Use of the PRO Onc Assay (Prometheus) to measure HER2 overexpression/activation in circulating tumor cells (CTCs) in women with HER2-negative metastatic breast cancer (MBC): A Sarah Cannon Research Institute (SCRI) trial.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 618-618
Author(s):  
John D. Hainsworth ◽  
Howard A. Burris ◽  
Patrick Brian Murphy ◽  
Ruth E. Lamar ◽  
Mythili Shastry ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Targeted Therapy ◽  
Accurate Determination ◽  
Metastatic Breast ◽  
Reference Value ◽  
Assay Method ◽  
Her2 Status ◽  
Her2 Overexpression ◽  
Her2 Positive ◽  
Improve Patient Management

618 Background: HER2- targeted therapy has markedly improved the treatment of women with HER2- positive breast cancer. FISH testing for HER2 overexpression is the most reliable assay method; treatment decisions are usually based on HER2 expression of the breast primary tumor. Accurate determination of HER2 status by testing CTCs may improve patient management by allowing ongoing assessment of HER2 status during treatment and/or identifying additional patients (pts) for HER2- targeted therapy. Methods: The PRO Onc assay uses a multiplexed immunoassay format to provide expression and activation profiling of HER2 and other signal transduction molecules. The assay can detect overexpression and activation (phosphorylation) of HER2, with sensitivity at a single CTC level. We obtained blood specimens from 57 women with metastatic HER2- negative breast cancer who were receiving standard chemotherapy. In these women, HER2 status had previously been determined by FISH (32) or 0 – 1+ IHC testing (25). All specimens were tested for the presence of CTCs; the PRO Onc assay was performed when CTCs were identified. The HER2 overexpression cutoff (>3.0 CU) was based on the reference value (average + 4SD) determined by analyzing normal blood obtained from 42 healthy donors. Results: 31 of 57 pts (54%) had CTCs identified. 6 of 31 pts (19%) had HER2 overexpressed, and 4 pts (13%) had HER2 activation without overexpression. 7 of 10 pts with HER2 overexpression/activation by PRO Onc Assay were FISH- negative; 3 were IHC- negative. Since initial HER2 determination, these 10 pts had received a median of 3 chemotherapy regimens (range 1 - 5). Conclusions: When CTCs were present, the PRO Onc assay identified HER2 overexpression or activation in 31% of women with HER2- negative MBC. The therapeutic significance of this finding is unknown. Since the predetermined threshold of ≥10% HER2- positive assay results was exceeded, this trial will proceed to a planned second portion, in which women with HER2- negative MBC (by FISH testing) and HER2 overexpression or activation in CTCs will receive a trial of HER2- targeted therapy.

DETECT III: A multicenter, randomized, phase III study to compare standard therapy alone versus standard therapy plus lapatinib in patients (pts) with initially HER2-negative metastatic breast cancer but with HER2-positive circulating tumor cells (CTC).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS1146-TPS1146
Author(s):  
Carsten Hagenbeck ◽  
Carola Anna Melcher ◽  
Johann Wolfgang Janni ◽  
Andreas Schneeweiss ◽  
Peter A. Fasching ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Targeted Therapy ◽  
Clinical Benefit ◽  
Standard Treatment ◽  
Metastatic Breast ◽  
Phase Iii ◽  
Her2 Status ◽  
Her2 Positive ◽  
Phase Iii Study

TPS1146 Background: HER2 status may change over the course of disease in breast cancer pts. Approx. 20-30% of pts with initially HER2-negative breast cancer have HER2-positive metastasis (Zidan et al. 2005; Tewes et al. 2009). Determining HER2 status on CTC is one option to re-evaluate HER2 status at the time metastasis is diagnosed. Currently it is unclear if HER2-targeted therapy based on the assessment of HER2 status of CTC reveals a clinical benefit. Methods: This is a randomized, open-label, two arm phase III study to investigate the clinical efficacy of lapatinib, as a HER2-targeted therapy in initially HER2-negative metastatic breast cancer pts with HER2-positive CTC at the time of distant disease. As only half of the pts with HER2-negative metastatic breast cancer show CTC-positivity and of those approx. 32% will exhibit HER2-positive CTC (Fehm et al. 2010), screening of about 1420 pts is required to enroll 228 pts. Main inclusion criteria: metastatic breast cancer with HER2-negative primary tumor tissue and/or biopsies from metastatic sites or locoregional recurrences, evidence of ≥1 HER2-positive CTC and ≥1 measurable metastatic lesion according to RECIST. Eligible pts will be randomized 1:1 to receive standard treatment vs. standard treatment plus lapatinib. Standard chemo- or endocrine therapy must be approved in combination with lapatinib or been investigated in prior clinical trials. Primary endpoint is progression free survival. Secondary endpoints include overall response rate, clinical benefit rate, overall survival and dynamic of CTC. The DETECT III trial is one of the first trials where treatment is based on phenotypic characteristics of CTC. If this trial succeeds in proving efficacy of lapatinib in pts with initially HER2-negative metastatic breast cancer but HER2-positive CTC, this will establish a new strategy in the treatment of metastatic breast cancer.

Mutations of HER2 gene in HER2-positive metastatic breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13118-13118 ◽  
Author(s):  
T. Prempree ◽  
C. Wongpaksa
Keyword(s):  
Breast Cancer ◽  
Gene Mutations ◽  
Metastatic Breast ◽  
Her2 Status ◽  
Trastuzumab Resistance ◽  
Her2 Gene ◽  
Her2 Positive ◽  
Primary Tumors ◽  
Trastuzumab Therapy ◽  
One Year

13118 Background: HER2 status of Breast Cancer has been assessed by IHC and FISH and used for therapeutic decision with a high degree of success. However, there were numbers of HER2-positive MBC who finally failed the Trastuzumab treatment after initial good response. Mechanisms of intrinsic and acquired Trastuzumab resistance are not yet known. Our Objective is to identify factor or factors responsible for Trastuzumab resistance. Methods: DNA extraction and Sequencing of HER2 gene were performed on primary tumors of HER2-positive 14 MBC patients undergoing Trastuzumab therapy. Re-biopsy were done on new metstatic sites of those cases discovered to have Trastuzumab resistance. Results: Of 14 MBC cases whose tumors showing positive IHC and FISH, there were no mutation found in their HER2 gene, exons 18,19, 20 and 21. However, 3 of 14 cases of MBC undergoing continuous Trastuzumab therapy with excellent response for more than one year, developed the resistance. All three cases had new metstatic sites biopsied, and showed D880N and E837Y mutations in the exon 21 of their HER2 genes. All three cases showed no response to trastuzumab therapy. Conclusions: 1) HER2-positive MBC tumors did not have any HER2 gene mutations in them. 2) Mutations arised in their HER2 gene, exon 21 may be responsible for the intrinsic and acquired Trastuzumab resistance. Additional work in this area is needed to further substantiate our findings. No significant financial relationships to disclose.

Myocardial HER2 expression with 111In-DTPA-trastuzmab scan in patients shortly after anthracycline treatment

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3057-3057
Author(s):  
P. J. Perik ◽  
M. N. Lub-De Hooge ◽  
P. L. Jager ◽  
M. A. De Korte ◽  
J. A. Gietema ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Xenograft Model ◽  
Metastatic Breast ◽  
Optimal Timing ◽  
Her2 Overexpression ◽  
Compensatory Mechanism ◽  
Her2 Expression ◽  
Breast Cancer Patients ◽  
Her2 Positive ◽  
Adjuvant Trastuzumab

3057 Background: The monoclonal antibody trastuzumab, apart from antitumor effect, can induce cardiotoxicity, particularly when combined with anthracyclines. Myocardial HER2 upregulation may serve, transiently, as a compensatory mechanism induced by cardiac stress. Previously we showed in a xenograft model that 111In-DTPA-trastuzumab scintigraphy can detect HER2 positive lesions (Br J Pharmacol 2004;143:99–106) but that myocardial 111In-DTPA-trastuzumab uptake was found in only 1 of 17 anthracycline-pretreated HER2-positive metastatic breast cancer patients (ESMO 2004#50). This low number may be related to the long interval between anthracycline administration (median 11 months) and performed scan in these patients. To evaluate whether myocardial HER2 expression is induced by anthracyclines, we performed 111In-DTPA-trastuzumab scans in patients shortly after anthracycline treatment. Methods: Patients who completed 4–6 cycles of anthracycline-based chemotherapy (< 3 weeks after last dose) underwent gammacamera imaging 48 and 96 h after iv administration of 150 MBq 111In-DTPA-trastuzumab (5mg). Results: 10 anthracycline-treated patients, 8 as adjuvant breast cancer treatment and 2 for metastatic sarcoma have been enrolled. Myocardial 111In-DTPA-trastuzumab uptake was observed in 5/10 anthracycline-treated patients who all were without symptomatic cardiac dysfunction. Conclusions: Shortly after completion of anthracycline treatment myocardial HER2 overexpression was detectable in 50% of the patients. This may be a transient phenomenon. 111In-DTPA-trastuzumab scan after anthracycline treatment prior to adjuvant trastuzumab may identify patients more susceptible for trastuzumab-induced cardiotoxicity. This important observation may add to optimal timing of trastuzumab therapy i.e. when HER2/neu expression in the heart is negative (again). [Table: see text]

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.

Quantitative HER2 measurement and PI3K mutation profile in matched primary and metastatic breast cancer tissues.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 614-614
Author(s):  
Weidong Huang ◽  
Jonathan F. Lara ◽  
Richard Michaelson ◽  
Xiu Sun ◽  
Pierfranco Conte ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Catalytic Domain ◽  
Pik3ca Mutation ◽  
Metastatic Breast ◽  
Her2 Status ◽  
Her2 Positive ◽  
Pik3ca Mutations ◽  
Meta Analyses ◽  
Negative Conversion

614 Background: HER2 status of primary breast cancer (PBC) is routinely used to determine systemic treatment for metastatic breast cancer (MBC) patients. Discordance rates of HER2 status between PBC and MBC range from 5.5% to 29% based on published meta-analyses. The clinical benefit of re-assessing HER2 in MBC tissues remains controversial. In this study, we measured quantitative HER2 expression in matched PBC and MBC tissues and correlated changes of HER2 with mutations in the catalytic domain of PI3 kinase(PIK3CA). Methods: Total HER2 protein expression (H2T) was quantified by the HERmark assay in 41 matched PBC and MBC formalin-fixed, paraffin-embedded specimens. PIK3CA mutation status in exons 9 (E545K and E542K) and 20 (H1047R) was determined using a validated pyrosequencing assay. Results: MBC samples included 5 lymph node, 13 viscera, 6 brain, and 17 soft tissue lesions (N=41). 27 (66%) cases showed higher H2T in MBC than in matched PBC; and 14 (34%) cases had higher H2T in PBC than in matched MBC, indicating an overall increase of H2T in matched MBC lesions (fold change 0.25-17.57; p=0.005, paired Wilcoxon rank sum test). HER2 positive conversion (HERmark negative/equivocal in PBC, but positive in matched MBC) was found in 6 (15%) cases, while HER2 negative conversion (HERmark positive in PBC, but negative/equivocal in matched MBC) was seen in 2 (5%) cases. HER2 status was unchanged in 33 (80%) cases. PIK3CA mutations were detected in 13 (32%) of PBC and 19 (46%) of MBC samples. Among the HER2 positive conversion cases, PIK3CA mutation was identified in 50% (3/6) PBC and 67% (4/6) MBC, compared to 0% (0/2, PBC or MBC) in the HER2 negative conversion cases. Among cases with unchanged HER2 status, PIK3CA mutation was observed in 30% (10/33) PBC and 42% (14/33) MBC. Conclusions: Quantitative HER2 assessment revealed a 20% discordance in HER2 status between matched PBC and MBC tissues, with more frequent conversion from low HER2 in PBC to high HER2 in MBC. PIK3CA mutation was observed more frequently in patients who converted from HER2 negative PBC to HER2 positive MBC. These results suggest that re-assessment of biomarkers in MBC tissues may better inform the selection of therapeutic options for patients with MBC.

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.

A phase Ib, first-in-human, dose escalation and expansion study of XMT-1522, a novel antibody-drug conjugate (ADC) directed against HER2, in patients with advanced breast cancer and other advanced tumors expressing HER2.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS2606-TPS2606 ◽  
Author(s):  
Howard A. Burris ◽  
Minal A. Barve ◽  
Erika Paige Hamilton ◽  
Aditya Bardia ◽  
Hatem Hussein Soliman ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Gastric Cancer ◽  
Advanced Breast Cancer ◽  
Dose Escalation ◽  
Metastatic Breast ◽  
Advanced Breast ◽  
Her2 Status ◽  
Her2 Positive ◽  
Post Dose ◽  
Human Dose

TPS2606 Background: XMT-1522 is an ADC consisting of a novel human IgG1 anti-HER2 monoclonal antibody conjugated to an auristatin-based cytotoxic payload (AF-HPA). An average of 12 AF-HPA molecules is conjugated to each antibody via a biodegradable polymer. In pre-clinical xenograft experiments XMT-1522 achieved complete, durable tumor regressions in models of HER2-positive and HER2 1+/2+ breast cancer, HER2 2+/3+ NSCLC, and HER2-positive and HER2 1+ gastric cancer. Methods: This study (NCT02952729) is comprised of two parts: a dose escalation segment (DES) and an expansion segment (EXP). The primary objectives of the DES are determination of the maximum tolerated dose and recommended Phase 2 dose (RP2D) and assessment of safety and tolerability. The DES will enroll patients with advanced or metastatic breast cancer who have progressed following standard therapies and have HER2 protein at least 1+ by IHC. XMT-1522 will be administered intravenously every 3 weeks. DES uses a 3+3 design. Post-dose assessments include LVEF measurement at the end of cycles 1, 3, then every 3 cycles, ophthalmologic exams at the end of cycles 1, 2, then every 2 cycles, and re-staging CT scans every 2 cycles. Pharmacokinetics of antibody, AF-HPA payload and an AF-HPA metabolite will be measured. Two patients have completed dose level 1 without DLT. The EXP segment will open at the RP2D and will further assess safety and tolerability of XMT-1522 and assess efficacy in selected patient populations. EXP will enroll 4 cohorts (N = 20 each). Cohort 1: HER2 1+/2+ advanced breast cancer with 2-3 prior chemotherapy regimens Cohort 2: HER2-positive advanced breast cancer with prior pertuzumab and ado-trastuzumab emtansine (T-DM1) Cohort 3: HER2-positive advanced gastric cancer with prior trastuzumab Cohort 4: HER2 2+/3+ NSCLC with at least 1 prior platinum regimen The protocol requires archival tumor tissue for central confirmation of HER2 status, alternative HER2 measurements, and targeted gene expression and sequencing studies. Tumor biopsies will be requested at the time of progression from patients who responded to XMT-1522. Clinical trial information: NCT02952729.

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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