Gute Remission unter HER2-Blockade bei einem fortgeschrittenen Karzinom des ösophagogastralen Überganges bei nur fokaler HER2-Überexpression

2017 ◽  
Vol 55 (09) ◽  
pp. 866-871
Author(s):  
Timo Gaiser ◽  
Daniela Hirsch ◽  
Ralf-Dieter Hofheinz
Keyword(s):  
Her2 Status ◽  
Her2 Expression ◽  
Prädiktiver Faktor

ZusammenfassungDas Magenkarzinom und das Karzinom des ösophagogastralen Überganges werden in 55 – 65 % der Fälle im lokal fortgeschrittenen bzw. metastasierten Stadium diagnostiziert und in der Regel mit einer perioperativen bzw. palliativen Chemotherapie behandelt. Im metastasierten Stadium muss der HER2-Status als positiver prädiktiver Faktor für eine Therapie mit Trastuzumab vor Therapieeinleitung zuverlässig bestimmt werden. Leider ist diese Bestimmung aber nicht trivial und sowohl mit dem Problem der ausgesprochenen Tumorheterogenität für HER2 als auch mit Problemen des HER2-Auswertungsalgorithmus behaftet. Wir berichten über einen 80 Jahre alten Patienten, welcher bei neu aufgetretenen Schluckbeschwerden mit einem fortgeschrittenen Adenokarzinom des ösophagogastralen Überganges diagnostiziert wurde (uT3 uN+ cM0; Siewert II). Die initiale auswärtige HER2-Testung verlief negativ (HER2-Score 1 +) wurde aber in domo an umfangreicheren Biopsien wiederholt. Nach nachgewiesener fokaler, aber starker HER2-Positivität (HER2-Wert 3 +, ~10 % der Tumorzellen positiv) wurde eine Kombinationstherapie von Oxaliplatin, 5-Fluoruracil/Folinsäure und Trastuzumab eingeleitet, welche zur Besserung der Beschwerden und zu einer Remission führte. Die hier vorliegende Diskrepanz der zwei durchgeführten HER2-Testungen wurde verursacht durch eine Heterogenität der HER2-Expression, welche in den initialen, eher spärlichen Biopsien nicht erfasst wurde. Außerdem könnten Unterschiede zwischen dem bekannten, weitverbreiteten HER2-Auswertungsalgorithmus des Mammakarzinoms und dem mit Unschärfe behafteten, weniger oft verwendeten Magenkarzinom-Algorithmus eine Rolle gespielt haben. Dieser Fallbericht beschreibt einen Patienten mit gutem Ansprechen auf eine anti-HER2-Therapie in Kombination mit einer Chemotherapie bei einem offensichtlich nur in geringfügigen Anteilen HER2-positiven fortgeschrittenen Karzinom des ösophagogastralen Übergangs und illustriert, welche Probleme mit der HER2-Testung verbunden sind, gerade wenn nur wenig tumortragende Biopsien gewonnen werden konnten.

scholarly journals Parietal cell/oncocytic gastric carcinoma: systematic review and first-time assessment of HER2 status in two new cases

2020 ◽  
Vol 102 (4) ◽  
pp. 300-307 ◽  
Author(s):  
VK Mavroeidis ◽  
ID Gkegkes ◽  
F Saffioti ◽  
K Kandilaris ◽  
K Alexiou ◽  
...  
Keyword(s):  
Systematic Review ◽  
Parietal Cell ◽  
Early Stage ◽  
Survival Rates ◽  
Growth Factor Receptor ◽  
Lymph Node Involvement ◽  
Her2 Status ◽  
Interventional Treatment ◽  
Her2 Expression ◽  
First Time

Introduction Parietal cell/oncocytic gastric carcinomas are very rare and various aspects of this group remain unclear. The human epithelial growth factor receptor 2 (HER2) status of these tumours is largely unknown. Methods We performed a systematic electronic search of the literature and clinicopathological presentation of two cases including first-time complete assessment of HER2 status. Thirty-two patients with a mean age of 64.3 years, 87.5% of whom were male, were included in this review. Findings Half of the cases were recorded in Asia. Median follow-up was 24 months. There was no predominant site of development, while underlying histological abnormalities were present in 25%. At initial presentation, lymph node involvement was evident in 46.6% while distant metastatic disease was present in 9.3%. Presentation at stage I occurred in 55.6%. Potentially curative surgical/interventional treatment was intended in 90.6%. Recurrence occurred in 6.6%, while death was recorded in 19.2%, with cancer-related deaths reaching 11.5%. The one- and three-year survival rates were 84.2% and 79%, respectively. Our two cases displayed negative HER2 expression. Conclusions This systematic review demonstrates that this group of malignancies is very rare but possibly underdiagnosed. The disease commonly presents at early stage, mainly affecting middle-aged men. The prognosis is generally favourable even in cases of advanced disease. The HER2 expression and its correlation with the outcomes need to be further explored.

Correlation of quantitative total HER2 expression and HER2 homodimers with histopathologic characteristics of breast cancers in the FinHer study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 11061-11061
Author(s):  
W. Huang ◽  
J. Weidler ◽  
Y. Lie ◽  
J. Whitcomb ◽  
M. Leinonen ◽  
...  
Keyword(s):  
Lymph Node ◽  
Lymph Node Metastasis ◽  
Tumor Size ◽  
Dynamic Range ◽  
Tumor Grade ◽  
Her2 Status ◽  
Breast Cancers ◽  
Her2 Expression ◽  
Node Metastasis ◽  
Formalin Fixed Paraffin Embedded

11061 Background: We recently reported that the HERmark assay (Monogram Biosciences) accurately measures continua of total HER2 expression (H2T) and HER2 homodimers (H2D) over a wide (∼3 logs) dynamic range, and that a higher concordance was observed between H2T and HER2 status with more stringent central tests as compared with IHC tests performed locally (Joensuu et al, 2008 SABCS,abstract 2071). H2D/H2T ratio was reported as a marker of activated HER2 and a prognosticator of disease progression in HER2+ patients not treated with trastuzumab in the adjuvant setting (Bates et al, 2008 SABCS,abstract 1074). In this follow-up analysis, H2T, H2D, and H2D/H2T ratio were correlated with histopathologic characteristics of breast cancers in the FinHer study. Methods: The HERmark assay was used to measure H2T and H2D in 899 formalin-fixed, paraffin-embedded FinHer specimens. The results were correlated with histopathologic characteristics of breast cancers in the FinHer study (Joensuu et al, N Engl J Med2006;354), including estrogen receptor/progesterone receptor (ER/PR), tumor grade, tumor size, lymph node metastasis, and stage. Results: Higher H2T and H2D levels correlated with ER/PR negativity and high tumor grade (P<0.0001). 42% (102/244) of ER- and 37% (137/374) of PR- cases were HERmark Positive; while 17% (110/655) of ER+ and 14% (75/524) of PR+ cases were HERmark Positive. 10% (13/136) of grade 1, 18% (65/353) of grade 2, and 35% (131/375) of grade 3 tumors were HERmark Positive. No significant association was found between H2T or H2D and tumor size, lymph node metastasis or stage. ER/PR negative and poorly differentiated cancers had higher H2D/H2T ratios (P=0.013), and H2D/H2T ratios >0.6 were associated with smaller primary tumor diameters at the time of cancer detection (P=0.009). Conclusions: The quantitative H2T measurement confirms the known correlations between HER2 expression and histopathologic characteristics of breast cancer. The novel H2D measurement and H2D/H2T ratio may provide further insights into HER2 activation and better diagnostic tests for targeted HER2 therapy. [Table: see text]

Responsiveness of adjacent ductal carcinoma in situ and changes in HER2 status after neoadjuvant chemotherapy/trastuzumab treatment in early breast cancer: Results from the GeparQuattro study (GBG 40).

2011 ◽  
Vol 29 (27_suppl) ◽  
pp. 6-6
Author(s):  
G. Von Minckwitz ◽  
S. Darb-Esfahani ◽  
S. Loibl ◽  
J. B. Huober ◽  
H. Tesch ◽  
...  
Keyword(s):  
Neoadjuvant Chemotherapy ◽  
Ductal Carcinoma In Situ ◽  
Carcinoma In Situ ◽  
Ductal Carcinoma ◽  
Her2 Status ◽  
Her2 Overexpression ◽  
Her2 Expression ◽  
Her2 Positive ◽  
Complete Eradication

6 Background: Adjacent ductal carcinoma in situ (DCIS) is in found in approximately 45% of invasive ductal carcinomas (IDC) of the breast. Pure DCIS overexpresses HER2 in approximately 45%. There is uncertainty whether adjacent DCIS impacts on the response to neoadjuvant chemotherapy and trastuzumab as well as whether HER2 expression in IDC component or adjacent DCIS changes throughout treatment. Methods: Core biopsies and surgical tissue from participants of the GeparQuattro study with HER2-positive IDC were centrally examined for the area of invasive ductal component and adjacent DCIS before and after receiving neoadjuvant anthracycline-taxane-trastuzumab containing chemotherapy. HER2 overexpression in IDC and adjacent DCIS was quantified separately by immunohistochemistry using the Ventana automated staining system. Pathological complete response (pCR) was defined as no residual invasive or non-invasive tumor tissue. Results: Fifty nine (37.3%) of 158 IDCs presented with adjacent DCIS at diagnosis. These tumors showed lower regression grades than pure IDC (p=0.033). Presence of adjacent DCIS was an independent negative predictor of pCR (odds ratio 0.42 [95% CI 0.2-0.9], p=0.027). Adjacent DCIS area decreased from pre-treatment to surgery (r=0.205) with 30 (50.8%) IDCs with adjacent DCIS showing complete eradication of adjacent DCIS. HER2 status of adjacent DCIS was highly correlated with HER2 status of IDC component before (r=0.892) and after treatment (r=0.676). Degree of HER2 overexpression of the IDC component decreased in 16 (33.3%) out of 49 patients without a pCR. These 16 IDCs showed lower RGs compared to the 33 IDCs with unchanged HER2 expression (p=0.055). Conclusions: HER2-positive IDCs with adjacent DCIS is less responsive to neoadjuvant chemotherapy and trastuzumab compared to pure IDC. However, complete eradication of adjacent DCIS is frequently observed. HER2-overexpression of the invasive ductal component decreases in a subset of tumors, which showed less tumor regression.

Hormone replacement therapy and its effect on HER2 neu status in primary breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11057-e11057
Author(s):  
Tina Ashley Khair ◽  
Priyanka Mittar ◽  
Susan K. Boolbol ◽  
Kwadwo Boachie-Adjei ◽  
Paula Klein
Keyword(s):  
Breast Cancer ◽  
Hormone Replacement Therapy ◽  
Replacement Therapy ◽  
Primary Breast Cancer ◽  
Hormone Replacement ◽  
Her2 Status ◽  
Her2 Expression ◽  
Data Set ◽  
The Relationship ◽  
Her2 Positivity

e11057 Background: Controversy has developed over the use of hormone replacement therapy (HRT) and its association with the future risk of breast cancer. The biology of breast cancer diagnosed after the use of HRT is different than in non HRT users. One such pathologic feature that may be affected by the use of HRT is HER2 neu. While there is existing data illustrating the relationship between HRT and breast cancer, there is little data examining the relationship between HRT and HER2 neu. The purpose of this study is to investigate that relationship and determine whether or not the use of HRT has any effect on the HER2 neu status of primary breast cancers. Methods: A retrospective review of a prospective database identified 2,928 patients with primary breast cancer with a history of prior/current HRT use. Tumor specimens were evaluated for HER2 neu expression at the time of surgery using either IHC or FISH. Pearson’s χ² test along with evaluation of odds ratios were used to determine whether or not there was an association of HER2 neu expression with HRT use. Results: Table 1A illustrates the lack of a correlation between increasing HER2 expression and HRT. There was no significant change in odds of HRT use as HER2 expression increased. After confirming HER2 neu status using FISH, the odds of HER2 positivity among HRT users was OR= 1.05 times the odds of HER2 neu positivity among non-HRT users [C.I. 0.85, 1.29; p = 0.63] (Table 1B). Conclusions: Contrary to our expectation of an inverse relationship between HRT use and HER2 negative phenotype, we found no clear association between the two. Limitations of this study include the inability to discriminate from our data set between current and prior users, and between estrogen alone and combination estrogen/progesterone supplementation. Additionally, the definition of HER2 positivity by membranous staining has changed over the last decade, which may be contributory. We plan on determining the relationship between HER2 status and ER status as it relates to HRT use in future studies. [Table: see text] [Table: see text]

Central review of discordant samples for microarray-based ER, PR, and HER2 and local IHC/FISH assessment worldwide from 827 patients.

2012 ◽  
Vol 30 (27_suppl) ◽  
pp. 11-11
Author(s):  
Jelle Wesseling ◽  
Corrado Tinterri ◽  
Anna Sapino ◽  
Fabrizio Zanconati ◽  
Martijn Lutke Holzik ◽  
...  
Keyword(s):  
Gene Expression ◽  
Her2 Status ◽  
Fish Analysis ◽  
Mrna Expression Level ◽  
Her2 Expression ◽  
Her2 Positive ◽  
High Quality ◽  
Standard Procedures ◽  
Local Standard ◽  
Er Positive

11 Background: Differences in fixation and IHC and subjective interpretation can substantially affect the accuracy and reproducibility of estrogen receptor (ER), progesterone receptor (PR) and HER2 expression. The commercially available TargetPrint test measures the mRNA expression level of ER, PR and HER2 and is 98% concordant with centrally assessed ER as presented by Viale et al, SABCS 2011. This study compares results from the microarray-based TargetPrint with IHC and FISH (for HER2 IHC2+) generated by local standard procedures. Methods: Fresh tumor samples (core needle biopsies or surgical) were collected for 831 patients diagnosed with breast cancer stage I to IV (Feb 2008 - Jan 2011) from 22 hospitals from Europe, New Zealand, Japan and US. The results of the IHC/FISH assessments performed according to the local standards at the hospitals were compared to the quantitative gene expression readouts with TargetPrint. Discordant cases were centrally reviewed for IHC/FISH assessment. Results: Of the 831 samples, IHC assessment was unknown for 4 ER/ PR samples; HER2 was unknown for 12 samples. Comparison of IHC and gene expression read out by TargetPrint showed a concordance of 95% for ER; 83% for PR and 94% for HER2. In this study, 3% of all IHC ER positive samples were classified negative by microarray, and 11% of IHC PR positive samples were classified negative by microarray. For HER2, 4% of IHC/FISH HER2 positive samples were classified negative by microarray and 2% of IHC/FISH HER2 negative samples were classified positive by microarray. Most notably, all available 5 ER IHC negative/TargetPrint positive samples turned out to be positive with central re-assessment. HER2 IHC2+ samples with discordant classifications for TargetPrint and local assessment are currently being reviewed for FISH/SISH assessment. Conclusions: Microarray based readout of ER, PR and HER2 status using TargetPrint is fairly comparable to local IHC and FISH analysis in 827 analyzed samples in various hospitals worldwide. However, re-assessment of discordant cases–especially IHC ER-/TargetPrint ER+ cases- confirms TargetPrint to be a useful high quality second opinion for local IHC/FISH assessment.

Persistence of HER2 overexpression on circulating tumor cells in patients after systemic treatment for HER2-positive breast cancer: Follow-up results of the German Success B trial.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11043-11043 ◽  
Author(s):  
Julia Katharina Neugebauer ◽  
Brigitte Kathrin Rack ◽  
Bernadette Anna Sophia Jaeger ◽  
Ulrich Andergassen ◽  
Aurelia Pestka ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Cells ◽  
Circulating Tumor Cells ◽  
Peripheral Blood ◽  
Her2 Status ◽  
Her2 Overexpression ◽  
Her2 Expression ◽  
Her2 Positive ◽  
Before And After

11043 Background: The discordance between HER2-expression on circulating tumor cells (CTC) in peripheral blood and the primary tumor has already been shown by our study group for early breast cancer patients with HER2-positive tumors. Here, we compare the results to CTC prevalence and HER2-status of CTC after adjuvant chemotherapy. Methods: The SUCCESS B trial compares FEC-Docetaxel vs. FEC-Docetaxel-Gemcitabine and HER2-targeted therapy as adjuvant treatment for patients with early, HER2-positive, node positive or high risk node negative primary breast cancer. We prospectively analyzed 23ml peripheral blood before and after chemotherapy. CTC and HER2-status were assessed with the CellSearchSystem (Veridex, USA). After immunomagnetic enrichment with an anti-Epcam-antibody, cells were labeled with anti-CK 8/18/19, anti-CD45 antibodies as well as a fluorescein conjugate antibody for HER2-phenotyping. Cutoff for CTC positivity was ≥ 1 CTC. HER-positivity of CTC was assigned if at least one CTC showed strong HER2 staining (3+). Results: CTCs and their HER2-status both before and after chemotherapy were available for 392 patients. In 179 (45.7%) patients no CTC were detected before and after chemotherapy. CTC status changed from positive before to negative after chemotherapy in 104 (26.5%) patients and from negative before to positive after chemotherapy in 69 (17.6%) patients, while 40 (10.2%) patients had a consistently positive CTC status. Patients were significantly more likely to change their CTC status from positive to negative than from negative to positive (p = 0.01). Of the 40 patients with CTC both before and after chemotherapy, 14 (35%) patients had HER2-positive CTC before and after therapy, and 9 (22%) patients had HER2-negative CTC at both time points. 7 (18%) patients had HER2-positive CTC before but not after chemotherapy, while 10 (25%) patients showed the reverse pattern (p = 0.63). Conclusions: Cytotoxic treatment does not seem to influence the HER2-status on CTC. Follow-up data within the Success B trial will analyze the relevance of the HER2-expression of CTC to predict the efficacy of targeted treatment.

Activation of P38MAP kinase in estrogen-positive invasive breast cancers: Relation with HER2 and downstream signaling phosphorylated proteins expression.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11560-e11560
Author(s):  
Jean-Louis Merlin ◽  
Alexandre Harle ◽  
Maeva Lion ◽  
Anne-Sophie Chrétien ◽  
Carole Ramacci ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Mitogen Activated Protein Kinase ◽  
Her2 Status ◽  
Signaling Proteins ◽  
Breast Cancers ◽  
Her2 Expression ◽  
Downstream Signaling ◽  
Phosphorylated Proteins ◽  
Significant Difference ◽  
Mitogen Activated Protein

e11560 Background: P38 kinases are members of the mitogen-activated protein kinase (MAPK) family. In breast cancers MAPK, as well as PI3 kinase-AKT pathway signaling proteins have major implication in molecular oncogenesis and are extensively investigated as putative targets for therapy. The present study reports the investigation of the expression of P38MAPK and its phosphorylated form (p-P38MAPK) in clinical specimens of invasive breast carcinomas in relation with estrogen receptor and HER2 expression, as well as MAPK and PI3K signaling phosphorylated proteins. Methods: The expression of P38MAPK and p-P38MAPK as well as p-AKT, p-GSK3β, p-S6 kinase, p-MEK1, p-ERK1/2 were semi-quantitatively assessed using multiplex bead immuno-assay. The analyses were performed retrospectively in frozen specimens from 46 invasive breast tumors classified according to estrogen receptor (ER) and HER2 status. Results: All specimens were taken at diagnosis and validated for tumor content >50%. Twenty-nine were ER+, 17 were HER2+, 10 were triple negative (TN) tumors. Analyses were performed in triplicate from total protein extracts and were achievable in all specimens. P38MAPK was found to be expressed in all tumor specimen and significantly (P=0.002) overexpressed in ER+ tumors. P38MAPK was lower in TN tumors than in all others. The median expression of phosphorylated-P38MAPK was also higher in ER+ than in ER- tumors and lower in TN tumors than in all others. HER2 status had no influence on P38MAPK and p-P38MAPK expression. No variation in the phosphorylation rate of P38MAPK was observed in relation with ER, HER2 or TN status. Significantly higher (P=0.0048) expression of p-AKT tumors was observed in HER2+ tumors. No significant difference in p-MEK1, p-GSK3β and p-S6K expression was evidenced in any other comparisons based on ER and HER2 expression subtypes. Conclusions: Investigation of the expression of multiple phosphorylated signaling proteins can be used as molecular biomarkers for personalized targeted therapy. In ER+ invasive breast cancer, the overexpression of P38MAPK could serve as biomarker for evaluation of P38MAPK inhibitors.

The characteristics of c-MET and HER2 expression in gastric carcinoma and its correlation with clinical-pathological parameters.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e15566-e15566
Author(s):  
Patrick Stuebs ◽  
Florian Dittmar ◽  
Kathrin Zierau ◽  
Joerg Fahlke ◽  
Karsten Ridwelski ◽  
...  
Keyword(s):  
Gastric Carcinoma ◽  
Expression Patterns ◽  
Lymph Vessel ◽  
Her2 Status ◽  
Her2 Expression ◽  
Her2 Positive ◽  
Observation Study ◽  
Significant Difference ◽  
Poorly Differentiated ◽  
Vessel Infiltration

e15566 Background: The aim of this study was to determine whether overexpression of c-MET or HER2 had an effect on the clinical-pathological parameters and / or the prognosis of gastric carcinoma, as well as a direct correlation among those parameters. Methods: 134 gastric resectates were archived between 2007-2012 and retrospectively examined for c-MET and HER2 expression via immunohistochemistry (IHC). The HER2 status IHC2 + was additionally verified by means of Chromogenic in situ hybridization (CISH). Statistical data analysis was performed on the basis of the parameters acquired in the prospective multicentre observation study QCGC'07 / 09. Results: A total of 71 patients (53%) were found to express c-MET low and 63 patients (47%) expressed c-MET high, 122 patients (91%) were found to be HER2 negative and 12 persons (9%) were HER2 positive. C-MET high was significantly more pronounced in the Lauren intestinal type (63.8%, p = 0.001) and moderately to poorly differentiated tumour tissue (G2 50.9%, G3 43.9%, p = 0.038) as well es tissue with lymph vessel infiltration (L1 59.1%, p = 0.039). HER2 showed no significant effect on the clinical-pathological parameters. The median overall survival was shown to be shortened for the c-MET high-expressing (c-MET low 56 months, SD: ± 24.67; 95% CI: 7.65-104.36 vs. c-MET high 32 months, SD: ± (median-OS HER2 negative 38 months, SD: ± 14.11, 95% CI: 10.35-65, p = 0.839), and HER2 negative, 65, median-OS HER2 positive not reached, p = 0.305) patients. 8/134 resectates (5.97%, p = 0.135) were high and positive in both expression patterns, showing no significant difference to the OS (p = 0.393). Conclusions: In our studies, c-MET high or HER2 negative expression was associated with a poorer OS. However, no direct correlation between HER2 and c-MET could be demonstrated

Targeted next generation sequencing to expand HER2 status detection: Implication for newer HER2-directed agents.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 1047-1047
Author(s):  
Ning Liao ◽  
RongFeng Song ◽  
FangQin Xue ◽  
Shuirong Zhang ◽  
Samuel J Klempner ◽  
...  
Keyword(s):  
Clinical Laboratory ◽  
False Negative ◽  
High Sensitivity ◽  
Expression Level ◽  
Her2 Status ◽  
Genomic Alteration ◽  
Her2 Expression ◽  
Specificity And Sensitivity ◽  
Sensitivity Specificity ◽  
Erbb2 Amplification

1047 Background: Establishment of ERBB2 ( HER2) amplification status in breast carcinoma (BC) and gastric carcinoma (GC) is essential for treatment selection, but no anti- HER2 therapies have been approved for tumors with low level of HER2 expression. The clinical trial ( NCT02564900 ) was initiated to evaluate the safety and efficacy of trastuzumab deruxtecan (DS-8201a) in BC patients with lower HER2 expression by current methods. This study aims to validate NGS-based detection for HER2 low expression. Methods: 275 BC and 425 GC were collected and subjected to NGS for genomic alteration detection. The testing was carried out by a College of American Pathologists (CAP) accredited and Clinical Laboratory Improvement Amendments (CLIA) certified laboratory, Shanghai, China. Protein expression was analyzed by using IHC. FISH was carried out on 108 samples, including 63 BC and 45 GC. To set up NGS cutoff, FISH was performed on additional 34 samples. Sensitivity, specificity and accuracy were evaluated based on FISH as a gold-standard reference. Results: In BC, the expression level of HER2 protein detected by IHC was overall IHC 0 in 28.7%, 1+ in 18.9%, 2+ in 27.3% and 3+ in 25.1%, respectively, while in GC, the expression level was 60.7%, 18.6%, 14.8% and 5.9%, respectively. Log2ratio was used to assess ERBB2 amplification status detected by NGS. According to the FISH results of 34 other samples with high sensitivity (98%) and specificity (100%), the threshold was determined as 0.5. 8 and 10 samples of IHC 1+/2+ met the cutoff in BC and GC, respectively. In 63 BC, there were 17 positive and 46 negative by FISH. According to the threshold, the sensitivity and specificity of NGS detection was 94.1% and 97.8%, respectively. The proportion of samples with IHC 2+ that couldn't determine NGS ERBB2 status was 49.2%. However, except for false positive and false negative, the NGS results were concordant with FISH. In 45 GC, there were 5 positive and 40 negative by FISH. The specificity and sensitivity was 97.5% and 40%, respectively. In 4 samples with IHC 2+, 2 of them were discordant with the results of NGS and FISH. All IHC 1+ didn't meet the cutoff of NGS and was FISH negative in 108 samples. The accuracy of NGS in ERBB2 detection was 96.8% and 91.1% for BC and GC, respectively. Conclusions: Our data indicated that the NGS-based detection of ERBB2 amplification had high sensitivity, specificity and accuracy. In samples with IHC 1+/2+, the results of NGS detection were high concordant with FISH detection.

Next-generation sequencing (NGS) identifies a new breast cancer subtype with HER2 low-amplification status as a candidate for targeted therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 553-553
Author(s):  
Guo-Chun Zhang ◽  
Ning Liao ◽  
Bo Chen ◽  
Jiali Lin ◽  
Jianguo Lai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Copy Number ◽  
Breast Cancer Subtype ◽  
Metastatic Breast ◽  
Receiver Operating Curve ◽  
Her2 Status ◽  
Her2 Expression ◽  
Her2 Amplification ◽  
Her2 Positive ◽  
Mutation Profile

553 Background: HER2 expression or amplification qualify patients to receive targeted therapeutics against HER2; however, traditional methods of quantifying HER2 amplification using fluorescence in situ hybridization (FISH) do not include a reliable definition for low level amplification. With the promising response rate of patients with low HER2 amplified-metastatic breast cancer to subsequent-line trastuzumab deruxtecan (DS-8201a) therapy, there is a need to improve the existing criteria to accurately identify patients with low HER2. In our study, we investigate whether HER2 amplification quantified by NGS could provide a method to stratify patients into subgroups. Methods: A total of 774 patients diagnosed with breast cancer from Guangdong Provincial People's Hospital (GDPH) who underwent targeted NGS using 520 or 33 cancer-related genes and had their HER2 status evaluated with either FISH or IHC were included in this study. HER2 status were defined as per 2018 ASCO/ACP guidelines. Results: Our results demonstrate that NGS could quantify HER2 amplification with high sensitivity and specificity, with area under the curve of 0.990 [95%CI: 0.982-0.999]. The receiver operating curve indicated an optimal cut-off of 2.62 copy number (CN) for identifying IHC/FISH HER2-negative status with 97.8% specificity. Meanwhile, the cut-off of ≥ 3.62 CN identified patients with IHC/FISH HER2-positive status with 99.8% specificity. Among the 774 patients, 65.8% (n = 509) had HER2 CN of ≤ 2.62 and were classified as HER2 non-amplified, while 25.8% (n = 199) had HER2 CN of ≥ 3.62, classified as HER2-amplified. The remaining 66 patients (8.5%) had HER2 CN between 2.62 and 3.62, and were the patients with heterogeneous IHC/FISH results, classified using NGS as HER2 low-amplified. Patients with low-amplified (49.0% vs. 38.8%, P < 0.001) and amplified (50.3% vs. 38.8%, P < 0.001) HER2 had significantly more number of copy number amplifications in other gene, including CDK12, RARA, and SPOP (P < 0.001, P < 0.001) than patients with HER2 non-amplified, indicating distinct mutation profile. Conclusions: Our results demonstrate that NGS could provide a more accurate stratification of patients based on their HER2 amplification levels. Patients with low levels of HER2 amplification has a distinct mutation profile, suggesting that NGS could serve as a robust tool to identify patients with HER2 amplification, whether high or low, who could benefit treatment with targeted agents designed against heterogeneous HER2 expression.

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