Proposal to distinguish HER2-low from HER2-normal breast cancer by in situ hybridisation.

AIMS: 'HER2-low' breast cancer is an emerging issue as the clinical trials for anti-HER2 antibody-drug conjugates (trastuzumab deruxtecan) are making progress. A reliable method to identify HER2-low cancers is needed. This study aimed to evaluate immunohistochemistry (IHC) and in situ hybridisation (ISH) in detecting HER2-low status. METHODS: We evaluated the HER2 ISH data grouped by the IHC consensus in proficiency tests (PTs), and compared the HER2 ISH results between HER2 IHC scored 0 (IHC-0) and IHC scored 1+ (IHC-1+) tumours from in-house tissue microarrays (TMAs). Since benign/normal glands have HER2 expression and ideally should not be affected by targeted therapy, we evaluated HER2 ISH results in peritumoural benign glands of 52 breast cancers as reference values. RESULTS: None of the 565 tissue cores in PTs achieved an 80% participant agreement of IHC-1+. In PTs and in-house TMAs, HER2 signals of the IHC-1+cores (median: 2.6 and 2.0, respectively) were significantly higher than those of IHC-0 cores (median: 2.0 and 1.7, respectively). But the ranges of HER2 signals had a considerable overlap between IHC-1+and IHC-0 cores. The HER2 signals and HER2:CEP17 ratios of peritumoural benign glands exhibited normal distributions, and their upper bounds of the 95% reference intervals were 2.10 and 1.30, respectively. CONCLUSIONS: Current HER2 testing algorithms are unsatisfactory in detecting HER2-low cases. Using ISH to detect tumour with HER2 signals and HER2:CEP17 ratio higher than the upper bound of the benign glands can be an alternative method.

Research progress of precise targeted therapy for human epidermal growth factor receptor-2 in biliary tract cancers / 中华肝胆外科杂志

Biliary tract cancers (BTC) are highly heterogeneous tumours. Currently, the global demand for advanced BTC treatment is far from being met, and the survival benefit from advanced chemotherapy is limited. In recent years, with the rise of precision treatment, there are more and more treatment options available for advanced BTC. Human epidermal growth factor receptor-2 (HER2) inhibitors, including monoclonal antibodies, tyrosine kinase inhibitors, antibody drug conjugates, and bispecific antibodies, have been explored in BTC. This article reviews the research progress and prospects of HER2 inhibitors in BTC in recent years, so as to provide a better clinical guidance.

CT Findings From Interstitial Lung Diseases in Patients With Metastatic Breast Cancer Treated With Fam-Trastuzumab Deruxtecan: A Single Institutional Experience.

This single-institute, retrospective cohort study enrolled patients with human epidermal growth factor receptor 2-positive metastatic breast cancer treated with trastuzumab deruxtecan between August 2017 and January 2021 from four previous studies. Of 31 patients, 4 (12.9%) had interstitial lung disease (ILD). The dominant pattern observed on computed tomography was organizing pneumonia (100%), comprising subpleural consolidations in the lung periphery. However, no dominant distribution was observed in radiological lesions of the lungs. Of all the tested patients, lower lobe predominance was noted in 2 (50.0%) patients, upper lobe predominance in 1 (25.0%) patient, and diffused lobe distribution in 1 (25.0%) patient. All events were confined to the Common Terminology Criteria for Adverse Events grade 1 or 2 (100%). None of the patients died. Despite the small number of cases investigated, the incidence of trastuzumab deruxtecan-induced ILD in the Korean population was comparable to that previously reported.

Case series of docetaxel, trastuzumab, and pertuzumab (DTP) as first line anti-HER2 therapy and ado-trastuzumab emtansine (T-DM1) as second line for recurrent or metastatic HER2-positive salivary duct carcinoma.

OBJECTIVE: Salivary duct carcinoma (SDC) overexpresses Human Epidermal growth factor Receptor 2 (HER2) in 29-46% of cases, favoring anti-HER2 therapy. Here, we present the results of patients with recurrent or metastatic HER2-positive SDC treated with docetaxel, trastuzumab, and pertuzumab (DTP) as first line anti-HER2 therapy and subsequently ado-trastuzumab emtansine (T-DM1) in second line. Furthermore, we searched for potential biomarkers. METHODS: Retrospective case series from a tertiary hospital. First line anti-HER2 treatment consisted of DTP, after progression T-DM1 was considered for patients with an adequate performance status. Objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were assessed and related to mRNA-based PI3K and MAPK signaling pathway activity scores. RESULTS: Thirteen SDC HER2 + patients received DTP. In twelve evaluable patients, one complete response (CR) and six partial responses (PR) were observed (ORR 58%), with a median PFS of 6.9 months (95%-CI 5.3-8.5). Seven patients received subsequent T-DM1 in second line, resulting in four PR (ORR 57%), with a median PFS of 4.4 months (95%-CI 0-18.8). Median OS after start of DTP was 42.0 months (95%-CI 13.8-70.1). Grade ≥ 3 toxicity on DTP was seen in 39% of patients, and 14% on T-DM1. Highest combined PI3K and MAPK signaling was seen in the patient with CR and lowest in the patient with progressive disease on DTP. CONCLUSION: In R/M HER2-positive SDC patients DTP followed by T-DM1 upon progression are promising treatments, leading to responses in the majority (58%) of the patients at an acceptable toxicity profile.

Carcinoma mamario RH negativo en el Hospital Clínico Quirúrgico Docente Celestino Hernández Robau / Rh negative breast carcinoma at the Teaching Clinic Surgical Hospital Celestino Hernandez Robau

RESUMEN Introducción: El carcinoma mamario negativo a la expresión de receptores hormonales (RH negativo) incluye los subtipos moleculares Her-2/neu y triple negativo, asociados ambos a una mayor actividad biológica del tumor y un pronóstico desfavorable. Objetivo: Determinar la incidenciade los carcinomas triples negativos y Her-2/neu en carcinomas mamarios y su relación con variables clínico-patológicas de valor pronóstico. Métodos: Se realizó unestudio descriptivo, de corte transversal, en el Hospital Celestino Hernández, Villa Clara, entre enero de 2017 a junio de 2019. Se incluyeron 293 mujeres con diagnóstico de carcinoma de mama infiltrante, a cuyas biopsias se les realizó estudio inmunohistoquímico determinando la incidencia de los subtipos moleculares triple negativo y Her2/neu y su relación con otras variables de valor pronóstico. Resultados: En la serie se determinó la incidencia de los subtipos moleculares triples negativo y Her2/neu. En ambos subtipos moleculares, más de las dos terceras partes de las pacientes fueron mayores de 50 años, presentaron tallas tumorales mayor de 2 cm en el momento del diagnóstico y tuvieron histología ductal. Destaca además la relación de ambos subtipos moleculares con formas histológicas moderada y pobremente diferenciadas del carcinoma mamario. De igual forma, en ambos subtipos, el índice de proliferación determinado por Ki67 fue alto en más de las dos terceras partes de las pacientes estudiadas. Conclusiones: La edad posmenopáusica, el tipo histológico ductal, el grado histológico alto, el alto índice de Ki67 y la talla tumoral mayor de 2 cm se asocian con frecuencia a subtipos moleculares del carcinoma mamario negativos a receptores hormonales.

ABSTRACT Introduction: The breast carcinoma which is negative to the expression of hormonal receptors (negative RH) includes the molecular subtypes Her2/neu and triple negative, that are both associated to higher biological activity and a worse forecast. Objective: To determine the real incidence of the subtypes triple negative and Her2/neu in breast carcinoma and its correlation with prognostic value clinic-pathological variables. Methods: A descriptive, cross-sectional study was done in the Hospital Celestino Hernández, Villa Clara, from January 2017 to June 2019. It was included 293 women with diagnosis of infiltrating breast carcinoma, whose biopsies were studied by immunohistochemistry, determining the incidence of the molecular subtypes triple negative and overexpression of Her-2 and its correlation with others prognostic value variables. Results: In the series it was determined the incidence of the molecular subtypes triple negative and Her2/neu. In both molecular subtypes more two third of patients were older than 50 years old, had tumor size larger than 2 cm at the moment of diagnosis and had ductal histology. The correlation of the both molecular subtypes with moderately and poorly histological types of breast carcinoma stands out. In the same way the proliferation index determined by Ki67 was high in more two third of the studied patients. Conclusions: The post-menopausal age, the ductal histologic type, high histologic grade, high index of Ki67 and tumor size larger than 2 cm are often associated to molecular subtypes of breast carcinomas which are negative to the expression of hormonal receptors.

The role played by human epidermal growth factor receptor 2 amplification/overexpression in gallbladder cancer and its association with clinico-pathology and prognosis / 中华肝胆外科杂志

Objective:To study the amplification / overexpression of human epidermal growth factor receptor 2 (HER2) in patients with gallbladder cancer, and to analyze the correlation between amplification/overexpression of HER2 with clinicopathological features and survival in patients after R 0 resection. Methods:There were 14 males and 26 females, aged (60.3±8.7) years old and treated at the Cancer Hospital of Chinese Academy of Medical Sciences from January 2011 to December 2016 who met the inclusion criteria of the study. Immunohistochemistry and fluorescence in situ hybridization were used to detect amplification / expression of HER2 in resected tumor tissues. Patients were divided into two groups according to the HER2 gene expression: the HER2-negative group ( n=40) and the HER2-positive group ( n=10). The Chi-square test was used to analyze the relationship between amplification/expression of HER2 and clinicopathological parameters. Patients were followed up by telephone for prognosis. The Kaplan-Meier method was used for survival analysis. The Cox proportional hazard model was used to explore factors affecting prognosis of gallbladder cancer patients. Results:HER2 amplification/overexpression was found in 10 patients with gallbladder cancer, with a positive rate of HER2 being 20.0% (10/50). There was a significant difference in the proportion of patients with vascular tumor thrombus between the HER2 negative group and the HER2 positive group [7.5%(3/40) vs. 30.0%(3/10), P<0.05]. On follow-up, data of 46 patients was available. There were 36 patients in the HER2-negative group and 10 patients in the HER2-positive group. Compared with the HER2-negative group, the median recurrence-free survival (10.10 vs. 75.07 months) and the median overall survival (16.77 vs. 83.07 months) of the HER2-positive group were both significantly lower (both P<0.05) than the HER2-negative group. Univariate analysis showed HER2 positivity to be a risk factor for recurrence-free and overall survival in patients with gallbladder cancer after radical resection. Cox multivariable analysis revealed that lymph node metastasis was an independent risk factor for both recurrence-free ( HR=4.31, 95% CI: 1.92-9.68, P<0.001) and overall survival ( HR=3.44, 95% CI: 1.08-11.00, P=0.037). Conclusion:Amplification / overexpression of HER2 was associated with venous invasion and worse prognosis in patients with gallbladder cancer.

HER-2 positivity is a high risk of recurrence of stage I gastric cancer.

BACKGROUND/AIMS: The treatment of gastric cancer remains unsatisfactory. We aimed to investigate the prognostic value of immunohistochemical staining in gastric cancer. METHODS: We analyzed 505 (279 early staged, 226 advanced-staged) gastric cancer tissues from patients who underwent radical gastric resection between January 2014 and December 2016. Available surgical specimens immunohistochemically stained for p53, epidermal growth factor receptor (EGFR), human EGFR 2 (HER-2), E-cadherin, and Ki-67 were reviewed. We evaluated the association between positivity to various biomarkers and disease recurrence, disease-free survival, lymph node metastasis, and microscopic lymphovascular invasion. RESULTS: The median follow-up duration was 32.5 months (range, 7 to 70). Advanced gastric cancer cases showed high Ki-67 expression; other cases showed unremarkable expression. Concerning disease recurrence, lymphatic invasion, and disease-free interval, all biomarkers had no prognostic effects. HER-2-positive stage I gastric cancer tended to occur in old patients and in the upper one-third of the stomach (p = 0.01). HER-2 positivity was significantly correlated with disease recurrence (p = 0.01), lymphatic invasion (p = 0.03), and vascular invasion (p = 0.03) in stage I cases. CONCLUSION: Only HER-2 was associated with the recurrence of stage I gastric cancer. HER-2-positive stage I gastric cancer requires additional therapy despite curative resection.

Clinical Features of Breast Cancer in South Korean Patients with Germline TP53 Gene Mutations.

PURPOSE: Li-Fraumeni syndrome (LFS) is a rare autosomal cancer syndrome caused by a germline mutation in the TP53 gene. Breast cancer in LFS patients is of various subtypes; however, limited data are available on the clinicopathological features of these subtypes and their appropriate treatments. This study aimed to review the clinical features and treatments for breast cancer in South Korean patients with germline TP53 mutations. METHODS: Data on the clinicopathological features and treatment of all breast cancer patients with LFS were collected retrospectively from the available database of 4 tertiary hospitals in the Republic of Korea. RESULTS: Twenty-one breast cancer cases in 12 unrelated women with confirmed germline TP53 mutations were included in the study. The median age at diagnosis was 33.5 years. The histopathological diagnosis included invasive ductal carcinoma (n = 16), ductal carcinoma in situ (n = 3), and malignant phyllodes tumor (n = 2). While 42% and 31% of the cases were positive for estrogen and progesterone receptors, respectively, 52.6% were human epidermal growth factor receptor 2 (HER2) positive, and 21% were triple-negative. The treatments included mastectomy (52%) and breast-conserving surgery (38%). Five patients underwent radiotherapy (RT). The median follow-up period was 87.5 (8-222) months. There were 3 ipsilateral and 4 contralateral breast recurrences during the follow-up, and 8 patients developed new primary cancers. In the post-RT subgroup, there were 2 ipsilateral and 2 contralateral breast recurrences in 1 patient, and 4 patients had a new primary cancer. CONCLUSION: As reported in other countries, breast cancer in LFS patients in South Korea had an early onset and were predominantly but not exclusively positive for HER2. A multidisciplinary approach with adherence to the treatment guidelines, considering mastectomy, and avoiding RT is encouraged to prevent RT-associated sequelae in LFS patients.

Elastosis in Breast Cancer as a Surrogate Marker for Estrogen Receptor Positivity.

OBJECTIVES: We sought to describe the occurrence of stromal elastosis in breast carcinoma among Omani female patients using semi-quantitative methods. We also sought to investigate the relationship between stromal elastosis and estrogen receptor (ER), progesterone receptor (PR), HER2/neu receptor tumor grade, and Ki-67 index. Furthermore, we evaluated the diagnostic accuracy of hematoxylin and eosin (H&E) stain method in quantifying elastosis compared to Elastin van Gieson (EVG) stain and if elastosis can be used as prognostic marker for overall survival. METHODS: The content of elastic tissue in primary infiltrating carcinomas of the breast was assessed using semi-quantitative methods (H&E and EVG stains) in 80 female Omani patients by two independent pathologists. Data of primary breast cancer patients who were not treated with neoadjuvant therapy from 2009 to 2019 at the Armed Forces Hospital of Oman were collected from medical records. Demographic and clinical data, including age, menstrual status, tumor type and grade, ER, PR, HER2/neu status, and Ki-67 index were obtained. Follow-up data, including clinical remission, evidence of metastasis, death, or lost follow-up were traced from medical records. RESULTS: Among the 80 cases studied, 80.0% were diagnosed with invasive ductal carcinoma, not otherwise specified, while 12.6% were diagnosed with infiltrating lobular carcinoma. Interobserver agreement of grading elastosis on H&E and EVG was strong (Kappa coefficient = 0.858). Using EVG, absent elastosis, grade 1, grade 2, and grade 3 were observed in 12.5%, 37.5%, 30.0%, and 20.0%, respectively. A statistically significant relationship between high elastosis and ER positivity (p = 0.015) and negative HER2/neu receptor (p = 0.045) was observed. No statistically significant relationship between elastosis and other entities, including menopausal status, tumor type and grade, PR, Ki-67, and prognosis. The sensitivity and specificity of quantifying elastosis on H&E stained sections compared to EVG stain (the gold standard) were 68.75% and 96.88%, respectively. CONCLUSIONS: Elastosis occurrence varies in different breast cancer populations. Elastosis can be considered a surrogate marker for estrogen positivity and HER2/neu negativity in breast cancer patients. In addition, H&E stain is considered an accurate method for quantifying elastosis compared to the EVG staining method.

Advances in the amplification of HER2 in metastatic colorectal cancer / 国际肿瘤学杂志

Several studies have shown that human epidermal growth factor receptor 2 (HER2) amplification could be a predictive biomarker of resistance to anti-epidermal growth factor receptor monoclonal antibodies in patients with RAS wild-type metastatic colorectal cancer (mCRC). Dual HER2 inhibition with trastuzumab plus lapatinib or pertuzumab has shown promising preliminary anti-tumoral efficacy in RAS wild-type mCRC. HER2-targeted therapeutic strategies have the potential to change the treatment paradigm for a clinically relevant subgroup of patients with mCRC.

Analysis of the correlation of PELP1/MNAR expression with expressions of estrogen receptor, human epidermal growth factor receptor 2, Ki-67 and PIK3CA gene mutation in invasive breast cancer / 肿瘤研究与临床

Objective:To investigate the correlation of PELP1/MNAR expression with expressions of estrogen receptor (ER), Ki-67, human epidermal growth factor receptor 2 (HER2) and PIK3CA gene mutation.Methods:A total of 80 paraffin-embedded tissue specimens of primary invasive breast cancer patients in the Fifth People's Hospital of Datong in Shanxi Province from January 2008 to December 2018 were collected. The expression of PELP1/MNAR was examined by immunohistochemistry EliVision tow-step method. The polymerase chain reaction (PCR)-Sanger sequencing method was used to detect the mutation of PIK3CA gene. The expressions of PELP1/MNAR among patients with different expression status of ER, Ki-67, HER2 and with or without PIK3CA gene mutation were compared, and the correlations between each index and the expression of PELP1/MNAR were analyzed.Results:The high expression rates of PELP1/MNAR protein in patients with ER-positive [86.1% (31/36) vs. 59.1% (26/44)], Ki-67 high expression [100.0% (13/13) vs. 65.7% (44/67)], HER2-positive [81.0% (34/42) vs. 60.5% (23/38)] were high, and the differences were statistically significant (all P<0.05). There was no significant difference in the high expression rate of PELP1/MNAR protein between patients with mutant and wild-type PIK3CA [60.0% (12/20) vs. 75.0% (45/60), P = 0.199]. The expression of PELP1/MNAR was negatively correlated with the expression level of ER ( r = -0.195, P < 0.05), positively correlated with the expression level of Ki-67 ( r = 0.198, P < 0.05), positively correlated with the expression level of HER2 ( r = 0.225, P < 0.05), and negatively correlated with lymph node metastasis ( r = -0.269, P < 0.05). Conclusions:The expression of PELP1/MNAR in invasive breast cancer is negatively correlated with the expression level of ER, and positively correlated with the expression level of Ki-67 and HER2. There is no correlation between PELP1/MNAR expression and PIK3CA gene mutation, and the two may play their own role in the PI3K-AKT-mTOR regulatory pathway of breast cancer.

[Reevaluation of equivocal HER2 status detected by immunohistochemistry according to the 2019 guidelines for HER2 detection].

Objective To understand the effects and clinical significance of the 2019 guidelines for the human epidermal growth factor receptor 2 (HER2) detection. Methods: According to the 2014 guidelines, 548 cases of invasive breast cancer with equivocal HER2 (2+) detected by immunohistochemistry (IHC) in Taizhou Enze Medical Center, Zhejiang Province, China from 2013 to 2019 were selected. The results of IHC and HER2/CEPl7 double-probe were reevaluated and divided into groups according to the 2019 guidelines for the comparative analysis. Results: Among the 548 IHC HER2 (2+) invasive breast cancers, the number of positive, equivocal and negative cases for HER2 were 96 (17.52%), 81 (14.78%) and 371 (67.70%), respectively, according to the 2014 guidelines. However, according to the 2019 guidelines, 10 cases (1.82%) were reclassified as IHC 1+, 2 cases in the group 2 were reclassified as negative, and all the originally equivocal cases in group 4 were reclassified as negative. Finally, the total number of positive and negative cases for HER2 were 94 (17.15%) and 454 (82.85%), respectively. Conclusions: After applying the 2019 guidelines, the number of IHC 2+ cases decreases, and the positive rate for HER2 also decreases slightly due to the reevaluation change in groups 2 and 4, leading to reclassification of the cases that were deemed equivocal according to the 2014 guidelines. In general, the new 2019 guidelines are more reasonable and easier to use.

[Correlation between HER2 expression before neoadjuvant treatment and RCB classification after surgical treatment in breast cancer].

Objective: To explore the relationship between the expression of human epidermal growth factor receptor 2 (HER2) in core needle biopsy (CNB) specimens before neoadjuvant chemotherapy (NAC) and post NAC Residual Cancer Burden (RCB) classification in breast cancer. Methods: This retrospective study included 150 patients with CNB proven invasive breast carcinoma in the Fourth Hospital of Hebei Medical University from January 2013 to January 2014. Immunohistochemistry (IHC) or fluorescence in situ hybridization (FISH) was used to detect the expression of HER2 in the CNB specimens. RCB was used to assess the chemotherapy response of patients. SPSS 21.00 and GraphPad Prism 8.0.1 were used for data statistics; Chi square test and Fisher's exact test for correlation analysis, and Cox regression for survival analysis. P<0.05 was considered statistically significant. Results: Among the 150 patients, there were 38 RCB-0, 12 RCB-Ⅰ, 61 RCB-Ⅱ and 39 RCB-Ⅲ post NAC. RCB-0 meant pathological complete response (PCR). Statistical analysis found that the pre NAC HER2 expression was related to PCR and RCB classification after surgery (r1=‒0.217,r2=‒0.282;P<0.05). Further analysis demonstrated that in the HER2-positive group, PCR was associated with prolonged OS and DFS (HR=2.939, 2.359; P<0.05); the differences of OS and DFS in RCB classifications were more significant (P<0.05) in the HER2 positive than HER2 negative groups. Conclusion: There is a correlation between pre NAC HER2 expression and PCR and RCB classification after treatment. In HER2-positive patients, the prognostic stratification of RCB classification is more obvious, suggesting that pre NAC HER2 overexpression combined with RCB classification after surgery can more accurately predict the prognosis.

Prognostic value of PSMA, c-MET and E-cadherin in salivary duct carcinoma.

OBJECTIVES: Salivary duct carcinoma (SDC) is a rare and aggressive subtype of salivary gland cancer. Androgen receptor (AR) (96%) and HER2 (29-46%) expression, and a high propensity for regional lymph node metastases are hallmarks of the disease. We hypothesized that c-MET, E-cadherin, PSMA tumor and PSMA neovascular expression may be prognostic factors in SDC. MATERIALS AND METHODS: Expression levels of these proteins were established on tissue microarrays containing 165 primary SDC tumor specimens. Association with survival was studied with Kaplan-Meier curves, and univariable and multivariable Cox regression models. Furthermore, association with lymph node status, AR and HER2 expression, and gender was studied. RESULTS: We found that patients with high PSMA tumor expression showed a significantly longer overall survival (OS) (median 83 vs. 43 months, P = 0.022), a trend towards a longer DFS (median 51 vs. 22 months, P = 0.094), and significantly reduced hazard ratio for death in the univariable Cox regression model (HR 0.46, P = 0.034). In the multivariable model only a high number of tumor-positive lymph nodes and high age (>80) at diagnosis were prognostic for poor OS. High PSMA tumor expression was also significantly associated with low N-stage (P = 0.001) and expression was higher in women versus men (P = 0.029). High PSMA tumor expression and E-cadherin loss were significantly associated with strong and weak AR-expression, respectively (P = 0.033 and P = 0.007). None of the factors were significantly associated with HER2 expression. CONCLUSION: c-MET, E-cadherin, and tumor and neovascular PSMA expression are no independent prognostic factors in SDC.

Incidence of Brain Metastases in Nonmetastatic and Metastatic Breast Cancer: Is There a Role for Screening?

BACKGROUND: Current National Comprehensive Cancer Network and American Society of Clinical Oncology guidelines recommend against screening breast cancer patients for asymptomatic brain metastases. Because brain metastases are a major cause of morbidity and mortality from breast cancer, we undertook a literature review to ascertain whether there might be a role for brain metastases screening in high-risk patient subgroups. MATERIALS AND METHODS: A literature search was conducted on the OvidSP platform in the MedLine database, using MeSH terms and subject headings related to breast cancer, brain metastases, and incidence. The search was conducted without language or publication restrictions, and included articles indexed from January 1, 2006 to June 10, 2018. Experimental and observational studies that reported the incidence of brain metastases in patients with nonmetastatic or metastatic breast cancer were included. RESULTS: One hundred seventy studies were identified, with 33 included in the final analysis. Among nonmetastatic breast cancer patients, incidence of brain metastases as site of first recurrence per year of median follow-up ranged from 0.1% to 3.2%. Although incidence of brain metastases was much higher among the metastatic breast cancer population overall, it was particularly high among metastatic HER2-overexpressing (HER2+) and triple-negative populations, ranging between 22% and 36% for the former, and 15%-37% for the latter in the absence of screening. CONCLUSION: In patients with nonmetastatic breast cancer, screening for asymptomatic brain metastases cannot currently be justified. However, due to the high incidence of brain metastases among patients with metastatic HER2+ and triple-negative breast cancer, studies to determine the value of screening for brain metastases should be undertaken in these subgroups.

Systemic therapy for gallbladder cancer.

Gallbladder cancer is an aggressive cancer that continues to be an important health care issue in certain regions of the world such as Southeast Asia and Latin America. Most patients are diagnosed at an advanced, unresectable stage and systemic therapy is their only option. Gallbladder cancer patients have traditionally been included in clinical trials for biliary tract cancer. Thus, systemic chemotherapy options for this cancer are similar to those for cholangiocarcinoma, including gemcitabine and cisplatin in the first line and FOLFOX in the second-line setting. Ongoing phase III clinical trials may change the systemic therapy paradigm for this cancer. Molecular profiling has indicated important genetic differences between gallbladder cancer and cholangio-carcinoma, which affects choice of targeted therapy. Her2/neu amplification, PIK3CA mutations and DNA repair genetic aberrations are relatively frequent and represent actionable targets for this cancer.

[HER2 status in gastric adenocarcinoma of Chinese: a multicenter study of 40 842 patients].

Objective: To investigation HER2 status in gastric adenocarcinoma of Chinese and contributing factors to the HER2 expression. Methods: HER2 status of 40 842 gastric adenocarcinomas and clinical data were retrospectively collected from 23 hospitals dated from 2013 to 2016. The association between HER2 positivity and clinicopathologic features was analyzed. Results: Of the 40 842 patients the median age was 62 years, the male female ratio was 2.6∶1.0. The rate of HER2 positivity was 8.8% (3 577/40 842). HER2 expression was related to the tissue type, tumor location, Lauren classification and tumor differentiation (P values: 0.009, 0.001, <0.01 and <0.01, respectively). Different HER2 expression status was observed between primary and recurrent tumors in 7.6% (48/635) cases. The rates of HER2 positivity ranged from 2% to 10% among different institutions. The rates of HER2 FISH amplification were dramatically different among the 23 hospitals (0-100%) with an average rate of 10% (810/8 156) in patients with HER2 IHC 2+ . Conclusions: HER2 expression is associated with clinicopathologic characteristics. HER2 re-assessment of tumor tissue and use of in situ hybridization techniques increase HER2 positivity. The current retrospective study should reflect the HER2 status in gastric adenocarcinoma of Chinese patients.

[HER2 gene status and mRNA expression in immunohistochemistry 1+ breast cancer].

Objective: To investigate human epidermal growth factor 2 (HER2) gene status and in situ mRNA expression in breast cancers with immunohistochemistry(IHC) 1+ , and to reveal HER2 positive rate in these patients to provide reference data for obtaining precise HER2 results and modifying relevant clinical strategy to breast cancer. Methods: Sixty-five IHC 1+ formalin-fixed and paraffin-embedded samples of invasive breast carcinoma of no special type (IBC-NST) were collected by surgical operation at Peking Union Medical College Hospital during 2011 to 2013. HER2 status and in situ mRNA expression were tested by fluorescence in situ hybridization (FISH) and RNAscope, respectively, by using tissue microarray. Metastatic lymph node was re-tested by FISH if HER2 status was equivocal or negative and with high expression of mRNA in the primary lesion. Results: Four of 65 samples (6.2%) were FISH positive, which included 2 cases of HER2/CEP17>2 and average HER2 copy number>4 and 2 cases of HER2/CEP17<2 and average HER2 copy number>6. In the 4 samples of HER2 positive, 2 patients showed high in situ mRNA expression (3 scores by RNAscope), 2 patients showed moderate in situ mRNA expression (2 scores by RNAscope). In addition, 3 specimens with HER2/CEP17>2 and average HER2 copy number<4 were found in all patients, which included 2 cases of high in situ mRNA expression (3 and 4 scores by RNAscope) and 1 cases of moderate in situ mRNA expression (2 scores by RNAscope). There was no significant association between HER2 status or mRNA expression and clinicopathological characteristics, including tumor size, histopathological differentiation, lymph node metastasis and lymphovascular invasion (P>0.05). Conclusions: A small number of HER2 IHC 1+ patients exist mRNA expression by using FISH method, which suggested that these patients might benefit from anti-HER2 therapy potentially. Since the importance for patients with breast cancers to develop diagnostic and therapeutic strategies from accurate molecular typing, further studies based on a larger cohort are needed to validate our findings.

HER2 status in gastric adenocarcinoma of Chinese: a multicenter study of 40 842 patients / 中华病理学杂志

Objective@#To investigation HER2 status in gastric adenocarcinoma of Chinese and contributing factors to the HER2 expression. @*Methods@#HER2 status of 40 842 gastric adenocarcinomas and clinical data were retrospectively collected from 23 hospitals dated from 2013 to 2016. The association between HER2 positivity and clinicopathologic features was analyzed. @*Results@#Of the 40 842 patients the median age was 62 years, the male female ratio was 2.6∶1.0. The rate of HER2 positivity was 8.8% (3 577/40 842). HER2 expression was related to the tissue type, tumor location, Lauren classification and tumor differentiation (P values: 0.009, 0.001, <0.01 and <0.01, respectively). Different HER2 expression status was observed between primary and recurrent tumors in 7.6% (48/635) cases. The rates of HER2 positivity ranged from 2% to 10% among different institutions. The rates of HER2 FISH amplification were dramatically different among the 23 hospitals (0-100%) with an average rate of 10% (810/8 156) in patients with HER2 IHC 2+ . @*Conclusions@#HER2 expression is associated with clinicopathologic characteristics. HER2 re-assessment of tumor tissue and use of in situ hybridization techniques increase HER2 positivity. The current retrospective study should reflect the HER2 status in gastric adenocarcinoma of Chinese patients.

HER2 gene status and mRNA expression in immunohistochemistry 1+ breast cancer / 中华病理学杂志

Objective@#To investigate human epidermal growth factor 2 (HER2) gene status and in situ mRNA expression in breast cancers with immunohistochemistry(IHC) 1+ , and to reveal HER2 positive rate in these patients to provide reference data for obtaining precise HER2 results and modifying relevant clinical strategy to breast cancer.@*Methods@#Sixty-five IHC 1+ formalin-fixed and paraffin-embedded samples of invasive breast carcinoma of no special type (IBC-NST) were collected by surgical operation at Peking Union Medical College Hospital during 2011 to 2013. HER2 status and in situ mRNA expression were tested by fluorescence in situ hybridization (FISH) and RNAscope, respectively, by using tissue microarray. Metastatic lymph node was re-tested by FISH if HER2 status was equivocal or negative and with high expression of mRNA in the primary lesion.@*Results@#Four of 65 samples (6.2%) were FISH positive, which included 2 cases of HER2/CEP17>2 and average HER2 copy number>4 and 2 cases of HER2/CEP17<2 and average HER2 copy number>6. In the 4 samples of HER2 positive, 2 patients showed high in situ mRNA expression (3 scores by RNAscope), 2 patients showed moderate in situ mRNA expression (2 scores by RNAscope). In addition, 3 specimens with HER2/CEP17>2 and average HER2 copy number<4 were found in all patients, which included 2 cases of high in situ mRNA expression (3 and 4 scores by RNAscope) and 1 cases of moderate in situ mRNA expression (2 scores by RNAscope). There was no significant association between HER2 status or mRNA expression and clinicopathological characteristics, including tumor size, histopathological differentiation, lymph node metastasis and lymphovascular invasion (P>0.05).@*Conclusions@#A small number of HER2 IHC 1+ patients exist mRNA expression by using FISH method, which suggested that these patients might benefit from anti-HER2 therapy potentially. Since the importance for patients with breast cancers to develop diagnostic and therapeutic strategies from accurate molecular typing, further studies based on a larger cohort are needed to validate our findings.