HER2 in uterine serous carcinoma: Testing platforms and implications for targeted therapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5580-5580
Author(s):  
Tenley Klc ◽  
Sharon Wu ◽  
Annelise M. Wilhite ◽  
Nathaniel L. Jones ◽  
Matthew A. Powell ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Uterine Cancer ◽  
Statistical Significance ◽  
Single Gene ◽  
Serous Carcinoma ◽  
Her2 Testing ◽  
Her2 Breast Cancer ◽  
Uterine Serous Carcinoma ◽  
Cancer Guidelines ◽  
Her2 Positivity

5580 Background: HER2 is an emerging prognostic and therapeutic target in uterine serous carcinoma (USC). Testing algorithms and platforms in breast and gastric cancers are well studied and validated, but optimal HER2 testing in uterine cancer is not yet established. We aimed to assess the concordance of chromogenic in situ hybridization (CISH), immunohistochemistry (IHC), and next generation sequencing (NGS) platforms to aid in the development of USC specific testing guidelines. We also evaluated the rate of downstream mutations that may affect response to HER2 directed therapy. Methods: A total of 2,192 USC tumors were analyzed using NGS (NextSeq, 592 Genes and WES, NovaSEQ), a subset of 1,423 tumors were also tested by IHC and CISH (Caris Life Sciences, Phoenix, AZ). HER2 positivity through IHC (4B5, Ventana) and CISH (INFORM DUAL HER2 ISH Assay, Ventana) was determined based on 2007 and 2018 ASCO/CAP HER2 breast cancer guidelines. PD-L1 expression was tested by IHC using SP142 (Spring Biosciences) (positive cut-off >1%). Microsatellite instability (MSI) was tested by fragment analysis (FA), IHC and NGS. Tumor mutational burden (TMB) was measured by totaling somatic mutations per tumor (TMB-high cut-off > 10 mutations per Mb). Statistical significance was determined using chi-square. Results: Rates of HER2 positivity were comparable using the 2018 and 2007 breast cancer guidelines (19.5% vs 17.5%; p=0.25). Based on 2018 guidelines, the concordance between IHC and CISH was 98.9%. Specifically, 229/1423 patients (16%) were IHC+/CISH+, 5 patients (0.4%) were IHC+/CISH- and 11 patients (0.8%) were IHC-/CISH+ (Table). Common pathway alterations in HER2+ USC include TP53, RTK RAS, PI3K, NOTCH, chromatin remodeling and cell cycle genes. Single gene alterations in HER2+ tumors that may implicate HER2 therapy resistance (based on pathway analyses in other tumor types) included PI3K (36%), KRAS (2.6%), and PTEN (2.1%). HER2+ tumors had low immunotherapy biomarker profiles (0.3% MSI-H, 0.8% TMB, 17.1% PD-L1). Conclusions: High concordance rates were observed between CISH and IHC. Ultimately these testing platforms need to be validated by response to HER2 targeted therapies in order to develop USC specific HER2 testing guidelines.[Table: see text]

scholarly journals Exploratory Analysis of Single-Gene Predictive Biomarkers in HERA DASL Cohort Reveals That C8A mRNA Expression Is Prognostic of Outcome and Predictive of Benefit of Trastuzumab

2018 ◽  
pp. 1-12 ◽  
Author(s):  
Scooter Willis ◽  
Varvara Polydoropoulou ◽  
Yuliang Sun ◽  
Brandon Young ◽  
Zoi Tsourti ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Mrna Expression ◽  
Cox Regression ◽  
Single Gene ◽  
Disease Free Survival ◽  
Predictive Biomarkers ◽  
Exploratory Analysis ◽  
Treatment Benefit ◽  
Significant Treatment ◽  
Her2 Breast Cancer

Purpose The Herceptin Adjuvant study is an international multicenter randomized trial that compared 1 or 2 years of trastuzumab given every 3 weeks with observation in women with human epidermal growth factor 2–positive (HER2+) breast cancer after chemotherapy. Identification of biomarkers predictive of a benefit from trastuzumab will minimize overtreatment and lower health care costs. Methods To identify possible single-gene biomarkers, an exploratory analysis of 3,669 gene probes not expected to be expressed in normal breast tissue was conducted. Disease-free survival (DFS) was used as the end point in a Cox regression model, with the interaction term between C8A mRNA and treatment as a categorical variable split on the cohort mean. Results A significant interaction between C8A mRNA and treatment was detected ( P < .001), indicating a predictive response to trastuzumab treatment. For the C8A-low subgroup (mRNA expression lower than the cohort mean), no significant treatment benefit was observed ( P = .73). In the C8A-high subgroup, patients receiving trastuzumab experienced a lower hazard of a DFS event by approximately 75% compared with those in the observation arm (hazard ratio [HR], 0.25; P < .001). A significant prognostic effect of C8A mRNA also was seen ( P < .001) in the observation arm, where the C8A-high group hazard of a DFS event was three times the respective hazard of the C8A-low group (HR, 3.27; P < .001). C8A mRNA is highly prognostic in the Hungarian Academy of Science HER2+ gastric cancer cohort (HR, 1.72; P < .001). Conclusion C8A as a single-gene biomarker prognostic of DFS and predictive of a benefit from trastuzumab has the potential to improve the standard of care in HER2+ breast cancer if validated by additional studies. Understanding the advantage of overexpression of C8A related to the innate immune response can give insight into the mechanisms that drive cancer.

scholarly journals HER2 antibody-drug conjugate controls growth of breast cancer brain metastases in hematogenous xenograft models, with heterogeneous blood–tumor barrier penetration unlinked to a passive marker

2020 ◽  
Vol 22 (11) ◽  
pp. 1625-1636 ◽  
Author(s):  
Brunilde Gril ◽  
Debbie Wei ◽  
Alexandra S Zimmer ◽  
Christina Robinson ◽  
Imran Khan ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastasis ◽  
Brain Metastases ◽  
Statistical Significance ◽  
Growth Factor Receptor ◽  
Antibody Drug Conjugate ◽  
Brain Penetration ◽  
Her2 Breast Cancer ◽  
Antibody Drug

Abstract Background Brain metastases of HER2+ breast cancer persist as a clinical challenge. Many therapeutics directed at human epidermal growth factor receptor 2 (HER2) are antibodies or antibody-drug conjugates (ADCs), and their permeability through the blood–tumor barrier (BTB) is poorly understood. We investigated the efficacy of a biparatopic anti-HER2 antibody-tubulysin conjugate (bHER2-ATC) in preclinical models of brain metastases. Methods The compound was evaluated in 2 hematogenous HER2+ brain metastasis mouse models, SUM190-BR and JIMT-1-BR. Endpoints included metastasis count, compound brain penetration, cancer cell proliferation, and apoptosis. Results Biparatopic HER2-ATC 3 mg/kg prevented metastasis outgrowth in the JIMT-1-BR model. At 1 mg/kg bHER2-ATC, a 70% and 92% reduction in large and micrometastases was observed. For the SUM190-BR model, an 85% and 53% reduction, respectively, in large and micrometastases was observed at 3 mg/kg, without statistical significance. Proliferation was reduced in both models at the highest dose. At the endpoint, bHER2-ATC uptake covered a median of 4–6% and 7–17% of metastasis area in the JIMT-1-BR and SUM190-BR models, respectively. Maximal compound uptake in the models was 19% and 86% in JIMT-1-BR and SUM190-BR, respectively. Multiple lesions in both models demonstrated ADC uptake in the absence or low diffusion of Texas Red Dextran, a marker of paracellular permeability. Using in vitro BTB assays, the ADC was endocytosed into brain endothelial cells, identifying a potentially new mechanism of antibody permeability. Conclusions Biparatopic HER2-ATC significantly prevented JIMT-1-BR brain metastasis outgrowth and showed activity in the SUM190-BR model. The bHER2-ATC penetration into metastases that are impermeable to fluorescent dye suggested an endocytic mechanism of brain penetration.

scholarly journals Correlation of the pathological response rate with the global disease and survival of patients with sub type her2 breast cancer submitted to neoadjuvant chemotherapy at hospital de câncer de Pernambuco

Mastology ◽  
2020 ◽  
Vol 30 (Suppl 1) ◽  
Author(s):  
Juliana Beatriz de Oliveira Ferreira ◽  
Jose Peixoto ◽  
Carolina de Souza Vasconcelos ◽  
Tainan de Morais Bispo
Keyword(s):  
Breast Cancer ◽  
Response Rate ◽  
Statistical Significance ◽  
Pathological Response ◽  
Time Data ◽  
Recurrence Rates ◽  
Logrank Test ◽  
Her2 Breast Cancer ◽  
Significant Difference ◽  
The Impact

Introduction: QT NEO starts from the premise of tumor downstaging, enabling excision of previously unresectable tumors, reducing surgical extension and, consequently, enabling higher rates of conservative surgery. It also allows an in vivo assessment of the neoplastic response to systemic therapy. PCR is a powerful indicator of the benefit of QT NEO and is associated with better outcomes for relapse, DFS and OS. Objectives: This study aimed to evaluate the pathological response rate of patients with CM HER2 who underwent QT NEO, treated at HCP in the years 2014-2016 and to correlate with the recurrence rates, DFS and OS, observing whether the data are in agreement with those reported in the literature. Methods: The study evaluated patients with BC HER2, confirmed by IHC and/or FISH, who underwent QT NEO followed by surgery from 2014 to 2016, treated at the HCP. It is a retrospective, observational, and descriptive study. The information collected comes from a questionnaire formulated by the researcher with the relevant points to be analyzed in the project. The data were stored and analyzed using SPSS, version 20.0. The Kolmogorov-Smirnov test, χ2 test or Fisher’s exact test were used to assess the variables. The DFS and OS time data were represented by the Kapplan-Meier curves and the Logrank test was used to verify a significant difference between the categories with or nPRC. A significance level of 5% was assigned to it. Results: The medical records of 58 patients with BC subtype HER 2 who received QT NEO followed by surgery were analyzed. During a mean follow-up of 35 months, 5 (8.6%) local recurrences and 20 (34.5%) distant ones and 18 deaths from breast cancer (31%) were observed. A result of 50% of PRC was achieved, with no correlation of statistical significance between age, histological type, nuclear grade, staging prior to QT NEO and chemotherapy regimen used. The PRC group achieved lower recurrence rates (20.68 vs. 51.72%) with statistical significance. DFS in the PRC group is 75.9% and in the nPRC group it is 44.82%. OS of the group with PRC is 82.7 vs. 48.2% in the nPRC group. Patients with HR- and PRC were the ones that most benefited from obtaining PRC in the recurrence and DFS outcomes, reaching recurrence rates of 22% and DFS of 77.8% compared to the HR group – without PRC, which had recurrence rates of 72% and DFS of 27.3%. Conclusion: This study found significant data with lower recurrence rates and better rates of DFS and OS in patients who achieved PRC, thus evidencing the impact that PRC has on long-term outcomes, especially in the HR- subgroup of patients.

HER2 positivity in advanced gastric cancer is comparable to breast cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 15057-15057 ◽  
Author(s):  
J. León-Chong ◽  
F. Lordick ◽  
Y. K. Kang ◽  
S. R. Park ◽  
Y. J. Bang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Small Sample ◽  
Phase Iii ◽  
Her2 Positive ◽  
Efficacy Data ◽  
Her2 Testing ◽  
Methods Of Evaluation ◽  
Sample Set ◽  
Her2 Positivity

15057 Background: Accurate HER2 testing is required to identify patients eligible for treatment with trastuzumab (Herceptin®). HER2 positivity is reported as 6–35% in gastric cancer (GC). This range is due to small sample sets and differing methods of evaluation or scoring. A specific HER2-testing process was established for the Phase III ToGA trial, which is evaluating trastuzumab added to chemotherapy in HER2-positive advanced GC. Methods: A validation study was completed to standardise IHC (HercepTest™) and FISH (PharmDx™) protocols, and to establish a scoring system specific for GC (M Hofmann et al. ASCO Gastrointestinal Cancers Symposium 2006. Abstract no. 24). Tumour samples for ToGA were then centrally tested by both IHC and FISH to identify patients eligible for enrolment. Results: To date, 1024 tumour samples have been assessed (243 HER2 positive and 781 HER2 negative) giving an overall HER2-positivity rate of 23.7%. Both IHC and FISH results are available for 960 patients, with 87% concordance. Differences were largely due to FISH-positive cases that were IHC 0/1+. HER2 positivity differed significantly by histological subtype: 36% in intestinal, 7% in diffuse and 23% in mixed. HER2 positivity also varied according to the site of the tumour: 36% (8/22) for gastro-oesophageal junction tumours and 21% (60/291) for gastric tumours. Sample numbers were very small so these results must be treated with caution. The HER2- positivity rate was similar in specimens obtained by biopsy (168/689; 24%) and surgery (71/322; 22%). Conclusions: Using validated methodology and based on the large sample set from the ongoing ToGA trial, the HER2-positivity rate observed in advanced GC is as high as in breast cancer: ∼24%. The first efficacy data from ToGA are expected in 2009. No significant financial relationships to disclose.

Clinical and translational results of CALGB 40601: A neoadjuvant phase III trial of weekly paclitaxel and trastuzumab with or without lapatinib for HER2-positive breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 500-500 ◽  
Author(s):  
Lisa A. Carey ◽  
Donald A. Berry ◽  
David Ollila ◽  
Lyndsay Harris ◽  
Ian E. Krop ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Residual Disease ◽  
Statistical Significance ◽  
Stage Ii ◽  
Phase Iii ◽  
Weekly Paclitaxel ◽  
Gene Copy ◽  
Her2 Positive ◽  
Primary Tumors ◽  
Her2 Breast Cancer

500 Background: Recent trials in HER2-positive (HER2+) breast cancer (BrCa) demonstrate increased pathological complete response (pCR) using dual HER2-targeting in the neoadjuvant setting and increased progression-free survival in metastatic disease. CALGB 40601 aimed to further quantify the pCR rates of weekly paclitaxel (T) and trastuzumab (H) alone or combined HER2-blockade of H with the small molecule lapatinib (L), and to identify biomarkers of sensitivity to these HER2-targeted agents. Methods: Eligible patients had newly diagnosed, noninflammatory stage II-III HER2+ BrCa and were randomized to receive T (80mg/m2/week IV) + H (4mg/kg then 2mg/kg/week IV) alone (TH) or with the addition of L (750 mg/d PO) (THL) for 16 weeks preoperatively. A third arm, T + L (1500 mg/d) (TL), was closed early when negative efficacy and toxicity data emerged from preliminary analysis of ALTTO. After surgery, 4 cycles of adjuvant dose-dense AC and 1 year H was recommended. Tumors were biopsied for research before therapy; post-Rx samples of residual disease were requested. The primary endpoint was in-breast pCR rate; the study had 85% power to detect an increase from 30% (TH) to 50% (THL). Results: 305 patients were randomized (118 THL, 120 TH, 67 TL); 68% were clinical stage II and 59% hormone receptor-positive. Grade 3+ toxicity was higher among L-containing arms, including neutropenia (12% TL, 7% THL, 2% TH), rash (15% TL, 14% THL, 2% TH), and diarrhea (20% TL, 20% THL, 2% TH). Breast pCR rates with 95% confidence limits were: 51% (42-60%) THL, 40% (32-49%) TH, 32% (22-44%) TL. pCR rate in the TH arm was higher than previous studies, and was not significantly different from THL (p=0.11). We will present molecular subtype, sequence and gene copy number abnormalities in primary tumors and residual disease. Conclusions: pCR rate was higher with combined THL compared with standard TH but did not reach statistical significance. These results are qualitatively similar to other neoadjuvant studies in HER2+ BrCa, and contribute to estimates of pCR rates after these agents. Tissue-based studies may illuminate which patients benefit from HER2-targeting using these agents. Clinical trial information: NCT00770809.

Comparative Analysis of Human Epidermal Growth Factor Receptor 2 Testing in Breast Cancer According to 2007 and 2013 American Society of Clinical Oncology/College of American Pathologists Guideline Recommendations

2017 ◽  
Vol 35 (26) ◽  
pp. 3039-3045 ◽  
Author(s):  
Wedad M. Hanna ◽  
Elzbieta Slodkowska ◽  
Fang-I Lu ◽  
Houman Nafisi ◽  
Sharon Nofech-Mozes
Keyword(s):  
Breast Cancer ◽  
Epidermal Growth Factor Receptor ◽  
Targeted Therapy ◽  
Growth Factor ◽  
Clinical Oncology ◽  
Growth Factor Receptor ◽  
Her2 Testing ◽  
Epidermal Growth ◽  
American Society ◽  
Her2 Positivity

Purpose To study the effect of the 2013 updates to the 2007 American Society of Clinical Oncology/College of American Pathologists recommendations for human epidermal growth factor receptor 2 (HER2) testing in breast cancer on testing patterns and interpretation in a large regional reference laboratory. Patients and Methods Patient cases with HER2 testing scores for breast biomarker evaluation were selected from our laboratory information system during two 12-month periods (2012 and 2014). The number of tests performed, type of specimens, proportion of HER2-positive and equivocal patient cases, and number of repeat tests on subsequent excisional specimens were examined and compared. Results Although the number of samples tested increased between 2012 and 2014 (2,201 v 2,558 patient cases; 2,278 v 2,659 tumors), HER2 positivity remained constant (15.7% v 15.5%, respectively). The number of repeat tests performed within 6 months more than doubled (122 [5.5%) of 2,201 v 302 [11.8%] of 2,558; P < .001), and the proportion of immunohistochemistry (IHC) 2+ tumors was significantly lower in 2014 than in 2012 (20.3% v 25.3%; P < .001). However, the proportion of patient cases with unresolved HER2 statuses (equivocal by IHC and in situ hybridization) was significantly higher in 2014 (four of 2,278 v 90 of 2,660; P < .001). Conclusion Our findings indicate that the 2013 updates to the American Society of Clinical Oncology/College of American Pathologists recommendations for HER2 testing in breast cancer did not affect the overall HER2-positivity rate or the proportion of patients eligible for HER2-targeted therapy. The proportion of tests and repeat tests performed increased, as did the number of patient cases categorized as ISH equivocal. The benefit of targeted therapy in the equivocal group is not proven, so targeted therapy should not be considered for patients in this category which should be redefined in future iterations of the recommendations.

Immune-response markers and actual response to immune-oncology therapy in uterine serous carcinoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5590-5590
Author(s):  
Nathaniel L. Jones ◽  
Sharon Wu ◽  
Joanne Xiu ◽  
Amaranta Craig ◽  
Gina Mantia-Smaldone ◽  
...  
Keyword(s):  
T Cells ◽  
Median Survival ◽  
Survival Benefit ◽  
Immune Cell ◽  
Statistical Significance ◽  
Serous Carcinoma ◽  
Myeloid Dendritic Cells ◽  
Primary Tumors ◽  
Uterine Serous Carcinoma ◽  
Immune Oncology

5590 Background: Uterine serous carcinoma (USC) is an aggressive subtype of endometrial cancer with poor prognosis and limited treatment options. Immune-oncology (IO) agents have shown promise USC, however data is limited regarding which patients benefit most from IO therapy. In other malignancies, PD-L1, MSI-H status and high TMB have been predictive of IO response. We sought to characterize the immune profiles of USC and investigate treatment response to IO therapy. Methods: Tumor samples were analyzed using Nex-Gen sequencing of the DNA (NextSeq, 592 genes or NovaSeq, whole exome sequencing) and RNA (NovaSeq, whole transcriptome sequencing) and immunohistochemistry (IHC) (Caris Life Sciences, Phoenix, AZ).PD-L1 IHC used SP-142 (cut-off >1%). MSI was tested by FA, IHC and NGS. TMB was measured by totaling somatic mutations per tumor (high > 10 mutations per MB). Immune cell fraction was calculated by QuantiSeq. Real-world overall survival (OS) information was obtained from insurance claims data and Kaplan-Meier estimates were calculated for molecularly defined patient cohorts. Statistical significance was determined using chi-square and Wilcoxon rank sum test and p values adjusted for multiple comparisons (q) to be < 0.05. Results: Molecular analysis was performed on 2,806 USC tumors. The median age was 67 years. 65.3% were from primary tumors, 34.7% from metastatic sites. In total, 92 patients were treated with IO therapy and had a significantly longer median survival than those not treated with IO (months: 59.6 vs 31.2; HR(95% CI): 0.38(0.24-0.61) p < 0.001), resulting in a survival advantage of 867 days. PD-L1 expression was present in 19.1% of cases, but only 2.3% of tumors were MSI-H and 4.2% were TMB-H. Patients with these markers trended toward a better median survival, but this was not significant; PD-L1 (months: 34.4 vs 31.2; HR(95% CI): 0.90 (0.74-1.1), MSI-H (OS not yet reached vs 31.6 months; HR(95% CI): 0.69(0.38-1.25) and TMB-H (months: 36.4 vs 31.6; HR(95% CI): 0.84(0.50-1.39). Regarding the immune microenvironment, the most common infiltrating immune cells were M2 Macrophages (5.35%), B cells (4.71%), myeloid dendritic cells (3.45%), NK cells (2.94%) and regulatory T cells (1.59%). There were few CD8 T cells and non-regulatory CD4 T cells. Conclusions: IO therapy was associated with a median survival benefit of more than 2 years in USC. We did not identify any prognostic markers of IO-therapy response. MSI-H and TMB-H are rare in USC, but PD-L1 is present in nearly 20% of cases. Notably these markers did predict a significant survival benefit, which has important clinical implications. Further study is warranted.

Is uterine serous carcinoma a part of hereditary breast cancer syndrome?

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 5587-5587
Author(s):  
Saeed Rafii ◽  
Philip Dawson ◽  
Sarah Williams ◽  
Jennifer S. Pascoe ◽  
James E. Nevin ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Hormone Receptor ◽  
Personal History ◽  
Tamoxifen Treatment ◽  
Serous Carcinoma ◽  
Cancer Syndrome ◽  
Younger Age ◽  
History Of ◽  
Uterine Serous Carcinoma ◽  
History Of Cancer

5587 Background: Whilst the association between breast cancer and uterine serous carcinoma (USC) is attributed to tamoxifen treatment, few studies have reported that this increased risk is independent of tamoxifen. Methods: To further investigate the relationship between breast cancer and USC, we retrospectively studied 216 patients from 5 hospital trusts in Birmingham, UK who were diagnosed with USC between 1993 and 2012. We collected personal history of cancer in these cases before or after USC diagnosis. In addition FIGO staging, clinical and survival data were collected from our local cancer registry and patients’ clinical records. Results: In this case series, 56 patients (25.9%) had personal history of at least one cancer before and 18 patients (8.3%) had history of at least one cancer after the diagnosis of USC. Within the group of patients with the history of cancer before the USC, 38 patients (68%, 17.5% of all cases) had personal history of breast cancer prior to the development of USC, higher than the UK expected age standardised relative incidence of breast cancer (350 in 100,000, CRUK 2006-2008). Although 27/38 cases (71%) had endocrine treatment for their primary breast cancer, 11/38 patients (29%) did not have any tamoxifen treatment due to hormone receptor negative breast cancer. Additionally the median age of breast cancer diagnosis for the hormone receptor negative group was significantly lower than those patients who had hormonal treatment for their breast cancer (56 vs. 64 years, p :0.036) compatible with the younger age at diagnosis expected of the familial (BRCA mutated) or triple negative breast cancer. Of 18 patients with a second cancer after diagnosis of USC, 6 patients (33%) were diagnosed with breast/ovarian cancer. This group also had no treatment with tamoxifen. Conclusions: Lack of exposure to tamoxifen and younger age at diagnosis in this subgroup suggest that other factors such as a common underlying genetic predisposition may be responsible for the development of both malignancies. We propose that at least a subgroup of USC may be a part of hereditary breast cancer syndrome. This may have implications in prevention (prophylactic hysterectomy) or trials of targeted treatments (PARP inhibitors) for a subgroup of USC patients.

Sign in / Sign up

Export Citation Format

Share Document