Equivocal results of  HER2 fluorescent in situ hybridization (FISH) assessment in breast cancer: Diagnostic limitations and therapeutical implications.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e11058-e11058
Author(s):  
Marcelo Rocha De Sousa Cruz ◽  
Adriana Regina G. Ribeiro ◽  
Fábio Nasser Santos ◽  
Isabela Werneck Cunha ◽  
Vladmir C. Lima
Keyword(s):  
Breast Cancer ◽  
Breast Biopsy ◽  
Cancer Center ◽  
Breast Cancer Patients ◽  
Her2 Amplification ◽  
Her2 Positive ◽  
Tissue Samples ◽  
Status Assessment ◽  
Fish Cohort ◽  
Metastatic Sites

e11058 Background: HER2/neu status is a well established prognostic and predictive factor for breast cancer (BC) patients. However, HER2 testing remains controversial because of technical issues, lack of consensus on cut point determinations and pathology interpretation. As a result, some patients present tumors with inconclusive or equivocal tests, making the indication of anti-HER2 therapy questionable. Methods: We evaluated the incidence of inconclusive and equivocal HER2 amplification by FISH after an equivocal HER2 immunohistochemical (IHC) result in a cohort of breast cancer patients treated at a cancer center. Equivocal IHC was defined as tumor cells showing 2+ membranous immunoreactivity out of a possible 3+. Inconclusive FISH was considered when probe signs were weak and did not allow proper evaluation. Equivocal FISH was defined according to ASCO/CAP recommendation. Patients’ clinical characteristics, treatments and outcomes were evaluated. Results: From 2006 to 2011 we analyzed BC tissue samples from 404 patients that underwent HER2 FISH assessment after equivocal IHC. Gene amplification was found in 28,7% (n=116) of samples; 65,5% (n=265) showed non-amplification results. Inconclusive (n=12) plus equivocal (n=11) FISH results were found in 5,7% (n=23) of patients. In the inconclusive/equivocal FISH cohort, 78% of evaluated tissue came from breast biopsy and 22% were extracted from metastatic sites. When HER2 amplification by FISH was reclassified according to the FDA criteria (HER2/CEP17 FISH ratio above 2.0), 45% of patients previously classified as equivocal became HER2 positive. None of equivocal HER2 FISH patients received anti-HER2 therapy. Conclusions: The incidence of BC patients with equivocal HER2 FISH at our institution is similar to other large series, reflecting our adequate quality assurance methods. Anti-HER2 therapy is the backbone for HER2-positive BC patients irrespective of hormone receptor status. Further analyses using different techniques for HER2 expression and amplification status assessment are urged in order to better select patients for appropriate therapy.

Correlation of efficacy between rash and lapatinib/capecitabine therapy in Japanese HER2-positive metastatic breast cancer patients.

2011 ◽  
Vol 29 (27_suppl) ◽  
pp. 62-62 ◽  
Author(s):  
S. E. Nagai ◽  
K. Inoue ◽  
S. Kaneko ◽  
S. Uchida ◽  
T. Higuchi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Clinical Outcome ◽  
Cancer Patients ◽  
Response Rate ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Cancer Center ◽  
Breast Cancer Patients ◽  
Her2 Positive

62 Background: Lapatinib (L) is an oral dual-tyrosine kinase inhibitor with specificity for both EGFR and HER2. A phase III randomized trial (EGF100151) demonstrated that L+ capecitabine (C) is superior to C alone in patients with HER2-positive advanced breast cancer that progressed following prior therapy including trastuzumab. Although, Japanese phase I/II trial (EGF109749) demonstrated better response rate and higher rate of rash over a previous phase III trial. Recent reports demonstrated the correlation of efficacy between EGFR targeted therapy and rash in colon cancer. In lung cancer EGFR mutation, which are predominantly found in patients of East Asia origin are highly sensitive to EGFR-TKI. Analyzing correlation of efficacy between rash and EGFR targeted therapy is important in breast cancer. Methods: From June 2009 to February 2010, we treated 28 HER2-positive MBC patients who developed progression after anthracyclines, taxanes and trastuzumab based regimens with L 1,250 mg p.o. daily plus C 2,000 mg/m2 p.o. days 1-14 q 21 in Saitama Cancer Center. EGFR status was evaluated by immunohistochemistry. We analyzed the correlation among rash, clinical outcome and EGFR status. Results: Fourteen (50%) patients experienced rash, which were two grade 3, four grade 2 and eight grade 1. Rash experienced group showed superior response rate (77% : 24%, p<0.05) and median survival time (N/A: 259 days, p<0.05) over non-rash group. EGFR status has no correlation between rash and clinical outcome. Conclusions: According to our single institute experience, rash might be predictive factor in Japanese HER2 positive breast cancer patients treated with L+C therapy.

scholarly journals Rate of reclassification of HER2-equivocal breast cancer cases to HER2-negative per the 2018 ASCO/CAP guidelines and response of HER2-equivocal cases to anti-HER2 therapy

PLoS ONE ◽  
2020 ◽  
Vol 15 (11) ◽  
pp. e0241775
Author(s):  
James Crespo ◽  
Hongxia Sun ◽  
Jimin Wu ◽  
Qing-Qing Ding ◽  
Guilin Tang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Disease ◽  
Cancer Center ◽  
Her2 Status ◽  
Breast Cancers ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Testing ◽  
Primary Disease ◽  
The Impact

Purpose The 2018 American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guideline on HER2 testing in breast cancer permits reclassification of cases with HER2-equivocal results by FISH. The impact of such reclassification is unclear. We sought to determine the proportion of HER2-equivocal cases that are reclassified as HER2-negative and the impact of anti-HER2 therapy on survival in HER2-equivocal cases. Methods We reviewed medical records of breast cancer patients who had HER2 testing by fluorescence in stitu hybridization (FISH) and immunohistochemistry (IHC) performed or verified at The University of Texas MD Anderson Cancer Center during April 2014 through March 2018 and had equivocal results according to the 2013 ASCO/CAP guideline. The population was divided into 2 cohorts according to whether the biopsy specimen analyzed came from primary or from recurrent or metastatic disease. HER2 status was reclassified according to the 2018 ASCO/CAP guideline. Overall survival (OS) and event-free survival (EFS) were calculated using the Kaplan-Meier method, and the relationship between anti-HER2 therapy and clinical outcomes was assessed. Results We identified 139 cases with HER2-equivocal results according to the 2013 ASCO/CAP guideline: 90 cases of primary disease and 49 cases of recurrent/metastatic disease. Per the 2018 ASCO/CAP guideline, these cases were classified as follows: overall, HER2-negative 112 cases (80%), HER2-positive 1 (1%), and unknown 26 (19%); primary cohort, HER2-negative 85 (94%), HER2-positive 1 (1%), unknown 4 (4%); and recurrent/metastatic, HER2-negative 27 (55%) and unknown 22 (45%). Five patients in the primary-disease cohort and 1 patient in the recurrent/metastatic-disease cohort received anti-HER2 therapy. There was no significant association between anti-HER2 therapy and OS or EFS in either cohort (primary disease: OS, p = 0.67; EFS, p = 0.49; recurrent/metastatic-disease, OS, p = 0.61; EFS, p = 0.78. Conclusions The majority of HER2-equivocal breast cancer cases were reclassified as HER2-negative per the 2018 ASCO/CAP guideline. No association between anti-HER2 therapy and OS or EFS was observed. HER2-equivocal cases seem to have clinical behavior similar to that of HER2-negative breast cancers.

scholarly journals The Frequency of Low HER2 Expression in Breast Cancer and A Comparison of Prognosis Between Patients With HER2-Low and HER2-Negative Breast Cancer By HR Status

2021 ◽  
Author(s):  
Nanae Horisawa ◽  
Yayoi Adachi ◽  
Daiki Takatsuka ◽  
Kazuki Nozawa ◽  
Yuka Endo ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Treatment Strategies ◽  
Biological Data ◽  
Breast Cancers ◽  
Her2 Expression ◽  
Breast Cancer Patients ◽  
Her2 Amplification ◽  
Her2 Positive ◽  
Positive Breast Cancer

Abstract PurposeThe DESTINY-Breast04 clinical trial is currently investigating whether trastuzumab deruxtecan (T-DXd) is effective in HER2-low as well as HER2-positive breast cancer. This highlights the interest in treatment strategies for patients with HER2-low breast cancer. The current study was therefore designed to determine the frequency of HER2-low among all breast cancers, and to compare the prognosis of HER2-low patients with that of HER2-negative patients. MethodsWe retrospectively reviewed the biological data from 4,918 of 4,977 primary breast cancer patients who attended our institute. We quantified the overall frequency of breast cancer patients with a new HER2-low subtype that was defined by an immunohistochemistry score of IHC1+ or IHC2+/ISH-. We then compared the clinical characteristics and prognosis of HER2-low patients with that of patients who did not have HER2 amplification (HER2-0). ResultsLow HER2 expression was found in 3169 (64.4%) patients; 2860 (58.1%) were HR-positive and 309(6.3%) were HR-negative. Among HER2-0 patients, 681(13.9%) were HR-positive and 157(3.2%) were HR-negative. The HER2-0 group tended to have more poor prognostic factors than the HER2-low group, irrespective of HR status. There were no statistically significant differences between the prognosis of HER2-low and HER2-0 patients, regardless of HR status. However, patients in the HER2-low group tended to have better prognosis than those in the HER2-0 group.ConclusionHER2-low patients did not have a significantly different prognosis than HER2-0 patients, regardless of HR status. However, we should consider tailoring therapies for patients with HRE2-low early breast cancer according to their HR status.

scholarly journals Neratinib is effective in breast tumors bearing both amplification and mutation of ERBB2 (HER2)

2018 ◽  
Vol 11 (551) ◽  
pp. eaat9773 ◽  
Author(s):  
Emiliano Cocco ◽  
F. Javier Carmona ◽  
Pedram Razavi ◽  
Helen H. Won ◽  
Yanyan Cai ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Lines ◽  
Xenograft Model ◽  
Growth Factor Receptor ◽  
Poor Response ◽  
Breast Cancer Patients ◽  
Her2 Amplification ◽  
Sequencing Data ◽  
Her2 Positive ◽  
Her2 Mutation

Mutations in ERBB2, the gene encoding epidermal growth factor receptor (EGFR) family member HER2, are common in and drive the growth of “HER2-negative” (not ERBB2 amplified) tumors but are rare in “HER2-positive” (ERBB2 amplified) breast cancer. We analyzed DNA-sequencing data from HER2-positive patients and used cell lines and a patient-derived xenograft model to test the consequence of HER2 mutations on the efficacy of anti-HER2 agents such as trastuzumab, lapatinib, and neratinib, an irreversible pan-EGFR inhibitor. HER2 mutations were present in ~7% of HER2-positive tumors, all of which were metastatic but not all were previously treated. Compared to HER2 amplification alone, in both patients and cultured cell lines, the co-occurrence of HER2 mutation and amplification was associated with poor response to trastuzumab and lapatinib, the standard-of-care anti-HER2 agents. In mice, xenografts established from a patient whose HER2-positive tumor acquired a D769Y mutation in HER2 after progression on trastuzumab-based therapy were resistant to trastuzumab or lapatinib but were sensitive to neratinib. Clinical data revealed that six heavily pretreated patients with tumors bearing coincident HER2 amplification and mutation subsequently exhibited a statistically significant response to neratinib monotherapy. Thus, these findings indicate that coincident HER2 mutation reduces the efficacy of therapies commonly used to treat HER2-positive breast cancer, particularly in metastatic and previously HER2 inhibitor–treated patients, as well as potentially in patients scheduled for first-line treatment. Therefore, we propose that clinical studies testing the efficacy of neratinib are warranted selectively in breast cancer patients whose tumors carry both amplification and mutation of ERBB2/HER2.

scholarly journals Immune cell profiles of metastatic HER2-positive breast cancer patients according to the sites of metastasis

2021 ◽  
Author(s):  
Tiia J. Honkanen ◽  
Milla E. K. Luukkainen ◽  
Antti Tikkanen ◽  
Peeter Karihtala ◽  
Markus Mäkinen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Liver Metastases ◽  
Immune Cell ◽  
Pulmonary Metastases ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Immunological Markers ◽  
Metastatic Sites ◽  
Positive Breast Cancer

Abstract Purpose Recent works have characterized that metastatic site can affect the tumour immune profiles and efficiency of cancer immunotherapies. The prognosis of HER2-positive breast cancer is associated with the characteristics of the tumour immune microenvironment, with immunological cells playing a central role in efficiency of HER2-targeted antibodies. Here we investigated the prognostic significance of different metastatic sites and their correlation to tumour immune profiles in HER2-positive breast cancer treated with trastuzumab. Methods We collected all (n = 54) HER2-positive metastatic breast cancer patients treated with trastuzumab containing regimens at Oulu University Hospital 2009–2014. Pathological and clinical data were collected from electronic patient records. The tumour immune profiles were analysed from pre-treatment primary tumours using well-characterized immunological markers with computer-assisted immune cell counting. Results Of the metastatic sites, only liver metastases were associated with poor prognosis (hazard ratio 1.809, 95% confidence interval 1.004–3.262), especially when presented as the primary site of metastases. Of the other sites, pulmonary metastases characterized a patient profile with trend to improved survival. Of the studied tumour immunological markers, patients with liver metastases had low densities of CD3+ T cells (p = 0.030) and M1-like macrophages in their primary tumours (p = 0.025). Of the other studied markers and sites, patients with pulmonary metastases had low STAB1+-immunosuppressive macrophage density in their primary tumours. Conclusion Our results suggest that the site of metastasis is associated with prognosis in HER2-positive breast cancer, highlighted by the poor prognosis of liver metastases. Furthermore, liver metastases were associated with adverse tumour immune cell profiles.

scholarly journals Immune Cell Profiles of Metastatic HER2 Positive Breast Cancer Patients According To The Sites of Metastasis

2021 ◽  
Author(s):  
Tiia J Honkanen ◽  
Milla E K Luukkainen ◽  
Antti Tikkanen ◽  
Peeter Karihtala ◽  
Markus Mäkinen ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Liver Metastases ◽  
Immune Cell ◽  
Pulmonary Metastases ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Her2 Positive Breast Cancer ◽  
Immunological Markers ◽  
Metastatic Sites ◽  
Positive Breast Cancer

Abstract Purpose: Recent works have characterized that metastatic site can affect the tumour immune profiles and efficiency of cancer immunotherapies. The prognosis of HER2 positive breast cancer is associated with the characteristics of the tumour immune microenvironment, with immunological cells playing a central role in efficiency of HER2 targeted antibodies. Here we investigated the prognostic significance of different metastatic sites and their correlation to tumour immune profiles in HER2 positive breast cancer treated with trastuzumab. Methods: We collected all (n=54) HER2 positive metastatic breast cancer patients treated with trastuzumab containing regimens at Oulu University Hospital 2009-2014. Pathological and clinical data were collected from electronic patient records. The tumour immune profiles were analysed from pre-treatment primary tumours using well-characterized immunological markers with computer-assisted immune cell counting. Results: Of the metastatic sites, only liver metastases were associated with poor prognosis (hazard ratio 1.809, 95% confidence interval 1.004 – 3.262), especially when presenting as the primary site of metastases. Of the other sites, pulmonary metastases characterized a patient profile with trend to improved survival. Of the studied tumour immunological markers, liver metastases had low densities of CD3+ T-cells (p=0.030) and M1-like macrophages in their primary tumours (p=0.025). Of the other studied markers and sites, pulmonary metastases had low STAB1+ immunosuppressive macrophage density in their primary tumours.Conclusions: Our results suggest that the site of metastasis is associated with prognosis in HER2 positive breast cancer, highlighted by the poor prognosis of liver metastases. Furthermore, liver metastases were associated with adverse tumour immune cell profiles.

Co-expression of ER-beta and HER2 associated with poorer prognosis in primary breast cancer

2009 ◽  
Vol 32 (3) ◽  
pp. 250 ◽  
Author(s):  
Wen-sheng Qui ◽  
Lu Yue ◽  
Ai-ping Ding ◽  
Jian Sun ◽  
Yang Yao ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Differentiation ◽  
Primary Breast Cancer ◽  
Tumour Size ◽  
Univariate Analysis ◽  
Growth Factor Receptor ◽  
Disease Free Survival ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Er Alpha

Purpose: To assess the prognostic value of co-expression of estrogen receptor (ER)-beta and human epidermal growth factor receptor 2 (HER2) in primary breast cancer patients in China. Methods: Tumour specimens from 308 patients undergoing surgery for primary breast cancer were evaluated. Expression of ER-beta and HER-2 was investigated by the immunohistochemistry. Results: 123 patients (40%) were ER-beta positive and 58 (18.5 %) were HER2 positive. Among the 58 HER2 positive patients, 44 were ER-beta positive and 14 were ER-beta negative. ER-beta positive was associated with HER2 positive (75.9%, P=0.018) as well as ER-alpha positive (79.7%, P=0.023), poor cell differentiation (77.2% grade 2 or 3, P=0.010) and menopause age < 45 yr (55.3%, P=0.031). HER2 positive was associated with poor cell differentiation (93.1%, P=0.001), ?3cm tumour size (67.2%, P=0.011). Conclusion: Both ER-beta positive and HER2 positive status was associated with poorer overall survival (OS) by univariate analysis. In both HER2 positive and HER2 negative subgroups, ER-beta positive was associated with poorer distant disease free survival (DDFS) but not OS, which implied that ER-beta might relate to metastasis in breast cancer.

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