HER2-positive Metastases Research Articles

Abstract P4-01-17: Molecular imaging and quantification of HER-2 status in metastatic breast cancer by using 68Ga-ABY-025/PET-CT

Abstract Background: Molecular imaging, in particular, positron emission tomography (PET) provides unique possibility to non-invasively quantify the biomarkers. A small peptide, ABY-025, is targeting a unique epitope of the HER2-receptor and can be labeled with 111In or 68Ga. It is non-competitive with current antibody-targeted epitopes and is approximately 25 times smaller than an antibody and posses superior pharmacokinetics as imaging agent. We have earlier reported promising results of lesion visualization and determination of HER2 status by 111In-ABY-025/SPECT-CT in seven patients with metastatic breast cancer (MBC). As PET-CT provides superior possibilities for quantification and allows for imaging with shorter time frames, we now investigate 68Ga-ABY-025 in HER2-positive and HER2-negative MBC patients in a prospective study. The influence of the administered amount of ABY-025 on the discrimination between HER2-positive and HER2-negative metastases as well as detection rate and image contrast is investigated. The HER2 status changes will be followed at disease progression. We report here promising data on the first three patients. Patients and methods: The study considers twenty patients in two cohorts. Of the first 10 patients, 4 should have HER2-negative MBC and 6 patients HER2-positive disease. Metastases were localized by 18F-FDG/PET-CT prior HER2 imaging. Each patient (two HER2-positive and one HER-negative) underwent two subsequent examinations. First, 68Ga-ABY-025 PET/CT (ABY-025: 75±14 μg) was performed with dynamic acquisition during 0-45 minutes and static images after 1, 2 and 4 hours. The procedure was repeated after one week with a higher dose of 68Ga-ABY-025 (ABY-025: 445±10 μg) to identify the optimal dosage for the discrimination between HER2-positive and HER2-negative metastases. Blood levels of radioactivity, anti-ABY-025-antibodies, shed serum HER2 and toxicity markers were evaluated. Biopsies were taken to verify the HER2 status of the lesions. The second cohort of 10 patients (all with HER2-positive disease), will have their primary PET-CT with the optimal dose of 68Ga-ABY-025 and will, as the HER-positive from the first cohort, have a follow-up 68Ga-ABY-025 PET/CT after disease progression or, at latest, after 9 months. Results: The imaging agent was well tolerated by the patients without adverse events. The rapid blood clearance and normal tissue wash out allowed high contrast HER2 images within a few hours. The HER2 status was confirmed by histological analysis of biopsies. In one patient with HER2-negative primary tumor, imaging suggested a HER2-positive liver metastasis. The change of HER2 expression was verified with analysis of the corresponding biopsy. This finding resulted in the change of the treatment management. Preliminary validation suggests the preference of high dose ABY-025 in terms of image contrast and detection. The study is ongoing and more patients will be reported Conclusion: Preliminary results indicate strong potential of 68Ga-ABY-025 PET/CT for discriminating HER2-positive versus HER2-negative metastatic breast cancer, regardless of ongoing HER2-targeted antibody treatment. The method introduces rapid whole-body receptor mapping of primary tumor and metastases in a single examination. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-17.

トラスツズマブ療法中にHER2陰性肝転移をきたした胃癌の1例

トラスツズマブ療法中にHER2陰性肝転移をきたした胃癌の1例

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).

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.

Stability of HER2-positive status in breast carcinoma: a comparison between primary and paired metastatic tumors with regard to the possible impact of intervening trastuzumab treatment

BackgroundTo date, the stability of human epidermal growth factor receptor 2 (HER2)-positive primary breast carcinomas during disease progression and the role of intervening trastuzumab treatment in the loss of HER2-positive status in paired metastases remain under-investigated. Materials and methodsSixty-six patients with HER2-positive primary carcinoma and paired metastasis were evaluated. We examined the overall agreement of the HER2 status and compared the status agreement between 38 trastuzumab-treated patients and 28 trastuzumab-naive control patients. The impact of chemotherapy, endocrine therapy, metastatic site (locoregional or distant), and time to relapse (≥5 or <5 years) on the HER2 status change was assessed. ResultsFifty-six (84.9%) patients had HER2 status agreement between paired tumors; 10 patients had HER2-positive-to-negative conversion. The agreement rate in the trastuzumab-treated group and in the control group was comparable (86.8% versus 82.1%) (P = 0.858). Chemotherapy, endocrine therapy, metastatic site, and time to relapse did not significantly affect HER2 stability in either group. In the discordant tumor pairs, variations in testing methods and borderline scores were common. ConclusionsHER2-positive status remained unchanged in most paired metastases. Loss of HER2-positive status did not seem to be affected by trastuzumab treatment. Differences in testing and interpretation may account for the discordance in some cases.

HER2 discordance between primary breast cancer and its paired metastasis: tumor biology or test artefact? Insights through meta-analysis

The proto-oncogene, HER2, has prognostic and predictive relevance in invasive breast cancer (IBC). HER2 testing of primary IBC guides treatment selection and is assumed to reflect HER2 status of associated metastases, although HER2 discordance between IBC and metastasis has been reported. Systematic review and meta-analysis of HER2 status in IBC and its paired loco-regional or distant metastasis were done. Quality appraisal considered whether (within-subject) testing conditions were maintained for paired primary and metastasis. Random effects logistic regression models were used to estimate pooled within-subject HER2 discordant proportions and to examine study-level covariates, including tumor-related and testing-related variables, potentially associated with HER2 discordance differences across (between) studies. Modelled paired HER2 data for primary and metastatic cancer (2520 subjects, 26 studies) showed a pooled HER2 discordance of 5.5% (3.6-8.5%). Sensitivity analysis, excluding the only study not maintaining same conditions for paired testing, gave a pooled estimate of 5.2% (3.5-7.8%). Pooled discordant proportion was not associated with differences between studies in test type, test scoring or interpretation criteria, subjects' median age, study time-frame, or HER2 positivity in primary cancer (all P > 0.05). However, type of metastasis was significantly associated with estimated HER2 discordance (P = 0.0017): studies of primary tumor paired with distant metastases had higher discordance [11.5% (6.9-18.6%)] than studies of primary paired with lymph node metastases only [4.1% (2.4-7.2%)], or those paired with nodal or various metastases [3.3% (2.0-5.6%)]; P < 0.01. HER2 discordant proportion was higher where paired metastases were metachronous relative to synchronous to primary IBC (P = 0.0024). Sensitivity analysis provided weak evidence (P = 0.074) that discordance in the direction of change from HER2-negative primary cancer to HER2-positive paired metastasis was more likely than the reverse. Study-level meta-analysis suggests factors associated with the type of metastasis as underlying mechanisms for observed HER2 discordance between primary IBC and paired metastasis. Test-related factors did not account for differences across studies in the HER2 discordant proportion.

Breast cancer brain metastases express the sodium iodide symporter

Breast cancer brain metastases are on the rise and their treatment is hampered by the limited entry and efficacy of anticancer drugs in this sanctuary. The sodium iodide symporter, NIS, actively transports iodide across the plasma membrane and is exploited clinically to deliver radioactive iodide into cells. As in thyroid cancers, NIS is expressed in many breast cancers including primary and metastatic tumors. In this study NIS expression was analyzed for the first time in 28 cases of breast cancer brain metastases using a polyclonal anti-NIS antibody directed against the terminal C-peptide of human NIS gene and immunohistochemical methods. Twenty-five tumors (84%) in this retrospective series were estrogen/progesterone receptor-negative and 15 (53.6%) were HER2+. Overall 21 (75%) cases and 80% of HER2 positive metastases were NIS positive. While the predominant pattern of NIS immunoreactivity is intracellular, plasma membrane immunopositivity was detected at least focally in 23.8% of NIS-positive samples. Altogether, these findings indicate that NIS expression is prevalent in breast cancer brain metastases and could have a therapeutic role via the delivery of radioactive iodide and selective ablation of tumor cells.

HER-2/neu expression/amplification is not stable during tumor progression. A single institution study with intrapatient comparisons years 1999 through to 2007.

Abstract Abstract #6033 Background: HER-2/neu (HER2) expression/amplification has been considered to be intrapatient stable in primary breast cancer vs corresponding metastatic lesions. Treatment decisions, in many institutions, only rely on status in primary tumors. Few studies have been published on this subject. Single small studies reveal a high rate of concordance, while others reveal change in HER2 status (one study had 9 of 24 patients with no HER-2 amplification in the primary tumor changed genotype in circulating tumor cells, Meng et al PNAS 2004). At Radiumhemmet, Karolinska in Stockholm we have, whenever possible, morphologically verified all new metastases since 1999 using ultrasound-, CT- or X-ray guided or manually guided cytological aspirates. In addition to morphology, we aim to analyze receptors, HER-2 and proliferation MIB-1 on aspirates.&amp;#x2028; Materials and methods: Retrospective analysis of intra patient HER-2 over expression/amplification on routinely analyzed primary cancers and corresponding metastatic lesions during the time period 1999 to 2007. Data from the Pathology laboratory at the Karolinska University Hospital and the population based registry at the Regional Cancer Registry in Stockholm were used for patient identification. Most immunihistochical/immunocytochemical (IHC) with 2+ or 3+ samples (using several antibodies with cell line controls) were fluorescent in situ hybridization (FISH) verified. IHC 3+ and/or FISH amplification (av. &amp;gt;2 copies per cell) was considered HER2 positive.&amp;#x2028; Results: A total of 1067 breast cancers recurrences from the Stockholm hospitals were reported to the Regional Cancer Registry, 401 patients had a fine needle aspirate including a HER-2 analysis of recurrence/metastasis. 141 patients had HER-2 analyzed in both primary tumor (133 IHC, 8 FISH, 81 combined analyses) and the corresponding metastatic lesion (73 IHC, 67 FISH and 33 combined analyses). We identified 44 (31%) HER2 positive primary tumors and 44 (31%) HER2 positive metastases, respectively, in the 141 double tested tumors. 16 patients (11%) had a change in HER2 expression. 10 changed from negative to positive, and 6 changed from positive to negative (6/44 and 10/97, respectively altered their HER2 status). The metastatic sites of these patients were: loco-regional 3, liver 6, skeletal/ bone-marrow 2, lung 1, skin 4.&amp;#x2028; Discussion: Our study shows that there are discrepancies between primary tumor and corresponding metastasis in HER-2 expression/amplification, within the same patient. If this is related to the heterogeneity of both the primary tumor and the metastasis, or if it is a true change in tumor cells is not yet clear. We also need to establish eventual inter metastatic heterogeneity in HER-2 expression. Our findings may, to some extent, explain why some patients with “HER2 negative” cancers respond, and vice versa. Cytological confirmation of radiological lesions adds diagnostic precision and is in our hands a very safe procedure which has important impact on patient management, in this case the use of trastuzumab. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 6033.

ScFv-Mediated delivery of truncated BID suppresses HER2-positive osteosarcoma growth and metastasis

Osteosarcoma is the most common primary malignant bone tumor, with high rates of metastasis. Here, we examined the expression of human epidermal growth factor receptor-2 (HER-2) in osteosarcoma cell lines with different metastatic potential, finding that the expression was correlated with metastasis of implanted tumors. We then introduced an expression vector encoding the e23sFv-PEA II-Bid ∆1-60 gene, composed of a HER2-specific single-chain antibody fused with domain II of Pseudomonas exotoxin A (PEA) and the carboxy end of truncated active Bid. We demonstrated that the e23sFv-PEA II-Bid ∆1-60 molecule selectively recognized and killed HER2-overexpressing osteosarcoma cells in vitro. Subsequently, we introduced the e23sFv-PEA II-bid ∆1-60 gene into BALB/c athymic mice bearing HER2-positive osteosarcomas using i.m. injections of liposome-encapsulated vector. Expression of the e23sFv-PEA II-Bid ∆1-60 gene suppressed tumor growth, significantly prolonged animal survival, and inhibited metastasis, thereby suggesting it may represent a competitive approach to treating HER2/neu-positive osteosarcoma.