Neoadjuvant chemotherapy with trastuzumab in HER2-positive breast cancer: pathologic complete response rate, predictive and prognostic factors

The purpose of this study was to retrospectively review the pathologic complete response (pCR) rate from patients (n=86) with stage II and III HER2-positive breast cancer treated with neoadjuvant chemotherapy at our institution from 2008 to 2013 and to determine possible predictive and prognostic factors. Immunohistochemistry for hormone receptors and Ki-67 was carried out. Clinical and pathological features were analyzed as predictive factors of response to therapy. For survival analysis, we used Kaplan-Meier curves to estimate 5-year survival rates and the log-rank test to compare the curves. The addition of trastuzumab to neoadjuvant chemotherapy significantly improved pCR rate from 4.8 to 46.8%, regardless of the number of preoperative trastuzumab cycles (P=0.0012). Stage II patients achieved a higher response rate compared to stage III (P=0.03). The disease-free and overall survivals were not significantly different between the group of patients that received trastuzumab in the neoadjuvant setting (56.3 and 70% at 5 years, respectively) and the group that initiated it post-operatively (75.8 and 88.7% at 5 years, respectively). Axillary pCR post neoadjuvant chemotherapy with trastuzumab was associated with reduced risk of recurrence (HR=0.34; P=0.03) and death (HR=0.21; P=0.02). In conclusion, we confirmed that trastuzumab improves pCR rates and verified that this improvement occurs even with less than four cycles of the drug. Hormone receptors and Ki-67 expressions were not predictive of response in this subset of patients. Axillary pCR clearly denotes prognosis after neoadjuvant target therapy and should be considered to be a marker of resistance, providing an opportunity to investigate new strategies for HER2-positive treatment.

Her2 expression as a prognostic factor in metastatic gastric cancer

ABSTRACT Background - Human epidermal growth factor receptor 2 (EGFR2/HER2/ErbB2) is a transmembrane receptor that stimulates cell proliferation when activated. The correlation of HER2 expression with prognosis has been studied in many cancer types. However, its relationship with survival of patients with metastatic gastric cancer remains unknown. Moreover, there is a lack of information on this issue in a Brazilian population. Objective - To assess the proportion of patients whose tumor cells express HER2 and correlate this with clinical characteristics as well as treatment outcomes. Methods - This was a retrospective study. We included adult patients with metastatic gastric cancer treated at an University Hospital between 2011 and 2015. Patients did not receive anti-HER2 therapy. Receptor expression was evaluated by immunohistochemistry. Survival risk factors were assessed individually with univariate Cox regression, and a P value <0.05 was considered statistically significant. Results - Forty-nine patients were included in this study. However, only 32 had samples assessed for HER2 expression. Five (16%) patients were positive. Among HER2-negative patients, the average age was 54 years, 44% received a treatment protocol with three drugs, 70% had a performance status score 0-1, and 41% had well or moderately differentiated histology. Among HER2-positive patients, the average age was 58 years, 40% received three drugs, 100% had a performance status score 0-1, and 67% had well or moderately differentiated histology. Response rate was evaluated in 28 cases, and there was no difference between the groups (HER2-negative 52% vs. HER2-positive 40%; P=0.62). Survival outcomes were numerically worse among HER2-positive patients. Median progression-free survival was 8.3 months for HER2-positive patients and 10.6 months for HER2-negative patients (HR 1.61, 95% CI: 0.59-4.38); median overall survival was 14.8 months and 16.9 months for HER2-positive and HER2-negative patients, respectively (HR 1.52, 95% CI: 0.50-4.66). Conclusion - HER2 overexpression in metastatic gastric cancer patients may be a predictor of poor prognosis and further validation is warranted.

RESUMO Contexto - O receptor 2 do fator de crescimento epidermal humano (EGFR2/HER2/ErbB2) é um receptor transmembrana que estimula a proliferação celular quando ativado. A expressão de HER2 foi estudada em diversas neoplasias, como câncer gástrico. No entanto, sua relação com a sobrevida dos pacientes com câncer gástrico metastático permanece desconhecida. Além disso, há falta de informação sobre este assunto na população brasileira. Objetivo - Avaliar a proporção de pacientes cujas células tumorais expressam HER2 e correlacionar essa característica com aspectos clínicos e também com os desfechos do tratamento. Métodos - Este é um estudo retrospectivo. Foram incluídos pacientes adultos com câncer gástrico metastático tratados em um Hospital Geral Universitário entre 2011 e 2015. Nenhum paciente recebeu terapia anti-HER2. A expressão do receptor foi avaliada por imuno-histoquímica. Fatores de risco para a sobrevida foram avaliados com regressão de Cox univariada e valor P<0,05 foi considerado estatisticamente significativo. Resultados - Quarenta e nove pacientes foram incluídos neste estudo. No entanto, 32 tiveram amostras avaliadas para expressão de HER2. Cinco (16%) pacientes foram positivos. Entre os pacientes HER2 negativos: a idade média foi de 54 anos, 44% receberam um protocolo com três drogas, 70% apresentavam um score de status performance 0-1, 41% tinham histologia bem ou moderada diferenciada. Entre os pacientes HER2 positivos: a média de idade foi de 58 anos, 40% receberam três drogas, 100% apresentavam um score de status performance de 0-1, 67% tinham histologia bem ou moderada diferenciada. A taxa de resposta foi avaliada em 28 casos e não houve diferença entre os grupos (HER2 negativo 52% e HER2 positivo de 40%; P=0,62). A sobrevida foi menor entre pacientes HER2 positivos. As medianas de Sobrevida Livre de Progressão foram 8,3 meses e 10,6 meses, respectivamente (HR 1,61; IC 95%: 0,59-4,38). As medianas de Sobrevida Global foram 14,8 meses e 16,9 meses, respectivamente (HR 1,52; IC 95%: 0,50-4,66). Conclusão - A expressão tumoral de HER2 pode ser um fator de pior prognóstico para pacientes portadores de câncer gástrico metastático e uma validação futura desses achados se faz necessária.

Serum Her-2/Neu a potential biomarker in breast cancer patients: correlation with the clinico-pathological parameters

Background: Breast cancer is the most common malignancy in women, and a major cause of mortality and morbidity despite the advances in diagnosis and treatment. There is evidence that changes in HER2 protein expressions are associated with breast cancer progression

Objective: To investigate whether measuring this tumour marker in serum of breast cancer patients before and after treatment might also be useful markers in the diagnosis, screening and monitoring the malignant tumour progression and response to therapy

Methods: Serum samples were obtained from [28] apparently healthy women [Control Group] with a mean age of 40.9 +/- 7.6 years and [60] female patients complaining from primary breast cancer [Patients Group] with a mean age of 48.3 +/- 8.9 years. They were divided according to their clinical end point into: Pre-Surgical Group, Post-Surgical Group and post- chemotherapy Group. Serum Her-2/nue level was measured using ELISA kits

Results: Level of Her2/neu [3130.4 pg/ml] was significantly higher in after 6 cycles of chemotherapy group than each of control [1400.8 pg/ml], before surgery [1597 pg/ml] and after surgery [1487.4 pg/ml] [P <0.05]. Her2/neu is effective test only after 6 cycle chemotherapy with an accuracy of 95.2%. The best performance for Her2neu was observed at values >/= 1464 pg/ml [sensitivity = 95% and specificity = 6 1%]. There were significant influences of the studied personal and the pathological characteristics of the tumour upon the biomarker levels where the levels were significantly higher with the increase of tumour pathological stage and in the presence of positive status for Her2neu receptors [P <0.05]

Conclusion: In this study there was a statistically significant association between tissue HER-2/neu and serum HER-2 /neu levels in the extracellular domain. It could be concluded that using serum Her-2/neu in patients after six cycles chemotherapy could predict response to therapy

Pattern of human epidermal growth factor receptor 2 [HER2] expression in invasive breast carcinoma, immunohistochemical - study on patients in Upper Egypt

Breast cancer is a major public health problem throughout the world. It accounts for 38% of all new cancer cases among women living in Egypt. One of the most important prognostic and determinant factor of the line of its treatment is the human epidermal growth factor receptor 2 [HER2], it is associated with the more aggressive phenotype. Attention has been focused on the expression of HER2 receptor proteins in breast cancer cells especially its membranous domain, it resulted in variable results concerning its percentage of expression as well as its geographic distribution. So there is a need to study HER2 types of expression in breast cancer patients in our location as well as its correlation with the clinicopathological parameters. HER2 expression in 336 retrospective breast cancer specimens was examined immunohistochemically using tissue microarray. Expression was scored into 0, 1, 2 and 3 degrees and was correlated with clinicopathological criteria. HER2 expression in our specimens showed both membranous and cytoplasmic staining patterns. 18.6% of specimens showed membranous immunoreactivity and 74.1% specimens showed cytoplasmic staining pattern. Significant statistical association was found between cytoplasmic staining of HER2 and tumors of low grade, ER positivity [p<0.001, 0.001, 0.008] respectively. There was statistical significance difference between high membranous expression of HER2 and ER negativity [p=0.038], but our results didn't find significant difference with tumor size, lymphvascular invasion or lymph node metastasis. The frequency of high membranous expression of HER2 in our specimens is 18.6% and inversely correlated with ER positive tumors. This group of patients should be subjected to specific treatment with Trastuzumab, to improve their survival. Surprisingly cutoplasmic expression detected in most of our patients with frequency of 74.1% with positive relationship to low tumor grade and hormone receptor positive tumors. Since this group of patients may be resistant to trastuzumab and need specific treatment with tyrosine kinase drug inhibitors, this observation is going to be discussed and need to be followed up in the future

Clinical outcome of adjuvant endocrine treatment according to Her-2/neu status in breast cancer.

Background & objectives: An association between over-expression of proto-oncogene Her-2/neu and resistance to tamoxifen in estrogen receptor (ER) positive, primary and metastatic breast cancer has been suggested. HR+/Her-2/neu+ patients have a poor response to endocrine therapy, making this group a matter of debate. The present study was carried out to examin whether Her-2/neu expression in breast cancer patients predicted tamoxifen effectiveness. Methods: An enzyme-linked immunosorbent assay (ELISA) specific for the extracellular domain of the Her-2/neuoncoprotein product was used to detect serum Her-2/neu levels in 207 patients with histological confirmed breast cancer. Tissue Her-2/neu expression was studied in 100 breast cancer patients by immunohistochemistry (IHC) and compared with serum Her-2/neu levels by ELISA. Results: Among 207 histologically confirmed breast cancer patients, 53 were serum Her-2/neu positive. Patients who were treated with surgery, chemotherapy, and radiotherapy showed significantly (P<0.05) reduced serum Her-2/neu levels, showing good response to treatment. Patients who were treated with tamoxifen in addition to the above regimen did not show any significant reduction in serum Her-2/neu levels showing resistance to treatment. Interpretation & conclusions: The present findings study support the hypothesis that Her-2/neu overexpression contributes to tamoxifen resistance. Trastuzumab or other growth factor inhibitors should be used in combination with tamoxifen, since monotherapy is not likely to be optimal in HR+/Her-2/neu+ tumours.

Do survivin and HER-2/neu play a role in rheumatoid arthritis?

Rheumatoid arthritis [RA] is an inflammatory joint disease characterized by hyperplasia of synovial tissue and pannus formation growing invasively into the cartilage, followed by cartilage and bone destruction. In RA, the proliferation of synovial fibroblasts and their invasive growth are due to impairment in the regulation of the cell cycle. Survivin belongs to the apoptosis-inhibiting proteins [IAP] family and regulates the inflammatory and destructive process inside the joints of patients with RA. RA Synovial Fibroblasts [SFs] over express the ErbB2/HER2 member of the epidermal growth factor [EOF] receptor family relative to normal fibroblasts. The aim was to study the role of survivin and HER-2/neu in the pathogenesis of RA and the association between their level and the presence of erosion in RA patients and evaluation of the possible influence of the ongoing treatment on their serum level. In this study, serum survivin and serum HER-2/neu levels were measured in 35 erosive and non-erosive RA patients and compared with age and sex matched healthy population. There was a statistically significant difference in serum HER-2/neu between RA patients and controls and also between RA patients treated with methotrexate and those treated with methotrexate and others. There was a statistically significant difference in the serum level of survivin between erosive and non-erosive RA patients

[Correlation between serum and un-stimulated whole saliva c-erbB-2 concentrations in women with breast cancer]

Human saliva can be easily obtained by non-invasive techniques. It contains many analytes of interest for screening, diagnosis and monitoring of normal and abnormal conditions. The protein c-erbB-2, also known as Her2/neu, is a prognostic breast cancer marker in women diagnosed with malignant tumors. The aim of this study was to assess the relationship between serum and saliva levels of c-erbB-2 in healthy women and untreated and treated patients with breast cancer. A case-control study design was used for this investigation. A total of forty two women were included in the study. Participants were matched for age and were divided into three equal groups. The collected specimens were evaluated for the expression of c-erbB-2 levels in serum and unstimulated whole saliva by ELISA technique. The ANOVA and Pearson Correlation were used for data analyses. Significant lower unstimulated salivary flow rate was observed in untreated cases in comparison with healthy women. However, no significant difference was detected in whole saliva output, as well as serum and saliva concentration of c-erbB-2 between the three groups. The correlation of c-erbB-2 between serum and saliva concentrations [r=0.02] and between serum concentration and saliva output [r=0.18] were not statistically significant. It seems that salivary and serum c-erbB-2 concentrations have no correlation in early stages of breast cancer and non-metastatic conditions

Clinical utility of serum human epidermal receptor-2/neu detection in breast cancer patients.

BACKGROUND & OBJECTIVE: In breast cancer, the HER-2/neu gene is amplified in 20-30 per cent of cases. The mechanism by which the amplification/overexpression occurs is not known. Elevated serum HER-2/neu levels have been shown to be associated with a poor clinical prognosis and decreased survival in early stage breast cancer patients, and thus might help in management of the disease. The present study was therefore to estimate the serum HER-2/neu levels in breast cancer patients and associate with other prognostic factors. METHODS: Serum HER-2/neu levels were studied in 207 patients with cancer breast, 15 benign breast diseases (BBD) and 175 age-matched healthy controls. Patients' age, menopausal status, node and hormone receptor status were compared with serum HER-2/neu levels. RESULTS: Serum HER-2/neu overexpression was associated with age, disease stage and positive nodal status but not with menopausal status. Serum HER-2/neu levels were negatively related with hormone receptor positivity. INTERPRETATION & CONCLUSION: HER-2/neu serum test could be done more frequently in women with breast cancer irrespective of the hormone receptor status, to suggest modifications in systemic adjuvant therapy, including possibly the use of Herceptin.

Serum c-erbB-2 protein in breast cancer patients.

Measurements of c-erbB-2 protein were done in sera of 20 normal women, 22 benign breast disease patients and in respectively 43 and 51 samples from primary breast cancer patients obtained prior to and after surgical interventions. Mean value of serum c-erbB-2 in non-malignant women was insignificantly different from the value in the breast cancer group. Positivity rate of serum c-erbB-2 in the cancer group was 13.8 per cent. Increasing postoperative serum c-erbB-2 concentrations were in good association with severity, progressiveness and relapse of breast cancer independently of other variables such as age, menopausal status, tumor size, axillary node invasion, ER or PR status. Pretreatment serum c-erbB-2 positivity was inversely correlated to ER status but relation to other prognostic parameters of breast cancer was not found. Agreement between c-erbB-2 measured in serum by enzymeimmunoassay and in tissue by immunohistochemical assay was also found. Our data confirmed that in primary breast cancer patients, monitoring of circulating c-erbB-2 protein levels after operation are useful for detecting the recurrence and/or metastasis of the disease especially in ER positive breast cancer. Pretreatment serum c-erbB-2 concentrations do not have benefit for early diagnosis of the tumor.

Marcadores tumorais no câncer de mama / Tumors markers in breast cancer

Os marcadores tumorais representariam a possibilidade de se obter uma avaliaçäo da progressäo da doença e de seu tratamento de maneira simples, objetiva e específica. O marcador tumoral sérico ideal deveria apresentar alta especificidade e sensibilidade, o que ainda näo é disponível para o câncer de mama. Quatro tipos principais de marcadores séricos säo disponíveis: antígeneos de mucina (CA 15-3, CA 549, MUCI, entre outros), citoqueratinas (TPA, TPS), antígeno carcinoembriônico (CEA) e produtos séricos de oncogene (c-erbB2). A aplicabilidade clínica é limitada pela identificaçäo dos marcadores tumorais em pacientes com câncer em outros sítios primários, em doenças benignas e em pessoas sadias, sendo possível sua utilizaçäo no seguimento das pacientes tratadas e livres da doença, e no monitoramento do tratamento. Os antígenos de mucina säo os mais sensíveis para o carcinoma da mama, especialmente o CA 15-3. A combinaçäo do CEA com um marcador de mucina parece ser a maneira que apresenta maior sensibilidade no seguimento clínico no câncer de mama