Human Epidermal Growth Factor 2 Status Research Articles

Prognostic significance of epidermal growth factor receptor gene mutations and human epidermal growth factor 2 expression in breast carcinoma metastatic to the liver

Background: Breast cancer is the most prevalent cancer among females, and metastatic disease is not curable and is treated palliatively. Members of the ErbB family have an important role in the development and progression of breast cancer. The aim of this study was to determine the relationship between epidermal growth factor receptor (EGFR) gene mutation, human epidermal growth factor 2 (HER2) expression, hormone receptor statuses, and clinicopathological parameters in liver metastases from breast cancer. Materials and Methods: This study included 41 patients diagnosed with liver metastasis from breast carcinoma, based on morphological and immunohistochemical findings, in our pathology laboratory between 2011 and 2018. EGFR gene mutations were analyzed by polymerase chain reaction (PCR) in these cases. Results: EGFR gene mutation analysis was performed by PCR, and no mutations were detected. HER2 and ER statuses of the primary breast tumor were available in 23 cases. HER2 status conversions were present in 9 cases (39.1%); however, this was not statistically significant (P = 0.197). Estrogen receptor (ER) conversions were present in 4 cases (17.4%); however, this was not statistically significant (P = 1.000). Progesterone receptor (PR) conversions were detected in 10 cases (45.5%). There were 10 (45.5%) cases with PR-positive primary tumors and PR-negative liver metastases. No cases with a PR-negative primary tumor developed a PR-positive liver metastasis (P = 0.02). Conclusions: No EGFR gene mutations were detected in any of our cases by PCR. There was no statistically significant relationship between clinicopathological parameters and EGFR mutation. The comparison of ER, PR, and HER2 expression between the primary tumor and metastases revealed status conversions in some cases. However, only PR conversion was statistically significant. Studies on EGFR gene mutations that include larger series are warranted to identify the candidates who can benefit from targeted therapies.

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.

Rapid micro fluorescence in situ hybridization in tissue sections.

This paper describes a micro fluorescence in situ hybridization (μFISH)-based rapid detection of cytogenetic biomarkers on formalin-fixed paraffin embedded (FFPE) tissue sections. We demonstrated this method in the context of detecting human epidermal growth factor 2 (HER2) in breast tissue sections. This method uses a non-contact microfluidic scanning probe (MFP), which localizes FISH probes at the micrometer length-scale to selected cells of the tissue section. The scanning ability of the MFP allows for a versatile implementation of FISH on tissue sections. We demonstrated the use of oligonucleotide FISH probes in ethylene carbonate-based buffer enabling rapid hybridization within <1 min for chromosome enumeration and 10–15 min for assessment of the HER2 status in FFPE sections. We further demonstrated recycling of FISH probes for multiple sequential tests using a defined volume of probes by forming hierarchical hydrodynamic flow confinements. This microscale method is compatible with the standard FISH protocols and with the Instant Quality FISH assay and reduces the FISH probe consumption ∼100-fold and the hybridization time 4-fold, resulting in an assay turnaround time of <3 h. We believe that rapid μFISH has the potential of being used in pathology workflows as a standalone method or in combination with other molecular methods for diagnostic and prognostic analysis of FFPE sections.

Gastric cancer with brain metastasis and the role of human epidermal growth factor 2 status.

Central nervous system (CNS) metastases from cancers of the gastrointestinal tract (GIT) are rare, and occur in 0.16-0.69% of patients with gastric or gastro-esophageal (GE) junction cancer. Overexpression of the human epidermal growth factor 2 (HER-2) is associated with poor prognosis in the absence of HER-2-targeted therapy, and with an increased incidence of CNS metastases in patients with breast cancer. The role of HER-2 overexpression in CNS metastases is not well known in gastric adenocarcinoma. The purpose of the present retrospective study was to assess the incidence of CNS metastases and to evaluate the associations between the CNS and HER-2 status in a series of consecutive patients with gastric or GE junction cancer. Between 2007 and 2013, 300 patients with gastric cancer (GC) or gastroesophageal junction, were admitted to Piacenza General Hospital, Italy. These cases were retrospectively analyzed to evaluate CNS metastases. The metastases were diagnosed with imaging techniques performed on symptomatic patients. Gastric histological samples of patients with CNS metastases were reviewed and tested for HER-2. A total of 7 of the 300 patients (2.33%) with GC were observed to have CNS metastases and 6 (85.71%) had HER-2 positive disease. These patients exhibited a poor prognosis with a median overall survival rate of 4.1 months (range, 2.1-6.6 months). These results suggested there may be CNS recurrence susceptibility in patients with HER-2 positive GC. To the best of our knowledge, this is the first report that associates CNS metastases and HER-2 status in gastric or GE junction cancer.

Abstract P1-07-32: Validation of the new AJCC eighth edition of the TNM classification for breast cancer with a single center breast cancer cohort

Abstract Introduction : Our understanding of biology of breast cancer has led to significant changes in diagnostic and therapeutic approaches for breast cancer, The new eighth edition of the TNM classification of the AJCC for breast cancer (BC) determined by a multidisciplinary team of BC experts incorporate biologic factors, such as tumor grade, estrogen and progesterone receptor (ER and PR) expression, human epidermal growth factor 2 (HER2) expression, and gene expression prognostic panels in addition to traditional anatomic factors. In this study, we aimed to evaluate prognostic value of this new staging system compared to previous AJCC 7th staging system using single center, long term followed BC cohort. Methods : We conducted a retrospective analysis of women with stage I, II, or III BC who underwent curative surgery with/without adjuvant systemic therapy at Samsung Medical Center between July 2004 and December 2008 (n=3,029). We excluded patients who received neoadjuvant therapy (n=183), and patients with missing information about immunohistochemistry (n=7), HER2 status (n=82) or histologic grade (n=74). The final sample size was 2,683. Results: Of 2,683 BCs, 1,689 (63%) were hormone receptor (HR)-positive(+), 244(9%) were HR+ andHER2+, 289(11%) were HR-negative(-) andHER2+, 461(17%) were triple negative BCs. According to AJCC 7th pathologic staging system, there were 1,135 of stage IA, 4 of IB, 803 of stage IIA, 368 of stage IIB, 258 of stage IIIA, 11 of stage IIIB and 104 of stage IIIC. In terms of 10 year overall survival (OS) according to AJCC 7th staging system, 95.8% in stage IA, 100% in stage IB, 93.5% in IIA, 86.0% in stage IIB, 85.6% in stage IIIA, 90.9% in stage IIIB and 63.6% in stage IIIC were observed (p&amp;lt;0.001) (Medial follow up duration : 118 months). According to AJCC 8th clinical staging system, there were 722 of stage IA, 693 of IB, 306 of stage IIA, 201 of stage IIB, 251 of stage IIIA, 137 of stage IIIB and 160 of stage IIIC. In terms of 10 year overall survival (OS) according to new staging system, 96.7% in stage IA, 96.6% in stage IB, 91.4% in IIA, 92.1% in stage IIB, 86.2% in stage IIIA, 80.2% in stage IIIB and 66.8% in stage IIIC were observed (p&amp;lt;0.001). However, 213 BCs(7.9%) could not be staged by AJCC 8th clinical staging system. In depth analysis will be presented. Conclusions: AJCC 8th clinical staging system provides a good prognostic value and makes up for the weakness of AJCC 7th anatomical pathologic staging. But this system cannot count whole pathologic stages. Modification of AJCC 8th clinical staging system would be warranted. Citation Format: Kim J-Y, Lim JE, Jung HH, Cho SY, Cho EY, Lee SK, Yu JH, Lee JE, Kim SW, Nam SJ, Park YH, Ahn JS, Im Y-H. Validation of the new AJCC eighth edition of the TNM classification for breast cancer with a single center breast cancer cohort [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P1-07-32.

Ki-67 expression as an indicator of invasiveness in patients with breast cancer

Background: Tumor markers have a key role in guiding breast cancer management protocols and predicting prognosis. Objective: The aim of the study is to explore the role of Ki-67 expression in breast cancer and correlate it to well-known indicators of invasiveness such as age, tumor size, grade, hormonal receptors, and lymph nodes involvement. Materials and Methods: This retrospective study was conducted on (214) patients who were newly diagnosed with breast cancer and referred to Azadi Teaching Hospital/Duhok-Iraq, from November 1st, 2016, to October 31st, 2017. Data regarding patient's demographics, tumor size, histological type and grade, nuclear grade, and lymph node involvement were obtained from medical records. Patients underwent either mastectomy with axillary lymph node dissection or breast conservation surgery. Collected specimens were sent for histopathological examination and immunohistochemistry assessments of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor 2 (HER2), and Ki67 expressions. Results: Our study showed that histological grade, nuclear grade, mitotic index, and HER2 status were positively correlated to Ki67 index (P

Targeting HER2 in Nuclear Medicine for Imaging and Therapy.

Since its discovery, the human epidermal growth factor 2 (HER2) has been extensively studied. Presently, there are 2 standard diagnostic techniques to assess HER2 status in biopsies: immunohistochemistry and fluorescence in situ hybridization. While these techniques have played an important role in the treatment of patients with HER2-positive cancer, they both require invasive biopsies for analysis. Moreover, the expression of HER2 is heterogeneous in breast cancer and can change over the course of the disease. Thus, the degree of HER2 expression in the small sample size of biopsied tumors at the time of analysis may not represent the overall status of HER2 expression in the whole tumor and in between tumor foci in the metastatic setting as the disease progresses. Unlike biopsy, molecular imaging using probes against HER2 allows for a noninvasive, whole-body assessment of HER2 status in real time. This technique could potentially select patients who may benefit from HER2-directed therapy and offer alternative treatments to those who may not benefit. Several antibodies and small molecules against HER2 have been labeled with different radioisotopes for nuclear imaging and/or therapy. This review presents the most recent advances in HER2 targeting in nuclear medicine focusing on preclinical and clinical studies.

Alterations in three biomarkers (estrogen receptor, progesterone receptor and human epidermal growth factor 2) and the Ki67 index between primary and metastatic breast cancer lesions.

In recurrent breast cancer, the tumor phenotype, as assessed by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2 (HER2) status, occasionally changes. This change, in addition to the Ki67 index were evaluated at sites of recurrence and the correlation between changes in tumor phenotype and survival were assessed in breast cancer patients. Comparisons in pathological parameters between primary and metastatic lesions were drawn between ER, PR, HER2, and the Ki67 index in 70 patients with recurrent breast cancer. The association between changes in tumor phenotype and patient survival was assessed. The hormone receptor status changed from positive, in the primary lesions, to negative, in the metastatic lesions in 19.8% (ER) and 39.5% (PR) of patients, respectively. Conversion from negative to positive status was confirmed in 27.2% (ER) and 31.2% (PR) of patients, respectively. A change in HER2 status from negative (primary lesion) to positive (metastatic lesion) occurred in seven patients (10%). The mean Ki67 index of primary lesions with positive hormone receptor status was significantly lower than at sites of recurrence with any hormone receptor status, from 10.9±9.8 standard deviation (SD) to 22.9±18.6 (P=0.031) and 12.2±10.5 SD to 27.4±20.9 (P=0.023), for ER and PR, respectively. The mean overall survival of patients with ER status conversion from positive to negative was 7.4±1.2 standard error (SE) years, and 14.8±1.4 SE years for patients who retained positive ER status (P=0.005, log-rank), with a hazard ratio of 3.44 (95% confidence interval, 1.36-8.33). This difference in survival based upon change in ER status was similarly observed in patients with PR status conversion in the same direction. Thus, ER and PR status conversion at the time of recurrence strongly impact survival, particularly if the change is from positive (primary lesion) to negative (metastatic lesion). Monitoring the biological behavior of breast cancer may benefit a patient by allowing for a novel personalized treatment strategy.

Digital image analysis of HER2 immunohistochemistry in gastric- and oesophageal adenocarcinoma: a validation study on biopsies and surgical specimens.

To test the validity of diagnostics incorporating digital image analysis (DIA) for human epidermal growth factor 2 (HER2) immunohistochemistry (IHC) in gastro-oesophageal adenocarcinomas, as an alternative to current standard diagnostics using manual scoring. We included 319 consecutive gastro-oesophageal adenocarcinomas (232 biopsies and 87 surgical specimens). DIA was applied to determine HER2 IHC classification, using both standard breast cancer (BC) and modified gastro-oesophageal cancer (GEC) cut-offs. Consensus manual scores were established by four independent observers. Chromogenic in-situ hybridization (CISH) was performed on all 2+ cases by manual scoring, DIA or both. HER2 status was considered positive in 3+ and CISH-positive 2+ cases. Overall agreement between DIA and consensus manual scores was 76.5% (weighted κ = 0.66, BC cut-offs) and 85.6% (weighted κ = 0.80, GEC cut-offs). Agreement was similar for biopsies and surgical specimens. All disagreement occurred in the manual IHC equivocal cases. DIA resulted in a reduction of 2+ cases: 75.8% with BC cut-offs and 46.5% with GEC cut-offs. HER2 status was positive in 48 cases (15%) with standard diagnostics and DIA using GEC cut-offs, and 46 cases (14.4%) using BC cut-offs (all with CISH in 2+ cases). Considering standard diagnostics as a reference, DIA showed 93.8% sensitivity and 99.6% specificity (BC cut-offs) or 97.9% sensitivity and 99.6% specificity (GEC cut-offs). DIA is a reliable and feasible alternative to manual HER2 IHC scoring in gastro-oesophageal adenocarcinoma, both in biopsies and surgical specimens, leading to a reduction of 2+ cases for which subsequent ISH testing is required.

Prognostic role of progesterone receptor expression in a population-based analysis.

The role of progesterone (PR) expression in the management of breast cancer is controversial. The aim of this study is to evaluate the characteristics and prognosis of progesterone status among breast cancers patients in a population-based analysis. Through the Tuscan Cancer Registry data on all the invasive breast cancer cases diagnosed during the period 2004-2005 in the provinces of Florence and Prato, central Italy, were retrieved. Histological reports were re-examined to obtain information on the percentage of positive tumor cells for estrogen (ER), progesterone (PR) receptors, Ki67 marker and human epidermal growth factor 2 (HER2). Information on age, stage, differentiation grade were also obtained. Out of 1487 patients, 28% had PR-breast cancer. These patients were older (p 0.006) than PR+cancer patients, with more frequently high Ki67 (p<0.0001), HER2+(p<0.0001), ER- (p<0.0001) tumoral expression. The ER+/PR+subtype was the most represented (n.1053), while ER-/PR+was the most rare (n.23); 210 cases (14.1%) ER+PR- and 201 (13.5%) ER-/PR- cases were found. Analysis of survival by the Cox proportional hazards model showed an independent prognostic value of PR expression (p<0.0001), also when estrogen, Ki67, HER2 status and age were included. The 5-year cancer-specific survival was 82.1, 86.5, 100, 92% for ER-/PR-, ER+/PR-, ER-/PR+, ER+/PR+subtype, respectively. Our study revealed significant differences in clinicopathological characteristics among breast cancer according to PR expression and confirmed its prognostic independent role, suggesting a role of PR in the improvement of breast cancer prognostic characterization.

Clinicopathological characteristics and prognostic value of cancer stem cell marker CD133 in breast cancer: a meta-analysis.

BackgroundThe association of CD133 overexpression with clinicopathological significance and prognosis in patients with breast cancer remains controversial. We thus performed a meta-analysis to evaluate the role of CD133 expression in the development and prognosis of breast cancer.MethodsThe databases PubMed, Embase, and Cochrane Library (updated to August 1, 2016) were searched. Pooled odds ratios (ORs) or hazard ratios (HRs) with 95% confidence intervals (95% CI) were used to evaluate the impact of CD133 expression on clinicopathological features, overall survival, and disease-free survival.ResultsA total of 1,734 patients from 13 studies were subject to final analysis. The results showed a significant association between overexpression of CD133 and estrogen receptor status (OR 0.35, 95% CI 0.18–0.70), progesterone receptor status (OR 0.56, 95% CI 0.43–0.74), human epidermal growth factor-2 status (OR 1.81, 95% CI 1.33–2.45), lymph node metastasis (OR 1.98, 95% CI 1.34–2.92), and tumor histological grade (OR 1.79, 95% CI 1.26–2.54) in breast cancer. However, no significant correlation was found between upregulation of CD133 expression and onset age (OR 1.03, 95% CI 0.70–1.53) or tumor size (OR 1.29, 95% CI 0.80–2.09). Moreover, CD133-positive breast cancer patients had a higher risk of mortality (HR 1.91, 95% CI 1.21–3.03) and disease progression (HR 2.70, 95% CI 1.05–6.95).ConclusionThis meta-analysis suggested that CD133 might be a predictor of clinical outcomes as well as prognosis and could be a potentially new gene therapy target for breast cancer patients.

Short-term effects of night shift work on breast cancer risk: a cohort study of payroll data.

Objectives The objective was to examine if night shift work is a short-term risk factor for breast cancer, including combined estrogen receptor (ER) and human epidermal growth factor 2 (HER2) breast cancer subtypes. Methods The cohort comprised 155 540 public sector female workers in Denmark who were followed from 2007-2012. Day-to-day work-hour information was available from payroll registers and 1245 incident cases of breast cancer were identified in national cancer registries together with receptor subtype information. Results A rate ratio (RR) of 0.90 [95% confidence interval (95% CI) 0.80-1.01] was observed for workers ever working night shifts during the follow-up period compared with workers only working day shifts after adjustment for age, age at first child, parity, family history of breast or ovarian cancer, sex hormones, medications related to alcoholism, family educational level, mammography screening, and other potential confounders. Comparable results were seen for the inception population of employees with first recorded employment after 2007. Modestly increased RR were suggested for breast cancer subtypes characterized by a positive HER2 status irrespective of ER status. Conclusions These findings do not support an overall short-term effect of night shift work on breast cancer risk. Future studies should explore further the impact of HER2 status.

The association of soy food consumption with the risk of subtype of breast cancers defined by hormone receptor and HER2 status.

Soy food intake has previously been associated with reduced breast cancer risk. Epidemiological evidence for subgroups of breast cancer, particularly by menopausal and hormone receptor status, is less consistent. To evaluate the role of hormone receptor and menopausal status on the association between soy food intake and breast cancer risk, we measured usual soy food intake in adolescence and adulthood via food frequency questionnaire in 70,578 Chinese women, aged 40-70 years, recruited to the Shanghai Women's Health Study (1996-2000). After a median follow-up of 13.2 years (range: 0.01-15.0), 1,034 incident breast cancer cases were identified. Using Cox models, we found that adult soy intake was inversely associated with breast cancer risk [hazard ratio (HR) for fifth versus first quintile soy protein intake = 0.78; 95% confidence interval (CI):0.63-0.97]. The association was predominantly seen in premenopausal women (HR = 0.46; 95% CI:0.29-0.74). Analyses further stratified by hormone receptor status showed that adult soy intake was associated with significantly decreased risk of estrogen receptor (ER)+/progesterone receptor (PR)+ breast cancer in postmenopausal women (HR = 0.72; 95% CI:0.53-0.96) and decreased risk of ER-/PR- breast cancer in premenopausal women (HR = 0.46; 95% CI:0.22-0.97). The soy association did not vary by human epidermal growth factor-2 (HER2) status. Furthermore, we found that high soy intake during adulthood and adolescence was associated with reduced premenopausal breast cancer risk (HR = 0.53; 95% CI: 0.32-0.88; comparing third vs. first tertile) while high adulthood soy intake was associated with postmenopausal breast cancer only when adolescent intake was low (HR = 0.63; 95% CI: 0.43-0.91). Our study suggests that hormonal status, menopausal status and time window of exposure are important factors influencing the soy-breast cancer association.

Abstract P1-14-07: Association between quantitative values of estrogen receptor expression level and pathological complete response in human epidermal growth factor 2-negative breast cancer: Should the clinical definition of triple-negative breast cancer be redefined?

Abstract Background: The American Society of Clinical Oncology/College of American Pathologists recommended that the cut-off for negative status of estrogen receptor (ER) should be &amp;lt;1% positively staining cells, although a 10% cut-off has often been used clinically. Prior studies reported that patients with ER ranging from 1% to 9% showed survival outcomes and molecular features similar to those of patients with ER positivity of &amp;lt;1%; however, those studies did not take into account patients' human epidermal growth factor 2 (HER2) status. This means we have yet to clarify the exact clinical definition of triple-negative breast cancer (TNBC) on the basis of response to preoperative chemotherapy. Previous studies reported that hormone receptor–positive tumors were less sensitive to systemic chemotherapies. On the basis of these facts, we hypothesized that in patients with HER2-negative breast cancer ER expression level as a continuous variable has an inverse linear association with pathological complete response (pCR) rate. Our primary objective was to determine whether a quantitative value of ER between 0% and 10% is predictive of pCR rate in HER2-negative patients treated with neoadjuvant chemotherapy. Secondary objective was to find the ideal cut-off value of ER expression. Methods: We included newly diagnosed stage I-III HER2-negative breast cancer patients with available ER (0%≤ER&amp;lt;10%) who were treated with neoadjuvant systemic chemotherapy. ER status was determined by immunohistochemical (IHC) staining; HER2 status was determined by IHC and/or FISH. We used univariate and multivariate logistic regression models to determine the association between baseline variables and pCR. A backward stepwise method was used to select the covariates for the multivariate analysis. Recursive partitioning and regression tree method were used to identify the potential significant cut-off of ER. Results: The analysis included 1155 patients with newly diagnosed HER2-negative invasive breast cancer. The univariate logistic regression analysis showed that ER as a continuous variable was not a statistically significant factor for predicting pCR (ER: OR=0.98, 95%CI: 0.9-1.07, P=0.68). In the multivariate analysis, ER status again was not a significant factor for predicting pCR (OR=0.97, 95%CI 0.9-1.06, P=0.55). ER as a categorical variable, there was no significant difference of the pCR rate between 0&amp;lt;ER&amp;lt;1 and 1≤ER&amp;lt;10 groups (OR=1.27, 95%CI: 0.62-2.62, P=0.52). Among ER&amp;gt; 0 (n=229), the recommended cut-off value of ER was 5.5. However, the odds ratio of pCR rate divided by this value of 5.5 was not significant (ER≤5 vs ER&amp;gt;5; OR 1.94 95%CI 0.54-6.95 P=0.31). Conclusion: Evaluating ER (&amp;lt;10%) as a continuous variable showed no association with pCR rate, and no cut-off of ER was identified with which to stratify patients into groups more or less likely to achieve pCR. A potential meaningful cut-off ER value might exist between 10% and 100% in HER2-negative patients. We will explore whether a meaningful cut-off ER value exists that will change the pCR rate and possibly lead to redefining the clinical definition of TNBC. Citation Format: Fujii T, Kogawa T, Dong W, Moulder S, Litton JK, Tripathy D, Lim B, Shen Y, Ueno NT. Association between quantitative values of estrogen receptor expression level and pathological complete response in human epidermal growth factor 2-negative breast cancer: Should the clinical definition of triple-negative breast cancer be redefined?. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P1-14-07.

Discordance of receptor status in breast cancer throughout tumor progression and the associated prognostic implications: A case report and review of the literature

The receptor status of a breast cancer, including estrogen receptor (ER) status, progesterone receptor (PR) status, and human epidermal growth factor 2 (HER2), play a critical role in the development of a treatment plan. Typically, the primary receptor status has been used to make treatment decisions at the time of relapse, which occurs in approximately 20% of early-stage breast cancers [1]. However, multiple studies, including both prospective and retrospective, have shown that receptor status is dynamic and is unstable throughout tumor progression and during advanced stage disease [1,2,7]. National Comprehensive Cancer Network (NCCN) guidelines recommend that breast cancer patients with relapsed disease be re-biopsied secondary to the possibility of change in receptor status. Change in receptor status not only has clinical relevance when deciding on a treatment plan, it also has an impact on survival [1,2,4,7]. Of the 20% of patients that will relapse, up to one-third will have discordance between their original ER/PR receptor status and relapsed status, and up to 15% have discordance with regard to HER2 status [1]. Loss of receptor status is associated with a decrease in overall survival [1,2]. We present a case in which receptor status changed 3 times

HER2 Expression in Gastric Adenocarcinoma-a Study in a Tertiary Care Centre in South India.

According to the literature available, HER2(human epidermal growth factor 2)status in gastric carcinoma has been studied worldwide, however there is a paucity of published data from India. Hence, this study was taken up to evaluate HER2 overexpression in gastric adenocarcinoma patients and to assess the relationship between its expression and clinicopathological tumor parameters. Prospective study was conducted in a teaching hospital over a period of 27months. Total or subtotal gastrectomy resection specimens and small biopsies were included in the study. Immunohistochemistry (IHC) was carried out on all the cases to evaluate the expression of HER2 in formalin-fixed paraffin-embedded tissue samples. Fluorescence Insitu Hybridization (FISH) was done for equivocal cases on IHC. The data was analyzed using Chi square test / Fisher's Exact Test. Odds ratio was computed between HER2 and other pathologic variables. HER2 overexpression was confirmed in 16 (27.6%) cases of which 15 (93.8%) cases were of intestinal type whereas only 1 (6.2%) case of diffuse type adenocarcinoma. Hence, HER2 positivity was significantly more common in the intestinal type of gastric cancer compared to the diffuse type (p = 0.045). Positivity of HER2 was more in small biopsies as compared to the resection specimens in this study but the p value was not significant. There was no difference in HER2 overexpression in relation to the age, gender, tumor site, tumor differentiation and stage. HER2 overexpression is more prevalent in the intestinal subtype. The relatively high percentage of HER2 positive tumors may provide a useful target for immunotherapy of these cancers.

Clinical Implications of Growth Pattern and Extension of Tumor-Associated Intraductal Carcinoma of the Breast

IntroductionThe goal of the present study was to identify the clinically relevant features of tumor-associated intraductal component (IDC) surrounding invasive breast cancer. Patients and MethodsThe tumor specimens from 410 patients with primary invasive breast cancer were investigated. The distance between the surgical margins and tumor edge (invasive and intraductal areas) was measured prospectively. ResultsOf the 410 investigated patients, 395 were eligible for analysis. An IDC was observed in 241 specimens (61.0%) and was associated with a younger age at diagnosis, postmenopausal status, and positive estrogen receptor, progesterone receptor, and human epidermal growth factor 2 (HER2) expression status. Most cases with tumor-associated ductal carcinoma in situ (DCIS) were found in the upper-outer quadrants of the breasts. An extended intraductal component (EIC) tended to be present in the outer and lower quadrants of the breasts. In the study cohort of 187 patients with tumor-associated DCIS, 1496 surgical margins were investigated. IDC was associated with invasive tumor growth predominantly in the nipple direction. The nipple-associated growth of DCIS correlated with patient age > 40 years, tumor size ≤ 2 cm, poor histologic differentiation of the noninvasive and invasive components, and positive estrogen and progesterone receptor status and negative HER2 status. ConclusionsOur data provide evidence that in patients with primary breast cancer, the EIC areas will be mostly segmentally localized between the invasive tumor and the nipple. Therefore, if EIC is present or assumed, surgery should consist of segmental resection of the breast tissue, at least in patients with breast cancer who are > 40 years old, with a tumor size of < 2 cm, and with hormone receptor-positive and HER2-negative, poorly differentiated tumors.

Molecular phenotype is associated with survival in breast cancer patients with spinal bone metastases.

To aid in therapy selection for patients with spinal bone metastases (SBM), predictive models have been developed. These models consider SBM from breast cancer a positive predictive factor, but do not take phenotypes based on estrogen (ER), progesterone (PR) and human epidermal growth factor 2 (HER2) receptors into account. The aim of this study was to ascertain whether receptors are associated with survival, when the disease has progressed up to SBM. All patients who were treated for SBM from breast cancer between 2005 and 2012 were included in this international multi-center retrospective study (n = 111). Reports were reviewed for ER, PR and HER2 status and subsequently subdivided into one of four categories; luminal A, luminal B, HER2 and triple negative. Survival time was calculated as the difference between start of treatment for SBM and date of death. Analysis was performed using the Kaplan-Meier method and log-rank tests. Median follow-up was 3.7 years. Survival times in the luminal B and HER2 categories were not significantly different to the luminal A category and were joined into a single receptor positive category. Eighty-five patients (77 %) had a receptor positive phenotype and 25 (23 %) had a triple negative phenotype. Median survival time was 22.5 months (95 %CI 18.0-26.9) for the receptor positive category and 6.7 months (95 %CI 2.4-10.9) for the triple negative category (p < 0.001). Patients with SBM from breast cancer with a triple negative phenotype have a shorter survival time than patients with a receptor positive phenotype. Models estimating survival should be adjusted accordingly.

Prognostic implications of receptor discordance between primary and recurrent breast cancer.

Discordance rates of hormone receptor (HR) and human epidermal growth factor-2 (HER2) status between primary and recurrent breast cancer were reported to be in the wide range of 10-40 %, although its prognostic relevance remains to be elucidated. Fifty-five breast cancer patients had biopsies or resections of recurrent lesions. Pathological assessments of the HR and HER2 status of primary and recurrent lesions were performed in a single laboratory at Keio University Hospital. Tumors were classified as luminal (HR+ and HER2-), luminal/HER2 (HR+ and HER2+), HER2 (HR- and HER2+), or triple negative (HR- and HER2-). Discordance rates in estrogen receptor (ER), progesterone receptor (PgR) and HER2 status between primary tumors and recurrent lesions were 16.4, 30.9 and 10.2 %, respectively. Overall, 14 patients (25.5 %) changed subtypes at recurrent lesions. Patients with a gain in ER and PgR status had a significantly longer disease-free interval compared with the corresponding concordant-negative patients (ER: 99.0 vs. 18.5 months, p = 0.037, PgR: 141.0 vs. 24.4 months, p = 0.011). Patients with a loss of HER2 status experienced a trend toward shorter time to progression, compared with patients who maintained HER2 positivity (4.0 vs. 18.4 months, p = 0.051). Discordance in receptor status between primary and recurrent breast cancers were seen in 10-30 %. A gain in HR status was significantly associated with better prognosis.

US incidence of breast cancer subtypes defined by joint hormone receptor and HER2 status.

In 2010, Surveillance, Epidemiology, and End Results (SEER) registries began collecting human epidermal growth factor 2 (HER2) receptor status for breast cancer cases. Breast cancer subtypes defined by joint hormone receptor (HR; estrogen receptor [ER] and progesterone receptor [PR]) and HER2 status were assessed across the 28% of the US population that is covered by SEER registries. Age-specific incidence rates by subtype were calculated for non-Hispanic (NH) white, NH black, NH Asian Pacific Islander (API), and Hispanic women. Joint HR/HER2 status distributions by age, race/ethnicity, county-level poverty, registry, stage, Bloom-Richardson grade, tumor size, and nodal status were evaluated using multivariable adjusted polytomous logistic regression. All statistical tests were two-sided. Among case patients with known HR/HER2 status, 36810 (72.7%) were found to be HR(+)/HER2(-), 6193 (12.2%) were triple-negative (HR(-)/HER2(-)), 5240 (10.3%) were HR(+)/HER2(+), and 2328 (4.6%) were HR(-)/HER2(+); 6912 (12%) had unknown HR/HER2 status. NH white women had the highest incidence rate of the HR(+)/HER2(-) subtype, and NH black women had the highest rate of the triple-negative subtype. Compared with women with the HR(+)/HER2(-) subtype, triple-negative patients were more likely to be NH black and Hispanic; HR(+)/HER2(+) patients were more likely to be NH API; and HR(-)/HER2(+) patients were more likely to be NH black, NH API, and Hispanic. Patients with triple-negative, HR(+)/HER2(+), and HR(-)/HER2(+) breast cancer were 10% to 30% less likely to be diagnosed at older ages compared with HR(+)/HER2(-) patients and 6.4-fold to 20.0-fold more likely to present with high-grade disease. In the future, SEER data can be used to monitor clinical outcomes in women diagnosed with different molecular subtypes of breast cancer for a large portion (approximately 28%) of the US population.