HER2-positive Cases Research Articles

C-MET positivity and its relationship with histopathological findings in gastric carcinomas exhibiting HER2 gene expression.

Co-expressions of receptor tyrosine kinases such as c-MET and HER2 were reported in many studies. The concomitant expression is associated with more aggressive clinical course. In this study, it was intended to investigate the correlation of the positivity of c-MET and HER2 with histopathologic findings and their impacts on prognosis. After the decision of the ethics committee, a total of 64 cases, whose HER 2 status was studied by dual silver in situ hybridization/immunohistochemistry method, were included in the study. Immunohistochemical staining for c-MET was performed to all cases and the evaluation was performed similarly to the criteria for HER2 evaluation, but cytoplasmic staining was also considered significant. The data were analyzed using SPSS 20 for Windows. c-MET positivity which is considered by the score of 2+ and 3+ was found only in 34.4% of HER2 positive cases while it was 59.3% in HER2 negative cases (P = 0.045). The sole histopathological feature associated with c-MET positivity was distal gastric localization (P = 0.016). Even though higher rates of c-MET positivity in HER2 positive cases were stated in the literature, contrary results were obtained in this study. Comparing the HER2+/c-MET + co-expression group with the other groups, no difference was found about age, sex, macroscopic and microscopic characteristics. The presence of c-MET positivity in cases with HER2 expression suggests that c-MET expression might be associated with the resistance to Trastuzumab.

Tumor immune microenvironment is influenced by frameshift mutations and tumor mutational burden in gastric cancer.

Immunoscore can effectively predict prognosis in patients with colon cancer; however, its clinical application is limited. We modified the Immunoscore and created a tumor immune microenvironment (TIM) classification system for gastric carcinoma. Unlike previous studies that used small sample sizes or focused on particular immune-cell subtypes, our simplified system enables pathologists to classify gastric carcinomas intuitively using H&E-stained sections. Samples from 326 patients with advanced gastric carcinoma were reviewed and analyzed by pathologists using simple determination and digital image analysis. Comprehensive results of cancer-panel sequencing, Epstein-Barr‒virus (EBV) status, and PD-L1, HER2, ATM, PTEN, MET, FGFR2, and EGFR immunohistochemistry were evaluated with respect to the TIM class. The TIM was classified as "hot" (n = 22), "immunosuppressed" (n = 178), "excluded" (n = 83), or "cold" (n = 43). TIM category was significantly associated with numbers of frameshift mutations (P < 0.001) and high tumor mutational burden (P < 0.004), and predicted overall survival. It was also significantly associated with age, histological type, degree of fibrosis, PD-L1 expression, loss of ATM and PTEN expression (P < 0.001), sex, EBV positivity, and HER2 overexpression (P < 0.04). "Hot" tumors were frequent in PD-L1 expressing and EBV-positive samples, and in those with ATM and PTEN loss. "Excluded" tumors were frequent in HER2-positive cases, whereas "cold" tumors were more frequent in younger patients with poorly cohesive histology and high fibrosis levels. TIM classification system for gastric carcinoma has prognostic significance and results in classes that are associated with molecular characteristics.

Molecular Subtyping of Invasive Breast Carcinoma by Immunohistochemistry and Five-Year Survival Study

Background: Global gene expression profiling for Invasive breast carcinoma (IBC) has identified intrinsic subtypes of IBC with differing clinical outcomes and response to therapy. As genotyping assays are limited by availability and cost, we have used Immunohistochemistry (IHC) surrogates to classify IBC into molecular subtypes.&#x0D; Methods: Representative tumor blocks of 158 surgical specimens of IBC between 2007 to 2017, were selected and IHC done for ER, PR, Her2, Ki67, CK 5/6 and EGFR. The cases were classified into 7 Molecular subtypes (Luminal A, Luminal B, Luminal HER2PR+, Luminal HER2PR-, HER2Enriched, Basal like (BLBC) and non classifiable (NCBC) and correlated with clinico-pathological findings. Five- year survival rate was calculated for patients diagnosed between 2007 to 2013.&#x0D; Result: The most common subtype was Luminal A (31.0%), followed by Luminal B (25.3%), NCBC (14.6%) and HER2 enriched (13.3%). Among post-menopausal women, common subtypes were Luminal A (33.8%) and Luminal B (24.4%). Among premenopausal women, most cases were NCBC (27.8%) and BLBC (22.2%). 61.2% of Luminal A were Grade2 and 22.4% were Grade 1. Many cases of Luminal B and HER2 positive cases were of Grade3 (45.0%) and (57.1%) respectively. Of the triple-negative category (BLBC &amp; NCBC), 73% were Grade3 with statistically significant correlation (p value &lt; 0.001). Most of these cases were in Tumor stage T2 (70%), followed by T1 (22.3%). Nodal metastasis was seen in 39.6% and 65% respectively of Luminal A and Luminal B subtypes. Distant metastases on follow-up were present in 15.8%, which included HER2 enriched subtype (28.5%), followed by BLBC (20.0%) and NCBC (17.4%). Luminal A cases, had better survival accounting for 88% of all survivors.&#x0D; Conclusion: Molecular subtyping of IBC using IHC was useful to understand the clinicopathological distinctiveness of each subtype.

Impact and clinical value of the revised 2019 Chinese HER-2 testing guidelines on the detect result evaluation of invasive breast cancer cases with equivocal HER-2 immunostaining by using fluorescence in situ hybridization

Objective: To investigate the impact and clinical significance of the revised 2019 Chinese HER-2 testing guidelines on the detecting result evaluation of invasive breast cancers with equivocal HER-2 immunostaining by using fluorescence in situ hybridization (FISH). Methods: A total of 569 cases of invasive breast cancers with HER-2 (+ + ) immunostaining evaluated according to the immunohistochemistry (IHC) guidelines of 2014 edition and 2019 edition from May to November 2019 were collected and further detected by FISH. The results of HER-2/CEPl7 double probe were respectively interpreted according to both the 2014 and 2019 Chinese HER-2 testing guidelines and the results were compared. Results: According to the 2014 guidelines, the number of HER-2 positive, equivocal and negative cases were 139 (24.43%), 67 (11.78%), and 363 (63.80%), respectively. Whereas according to the 2019 guidelines, 115 cases (20.21%) were the first group, 9 cases (1.58%) were the second group, 15 cases (2.64%) were the third group, 67 cases (11.78%) were the fourth group, and 363 cases were (63.80%) the fifth group, of which 130 cases (22.85%) were positive and 439 cases (77.15%) were negative by FISH detecting. Compared with the guideline of 2014 edition, the HER-2 positive rate of FISH detection reduced from 24.43% (139/569) to 22.85% (130/559) according to the application of the guideline of 2019 edition, but the difference was not statistically significant (P=0.567), while the negative rate increased from 63.80% (363/569) to 77.15% (439/569), with a statistically significant difference (P<0.05). Forty-three cases with incomplete weak to medium intensity of IHC membrane staining which were HER-2 (+ + ) according to 2014 guideline were changed to IHC (+ ) on the basis of the 2019 guideline. According to the FISH guideline of 2014 edition, 1 case (2.33%) was positive, 6 cases (13.95%) was equivocal and 36 cases (83.72%) was negative, while according to the 2019 FISH guideline, all of the 43 cases were negative. Conclusions: According to the guideline of 2019 edition, a proportion of cases changes from HER-2 (+ + ) to (+ ), and the HER-2 positive rate of FISH test decreases slightly, the negative rate increases, the equivocal result is eliminated, which provides a definite reference for screening patients who will be benefited from the targeted treatment of HER-2.

Utilization of Intravenous (IV) Curcumin, Genistein, and Trastuzumab to Reduce HER2 receptors in Breast Cancer Patients

In recent decades, due to the increased growth, spread, and onset of cancer, interest has arisen in studying the methods that could be used to combat it. Breast cancer is the most prevalent form of cancer in the world. Due to the growing pervasiveness of this issue, a larger body of research is forming in the area of breast cancer with the intent to contain the spread of the potentially ravaging disease or diagnose it earlier. This research is intended to propose an alternative, possibly more efficient method to inhibit the chances of metastasis and continued prevalence of breast cancer in a patient. The related work discusses similar research being done and builds on it to incorporate the novel method being proposed while explaining the components of the proposed treatment in question. The proposed method aims to deplete HER2 protein receptors in breast cancer patients through the intravenous (IV) administration of the tyrosine kinase inhibitors (TKIs) curcumin and genistein, as well as trastuzumab, which is more commonly known under the brand name Herceptin. Depleting HER2 protein receptors can potentially cause the severity of HER2-positive breast cancer to decrease substantially, as well as reduce the probability of metastasis and recurrence, the rate of which is considerably higher in HER2-positive cases when compared to that of HER2-negative cases. The future work deals with alternate methods that could be explored with a similar intent as this research study and describes the potential implications of the study.

Clinicopathological features of and neoadjuvant therapy for human epidermal growth factor receptor 2-positive classic invasive lobular carcinoma

Human epidermal growth factor receptor 2 (HER2)-positive classic invasive lobular carcinoma (ILC) is a rare entity, and its specific pathological characteristics and clinical behavior are unclear. Therefore, we retrospectively investigated the clinicopathological features of HER2-positive classic ILC and described HER2-targeted neoadjuvant chemotherapy outcome. Fourteen HER2-positive classic ILC cases were identified, their clinicopathological data were collected, and their clinical management was investigated. In general, HER2 positivity is associated with higher grade carcinoma in ductal lesions; however, our 14 cases had typical morphologic features of classic ILC. We did not identify unique morphologic features in HER2-positive classic ILC with the clinicopathological parameters examined, including age, menopausal status, histological grade, and hormone receptor status. Four of six patients who received HER2-targeted neoadjuvant chemotherapy had a pathological complete or partial response. Based on our findings, clinicopathological features of classic ILC may not predict HER2 overexpression or amplification. HER2-targeted neoadjuvant chemotherapy was effective against some HER2-positive classic ILCs. Taken together, these results demonstrate that HER2 immunohistochemistry and fluorescence in situ hybridization should be considered for all ILC patients regardless of subtype.

DAGM: A novel modelling framework to assess the risk of HER2-negative breast cancer based on germline rare coding mutations.

BackgroundBreast cancers can be divided into HER2-negative and HER2-positive subtypes according to different status of HER2 gene. Despite extensive studies connecting germline mutations with possible risk of HER2-negative breast cancer, the main category of breast cancer, it remains challenging to obtain accurate risk assessment and to understand the potential underlying mechanisms.MethodsWe developed a novel framework named Damage Assessment of Genomic Mutations (DAGM), which projects rare coding mutations and gene expressions into Activity Profiles of Signalling Pathways (APSPs).FindingsWe characterized and validated DAGM framework at multiple levels. Based on an input of germline rare coding mutations, we obtained the corresponding APSP spectrum to calculate the APSP risk score, which was capable of distinguish HER2-negative from HER2-positive cases. These findings were validated using breast cancer data from TCGA (AUC = 0.7). DAGM revealed that HER2 signalling pathway was up-regulated in germline of HER2-negative patients, and those with high APSP risk scores had exhibited immune suppression. These findings were validated using RNA sequencing, phosphoproteome analysis, and CyTOF. Moreover, using germline mutations, DAGM could evaluate the risk for HER2-negative breast cancer, not only in women carrying BRCA1/2 mutations, but also in those without known disease-associated mutations.InterpretationThe DAGM can facilitate the screening of subjects at high risk of HER2-negative breast cancer for primary prevention. This study also provides new insights into the potential mechanisms of developing HER2-negative breast cancer. The DAGM has the potential to be applied in the prevention, diagnosis, and treatment of HER2-negative breast cancer.FundingThis work was supported by the National Key Research and Development Program of China (grant no. 2018YFC0910406 and 2018AAA0103302 to CZ); the National Natural Science Foundation of China (grant no. 81202076 and 82072939 to MY, 81871513 to KW); the Guangzhou Science and Technology Program key projects (grant no. 2014J2200007 to MY, 202002030236 to KW); the National Key R&D Program of China (grant no. 2017YFC1309100 to CL); Shenzhen Science and Technology Planning Project (grant no. JCYJ20170817095211560 574 to YN); and the Natural Science Foundation of Guangdong Province (grant no. 2017A030313882 to KW and S2013010012048 to MY); Hefei National Laboratory for Physical Sciences at the Microscale (grant no. KF2020009 to GN); and RGC General Research Fund (grant no. 17114519 to YQS).

Texture Analysis Using Semiquantitative Kinetic Parameter Maps from DCE-MRI: Preoperative Prediction of HER2 Status in Breast Cancer.

ObjectiveTo evaluate whether texture features derived from semiquantitative kinetic parameter maps based on breast dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) can determine human epidermal growth factor receptor 2 (HER2) status of patients with breast cancer.Materials and MethodsThis study included 102 patients with histologically confirmed breast cancer, all of whom underwent preoperative breast DCE-MRI and were enrolled retrospectively. This cohort included 48 HER2-positive cases and 54 HER2-negative cases. Seven semiquantitative kinetic parameter maps were calculated on the lesion area. A total of 55 texture features were extracted from each kinetic parameter map. Patients were randomly divided into training (n = 72) and test (n = 30) sets. The least absolute shrinkage and selection operator (LASSO) was used to select features in the training set, and then, multivariate logistic regression analysis was conducted to establish the prediction models. The classification performance was evaluated by receiver operating characteristic (ROC) analysis.ResultsAmong the seven prediction models, the model with features extracted from the early signal enhancement ratio (ESER) map yielded an area under the ROC curve (AUC) of 0.83 in the training set (sensitivity of 70.59%, specificity of 92.11%, and accuracy of 81.94%), and the highest AUC of 0.83 in the test set (sensitivity of 57.14%, specificity of 100.00%, and accuracy of 80.00%). The model with features extracted from the slope of signal intensity (SIslope) map yielded the highest AUC of 0.92 in the training set (sensitivity of 82.35%, specificity of 97.37%, and accuracy of 90.28%), and an AUC of 0.79 in the test set (sensitivity of 92.86%, specificity of 68.75%, and accuracy of 80.00%).ConclusionsTexture features derived from kinetic parameter maps, calculated based on breast DCE-MRI, have the potential to be used as imaging biomarkers to distinguish HER2-positive and HER2-negative breast cancer.

Final report of Breast Cancer Care Registry at the Kenyatta National Hospital, Nairobi.

Retraction The abstract by Othieno-Abinya et al entitled, “Final report of Breast Cancer Care Registry at the Kenyatta National Hospital, Nairobi,” published in the Journal of Clinical Oncology 39, no. 15 suppl (May 20, 2021) e12552-e12552, was retracted by the authors as it did not meet the study sponsor's prior scientific verification and approval. This abstract was retracted on June 29, 2021. e12552 Background: Breast cancer is the commonest cancer among women in Kenya. We wanted to examine breast cancer seen at the Kenyatta National Hospital in relation to local factors that influence prognosis and quality of life, local variations in treatment and outcomes; describe the clinical care patterns, monitor the safety of the therapies provided to patients in a routine clinic setting. Methods: A prospective study of patients with breast cancer between 11.08.2011 and 11.09.2014 inclusive. Data included demographic details, diagnostic and staging procedures, stage, treatment and outcome. Estimates of relative survival used period approach. hi-square tests and analysis of variance (ANOVA) were utilised to make comparisons. Cross sectional data are presented in proportions, means and medians. Results: Four hundred patients were included, age range 20 to 83, median 49 years. Out 312, 65 (20.8%) were obese. Eight of 397 (2%) were smokers and 22(5.5%) took alcohol. Early disease was diagnosed in 269 out of 354 (76%) and metastatic disease in 85(24%). Breast lump presented in 388 out of 400 (97%), breast pain in 104 out of 388 (26.8%). Fifteen of 394 (3.8%) had second breast cancer, 4 (1%) had had ovarian cancer and 9 (2.3%) had had had other malignancy. History of breast cancer in first and second-degree relative was elicited in 41 out of 394 (10.4%). Ductal carcinoma NOS was commonest in 343 (88.2%), lobular carcinoma in 9(2.5%). Cases by T stage were T1 - 25(7.2%), T2 -130(37.4%), T3 - 96(27.6%), T4 - 87(25%). Of 322 cases, 187(58.1%) were ER positive and 175 (54.4%) PR positive. Her2 positive cases were 78 out of 322 (24.2%). Neo adjuvant and adjuvant chemotherapy mainly consisted of combinations of cyclophosphamide and doxorubicin [AC] +/- a taxane[AC→T] ( mainly by medical oncologists) or AC+ 5-FU [CAF] (mainly by clinical oncologists). Of 305 cases 272 (89.2%) completed adjuvant therapy, 8(2.6%) died during treatment. Median overall survival was 57.1 months (95% CI; 55.6 to 59.5 months). For metastatic disease, median PFS was worse for patients &lt; 40 years. Conclusions: Pathology and biology mirrored global situation, over 75% of patients had non metastatic disease. A significant proportion of early disease patients did not complete treatment.

Impact of updated 2013 human epidermal growth factor receptor-2 testing guidelines on HER2 positive invasive breast cancer diagnosis: A three year retrospective study.

e12554 Background: Breast cancer is a frequently diagnosed malignancy in the United States accounting for approximately 266,000 cases and 40,000 deaths annually. Human epidermal growth factor receptor 2 (HER2) is a surface protein shown to affect cell proliferation, migration and survival - the hallmarks of neoplastic cells. HER2 is overexpressed in 20-35% of breast cancer cases and has a strong prognostic and therapeutic significance. This discovery led to development of therapeutic agents targeting HER 2 receptor. In 2013, College of American Pathologists (CAP) updated their recommendations for HER2 testing by incorporating an algorithm with immunohistochemistry (IHC) and In situ hybridization (ISH). The primary objective of our study was to assess for variance in HER2 interpretation by applying the updated 2013 criteria to all diagnosed cases in our hospital for the immediate previous three years. Methods: We retrospectively reviewed charts of patients diagnosed with invasive breast carcinoma from January 1, 2010 to December 31, 2012 at our hospital. The new American college of pathology criteria assessing FISH HER2 copy number and HER2/CEP ratio for each patient was compared to the old criteria to assess for variance in HER2 interpretation. Categorical variables are presented as percentages and kappa statistic was used to assess for variance. Results: We reviewed 526 charts with an invasive breast cancer diagnosis over a 3-year period. 10.83% of patients were HER2 amplified, 86.12% were non-amplified and 3.04% were equivocal. Applying the updated 2013 CAP criteria, we found that 11.21% were amplified, 74.33% were non amplified, and 14.44% remained equivocal. Kappa statistic indicated substantial agreement (0.804) between the old and new criteria. A review of our cohort revealed an overall lower level of HER2 positive cases at 10.83% (old criteria) and 11.21% (updated criteria) when compared to historical studies. The increase in equivocal cases from 3.04% to 14.44% with the new criteria suggests under diagnosis of HER2 positive cases. Due to the lack of IHC performed (as per old standards), further classification of equivocal cases (based on new criteria) was not possible. While we saw some movement in our data from non-amplified to equivocal, our analysis indicated substantial statistical agreement between the old and the new diagnostic criteria Conclusions: Our study did not show a variance in HER2 interpretation between the 2007 and 2013 CAP criteria which is reassuring. An increase of 11.4% cases in the equivocal category was noted and may reveal a significant difference if further delineation is feasible. This variance could be important given the prognostic and therapeutic implications in HER2 positive breast cancer.[Table: see text]

64P Mammographic density to predict response to neoadjuvant chemotherapy for breast cancer

Mammographic density (MD) has been strongly associated with increased risk of breast cancer (BC). In view of this, we aimed to investigate the predictive value of MD in a large consecutive cohort of BC patients (pts) treated with neoadjuvant chemotherapy (NAC). Data on NAC treated pts prospectively collected in the registry of Fondazione IRCCS Istituto Nazionale dei Tumori, Milan (May 2009-Aprill 2020) were identified. Diagnostic mammograms were used to evaluate MD, which was categorized by the Breast Imaging-Reporting and Data System (BI-RADS). BI-RADS identify 4 categories of MD in keeping with the masking effect of fibroglandular tissue, as following: A (almost entirely fat), B (scattered areas of fibroglandular density), C (heterogeneously dense), and D (extremely dense). Multivariable logistic regression was used to assess the odds ratios (OR) for pathological complete response (pCR), ie absence of invasive tumor in breast and node surgical specimens, comparing BI-RADS categories with adjustment for patient age, BMI, and tumor characteristics. A total of 442 pts were analyzed, of which 120 (27.1%) attained a pCR. BI-RADS categories A, B, C, and D accounted for 10.0%, 37.8%, 37.1% and 15.2% of cases, respectively, with corresponding pCR rates of 20.5%, 26.9%, 30.5%, 23.9%. At multivariable analysis cases classified as BI-RADS C showed an increased likelihood of pCR as compared to A (odds ratio [OR]=2.79), B (OR=1.70), and D (OR=1.47) independently of age, BMI (OR underweight vs normal=3.76), clinical N and T (OR T1/Tx vs T4=3.87), molecular subtype (HER2 vs luminal=10.74; triple negative vs luminal=8.19). In subgroup analyses, the strongest association of MD with pCR was observed in triple negative (ORs of B, C and D versus A: 1.85, 2.49 and 1.55, respectively) and HER2 positive cases (ORs 2.70, 3.23, and 1.16). Notably, no significant differential effect of MD with respect to pCR was observed in luminal BC (ORs of B, C and D versus A: 0.88, 2.01 and 1.58). Patients with dense breast are more likely to attain a pCR after NAC at net of other current clinical and pathological predictive factors. The potential of MD to assist decisions on BC management and as a stratification factor in neoadjuvant clinical trials should be considered.

Is there a correlation between HER2 gene amplification level and response to neoadjuvant treatment with trastuzumab and chemotherapy in HER2-positive breast cancer?

There are contradictory data regarding the correlation between HER2 amplification level determined by in situ hybridization and evolution after treatment with anti-HER2 therapies. The aim of this study was to correlate quantitative results of FISH (ratio HER2/CEP17 and number of HER2 signals/nucleus) with pathological response achieved after neoadjuvant treatment with trastuzumab and chemotherapy. For this purpose, we analysed 100 consecutive HER2-positive cases of breast carcinoma treated with neoadjuvant therapy. HER2 amplification determined by FISH was found in 92 of the 100 cases studied. pCR was obtained in 58% of the patients whose tumours presented amplification. In contrast, no pCR was obtained in the 8 patients with non-amplified tumours. A significant direct correlation between HER2 high amplification (HER2/CEP17 ratio > 5 or HER2 signals/nucleus > 10) and pCR was found. In conclusion, HER2 amplification levels are clinically relevant because they provide oncologists with valuable information on the possibilities of achieving pCR after neoadjuvant treatment.

Clinical therapeutic effects of trastuzumab in HER2-positive breast cancer patients: A protocol for systematic review and meta-analysis.

Background:Despite the developments in diagnosis and treatment of HER2-positive metastatic breast cancer, there is a high likelihood in the development of resistance to trastuzumab. In general, HER2-positive patients with deteriorated health face negative clinical outcomes. The present study is conducted to systematically explore the medicinal properties of trastuzumab in HER2-positive breast cancer patients.Methods:Randomized controlled trials investigating the clinical properties of including trastuzumab to treat HER2-positive breast cancer cases will be sourced by exploring these online-based databases: MEDLINE, BIOSIS, China National Knowledge Infrastructure (CNKI), Cochrane Library, EMBASE, Central Register of Controlled Trials, and WanFang. Two independent authors will screen the literature, gather data, and assess the quality of selected studies. The significance of the relationship between the medical properties of trastuzumab when incorporated to treat HER2-positive breast cancer cases will be evaluated according to the relative risk, mean differences or standardized mean differences, and 95% confidence interval.Results:The outcomes from this review shall be issued in a journal that will be reviewed by peers.Conclusion:The conclusions presented in this review will serve as a reference for clinical practitioners and scholars to determine whether trastuzumab is an effective and safety intervention for treating HER2-positive breast cancer patients.Ethics and dissemination:Since this study is a systematic review of published studies, an ethical approval is not needed.Systematic review registration number:March 31, 2021.osf.io/wvqkf (https://osf.io/wvqkf/).

Correlation of Human Epidermal Growth Factor Receptor (Her2-neu) Marker with the Grades of Urothelial Carcinoma

Background: Urothelial carcinoma is the common carcinoma of urothelium. Its incidence is high in developed countries but itsoccurrence is increasing in developing countries like Pakistan with mortality rate of 3.8/100,000 in males and 1/100,000 in females.HER2 is a member of the human epidermal growth factor receptor (HER/EGFR/ERBB) family.Amplification or over-expression ofthis oncogene has been shown to play an important role in the development and progression urothelial carcinoma.Objective: To evaluate the relationship between HER2/NEU expression and grades of urothelial carcinoma bladderMaterial and Methods: This was a cross-sectional descriptive study for the period of six months from January to June, 2017conducted at Pathology section Rehman Medical Institute Peshawar. After approval from university Ethical board 63 cases wereselected by purposive sampling.The Tissue samples from diagnosed cases of urothelial carcinoma of urinary bladder were included.Cases of urothelial carcinoma from other sites were excluded. Paraffin embedded tissue blocks were cut and sections stained byH&amp;E to evaluate histopathological features and tumor grades. Immunohistochemical expression of HER2 was determinedapplying standard techniques of immunohistochemistry.Results: Out of total 63 cases, 47 were males and 16 were female with a mean age of 60.7 years (range 14-90 years). There were38 High grade, 23 Low grade and 2 cases of PUNLMP. 36 cases were positive for HER2 expression in which 26(72.2%) were Highgrade, 9(25%) of Low grade and 1(2.7%) of PUNLMP. High grade was more common in HER2 positive cases and this relationshipwas significant (p&lt;.05). Among positive 36 cases, 19 cases of +3 score were High grade, 05 in Low grade and 01 in PUNLMP whilescore 2+ was in 07 cases of High grade and 04 were in Low grade. The relationship of HER2 score was not significantly related tograde of tumor (p&gt;.05)Conclusion: HER2 is highly expressed in high grades of urothelial carcinoma bladder and this relationship between HER2expression and tumor grades is statistically significant.Keywords: HER2, Urothelial carcinoma, Grades, Immunohistochemistry

Progress in conversion therapy for stage IV gastric cancer

Gastric cancer is one of the most common malignancy in China. Most of the patients of gastric cancer treated clinically are in advanced stage. In the past years, with the progress of anti-cancer drug therapy, after the comprehensive treatment based on drugs therapy of inoperative stage IV gastric cancer, some cases can reduce the tumor stage and get the opportunity of radical operation. Some of the patients who underwent surgical treatment can get the chance of long-term survival. The results of REGATTA trial confirmed that palliative surgery plus chemotherapy could not improve the long-term survival of patients with stage IV gastric cancer. Neoadjuvant intraperitoneal plus intravenous chemotherapy can reduce the tumor stage of some cases of stage IV gastric cancer with peritoneal metastasis and receive surgical treatment, so as to gain the chance of long-term survival. Regimen of intraperitoneal hyperthermia chemotherapy combined with PHOENIX trial is expected to improve the conversion operation rate of gastric cancer with peritoneal metastasis. Paclitaxel-based three-drug chemotherapy can reduce the tumor stage of some inoperable advanced gastric cancer and obtain the opportunity of radical operation, improving the disease-free survival rate and overall survival rate of patients, thus has become the cornerstone of conversion therapy for stage IV gastric cancer. Antiangiogenic targeted drug apatinib combined with paclitaxel is safe and reliable, and can be used as an alternative for the conversion therapy of stage IV gastric cancer, which provides a new idea for cytotoxic drugs combined with targeted drugs. In the era of immunotherapy, the combined application and first-line application of immunosuppressive drugs has become a clinical consensus. For advanced Her-2 positive esophagogastric junction adenocarcinoma cases, the successful exploration of the four-drug combination of chemotherapy+ anti-Her-2 targeted drugs+ anti-PD1 monoclonal antibody combined with the first-line therapy has opened up a new era of transformational therapy for stage IV gastric cancer. Gastric cancer is a malignant tumor with high heterogeneity, the classification of stage IV gastric cancer represented by Yoshida classification is based on imaging, and a more reasonable classification method should be developed in combination with gene detection in the future. Based on this, an individualized and accurate conversion therapy plan is formulated, so as to effectively improve the long-term survival of patients with stage IV gastric cancer.

Abstract PS11-12: Statin use significantly improves outcome in luminal B relative to luminal A breast cancers

Abstract Cholesterol and statins may have a role in breast cancer progression where statins have been found to associate with reduced breast cancer recurrence risk in early breast cancer patients. Links between breast cancer progression and intra-tumoural cholesterol metabolism have been described, indicating possible underlying cancer biology. Here we set out to explore whether statin use correlated with differences in baseline tumour characteristics including biological tumour sub-type and whether outcomes were impacted by statin use, both overall and within sub-types. Two cohorts of invasive breast cancer patients from a single institution in Western Australia were studied; one comprised of cases across all sub-types (n=417) and one of hormone receptor positive cases only (n=1766), with available data on tumour biology, statin use, and relapse. Statin prescription data was available on 2183 patients, of whom 454 were taking a statin at some point from diagnosis through the end of the follow-up period. Of the patients where statin type was known, 38% were taking a hydrophilic and 62% a lipophilic statin. Although tumour stage did not vary by statin usage, those on a statin had less frequent high grade tumours (12.7 v 18.7%, p=0.025), and were more frequently estrogen receptor positive (96.1 v 93.1, p=0.022) although other receptor expressions did not differ. Finally, luminal A tumours were more common in statin users, at the expense of luminal B and HER2-enriched cancers (81.4 v 74.0, p=0.018) (Table 1). Overall breast cancer events were more common in statin non-users compared to users (16.7 v 9.3%, HR 1.80, p&amp;lt;0.0001). Due to the influence of the larger hormone receptor positive cohort, the majority of patients had luminal tumours. Looking to the influence of statins on events within sub-types, users compared to non-users experienced substantially less breast cancer events in luminal B cancers (8.8% v 22.3%, p=0.012 ) and modestly reduced events in luminal A cancers (8.3 v 12.6%, p=0.0326). Considering HER2 positive luminal B cancers relative to those afforded luminal B status by virtue of being high grade, the former group showed significantly less events in statin users v non-users (0 v 19.9%, p=0.0047) whereas no significant protection was observed in the latter (18.2 v 24.6%, p=0.294). Low numbers of HER2 positive hormone receptor negative cases precluded analyzing whether protection extended to all HER2 positive tumours, although none of these patients relapsed. No significant differential effect was found by statin type. In conclusion, statin usage after early breast cancer afforded substantial protection to HER2 positive hormone receptor positive patients, an effect that may extend to all HER2 positive cases. Further validation is warranted. Such patients could be considered for trials exploring statins as agents protecting against relapse. Table 1: Breast tumour demographics comparing statin users to non-users.Statin UseCasesCasesMedian sizeLN positiveLN positiveInvasive GradeInvasive gradeInvasive GradeER +iveER +ivePR -ivePR -iveHER2 +iveHER2 +iveSub-typeSub-typeSub-typen%mmn%n%n%n%n%n%lum A1117(74.0)Grade 144827.6Lum B336(22.3)NO1729(79.0)18607/1787(34.0)Grade 286753.51601/1719(93.1)1348/1565(86.1)144/1498(9.6)HER2 enrich7(0.5)Grade 330718.9TNBC50(3.3).lum A337(81.4)Grade 113130.2lum B68(16.4)YES454(21.0)17151/475(31.8)Grade 224757.0440/458(96.1)363/428(84.8)32/421(7.6)HER2 enrich1(0.2)Grade 35512.7TNBC8(1.9).p (Fishers)NS0.3820.0250.0220.4820.2510.018 Citation Format: Andrew David Redfern, Lisa J Spalding, Robin L Anderson, Hilary Martin. Statin use significantly improves outcome in luminal B relative to luminal A breast cancers [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-12.

Abstract PD7-06: Unstable mutational profile and heterogeneity of residual breast tumor following neoadjuvant therapy from comprehensive genomic and transcriptomic sequencing

Abstract Background: In patients with early breast cancer, neoadjuvant therapy is widely performed as standard of care. While the molecular targeting strategy makes progress in HER2 positive breast cancer, the optimal regimens for ER+/HER2- breast cancer (BC) and triple negative breast cancer (TNBC) remain undecided. Furthermore, there are few strategies for patients who do not achieve complete pathological response (pCR) who have worse prognosis. To address these unmet clinical needs, there is urgent need to examine the genomic alterations and immune microenvironment of residual tumors after neoadjuvant therapy. Here, we conducted a comprehensive analysis integrating genomic, transcriptomic, and clinical data to investigate the difference between primary breast cancer and residual disease. Materials and Methods: Using the large prospectively ascertained ethnically diverse Chicago Multi-Ethnic (ChiMEC) cohort of 562 participants with integrated genomic data, we identified 176 patients with breast cancer who underwent sequencing with Tempus xT next-generation sequencing panel including DNA- and whole-transcriptome RNA-sequencing. These included 131 primary breast tumors and 45 residual tumors after neoadjuvant therapy. We compared mutation rates between primary tumor and residual tumor in ER+/HER2- BC and TNBC. We also investigated homologous recombination deficiency (HRD) scores, tumor mutational burden (TMB), degree of immune infiltration, and microsatellite instability (MSI), and their association with survival. Results: Out of the 176 patients, there were 72 ER+/HER2- BC, 42 TNBC, and 44 HER2 positive cases. Among patients with HR+/HER2- BC, residual tumors had higher mutation rates in PIK3CA (61% vs 33%), CDH1 (33% vs 17%), CCND1 (39% vs 7%), FGF3 (28% vs 0%), FGF4 (33% vs 2%), FGF19 (33% vs 2%), and GATA3 (44% vs 7%) than primary tumors, but lower rates in TP53 (28% vs 48%), MAP3K1 (6% vs 40%), KMT2D (0% vs 33%), MCL1 (0% vs 30%), SPEN (6% vs 20%), ZFHX3 (0% vs 20%), ARID1A (11% vs 16%), KMT2C (0% vs 19%), LZTR1 (0% vs 19%), BCORL1 (6% vs 17%), NOTCH3 (6% vs 17%), FAT1 (0% vs 17%) and LPR1B (0% vs 17%). Relative to primary TNBC tumors, residual TNBC tumors exhibited higher mutation rates in PTEN (10% vs 3%), CCNE1 (10% vs 3%), CIC (10% vs 0%), and KMT2D (10% vs 3%). Conversely, residual TNBC tumors had relatively lower rates of MCL1 (0% vs 21%), RB1 (0% vs 12%), CDH1 (0% vs 12%), KMT2C (11% vs 18%), and PIK3CA (0% vs 15%), CDKN1B (0% vs 12%) and ETV6 (0% vs 12%). There was a significant trend of higher TMB (&amp;gt;5.0 mutations/megabase, m/MB) associated with improved disease-free survival among the 176 patients (P=0.031). TMB was not significantly different between primary tumors and residual tumors, or across subtypes. Microsatellite instability (MSI) status was high in 3 patients (1.6%) and equivocal in 5 patients (2.7%). TMB in MSI-high or MSI-equivocal tumors was significantly higher than TMB in tumors with microsatellite stability (37.7m/MB vs 5.3m/MB, P&amp;lt;0.001). HRD scores were highest in TNBC, and lowest in ER+/HER2- breast cancers (P=0.022). There was no significant association between the HRD scores and survival. To date, tumors from 106 patients have undergone immune profiling, with estimation of immune cell infiltration, macrophages, B cells, CD4, CD8, and NK cells. Initial analysis showed no association between immune profiling and survival. Conclusion: These comprehensive analyses demonstrated that mutation status in HR+/HER2- breast cancers and TNBC differs between primary and residual tumors after neoadjuvant therapy. We identified genomic alterations and pathways in residual tumors that could be further explored as potential targets in the adjuvant setting to improve long term outcomes for patients who do not achieve pCR. Citation Format: Minoru Miyashita, Masaya Hattori, Yonglan Zheng, Toshio Yoshimatsu, Joshua SK Bell, Padma Sheila Rajagopal, Anna Woodard, Jean Baptiste Reynier, Elisabeth Sveen, Galina Khramtsova, Fang Liu, Abiola Ibraheem, Gini Fleming, Nora Jaskowiak, Rita Nanda, Benjamin Leibowitz, Nike Beaubier, Kevin White, Dezheng Huo, Olufunmilayo I Olopade. Unstable mutational profile and heterogeneity of residual breast tumor following neoadjuvant therapy from comprehensive genomic and transcriptomic sequencing [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD7-06.

Abstract PS18-25: Concordance of immunohistochemical assays between peri-operative and post-operative breast tumor specimens: A prospective observational study of 18 cases

Abstract Background and Rationale: Biomarker evaluation on breast tumor tissue is an important component of clinical research. There is a concern that tissues collected at different times (pre- vs intra-op) and with different techniques (core biopsy vs. surgical excision) produce different results that may confound comparisons of patient samples. Our objective is to address the difference between tumor tissue from the same patient collected pre- vs intra-op and by core biopsy (Core Bx) vs surgical excision, with an emphasis on ER/PgR/HER2/Ki-67 and biomarkers related to insulin metabolism. Design: Following a protocol approved by the IRB, patients with Core Bx proven invasive breast cancer (BC) &amp;gt;1.5 cm in size by imaging underwent a peri-operative Core Bx followed by surgical excision. No neoadjuvant therapy was administered. Formalin-fixed paraffin-embedded tumor sections of the diagnostic and peri-operative Core Bx and surgical excision were immunohistochemically (IHC) stained for ER, PgR, HER2, Ki-67, insulin receptor (IR), phospho-AKT (pAKT), and phospho-AMPK (pAMPK) using standardized protocols on the same platforms. A pathologist (MCC) scored all sections in blinded order to yield H-Scores (which combine percentage of stain-positive cells and staining intensity). The level of agreement for each assay between specimens was assessed by using pairwise models based on normal theory. Results: 18 women (mean age = 66.8 years, 16/18 postmenopausal) provided all specimens. Mean (± SD) invasive tumor size was 2.7 (± 1.2) cm. 1 BC was Nottingham Grade 1 (6%), 9 Grade 2 (50%), and 8 Grade 3 (44%). An in situ component was present in 4/18 (22%) cases (all non-extensive). Lymphovascular invasion was present in 6/18 (33%) cases. 10/18 were node-negative (N0, 56%), 2/18 had isolated tumor cells (pN0[i+], 22%), 5/18 had 1 to 3 nodes (pN1, 28%), 1/18 had &amp;gt;9 nodes involved (pN3, 6%).There was high concordance between diagnostic Core Bx, peri-op Core Bx, and excisions for the standard prognostic markers ER, PgR, and HER2. ER was concordant in all samples including 16/18 (89%) ER-positive and 2/19 (11%) ER-negative BCs. PgR was concordant in 16/18 (89%) of cases. In the 2 discordant cases, PgR was negative in 2 of 3 tissue samples with low expression in the 3rd sample (1 diagnostic Core Bx and 1 excision). HER2 was concordant in all samples in 16/18 (89%) HER2-negative cases and in 2/18 (11%) HER2-positive cases including 1/18 cases (6%) positive by IHC, and 1/18 cases (6%) positive by ISH. Table 1 summarizes the agreement between samples for Ki-67, IR, pAKT, and pAMPK. Ki-67 scores were statistically similar between diagnostic and peri-op Core Bx and excision samples. The IR, pAKT, and pAMPK H-Scores were statistically similar between diagnostic and peri-op Core Bx, but significantly different between Core Bxs versus excisional specimens. There was a systematic tendency towards lower IHC H-Scores in the excisional specimen for IR, pAKT, and pAMPK. Conclusion: Tissue from surgical excisions are susceptible to reduced IHC staining for metabolic markers such as IR, and phosphorylated kinases, when compared to core biopsies. When evaluating non-standard biomarkers for research, core biopsies should be used when possible. Funding: This study was funded by the Hold'Em For Life Charity and the Breast Cancer Research Foundation Table 1: Concordance Between IHC Scores for Ki-67, Insulin Receptor, pAKT, and pAMPKScore: Mean ± Standard DeviationPeri-Operative Core Bx versus Diagnostic Core BxExcision versus Diagnostic Core BxDiagnostic Core BxPeri-Operative Core BxExcisionDifferenceP-valueDifferenceP-valueKi-67 (% Positive)33.5 ± 28.235.9 ± 31.034.2 ± 29.1Mean ± SD: 2.4 ± 5.60.09Mean ± SD: 0.6 ± 6.30.68Range: -7.7 to 12.3Range: -11.5 to 12.2Insulin Receptor (H-Score**)136 ± 102124 ± 9986 ± 78Mean ± SD: -13 ± 530.32Mean ± SD: -51 ± 540.001*Range: -215 to 40Range: -150 to 5Phospho-AKT (H-Score**)102 ± 70100 ± 8641 ± 41Mean ± SD: -1 ± 750.95Mean ± SD: -61 ± 520.0001*Range: -170 to 170Range: -144 to 0Phospho-AMPK (H-Score**)201 ± 79185 ± 78157 ± 86Mean ± SD: -15 ± 760.41Mean ± SD: -44 ± 690.016*Range: -225 to 120Range: -215 to 70* Statistically significant difference in pairwise values based on t-test** H-Score is the percentage of stain-positive cells multiplied by the average intensity score (0 = absent, 1 = faint, 2 = moderate, 3 = strong) Citation Format: Martin C. Chang, Marguerite Ennis, Jaime Escallon, Karina Bukhanov, Ryan JO Dowling, Vuk Stambolic, Pamela J Goodwin. Concordance of immunohistochemical assays between peri-operative and post-operative breast tumor specimens: A prospective observational study of 18 cases [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-25.

History and emerging trends in chemotherapy for gastric cancer.

Chemotherapy is indispensable for gastric cancer. For unresectable and/or recurrent gastric cancer, first‐line chemotherapy consists of multidrug regimens including oral 5‐FU agents such as S1/Xeloda and platinum preparations, as well as Trastuzumab, which is effective in HER2‐positive cases. Second‐ and third‐line chemotherapy regimens include taxanes, Ramucirumab (R‐mab), and Nivolumab (N‐mab), which have different mechanisms of action from first‐line chemotherapy. R‐mab is molecularly targeted to vascular endothelial growth factor receptor 2 in the host cells, but its indication is not conditional. For resectable gastric cancer, in Eastern countries, postoperative adjuvant chemotherapy has been successful, including S1, Docetaxel/S1 (DS), and Xeloda/Oxaliplatin (Xelox) regimens, whereas, in Western countries, the 5‐FU/Leucovorin/Oxaliplatin/Docetaxel (FLOT) regimen was recently shown to be effective in the perioperative chemotherapy setting. Most recently, however, in Eastern countries, perioperative SOX was demonstrated to be effective in specific advanced gastric cancer. For stage IV gastric cancer, new therapeutic strategies have been proposed such as neoadjuvant chemotherapy and conversion surgery, and cures can be conditionally obtained. Recent genomic understanding of gastric cancer proposed a diversity of molecular targets by molecular profiling. Such optimized chemotherapy regimens, according to the specific clinical situations, have been rigorously established for the best survival of advanced gastric cancer.

Expression of Biomarkers Estrogen Receptor, Progesterone Receptor, HER2 in Primary Breast Tumour and Synchronous Metastatic Axillary Lymph Node

Introduction: Estrogen Receptor (ER), Progesterone Receptor (PR), Human Epidermal growth factor Receptor 2 (HER2) status are routinely used to guide treatment decision for breast cancer. Treatment protocol in breast cancer is currently based on biomarker characteristic of primary tumour. But this biomarker status may change as the tumour progresses from primary to synchronous metastatic lymph node. Hence, it is important to know the biomarker status of these synchronous metastatic lymph nodes as it may serve as an important tool to guide management, evaluate prognosis and to anticipate the possibility of recurrent risk of primary invasive breast cancer. Aim: To study the expression of ER, PR, HER2 status in primary breast carcinoma and synchronous metastatic lymph node and to evaluate concordance and discordance between them. Materials and Methods: This study was observational, retrospective and prospective study conducted over a period of one and half years from February 2015 to October 2016 at ESI-PGIMSR, Maniktala, Kolkata, India, where 50 cases of breast carcinoma with positive axillary lymph node metastasis were studied. Haematoxylin and Eosin (H&amp;E) sections were reviewed and representative paraffin blocks were selected. Immunostains were performed and scoring was done following standard protocols. Standard statistical methods were applied for analysis of data using chi-square test and kappa statistics and data was analysed using Statistical Package for the Social Sciences (SPSS) version 6.1.3 software. Results: Out of 50 cases the mean age of the patients was 50.56±10.5 years. Amongst ER and PR status, 24 out of 50 (48%) and 18 out of 50 (36%) were ER and PR positive respectively. HER2 positive cases were 48% i.e., 24 out of 50 cases. The overall discordance rates of ER, PR and HER2 was found to be 10%, 8%, 18%, respectively. The discordance rates of ER positive and ER negative cases were 4.2% and 15.4%, respectively. The discordance rates of PR positive and PR negative cases were 5.6% and 9.4% respectively, whereas 29.2% of HER2 positive cases were discordant in lymph node metastases. Conclusion: There was discordance between ER, PR, HER2 status of primary tumour and metastatic lymph node. Hence, assessment of these biomarker status in axillary lymph node metastases may be considered along with primary tumour in breast carcinoma work-up.