-positive, and HER2-positive MC.

Invasive carcinoma of no special type with focal sebaceous differentiation in breast

Sebaceous carcinoma which is defined as breast carcinoma with prominent sebaceous differentiation in no less than 50% of cells is very rare.1 Breast carcinoma with sebaceous differentiation is also very rare with only 9 cases reported in the literature to our knowledge.2,3 Sebaceous differentiation has been reported in association with invasive ductal carcinoma, adenoid cystic carcinoma and metaplastic carcinoma.2 Hormone receptors and lymph node status vary between cases but none of the cases reported positive HER2 status. Here, we report a case of invasive carcinoma of no special type with focal sebaceous differentiation which is ER positive, PR positive, HER2 negative with two involved sentinel lymph nodes.

Increased assessment of HER2 in metastatic gastroesophageal cancer patients: a nationwide population-based cohort study

BackgroundAddition of trastuzumab to first-line palliative chemotherapy in gastroesophageal cancer patients with HER2 overexpression has shown to improve survival. Real-world data on HER2 assessment and administration of trastuzumab are lacking. The aim of this study was to assess HER2 testing, trastuzumab administration, and overall survival (OS) in a nationwide cohort of metastatic gastroesophageal cancer patients.MethodsData of patients with synchronous metastatic gastroesophageal adenocarcinoma diagnosed in 2010–2016 that received palliative systemic treatment (n = 2846) were collected from the Netherlands Cancer Registry and Dutch Pathology Registry. The ToGA trial criteria were used to determine HER2 overexpression. Proportions of HER2 tested patients were analyzed between hospital volume categories using Chi-square tests, and over time using trend analysis. OS was tested using the Kaplan Meier method with log rank test.ResultsHER2 assessment increased annually, from 18% in 2010 to 88% in 2016 (P < 0.01). Median OS increased from 6.9 (2010–2013) to 7.9 months (2014–2016; P < 0.05). Between the hospitals, the proportion of tested patients varied between 29–100%, and was higher in high-volume hospitals (P < 0.01). Overall, 77% of the HER2 positive patients received trastuzumab. Median OS was higher in patients with positive (8.8 months) and negative (7.4 months) HER2 status, compared to non-tested patients (5.6 months; P < 0.05).ConclusionIncreased determination of HER2 and administration of trastuzumab have changed daily practice management of metastatic gastroesophageal cancer patients receiving palliative systemic therapy, and possibly contributed to their improved survival. Further increase in awareness of HER2 testing and trastuzumab administration may improve quality of care and patient outcomes.

Clinical and molecular factors for selection of nivolumab or irinotecan as third-line treatment for advanced gastric cancer.

Background:The use of nivolumab or irinotecan as the third-line treatment for patients with advanced gastric cancer (AGC) remains controversial.Methods:This study analyzed patients with AGC treated with nivolumab or irinotecan (nivolumab group or irinotecan group, respectively) from May 2016 to April 2019 following two or more previous lines of chemotherapy. Univariate survival analysis was conducted to identify the clinical and molecular factors associated with progression-free survival (PFS).Results:A total of 156 patients (74 treated with nivolumab and 82 treated with irinotecan) were analyzed. The median PFS was 1.9 months in both treatment groups. The median overall survival (OS) was 7.2 and 6.2 months in the nivolumab and irinotecan groups, respectively. Eastern Cooperative Oncology Group performance status of 1 or more, liver metastasis, a large tumor size at baseline, and HER2-positive status were associated with a worse PFS in the nivolumab group compared with the irinotecan group. The nivolumab group showed a significantly longer PFS (median 3.1 versus 2.0 months) and OS (median 12.9 versus 7.8 months) than the irinotecan group in patients with 0 or 1 of these factors, whereas the irinotecan group showed a significantly longer PFS (median 1.0 versus 1.8 months) and a trend of longer OS (median 3.9 versus 6.1 months) in patients with ⩾2 of these factors.Conclusions:Some clinical and molecular factors were associated with outcomes following nivolumab or irinotecan as the third- or later-line treatment in patients with AGC. These factors must be considered while selecting an optimal treatment option.

Comparison of HER2 Status Before and After Trastuzumab-based Chemotherapy in Patients With Advanced Gastric Cancer.

The aim of the present study was to compare human epidermal growth factor receptor 2 (HER2) expression before and after trastuzumab-based chemotherapy in patients with advanced HER2-positive gastric cancer. We assessed HER2 expression using immunohistochemistry and/or fluorescence in situ hybridization in pre-treatment biopsied specimens and post-treatment resected specimens obtained from seven patients with advanced HER2-positive gastric cancer receiving trastuzumab-based chemotherapy. Four patients maintained the HER2-positive status and three patients had a change in HER2 expression from positive to negative. In patients showing the loss of HER2 expression after treatments, HER2-positive tumor cells with a dominant histological type disappeared, and HER2-negative tumor cells with another dominant histological type were identified. HER2 expression can change after trastuzumab-based chemotherapy in patients with advanced HER2-positive gastric cancer. Continuous monitoring of HER2 expression after treatments may be utilized to determine whether the continued use of trastuzumab is advisable.

MARCKS protein overexpression is associated with poor prognosis in male breast cancer.

Male breast cancer (MBC) is a rare and aggressive disease. Thus, identification of new therapeutic targets is crucial. Our objective was to evaluate the protein expression of MARCKS (Myristoylated Alanine-Rich C-Kinase Substrate) in MBC and to investigate its prognostic value. MARCKS protein expression in tumor and stromal cells was analyzed by immunohistochemistry (IHC) in a retrospective series of 96 pre-chemotherapy MBC samples and 80 normal breast samples, from Tunisian patients treated at Salah Azaiez Institute. Correlations were searched between MARCKS expression and clinicopathological features including overall survival (OS). MARCKS was overexpressed in epithelial tumor cells in 66% of the MBC samples versus 26% of normal samples (p= 1.40 × 10-7). Such positive MARCKS expression in epithelial tumor cells was associated with positive HER2 status (p= 4.0 × 10-3). It was associated with shorter OS in uni-and multivariate analysis. By contrast, stromal IHC MARCKS expression was correlated only with tumor grade. MARCKS tumor cell overexpression might in part explain the aggressiveness and the poor prognosis of MBC. MARCKS can represent a potential therapeutic target for MBC.