Human Epidermal Growth Factor Receptor-2 Overexpression Research Articles

Abstract PO5-16-08: Breast cancer in men: 15 years of experience in an oncology reference center in northern Mexico

Abstract Background Breast cancer in men accounts for about 1% of all breast cancers. Classic risk factors include increasing age, a family history of cancer, and mutations in predisposing genes. The alteration of the estrogen-androgen ratio has been as involved in the genesis of this cancer due to its increased risk in conditions such as liver dysfunction, obesity, marijuana use, thyroid disease, Klinefelter’s syndrome, hormonal therapies, orchitis, cryptorchidism, and testicular damage. Purpose Hereby we aim to update the analysis of the published demographic, clinical and treatment-related characteristics of this disease in our center including the last 15 years, as well as newly identified relevant variables that will serve as the basis for awareness and screening programmes for our population. Methods We performed a retrospective observational analysis of the medical records of men diagnosed with breast cancer that were treated in “Centro Universitario Contra el Cáncer” between January 2007 and December 2022. A total of seventeen cases of male breast cancer were included in the analysis. The variables included are age at diagnosis, body mass index, comorbidities, cigarette and alcohol use, method of diagnosis, histological type/grade, clinical stage, estrogen, progesterone, and human epidermal growth factor receptor-2 (HER2) receptor status, and treatment received. We also looked at the dates of symptom onset, diagnosis, and treatment to determine the intervals between these events. SPSS v25 software was used for data analysis. The Shapiro-Wilk test was employed to determine the normality of the variables. Variables with a normal distribution were described with median and interquartile range for the 25th and 75th percentiles. Categorical variables were expressed as absolute numbers and percentages. Results Although we found some similarities between the characteristics of our population and those reported in the American and European series, there were many significant differences. Mean age at diagnosis was 62.9 (±11.7) years, 5.5 years earlier than the reported age of 68.4 years. In terms of risk factors, our population was twice as likely to report a family history of cancer as the American series (41% vs. 15-20%). Overweight and obesity together accounted for 76.5% followed by alcohol consumption in 70.6% and cigarette smoking in 47.1% of patients. Diabetes mellitus and systemic arterial hypertension were present in 70% of our population. These entities are known to alter the estrogen-androgen ratio. The initial symptom in 88.2% of patients was a retroareolar tumor. The mean time from symptom onset to cancer diagnosis was 14.4 months. Estrogen and/or progesterone receptor status was positive in 82.3%. HER2 overexpression was not found. 17.6% of the cancers were classified as triple negative in contrast to the 0.3% reported in other series. Regarding treatment, 88.3% underwent upfront surgery, of which 76% were modified radical mastectomies. Axillary node dissection was performed in 86.6% of the cases and sentinel node biopsy in the rest. Seventy-six percent of patients received chemotherapy and radiotherapy in the adjuvant setting. Tamoxifen was the most common drug of choice (87.5%) in the patients considered as candidates for hormonal therapy Conclusions This study updates the results previously reported from our center with additional information that enabled new important conclusions to be drawn about our population. These findings provide the basis for a better understanding of this disease, which is necessary to establish public policies and recommendations to reduce the negative impact of this type of cancer. Table. Demographic and Clinical Characteristics of the Patients Citation Format: Fernando Peña, Javier A. Martínez-Moyano, Francisco Alvarado-Villarreal, Carlos Salazar-Mejía, David Hernández-Barajas, Oscar Vidal-Gutiérrez. Breast cancer in men: 15 years of experience in an oncology reference center in northern Mexico [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 PO5-16-08.

Decreased HER2 expression in residual disease following neoadjuvant therapy in patients with HER2-positive breast cancer.

e12621 Background: Human epidermal growth factor receptor-2 (HER2) overexpression is a defining feature of roughly 20% of localized breast cancer and represents a critical target for therapy. Since the demonstration that residual disease (RD) after neo adjuvant therapy (NAT) is associated with worse prognosis and that adjuvant ado trastuzumab emtansine (tDM1) improves survival, NAT has become the standard of care for localized HER2+ breast cancer. Retesting for HER2 overexpression post resection is variable, and data is conflicting regarding the prognostic significance of changes in HER2 expression pre and post therapy. The objective of this study was to evaluate the association of pre and post neo adjuvant therapy HER2 immunohistochemistry (IHC) expression on breast cancer outcomes in our institutional database. Methods: After IRB approval, data was gathered for patients with localized HER2+ breast cancer receiving NAT including trastuzumab/pertuzumab at Yale Cancer Center between 2012 and 2022. Pathologic complete response (pCR) was defined as no residual invasive tumor in breast and lymph nodes. Patients were divided into 3 cohorts by response and HER2 IHC: Cohort 1 pCR Cohort 2 pre-treatment 3+/post treatment 1-2+, and Cohort 3 pre-treatment 3+/post treatment 3+. A Kaplan-Meier survival analysis was done to assess recurrence free survival at 36 months. Results: Within the specified time interval, we identified 104 patients with localized HER2-IHC 3+ breast cancer who received neoadjuvant therapy. The pCR rate was 62.5% (65/104), while 37.5% (39/104) of patients had RD. Among patients with RD, 58.9% (23/39) remained HER2 IHC 3+ and 41% (16/39) had decreased HER2 expression IHC1+/IHC 2+. Median follow-up was 27.9 months at time of analysis. In patients with HER2 3+ RD 26% (6/23) developed local recurrence or distant metastasis while none of patients with HER2 IHC 1+ or 2+ RD had relapse ( p= 0.0309). In patients with pCR, 6.15% (4/65) had recurrence. Kaplan-Meier survival analysis showed a significant difference between the 3 groups (log rank p= 0.004). Conclusions: In our retrospective cohort, decreased HER2 expression by IHC following neoadjuvant treatment was associated with lower recurrence rates. If confirmed, RD HER2 IHC expression could be used as a prognostic biomarker to select patients for more or less aggressive adjuvant therapy, stratify patients in adjuvant trials, and identify patients who may benefit from more intensive post therapy surveillance.

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).

115P Human epidermal growth factor receptor-2 (HER-2) expression status in patients with cholangiocarcinoma

Cholangiocarcinoma is the most common primary cancer of liver in North-Eastern region of Thailand. Human epidermal growth factor receptor-2 (HER-2) overexpression is a poor prognostic factor of many types of cancer but there is limited data in cholangiocarcinoma. This study aimed to investigate prevalence of HER-2 overexpression in cholangiocarcinoma and analyzed its association with overall survival and clinicopathological features.

Signet Ring Cell Esophageal Adenocarcinoma: A Rare Histologic Variant

A 68-year-old man with a history of heavy smoking presented with 3 weeks of dysphagia to solids. Endoscopy revealed erythema in the lower esophagus with scattered white plaques covering umbilicated nodules (Figure A); on gastric retroflexion, these lesions extended beyond the esophagogastric junction (Figure B). Infectious esophagitis, specifically esophageal candidiasis or herpes esophagitis, was suspected, but surprisingly the biopsies revealed squamous mucosa with infiltrating adenocarcinoma containing copious signet ring cells (SRC) (Figure C: low [left] and high [right] magnification; arrows indicate SRC with large intracellular mucin-containing vacuoles displacing nuclei to the cell periphery). SRC comprised >50% of the tumor mass. Immunostaining detected overexpressed programmed death-ligand-1 (PD-L1) but not human epidermal growth factor receptor-2 (HER-2). Positron emission tomography/computed tomography revealed distal esophageal wall thickening with mild metabolic uptake but no enlarged, metabolically active lymph nodes. Endoscopic-ultrasonography revealed an irregular circumferential mucosal mass extending 36 cm from the incisors to 1 cm distal to the esophagogastric junction, invading the adventitia but not regional lymph nodes (Figure D). The cancer progressed despite neoadjuvant chemoradiotherapy, esophagectomy, and adjuvant immunotherapy; the patient died 8 months after presentation. SRC adenocarcinoma accounts for <10% of esophageal adenocarcinomas and portends a worse outcome. Clearly, the presence of esophageal skip lesions should not exclude the possibility of neoplasia. The prevalence and prognostic value of PD-L1 and HER-2 overexpression in esophageal SRC adenocarcinoma are unknown.

Analysis of the Influencing Factors of Sentinel Lymph Node Metastasis in Breast Cancer.

Objective To analyze and discuss the influencing factors of sentinel lymph node metastasis in breast cancer. Methods A total of 469 breast cancer patients admitted in the Department of Pathology of Guangdong Women and Children Hospital from October 2016 to December 2021 were retrospectively analyzed. The general information, immunohistochemical expression, tumor molecular subtype, tumor size, histological grade, pathological type, and tumor location were collected and the relationship with sentinel lymph node metastasis was analyzed. Results For patients with different age, Ki-67 and Human epidermal growth factor receptor-2 (HER-2) immunohistochemical expression level (invasive cancer), molecular subtype (invasive cancer), tumor size, histological grade (invasive cancer) and pathological type. The results of multivariate logistic regression analysis showed that the age was less than or equal to 40 years; the molecular subtype was Luminal B and HER-2 overexpression (invasive cancer); tumor was larger; the histological grade (invasive cancer) was higher; the pathological type was invasive carcinoma, there were independent risk factors for sentinel lymph node metastasis in breast cancer. The sentinel lymph node metastasis rates of invasive lobular carcinoma, invasive micropapillary carcinoma, and metaplastic carcinoma (all met the criteria for squamous cell carcinoma and histological grade III) were higher than 50% in special invasive carcinomas. Conclusion Age, expression level of Ki 67 and HER-2, molecular typing, tumor volume and histological grade are all high-risk factors related to sentinel lymph node metastasis of breast cancer. When one or more of the above factors are involved in an examination, pathologists should be more cautious in making a sentinel lymph node frozen diagnosis. By standardizing the sampling and increasing the number of frozen sections (slicing more frozen tissue layers), the section quality can be improved. This may be conducive to reducing the false negative rate and reducing the pain and risk of secondary surgery.

Targeted inhibition of HER-2 positive breast cancer cells by trastuzumab functionalized pullulan-doxorubicin nanoparticles

Human epidermal growth factor receptor-2 (HER-2) positive breast cancer is highly invasive with poor clinical outcomes and high risk of recurrence. Here, trastuzumab functionalized pullulan-doxorubicin nanoparticles (Tz-P-Dox) were developed and characterized as a new anticancer formulation for active targeting HER-2 overexpression of breast cancer cells. The obtained nanoparticles had the hydrodynamic diameter of 66.7 ± 2.0 nm and PDI of 0.218 ± 0.012. And the in vitro results showed significant difference of cell uptake and cytotoxic effect between Tz-P-Dox and non-targeted P-Dox against HER-2 positive cell lines (BT474 and MCF-7 cells). However, the differences between Tz-P-Dox and P-Dox were not observed in HER-2 negative cell lines (MDA-MB-231 cells). These results suggested that trastuzumab functionalized nanoparticles had great potential to be considered as a candidate drug for HER-2 positive breast cancer treatment.

Clinicopathological Characteristics and Survival Outcomes of Mammary Paget's Disease: A Retrospective Study Based on a Chinese Population.

BackgroundMammary Paget’s disease (PD) is a rare type of breast cancer. Most cases of PD are presented with underlying ductal carcinoma in situ (DCIS) or invasive breast carcinoma (IDC). This study aimed to investigate the clinicopathological characteristics and survival outcomes of PD patients.Materials and MethodsA total of 406 patients diagnosed with PD with IDC/DCIS at Fudan University Shanghai Cancer Center (FUSCC) were recruited as the PD group, 1218 patients diagnosed with IDC/DCIS alone during the same period were selected as the non-PD group, and the clinicopathological results of these two groups were compared. The Surveillance, Epidemiology, and End Results (SEER) database was used to investigate the clinicopathological features between PD and non-PD patients for validation.ResultsCompared with the non-PD group, the PD group was much more likely to have larger (≥2 cm: 43.1% vs 35.5%, P < 0.001), less hormone receptor (HR)-positive (68.5% vs 26.6%, P < 0.001), more human epidermal growth factor receptor-2 (HER-2)-positive (70.7% vs 27.5%, P < 0.001) and higher Ki-67 proportion (51.5% vs 42.5%, P < 0.001) tumors. The HER-2 overexpression subtype accounted for the largest proportion in the PD-IDC group and the lowest proportion in the non-PD-IDC group (54% vs 8%, P < 0.01). Moreover, the PD group had significantly worse disease-free survival (DFS) than the non-PD group (5-year DFS: 91.8% vs 97.3%, P = 0.001), and the SEER database showed a similar trend. Univariate and multivariate Cox regression analyses demonstrated that PD was an independent poor-risk factor. Our matched study showed that the PD group had worse survival than the non-PD group after excluding age, HR, HER-2, tumor size and lymph node status.ConclusionPD with IDC/DCIS is associated with more aggressive tumor characteristics and worse survival outcomes. More than half of PD breast cancers are HER-2 overexpression subtype. PD is an independent poor-risk factor for breast cancer survival.

Detection of Genetic Polymorphism of HER2 Gene in HER2 Positive Breast Cancer Women in Iraq

The human epidermal growth factor receptor-2 (HER2) gene plays a critical role in breast cancer development and progression. HER2 overexpression characterizes a biologically and clinically aggressive breast cancer subtype. In this study, 60 samples from Iraqi women with breast cancer were collected and investigated for HER2 protein in the tissue by immunohistochemistry. Also, 20 samples from healthy Iraqi women were used as a control. The results showed that 18 (30 %) patients expressed the HER2 protein. A molecular study for single nucleotide polymorphism (SNP) was conducted on samples metastasizing to lymph nodes. DNA was extracted and polymerase chain reaction (PCR) was performed to amplify exon 17 and intron 17 of HER2 gene. Sequencing of PCR product was achieved and two SNPs of HER2 gene, one in exon 17 (Ile655Val) and another close to it in intron 17 (rs903506) were studied. In exon 17, SNP Ile655Val was found in 41% of patients, while in intron 17, the non-coding SNP rs903506 was found in 27% of patients. However, no polymorphism was found in the control group. The results may suggest that HER2 gene can be used as a molecular marker for breast cancer.

Retrospective analysis of HER2-low in young breast cancer patients.

e12515 Background: Traditionally, breast cancer (BC) is considered human epidermal growth factor receptor-2 (HER2) positive based on HER2 overexpression or amplification (HER2 3+ or ISH positive HER2 2+). However, an emerging subgroup of HER2 negative (HER2 1+ or 2+ and ISH negative) known as HER2-Low is associated with poor prognosis than HER2-normal (HER2 0). Currently, there is an increased interest in developing new drugs targeting HER2-Low BC to improve survival. The fact that BC in young constitutes a significant minority outside the western world but is underrepresented in clinical trials, it is worth conducting a dedicated study of HER2-low in this population to determine whether it affects their outcome. Methods: Confirmed HER2 negative BC patients aged ≤40 diagnosed in 2012-2017 were retrospectively reviewed in two centers in Alexandria, Egypt. Patients were classified as HER2-low (1+, 2+) and HER2-normal. The clinicopathological characteristics and survival outcome were determined and compared. Results: There were five hundred HER2 negative BC patients; 82% were hormone receptor-positive (HR+) vs.18% triple-negative (TNBC). Among the HER2 negative, only 31% were HER2-Low (n = 155), of which 20% was HER2-Low 1+ while 11% was HER2-Low 2+. In comparison, HER2-Low was significantly more HR+ than HER2-normal (89% vs. 79% respectively, p = 0.009). Other tumor characteristics (T-size, nodal status, Ki-67, lymphovascular invasion - LVI, extracapsular extension - ECE) were similar in HER2-Low and HER2-normal. So were the disease-free survival (DFS) and overall survival (OS). Nevertheless, sub-grouping HER2-Low into 1+ and 2+ showed significant differences in tumor characteristics between HER2-normal, HER2-Low 1+, and HER2-Low 2+, in nodal status, tumor stage, ECE, and HR status. Moreover, DFS was significantly lower in HER2-Low 2+ (63.5%) compared to HER2-normal (70%) and HER2-Low 1+ (75%); p = 0.039. Also, the OS was also significantly lower in HER2-Low 2+ compared to HER2-normal, 90% vs 96% respectively, p = 0.023. Conclusions: Our results suggest no significant difference in DFS and OS between HER2-Low and HER2-normal in young BC patients. However, subdividing HER-low into HER2-low 1+ and HER2-Low 2+ better discriminates this group; HER2-Low 2+ had significantly poor DFS and OS and this should be considered in the clinical trials.

Somatic Mutations in HER2 and Implications for Current Treatment Paradigms in HER2-Positive Breast Cancer.

In one of every four or five cases of breast cancer, the human epidermal growth factor receptor-2 (HER2) gene is overexpressed. These carcinomas are known as HER2-positive. HER2 overexpression is linked to an aggressive phenotype and a lower rate of disease-free and overall survival. Drugs such as trastuzumab, pertuzumab, lapatinib, neratinib, and the more recent afatinib target the deregulation of HER2 expression. Some authors have attributed somatic mutations in HER2, a role in resistance to anti-HER2 therapy as differential regulation of HER2 has been observed among patients. Recently, studies in metastatic ER + tumors suggest that some HER2 mutations emerge as a mechanism of acquired resistance to endocrine therapy. In an effort to identify possible biomarkers of the efficacy of anti-HER2 therapy, we here review the known single-nucleotide polymorphisms (SNPs) of the HER2 gene found in HER2-positive breast cancer patients and their relationship with clinical outcomes. Information was recompiled on 11 somatic HER2 SNPs. Seven polymorphisms are located in the tyrosine kinase domain region of the gene contrasting with the low number of mutations found in extracellular and transmembrane areas. HER2-positive patients carrying S310F, S310Y, R678Q, D769H, or I767M mutations seem good candidates for anti-HER2 therapy as they show favorable outcomes and a good response to current pharmacological treatments. Carrying the L755S or D769Y mutation could also confer benefits when receiving neratinib or afatinib. By contrast, patients with mutations L755S, V842I, K753I, or D769Y do not seem to benefit from trastuzumab. Resistance to lapatinib has been reported in patients with L755S, V842I, and K753I. These data suggest that exploring HER2 SNPs in each patient could help individualize anti-HER2 therapies. Advances in our understanding of the genetics of the HER2 gene and its relations with the efficacy of anti-HER2 treatments are needed to improve the outcomes of patients with this aggressive breast cancer.

Correlation of Muscle Invasion in Bladder Cancer with Cell Adhesion Properties and Oncoprotein Overexpression Using E-Cadherin and HER2/neu Immunohistochemical Markers.

BACKGROUND: Most of bladder cancers are proven to be of urothelial origin (transitional cell carcinomas). Above 75% of them are of non-muscle invasive bladder cancer (NMIBC) type at presentation and the remainder are MIBC. Recent studies suggest that both are most probably two different categories based on both the histopathological and molecular features. The comprehensive understanding of the biomarkers expression in both categories will help in understanding the molecular event underlying each of them and may provide possible chances for targeted therapeutic options.&#x0D; AIM: This study aims to study the differential expression of both E-cadherin and human epidermal growth factor receptor-2 (HER2) in the two categories of bladder cancer NMIBCs and MIBCs.&#x0D; MATERIALS AND METHODS: A total of 40 blocks were collected retrospectively from cases of cancer bladder, segregated as 20 cases NMIBCs and 20 cases MIBCs, subjected for E-cadherin and HER2 immunostaining.&#x0D; RESULTS: E-cadherin showed positive expression in 65% of cases of NMI group and in 10% of the MI group, with high statistical significance (p &lt; 0.001). Regarding HER2, positive expression was seen in 25% of NMI cases and in 90% of MI cases, with statistical significance (p &lt; 0.001). Comparison of the results of both markers and their correlation per case showed that 90% of tumors with muscle invasion were E-cadherin negative and HER2 positive.&#x0D; CONCLUSION: The significant association of loss of E-cadherin immunohistochemistry expression and positive HER2 overexpression in MIBC versus NMIBC figured out more differences between the two categories and added to the understanding of their biology. The possibility of validation of HER2-targeted therapy in MIBC cases is now strongly suggested.

In vivo studies of a peptidomimetic that targets EGFR dimerization in NSCLC.

Studies related to lung cancer have shown a link between human epidermal growth factor receptor-2 (HER2) expression and poor prognosis in patients with non-small cell lung cancer (NSCLC). HER2 overexpression has been observed in 3-38% of NSCLC, while strong HER2 protein overexpression is found in 2.5% of NSCLC. However, HER2 dimerization is important in lung cancer, including EGFR mutated NSCLC. Since HER2 dimerization leads to cell proliferation, targeting the dimerization of HER2 will have a significant impact on cancer therapies. A peptidomimetic has been designed that can be used as a therapeutic agent for a subset of NSCLC patients overexpressing HER2 or possessing HER2 as well as EGFR mutation. A cyclic peptidomimetic (18) has been designed to inhibit protein-protein interactions of HER2 with its dimerization partners EGFR and HER3. Compound 18 exhibited antiproliferative activity in HER2-positive NSCLC cell lines at nanomolar concentrations. Western blot analysis showed that 18 inhibited phosphorylation of HER2 and Akt in vitro and in vivo. Stability studies of 18 at various temperature and pH (pH 1 and pH 7.6), and in the presence of liver microsomes indicated that 18 was stable against thermal and chemical degradation. Pharmacokinetic parameters were evaluated in nude mice by administrating single doses of 4 mg/kg and 6 mg/kg of 18 via IV. The anticancer activity of 18 was evaluated using an experimental metastasis lung cancer model in mice. Compound 18 suppressed the tumor growth in mice when compared to control. A proximity ligation assay further proved that 18 inhibits HER2:HER3 and EGFR: HER2 dimerization. Overall, these results suggest that 18 can be a potential treatment for HER2-dimerization related NSCLC.

The Association of HER-2 Over-expression in Relation to Hormonal Receptor Status and Common Clinico-pathological Parameters in Breast Carcinoma

Objective: To determine the association of Human Epidermal growth factor Receptor2 (HER-2) with hormonal receptor status and common clinico-pathological parameters of breast carcinoma. Study Design: Cross-sectional, observational study. Place and Duration of Study: Department of Surgery, Sir Salimullah Medical College Mitford Hospital, Dhaka, Bangladesh during the period from January 2009 to December 2009. Methodology: A total of 100 patients of female breast carcinoma with HER-2 status, hormonal receptor profile and clinico-pathological parameters were included in this study. Patient's age, menopausal status, tumour size, lymph node status, Estrogen Receptor (ER) and Progesterone Receptor (PR) status were evaluated and their association was determined with H.ER-2 over expression using the chi-square test for analysis. Results: Of these 100 cases, mean age of diagnosis was 48 years and mean tumour size 4.4 cm. Lymph node metastases were present in 50% cases. HER-2 over-expression was seen in 29% cases, while ER and PR expression was seen in 61 % and 43% respectively. ER and PR showed inverse association (p &lt;0.05) with HER-2 while positive association was seen with tumour size and lymph node metastases (p &lt;0.05). No association was seen with menopausal status. Further, among 61 ER positive cases, 4 cases also HER-2 over expressed. Conclusion: The study had indicated that Her-2 may be a powerful predictor of poor prognosis as its over-expression was strongly directly associated with tumor size and lymph node involvement and inversely associated with hormonal receptor status of breast carcinoma. ER positive cases can also be HER-2 over expressed (4%), so ER status cannot be used to select tumours for evaluation of HER-2 status. As treatment modalities of ER positive and HER-2 over expressed is different, so all the patients should be studied with both receptor and treat accordingly.&#x0D; Journal of Surgical Sciences (2012) Vol. 16 (2) : 59-67

Abstract P6-09-12: Using multiphoton laser scanning microscopy to assess neoadjuvant therapy outcome in core needle biopsies: A novel methodology

Abstract Background: Over-expression of Human Epidermal Growth Factor receptor-2 (HER2) in breast cancer is associated with an aggressive clinical course and poor prognosis. Targeting HER2 over-expression has been shown to be a remarkably effective therapeutic modality in the metastatic, adjuvant and neoadjuvant setting and the pathologic response to neoadjuvant treatment in HER2-positive breast cancer has been shown to be an excellent surrogate for a good outcome. The stromal tumor microenvironment is implicated in fostering tumor growth, facilitating cell migration and ultimately resulting in metastatic disease. Specifically, the collagenous extracellular matrix, which includes fibrillar collagen, has been suggested to play a role in the migration of malignant breast epithelial cells within the surrounding stroma. We have developed a novel methodology which uses an intrinsic optical signature to quantitatively evaluate fibrillar collagen (Burke et al. BMC Cancer 15 (2015): 929). Here, we evaluate the ability of this quantitative methodology to predict the pathologic response after neoadjuvant HER2-targeted treatment as assessed by the Residual Cancer Burden score/class (RCB). This quantitative evaluation in pre-treatment biopsies is then correlated with the pathologic response to treatment in the post-therapy resection. Material and Methods: Clinical pathologic variables for 29 cases of HER2-positive breast cancer that had undergone neoadjuvant chemotherapy plus HER2-targeted therapy were retrieved from the medical record database at URMC, including the post-treatment RCB score and ER/PR/HER2 status. Second harmonic generation (SHG) is an intrinsic optical signal produced by fibrillar collagen. To quantify collagen microstructure in the pre-treatment core biopsy, we used SHG imaging to determine the average forward to backward-light scattering ratio (F/B). The F/B ratio is sensitive to structural properties of collagen fibers. Results: Logistic regression was used to assess the association between F/B and the binary response variable RCB class (0/1 or 2/3). A likelihood ratio test was used to calculate the p-value to test whether the regression coefficient for F/B was zero (i.e. no effect) in the tumor-stromal interface. The average F/B ratio at the leading edge of the tumor stratified by RCB class is shown in Table 1. When evaluated in the bulk of the tumor tissue, F/B was not correlated with RCB status; however, when evaluated at the leading edge of the tumor stromal interface, F/B was significantly correlated with RCB status (p=0.035). Table 1:RCB class and average F/BRCB class (n)Average F/B ± SEM0/1 (19)16.95 ± 1.062/3 (10)12.32 ± 1.84 Conclusions: We have previously shown that the measurement of F/B in the primary tumor after resection is an independent prognostic indicator of metastasis-free survival in breast cancer. Our results in the current study furthers these observations and suggests that the evaluations of the microstructure of collagen fibers by F/B measurement from the pre-treatment biopsy, specifically at the leading edge of the tumor-stroma interface, may be useful for predicting pathologic response to trastuzumab-based neoadjuvant therapy. Further studies in a larger patient cohort are warranted. Citation Format: Desa DE, Turner BM, Buscaglia B, Hill RL, Strawderman RL, Hicks DG, Brown EB. Using multiphoton laser scanning microscopy to assess neoadjuvant therapy outcome in core needle biopsies: A novel methodology [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-09-12.

Elevated serum HER‐2 predicts poor prognosis in breast cancer and is correlated to ADAM10 expression

Human epidermal growth factor receptor‐2 (HER‐2) overexpression in breast tumor tissues is associated with a poor prognosis but may benefit from treatment with trastuzumab. The extracellular domain (ECD) of HER‐2 can be measured in serum and which has been a new inspection item in clinical laboratory of several hospitals. However, whether serum HER‐2 ECD can be a marker of HER‐2 status in tumor tissues still confused clinicians. This study is a retrospective observation to explore the correlation between serum HER‐2 ECD shedding and tissue HER‐2 status in breast cancer patients. Meanwhile, we will further uncover the potential clinical significance of serum HER‐2 ECD detection. A total of 545 unselected breast cancer patients from Fudan University Shanghai Cancer Center were enrolled in this study. At primary diagnosis without any treatment, serum HER‐2 ECD was measured on ADVIA Centaur assay; meanwhile, tissue HER‐2 from core needle biopsy was tested through immunohistochemistry (IHC) and fluorescent in situ hybridization (FISH). We showed that serum HER‐2 ECD concentration was related to tissue HER‐2 status. Nevertheless, 36.9% of patients with tissue HER‐2 overexpression had low levels of HER‐2 ECD shedding (<15 ng/mL) in serum. Here, we demonstrated that HER‐2 ECD shedding was also associated with protein expression and alpha‐secretase activity of a disintegrin and metalloproteinase 10 (ADAM10) using tumor tissues and cell lines. Progression‐free survival (PFS) data from breast cancer patients in TNM phase II and III with tissue HER‐2 IHC 3+ were analyzed using Kaplan‐Meier plotter. The patients with serum HER‐2 ECD above 15 ng/mL had lower progression‐free survival than those with serum HER‐2 ECD <15 ng/mL. Thus, serum HER‐2 ECD could be a biomarker to identify the subgroup of poorer outcome among HER‐2 overexpression breast cancer patients. Inhibition of ADAM10 activity may have potential therapeutic benefit for this most aggressive tumor subgroup.

HER2 status in patients with residual rectal cancer after preoperative chemoradiotherapy: the relationship with molecular results and clinicopathologic features.

The specific role of human epidermal growth factor receptor-2 (HER2) status in rectal cancers remains unclear. This study therefore aimed to explore clinicopathologic and molecular characteristics, and prognostic value of HER2-positivity in residual mid- and/or low-rectal cancers after preoperative chemoradiotherapy (CRT). Surgical specimens from 145 patients with residual rectal cancer after preoperative CRT between January 2006 and January 2011 were used to evaluate HER2 status. HER2 protein expression and gene amplification were determined using immunohistochemistry (IHC) and silver in situ hybridization (SISH) on whole tissue sections, respectively. Polymerase chain reaction was used to analyze molecular characteristics, including microsatellite instability (MSI) and mutations in KRAS exon 2 (codon 12 and 13) and BRAF V600E mutation. Of 139 eligible patients, 8 (5.8%) had HER2 overexpression (IHC 2+ and 3+) that was not associated with clinicopathologic characteristics and patient survival, except positive circumferential resection margin (CRM) (P = 0.012). SISH was performed on 24 patient samples with IHC 1+ (n = 16), 2+ (n = 6), and 3+ (n = 2). HER2 amplification was identified in 3 patients (2.2%); however, this was also associated with positive CRM (P = 0.009) but not survival (all P > 0.05). Moreover, HER2 overexpression and amplification had no relationship with KRAS or BRAF mutations, and MSI status (all P > 0.05). HER2 positivity was found in a minority of rectal cancer patients and was not significantly associated with clinicopathologic and molecular characteristics. Our findings can be helpful in understanding the clinicopathologic bases of HER2 status in rectal cancers.

An Intersection Between the Immune System and Cellular Signaling Pathways - The Impact of Anti-HER2 Monoclonal Antibodies on Individualized Approaches to Patients with Breast Cancer

1. Abstract Overexpression or gene amplification of Human Epidermal Growth Factor Receptor 2 (HER2) is present in approximately 20% of breast cancers, and indicates an aggressive tumor behavior. Activated HER homo and heterodimers orchestrate a downstream signaling network that regulates cell growth, proliferation and malignant spread. Trastuzumab, as a monoclonal antibody that inhibits the HER2, has immensely improved the outcome of patients with HER2-positive breast cancer. Since trastuzumab targets abnormal expression of HER2 in tumors, which are ‘addicted’ to HER2 activation, its therapeutic effects have been attributed to blocking of the intracellular signaling pathways. Moreover, the immune system is involved in the therapeutic impact of trastuzumab or similar anti-HER2 monoclonal antibodies. Various molecular pathways are relevant to HER2 overexpression, as well as the expression of other members of the Epithelial Growth Factor Receptor (EGRF) family. In addition, the estrogen and progesterone activity can interfere with the effects of trastuzumab and/or Chemotherapy (CHT) regimen, especially in patients with metastatic, HER2-positive malignancy. This article presents some insights to the signaling pathways, relevant to progression of breast cancer. It explains molecular characteristics that play a key role in affecting tumor response and resistance to HER2-targeted treatments. It also highlights the need for patient stratification, to develop the most reasonable de-escalation approaches, using HER2-targeted monoclonal antibodies. In addition, some practical strategies to overcome the resistance to trastuzumab, via targeting the main signaling pathways, in the context of HER2-positive and Hormone Receptor (HR)-positive metastatic or locally advanced breast cancer have been discussed, based on evidence from recent clinical trials. 2. Keywords: <span style=font-size:10.0pt;mso-ansi-language:EN-US;mso-fareast-language: PL>Breast Cancer; Estrogen Receptor (ER); Human Epidermal Growth Factor Receptor 2 (HER2) Monoclonal Antibodies; Trastuzumab; Signaling Pathways

HER2 Ile655Val polymorphism is negatively associated with breast cancer susceptibility.

The HER2 (human epidermal growth factor receptor-2) Ile655Val (rs1136201) genetic polymorphism can alter the receptor structure and its auto-activation, which can modify the signal transduction and, consequently, the cell cycle regulation. For this reason, this polymorphism has been extensively investigated as a candidate marker for breast cancer (BC). In this context, the aim of this study was to evaluate the possible influence of HER2 Ile655Val in BC susceptibility and prognostic factors in a Brazilian population. Polymorphism genotype was assessed through RFLP-PCR in 107 BC patients with clinicopathological data available and in 150 women with no evidence of neoplasia and with no familial history of BC as control group. Association between this polymorphism and BC susceptibility and clinical parameters was evaluated through odds ratio (OR) and chi-squared or Fisher's exact test, respectively. A significant negative association between valine allele and BC susceptibility in dominant model was found (OR 0.5; 95% CI 0.27-0.93, P=.036). No significant association was found in relation to BC clinicopathological features (tumor size, lymph nodes commitment, histological grade, HER2 overexpression, hormonal receptors, p53, and Ki-67). Although this polymorphism did not demonstrate potential as a prognostic marker, it may be a suitable susceptibility marker for BC.

Altered expression of HER-2 and the mismatch repair genes MLH1 and MSH2 predicts the outcome of T1 high-grade bladder cancer.

The identification of factors predicting the outcome of stage T1 high-grade bladder cancer (BC) is a major clinical issue. We performed immunohistochemistry to assess the role of human epidermal growth factor receptor-2 (HER-2) and microsatellite instability (MSI) factors MutL homologue 1 (MLH1) and MutS homologue 2 (MSH2) in predicting recurrence and progression of T1 high-grade BCs having undergone transurethral resection of bladder tumor (TURBT) alone or TURBT + intravesical instillations of bacillus Calmette-Guerin (BCG). HER-2 overexpression was a significant predictor of disease-free survival (DFS) in the overall as well as in the two patients' population; as for progression-free survival (PFS), it was significant in the overall but not in the two patients' population. MLH1 was an independent predictor of PFS only in patients treated with BCG and MSH2 failed to predict DFS and PFS in all populations. Most importantly, the higher the number of altered markers the lowers the DFS and PFS. In multivariate Cox proportional-hazards regression analysis, the number of altered molecular markers and BCG treatment were significant predictors (p = 0.0004 and 0.0283, respectively) of DFS, whereas the number of altered molecular markers was the only significant predictor (p = 0.0054) of PFS. Altered expression of the proto-oncogene HER-2 and the two molecular markers of genetic instability MLH1 and MSH2 predicted T1 high-grade BC outcome with the higher the number of altered markers the lower the DFS and PFS. These findings provide grounds for further testing them in predicting the outcome of this challenging disease.