HER2-positive Lesions Research Articles

Predictors of breast cancer HER2-receptor positivity by MRI intuitive imaging features

BackgroundToday, breast cancer is the most diagnosed cancer worldwide. There are many different clinical presentations, radiological characteristics, and histological types of breast cancer. HER2 is overexpressed in a significant number of breast cancer cases reaching 20% of all breast cancers, and its overexpression is seen directly proportionate with a poor outcome and prognosis.MethodsWe started this cross-sectional research from January 2022–December 2023 on 202 breast cancer patients who had 220 lesions. The molecular subtypes of the different lesions were determined in all the included cases. Magnetic resonance imaging (MRI) studies were conducted in all included cases. The MRI parameters included conventional MRI, diffusion-weighted analysis, and dynamic post-contrast T1-weighted imaging.ResultsThe prevalence of irregular margins (P < 0.001), linear and segmental distribution (P = 0.044), heterogeneous pattern (P < 0.001), and type 2 curve was statistically significantly higher in the HER2-positive lesions. Nipple infiltration incidence showed statistically significant elevation in the HER2-positive lesions (P = 0.017). The lesions’ ADC and perilesional ADC in the HER2-positive lesions were also statistically significantly elevated. The best cutoff point of ADC to detect lesions with positive HER2 expression was > 0.885 × 10–3 mm2/s, with 65.7% sensitivity and 60% specificity, with a statistically significant value (p = 0.005).ConclusionsMagnetic resonance imaging of breast imaging is a promising noninvasive method for identifying breast tumors with the HER2 molecular subtype. Combining various radiological features by MRI may provide a conclusion for recognizing positive HER2 lesions.

Detection of HER2 expression using 99mTc-NM-02 nanobody in patients with breast cancer: a non-randomized, non-blinded clinical trial

Background99mTc radiolabeled nanobody NM-02 (99mTc-NM-02) is a novel single photon emission computed tomography (SPECT) probe with a high affinity and specificity for human epidermal growth factor receptor 2 (HER2). In this study, a clinical imaging trial was conducted to investigate the relationship between 99mTc-NM-02 uptake and HER2 expression in patients with breast cancer.MethodsThirty patients with pathologically confirmed breast cancer were recruited and imaged with both 99mTc-NM-02 SPECT/computed tomography (CT) and 18F-fluorodeoxyglucose (18F-FDG) positron emission tomography (PET)/CT. According to the treatment conditions before recruitment, patients were divided into two groups, the newly diagnosed group (n = 24) and the treated group (n = 6). The maximal standard uptake value (SUVmax) of 18F-FDG and SUVmax and mean SUV (SUVmean) of 99mTc-NM-02 in the lesions were determined to analyze the relationship with HER2 expression.ResultsNo meaningful relationship was observed between 18F-FDG uptake and HER2 expression in 30 patients with breast cancer. 99mTc-NM-02 uptake was positively correlated with HER2 expression in the newly diagnosed group, but no correlation was observed in the treated group. 99mTc-NM-02 uptake in HER2-positive lesions was lower in those with effective HER2-targeted therapy compared with the newly diagnosed group. 99mTc-NM-02 SPECT/CT detected brain and bone metastases of breast cancer with a different imaging pattern from 18F-FDG PET/CT. 99mTc-NM-02 showed no non-specific uptake in inflamed tissues and revealed intra- and intertumoral HER2 heterogeneity by SPECT/CT imaging in 9 of the 30 patients with breast cancer.Conclusions99mTc-NM-02 SPECT/CT has the potential for visualizing whole-body HER2 overexpression in untreated patients, making it a promising method for HER2 assessment in patients with breast cancer.Trial registrationNCT04674722, Date of registration: December 19, 2020.

First-in-human validation of enzymolysis clearance strategy for decreasing renal radioactivity using modified [68Ga]Ga-HER2 Affibody.

Enzymolysis clearance strategy, characterized by releasing the non-reabsorbable radioactive fragment under the specific cleavage of enzymes, is confirmed to be a safe and effective way to reduce the renal radioactivity accumulation in mice. However, the effectiveness of this strategy in humans remains unknown. Human epidermal growth factor receptor 2 (HER2) is overexpressed in various types of tumors, and radiolabeled HER2 Affibody is believed to be an attractive tool for HER2-targeted theranostics. However, its wide application is limited by the high and persistent renal uptake. In this study, we intend to validate the effectiveness of enzymolysis clearance strategy in reducing renal accumulation by using a modified HER2 Affibody. A new HER2 Affibody ligand, NOTA-MVK-ZHER2:2891, containing a cleavable Met-Val-Lys (MVK) linker was synthesized and labeled with 68Ga. The microPET imaging study was performed in SKOV-3 tumor mice to assess the uptakes of the control ligand and the MVK one in tumors and kidneys. Seven healthy volunteers were included for biodistribution and dosimetric studies with both the control and MVK ligands performed 1week apart. Urine and blood samples from healthy volunteers were collected for in vivo metabolism study of the two ligands. Four HER2-positive and two HER2-negative patients were recruited for [68Ga]Ga-NOTA-MVK-ZHER2:2891 PET/CT imaging at 2 and 4h post-injection (p.i.). [68Ga]Ga-NOTA-MVK-ZHER2:2891 was stable both in PBS and in mouse serum. MicroPET images showed that the tumor uptake of [68Ga]Ga-NOTA-MVK-ZHER2:2891 was comparable to that of [68Ga]Ga-NOTA-ZHER2:2891 at all the time points, while the kidney uptake was significantly reduced 40min p.i. (P < 0.05). The biodistribution study in healthy volunteers showed that the kidney uptake of MVK ligand was significantly lower than that of the control ligand at 1h p.i. (P < 0.05), with the SUVmean of 34.3 and 45.8, respectively, while the uptakes of the two ligands in the other organs showed negligible difference. The effective doses of the MVK ligand and the control one were 26.1 and 28.7 µSv/MBq, respectively. The enzymolysis fragment of [68Ga]Ga-NOTA-Met-OH was observed in the urine samples of healthy volunteers injected with the MVK ligand, indicating that the enzymolysis clearance strategy worked in humans. The PET/CT study of patients showed that the range of SUVmax of HER2-positive lesions was 9.4-21, while that of HER2-negative lesions was 2.7-6.2, which suggested that the MVK modification did not affect the ability of ZHER2:2891 structure to bind with HER2. We for the first time demonstrated that enzymolysis clearance strategy can effectively reduce renal radioactivity accumulation in humans. This strategy is expected to decrease renal radiation dose of peptide and small protein-based radiotracers, especially in the field of radionuclide therapy.

Breast Cancer Surrogate Subtype Classification Using Pretreatment Multi-Phase Dynamic Contrast-Enhanced Magnetic Resonance Imaging Radiomics: A Retrospective Single-Center Study.

This study aimed to explore the potential of multi-phase dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) radiomics for classifying breast cancer surrogate subtypes. This retrospective study analyzed 360 breast cancers from 319 patients who underwent pretreatment DCE-MRI between January 2015 and January 2019. The cohort consisted of 33 triple-negative, 26 human epidermal growth factor receptor 2 (HER2)-positive, 109 luminal A-like, 144 luminal B-like HER2-negative, and 48 luminal B-like HER2-positive lesions. A total of 1781 radiomic features were extracted from manually segmented breast cancers in each DCE-MRI sequence. The model was internally validated and selected using ten times repeated five-fold cross-validation on the primary cohort, with further evaluation using a validation cohort. The most successful models were logistic regression models applied to the third post-contrast subtraction images. These models exhibited the highest area under the curve (AUC) for discriminating between luminal A like vs. others (AUC: 0.78), luminal B-like HER2 negative vs. others (AUC: 0.57), luminal B-like HER2 positive vs. others (AUC: 0.60), HER2 positive vs. others (AUC: 0.81), and triple negative vs. others (AUC: 0.83). In conclusion, the radiomic features extracted from multi-phase DCE-MRI are promising for discriminating between breast cancer subtypes. The best-performing models relied on tissue changes observed during the mid-stage of the imaging process.

Feasibility of Quantitative MRI Using 3D-QALAS for Discriminating Immunohistochemical Status in Invasive Ductal Carcinoma of the Breast.

Two-dimensional synthetic MRI of the breast has limited spatial coverage. Three-dimensional (3D) synthetic MRI could provide volumetric quantitative parameters that may reflect the immunohistochemical (IHC) status in invasive ductal carcinoma (IDC) of the breast. To evaluate the feasibility of 3D synthetic MRI using an interleaved Look-Locker acquisition sequence with a T2 preparation pulse (QALAS) for discriminating the IHC status, including hormone receptor (HR), human epidermal growth factor receptor 2 (HER 2), and Ki-67 expression in IDC. Prospective observational study. A total of 33 females with IDC of the breast (mean, 52.3 years). A 3-T, 3D-QALAS gradient-echo and fat-suppressed T1-weighted 3D fast spoiled gradient-echo sequences. Two radiologists semiautomatically delineated 3D regions of interest (ROIs) of the whole tumors on the dynamic MRI that was registered to the synthetic T1-weighted images acquired from 3D-QALAS. The mean T1 and T2 were measured for each IDC. Intraclass correlation coefficient for assessing interobserver agreement. Mann-Whitney U test to determine the relationship between the mean T1 or T2 and the IHC status. Multivariate logistic regression analysis followed by receiver operating characteristics (ROC) analysis for discriminating IHC status. A P value <0.05 was considered statistically significant. The interobserver agreement was good to excellent. There was a significant difference in the mean T1 between HR-positive and HR-negative lesions, while the mean T2 value differed between HR-positive and HR-negative lesions, between the triple-negative and HR-positive or HER2-positive lesions, and between the Ki-67 level > 14% and ≤ 14%. Multivariate analysis showed that the mean T2 was higher in HR-negative IDC than in HR-positive IDC. ROC analysis revealed that the mean T2 was predictive for discriminating HR status, triple-negative status, and Ki-67 level. 3D synthetic MRI using QALAS may be useful for discriminating IHC status in IDC of the breast. 1. Stage 2.

Association of Relative Cerebral Blood Volume from Dynamic Susceptibility Contrast-Enhanced Perfusion MR with HER2 Status in Breast Cancer Brain Metastases

With the development of HER2-directed therapies, identifying non-invasive imaging biomarkers of HER2 expression in breast cancer brain metastases has become increasingly important. The purpose of this study was to investigate whether relative cerebral blood volume (rCBV) from dynamic susceptibility contrast-enhanced (DSC) perfusion MR could help identify the HER2 status of breast cancer brain metastases. With IRB approval for this HIPAA-compliant cross-sectional study and a waiver of informed consent, we queried our institution's electronic medical record to derive a cohort of 14 histologically proven breast cancer brain metastases with preoperative DSC perfusion MR and HER2 analyses of the resected/biopsied brain specimens from 2011-2021. The rCBV of the lesions was measured and compared using Mann-Whitney tests. Receiver operating characteristic analyses were performed to evaluate the performance of rCBV in identifying HER2 status. The study cohort was comprised of 14 women with a mean age of 56 years (range: 32-81 years) with a total of 14 distinct lesions. The rCBV of HER2-positive breast cancer brain metastases was significantly greater than the rCBV of HER2-negative lesions (8.02 vs 3.97, U=48.00, p=0.001). rCBV differentiated HER2-positive lesions from HER2-negative lesions with an area under the curve of 0.98 (standard error=0.032, p<0.001). The accuracy-maximizing rCBV threshold (4.8) was associated with an accuracy of 93% (13/14), a sensitivity of 100% (7/7), and a specificity of 86% (6/7). rCBV may assist in identifying the HER2 status of breast cancer brain metastases, if validated in a large prospective trial.

Molecular Imaging of HER2 Expression in Breast Cancer patients Using the [99mTc] Tc-Labeled Small Peptide

PurposeThe accurate determination of human epidermal growth factor receptor 2 (HER2) status can predict response to treatment with HER2-targeted therapy for HER2-positive breast cancer patients. [99mTc]Tc-HYNIC-(Ser)3-LTVPWY ([99mTc]Tc-HYNIC-LY) is a small synthetic peptide molecule targeting of the HER2 receptor. This clinical study evaluated the pharmacokinetic, dosimetry, and efficacy of [99mTc]Tc-HYNIC-LY for determining the HER2 status in primary breast cancer patients. Materials and MethodsIn total, 24 women with suspected primary breast cancer received an intravenous injection of approximately 20 µg (∼740 MBq) of [99mTc]Tc-HYNIC-LY. In the first 3 patients, blood levels of radioactivity were analyzed for pharmacokinetic evaluation and planar gamma camera imaging was conducted at 30 min and 1, 2, 4, and 24 hour after injection for dosimetry assessment. In the last 21 patients, planar imaging was performed at the baseline, as well as 1, 2, 3, and 4 hour, followed by single-photon emission computed tomography (SPECT) imaging after 4 hour to evaluate the tumor-targeting potential in primary lesions. ResultsInjection of [99mTc]Tc-HYNIC-LY was safe and well tolerated. Fast blood clearance provided high-contrast HER2 imaging within 1 to 4 hour. The highest absorbed radiation dose was found for kidneys (6.78E-03 ± 2.62E-04 mSv/MBq), followed by the heart (3.73E-03 ± 1.98E-04 mSv/MBq). The [99mTc]Tc-HYNIC-LY peptide was able to detect HER2 status in primary tumors at an acceptable level. ConclusionThe findings of this study indicated that [99mTc]Tc-HYNIC-LY SPECT is safe and feasible for the identification of HER2-positive lesions in primary breast cancer patients, and may provide an accurate and non-invasive modality for guiding HER2 targeted therapy.

Synthesis and in vivo evaluation of [11C]tucatinib for HER2-targeted PET imaging

Tucatinib is a selective human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor approved by the U.S. Food and Drug Administration (FDA) in April 2020 for HER2-positive lesions in metastatic breast cancer patients, including CNS metastases. In this article, we attempted to develop the first small molecule, blood–brain-barrier (BBB) penetrant HER2 PET imaging probe based on tucatinib. [11C]tucatinib was synthesized via a Stille-coupling from the respective trimethylstannyl precursor and its biodistribution was evaluated in NMRI nude mice bearing HER2-overexpressing human ovarian cancer cells (SKOV-3). No significant tumor accumulation was observed despite its high affinity for HER-2 receptors (IC50 = 6.9 nM). High liver and intestinal uptake indicate that [11C]tucatinib is too lipophilic to be used as a tumor targeting PET tracer. Therefore, chemical modifications of [11C]tucatinib are needed to increase the polarity for tumor imaging. Tucatinib as an FDA approved drug is still an interesting platform to develop the first small molecule HER2-selective PET tracer. The study highlights the differences between a drug, which needs to be effective, and an imaging agent, which is dependent on contrast.

Magnetic resonance imaging correlation with molecular and epigenetic markers in assessment of breast cancer

BackgroundBreast cancer is a heterogeneous disease with a wide range of clinical behavior, histologic subtypes, therapeutic options, and outcomes. The different biology and histology of breast cancer display different tumor morphology at breast magnetic resonance imaging (MRI). However, few studies have examined the relationship between the MRI morphological, kinetic features and molecular and epigenetic markers in breast cancer assessment. The study aimed to evaluate the correlation between MRI morphological and kinetic features, molecular and an epigenetic marker (linc-ITGB1) in breast cancer cases. A total of 115 women (80 cases and 35 controls) with BIRAD 4 category breast lesions were included. The association between the MRI morphological & kinetic features, apparent diffusion coefficient (ADC) values, and molecular and the epigenetic marker (linc-ITGB1) was evaluated using Mann–Whitney and Chi-square tests.ResultsThe shape (p = 0.009), size of the lesion (p = 0.003), and pattern of enhancement (p ≤ 0.001) were significantly correlated with the molecular markers. Luminal subtypes are more likely to be presented with irregular shaped and non-circumscribed margin masses (97% for luminal A and 94.1% for luminal B). Triple-negative cancers are frequently presented with regular masses, circumscribed margins, and peripheral rim enhancement (50% of TN tumors). HER2-positive cancers are more likely to be multifocal/multicentric and are more associated with non-mass pattern of enhancement as compared to HER2-negative cancers. Perilesional edema was also significantly correlated with HER2-positive lesions (p = 0.009). Although the epigenetic marker linc-ITGB1 was overexpressed by 4.85-folds in breast cancer cases compared to benign controls, we could not find any significant correlation between its expression level and the MRI features or molecular subtypes (p = 0.948).ConclusionsMRI features can be a reliable predictor of breast cancer molecular subtypes. The epigenetic marker linc-ITGB1 has a potential role in breast cancer pathogenesis but with no significant correlation with either the MRI features or molecular subtypes of the lesions.

Evaluation of near-Infrared fluorescence-conjugated peptides for visualization of human epidermal receptor 2-overexpressed gastric cancer.

338 Background: HER2 is highly overexpressed in many kinds of cancers with a poor prognosis. Recently, near-infrared (NIR) fluorescence-based imaging is a growing field for both pre-clinical and clinical application. In this study, we aimed to synthesize Human Epidermal Receptor2 (HER2)-specific near-infrared (NIR) fluorescence probes and evaluate their applicability in cancer-specific image-guided surgeries using an animal model. Methods: An NIR dye emitting light of 800 nm (IRDye800CW, Li-COR, USA) was conjugated to trastuzumab and HER2-specific affibody using click mechanism. HER2 affinity was assessed by the surface plasmon resonance technique. HER2 positive/negative gastric cancer cell lines (NCI-N87 and SNU-601) were subcutaneously implanted into female BALB/c-nu (6 to 8 weeks old) mice. The biodistribution and fluorescence signal intensity were measured by Lumina II (Perkin Elmer, MA, USA) and a laparoscopic NIR camera (InTheSmart, Seoul, Korea) after injecting the probes intravenously. Results: Trastuzumab-IRDye800CW showed higher affinity to HER2 (K(D) = 2.093(3)pM) than unconjugated trastuzumab(K(D) = 25.75pM). The significant signal of fluorescence was targeted to the HER2-positive tumors at 24hr after injection, while no or low signal retention was observed in negative group. The peak appears at 24hr after injection. On the other hand, small difference of affinity was shown between HER2-target affibody-IRDye800CW (K(D) = 4.71nM) and unlabeled pure affibody(K(D) = 1.42nM). The renal clearance of HER2-target affibody conjugated with IRDye800CW was so fast that we could not detect the signal. Conclusions: Our results suggest that trastuzumab conjugated with IRDye800CW can be a feasible tool to monitor HER2 status in pre-clinical cancer imaging. Moreover, this probe can provide complementary means for assessment of HER2 expression in gastric cancer patients and/or be used to further detection of HER2-positive lesions during image-guided surgery.

HER2-targeted dual radiotracer approach with clinical potential for noninvasive imaging of trastuzumab-resistance caused by epitope masking.

Rationale: The decreased HER2-accessibility by epitope masking is a primary trastuzumab-resistance mechanism. In this study, we developed a HER2-targeted dual radiotracer approach to predict the HER2-trastuzumab engagement noninvasively.Methods: Two novel HER2-specific VHHs, MIRC208 and MIRC213, were acquired by immunizing alpaca with human HER2 protein, and were site-specifically labeled with 99mTc. Biodistribution and SPECT/CT imaging studies were performed in mice bearing HER2-positive and HER2-negative tumors. The HER2 binding sites of 99mTc-MIRC208 and 99mTc-MIRC213 were investigated by cell binding and SPECT/CT imaging studies. We evaluated the therapeutic predictive ability of our dual-radiotracer imaging approach for trastuzumab treatment in mice bearing MUC4-positive tumors (trastuzumab-resistant JIMT-1 and 87MUC4) and MUC4-negative tumors (trastuzumab-sensitive 7HER2 and NCI-N87). The preliminary clinical studies of 99mTc-MIRC208 were performed in two patients with HER2-positive breast tumors.Results: 99mTc-MIRC208 and 99mTc-MIRC213 clearly visualized HER2-positive tumors, but not HER2-negative tumors. 99mTc-MIRC208 competes with trastuzumab for HER2-binding while 99mTc-MIRC213 recognizes HER2 on an epitope that is not masked by MUC4. The SPECT/CT studies with 99mTc-MIRC208 and 99mTc-MIRC213 clearly showed that the MUC4-negative and trastuzumab-sensitive 7HER2 and NCI-N87 tumors had very similar tumor uptake with the SUV208/SUV213 (2 h) ratios of 1.11 ± 0.17 in 7HER2 and 1.25 ± 0.22 in NCI-N87. However, the MUC4-positive JIMT-1 tumors showed the decreased SUV208/SUV213 (2 h) ratio (0.63 ± 0.07), which correlated well with the low response rate to trastuzumab therapy. The SUV208/SUV213 (2 h) ratio was reduced to 0.72 ± 0.02 in MUC4-expressing NCI-N87 cells, and resulting in the decreased trastuzumab sensitivity, further supporting the correlation between the SUV208/SUV213 (2 h) ratio and trastuzumab-sensitivity. The primary and metastatic HER2-positive lesions of patients were clearly visualized by 99mTc-MIRC208 SPECT at 2 h post injection.Conclusion: Overall, we demonstrated that the dual radiotracer imaging strategy is a valid noninvasive approach for the cancer patient selection before trastuzumab therapy. 99mTc-MIRC213 SPECT is utilized to quantify the tumor HER2 expression and screen HER2-positive cancer patients, while 99mTc-MIRC208 SPECT is used to determine the HER2-accessibility of trastuzumab. The SUV208/SUV213 (2 h) ratio is an important biomarker to determine the responsiveness of trastuzumab therapy.

Performance of enhancement on brain MRI for identifying HER2 overexpression in breast cancer brain metastases

PurposeTo investigate whether enhancement on MRI could help identify HER2 overexpression in breast cancer brain metastases. MethodsWe derived a cohort of 38 histologically proven breast cancer brain metastases with preoperative contrast-enhanced brain MRI and HER2 fluorescent in-situ hybridization of the resected/biopsied brain specimens from 2018 to 2021. Enhancement of the lesions was measured and compared using t-tests. Receiver operating characteristic and logistic regression analyses were performed to evaluate the performance of MRI enhancement in identifying HER2 overexpression. ResultsThe study cohort was comprised of 29 women with a mean age of 55 years (range: 31–81 years) with a total of 38 distinct lesions. The HER2-positive subcohort was comprised of 17 patients, while the HER2-negative subcohort was comprised of 13 patients. The percent signal intensity change (PSIC) of HER2-positive breast cancer brain metastases was significantly greater than that of HER2-negative lesions (310 v. 153, P = 0.002). The PSIC differentiated HER2-positive lesions from HER2-negative lesions with an area under the curve of 0.88 (P < 0.001). In a model controlling for lesion size, lesion location, tumor grade, patient age, scanner magnetic field strength, and contrast agent, the PSIC had an accuracy of 92% (35/38), sensitivity of 96% (23/24), and specificity of 86% (12/14) in differentiating HER2-positive lesions from HER2-negative lesions. ConclusionEnhancement on MRI may assist in identifying HER2 overexpression in breast cancer brain metastases, if validated prospectively.

Al[ &lt;sup&gt;18&lt;/sup&gt;F]-AEEA-HER2-BCH Affibody PET Imaging Accurately Depict HER2 Positive Lesions

Al[ &lt;sup&gt;18&lt;/sup&gt;F]-AEEA-HER2-BCH Affibody PET Imaging Accurately Depict HER2 Positive Lesions

Phase I Trial of 131I-GMIB-Anti-HER2-VHH1, a New Promising Candidate for HER2-Targeted Radionuclide Therapy in Breast Cancer Patients.

131I-GMIB-anti-human epidermal growth factor receptor type 2 (HER2)-VHH1 is a targeted radionuclide theranostic agent directed at HER2-expressing cancers. VHH1 is a single-domain antibody covalently linked to therapeutic 131I via the linker N-succinimidyl 4-guanidino-methyl-3-iodobenzoate (SGMIB). The phase I study was aimed at evaluating the safety, biodistribution, radiation dosimetry, and tumor-imaging potential of 131I-GMIB-anti-HER2-VHH1 in healthy volunteers and breast cancer patients. Methods: In a first cohort, 6 healthy volunteers were included. The biodistribution of 131I-GMIB-anti-HER2-VHH1 was assessed using whole-body (anterior and posterior) planar images obtained at 40 min and at 2, 4, 24, and 72 h after intravenously administered (38 ± 9 MBq) 131I-GMIB-anti-HER2-VHH1. Imaging data were analyzed using OLINDA/EXM software to determine the dosimetry. Blood and urine samples were obtained over 72 h. In the second cohort, 3 patients with metastatic HER2-positive breast cancer were included. Planar whole-body imaging was performed at 2 and 24 h after injection. Additional SPECT/CT images were obtained after the whole-body images at 2 and 24 h if there was relevant uptake in known cancer lesions. Results: No drug-related adverse events were observed throughout the study. The biologic half-life of 131I-GMIB-anti-HER2-VHH1 in healthy subjects was about 8 h. After intravenous administration, the compound was eliminated from the blood with a 2.5-h half-life. The drug was eliminated primarily via the kidneys. The drug was stable in circulation, and there was no increased accumulation in the thyroid or stomach. The absorbed dose to the kidneys was 1.54 ± 0.25 mGy/MBq, and to bone marrow it was 0.03 ± 0.01 mGy/MBq. SPECT/CT imaging in patients with advanced breast cancer showed focal uptake of 131I-GMIB-anti-HER2-VHH1 in metastatic lesions. Conclusion: Because of its favorable toxicity profile and its uptake in HER2-positive lesions, this radiopharmaceutical can offer new therapeutic options to patients who have progressed on trastuzumab, pertuzumab, or trastuzmab emtansine, given its difference in mode-of-action. A dose escalation is planned in a subsequent phase I/II study to assess the therapeutic window of this compound (NCT04467515).

Correlation of apparent diffusion coefficient values and peritumoral edema with pathologic biomarkers in patients with breast cancer

PurposeTo investigate the relationship between breast cancer imaging features on magnetic resonance imaging (MRI) and histopathological characteristics. Methods and materialsWe prospectively enrolled 46 patients who underwent 1.5-T MRI with 68 breast malignant lesions from 2017 until 2019. Peritumoral edema was determined based on visual assessment on T2 weighted imaging. Lesions were categorized into two groups: A: with edema (48 lesions) and B: without edema (20 lesions). ResultsThe tumor size was not different among two groups but multifocal-multicentric lesions were more common in the group A (70% vs. 35%). The axillary lymph nodes are most involved in group A. ER and PR positive lesions were more common in group B (90% vs. 56.3%) but in the group A, HER2 positive lesions were found to be more common (31.3% vs. 15%). The mean ADC value in tumors and peritumoral regions were lower (0.97 × 10−3 mm2/s, P = 0.023) and higher (1.85 × 10−3 mm2/s, P < 0.0001) in group A, respectively. Peritumoral ADC value was significantly higher in HER2-positive group. ConclusionBreast carcinomas with peritumoral edema were found to be more multifocal-multicentric, with higher prevalence of axillary lymph node involvement, more HER 2-positive, with lower prevalence of ER/PR-positive, lower tumoral ADC and higher peritumoral ADC values.

Impact of 68Ga-NOTA-MAL-MZHER2 PET imaging in advanced gastric cancer patients and therapeutic response monitoring

Clinical PET imaging of human epidermal growth factor receptor 2 (HER2) can noninvasively detect HER2 overexpression in lesions. A novel 68Ga-NOTA-MAL-MZHER2 (68Ga-HER2) affibody was developed for clinical PET/CT, and its safety, tissue dosimetry, ability to detect HER2-positive lesions, and utility for HER2-targeted therapy in patients with advanced gastric cancer (AGC) were evaluated. Thirty-four patients with AGC (23 with HER2-positive and 11 with HER2-negative primary lesions) were included and underwent PET/CT after an injection of approximately 3.7MBq/kg body weight 68Ga-HER2 affibody. Thirteen patients (8 HER2-positive and 5 HER2-negative patients) were scanned at 1, 2, and 3h post-injection to determine the best imaging timepoint, and the remaining patients were scanned at the optimized timepoint. All patients underwent standard 18F-FDG PET/CT within 7d to identify viable lesions. The SUVmax of lesions larger than 1.0cm were analyzed. Five lesion maxima were analyzed for each organ. (1) The 68Ga-HER2 affibody was safe and effective, and optimal image contrast was observed 2h post-injection; the average effective absorbed dose was 0.0215mSv/MBq. (2) The HER2-positive group had significantly higher 68Ga-HER2 affibody uptake than the HER2-negative group (SUVmax 10.7 ± 12.5 vs 3.8 ± 1.7, p = 0.005). The specificity and sensitivity were 100 and 55.4%, respectively, with a SUVmax cutoff value of 6.6. The SUVmax of the lesions ranged from 1.6 to 73.0, suggesting heterogeneity in HER2 expression. (3) 68Ga-HER2 affibody uptake showed an organ-dependent difference in patients with HER2-positive expression. Bone metastases had the highest uptake (SUVmax 40.5 ± 24.9), followed by liver metastases (SUVmax 11.9 ± 3.9) and lymph node metastases (SUVmax 5.6 ± 3.7), while the uptake in other lesions, including in the primary lesion, was relatively lower (SUVmax 7.3 ± 3.7). (4) Patients receiving therapy had a non-significantly lower lesion SUVmax than patients not receiving therapy (SUVmax 8.8 ± 4.9 vs 11.8 ± 15.2) (p = 0.253). Additionally, the 68Ga-HER2 affibody detected positive lesions in 1/11 patients with HER2-negative primary gastric cancer, which was confirmed by second generation gene sequencing. (5) Moreover, ten patients underwent baseline PET/CT followed by targeted anti-HER2 therapy. Patients with lesions showing high avidity to the 68Ga-HER2 affibody showed longer progression-free survival (PFS) than those with lesions showing low avidity (4-9m vs 2-3m). 68Ga-HER2 affibody PET/CT is a feasible method to noninvasively detect the HER2 status in AGC patients and enable early detection with a low dose. Ongoing anti-HER2 therapy did not influence 68Ga-HER2 affibody imaging, which allowed repeated evaluations to monitor the HER2 status after anti-HER2 therapy. This method provides an in vivo understanding of AGC biology that will ultimately help oncologists improve individualized therapy plans.

Radiolabelled Trastuzumab PET/CT imaging: a promising non-invasive tool for the in vivo assessment of HER2 status in breast cancer patients

In patients with breast cancer, the overexpression of human epidermal growth factor receptor 2 (HER2) is associated with a worse prognosis and a better response to target therapy with monoclonal antibody, such as trastuzumab. HER2 status is usually revealed by immunohistochemistry (IHC) and/or fluorescence in situ hybridization (FISH) on tumour tissue sample. Recently, PET/CT with radiolabelled trastuzumab has been described as a non-invasive tool for the identification of HER2-positive lesions in patients with BC, with a potential role in the selection of patients candidates to target therapy. The purpose of this mini-review of current literature is to summarize the state of the art of PET/CT imaging with these new radiopharmaceuticals. PubMed/MEDLINE database was screened to find articles regarding the role of radiolabelled trastuzumab PET/CT in detecting HER2-positive breast cancer lesions. Terms breast cancer AND (PET OR positron emission tomography) AND (trastuzumab OR radiolabelled monoclonal) were used. Fourteen studies exploring the role of radiolabelled trastuzumab PET/CT in BC patients were included. Three different radiopharmaceuticals were used (89Zr-Trastuzumab, 64Cu-Trastuzumab and 68Ga-DOTA-F(abʹ)2-Trastuzumab). Clinical data were not available for all studies and quite heterogeneous within the same studies; methodological aspects were also quite different among studies, while the comparison with conventional imaging techniques was common. Additional studies are needed to validate the potential role of radiolabelled trastuzumab PET/CT, demonstrating its effectiveness in detection of HER2-positive lesions and in identification of BC patients who could benefit from specific and personalized therapy.

Construction of 124I-trastuzumab for noninvasive PET imaging of HER2 expression: from patient-derived xenograft models to gastric cancer patients.

Here, we sought to develop a PET radioligand based on trastuzumab labeled with 124I, 124I-trastuzumab, to evaluate its distribution, internal dosimetry, and initial PET images of HER2-positive lesions in gastric cancer (GC) patients. In animal studies, micro-PET imaging and bio-distribution were performed to examine the specificity of 124I-trastuzumab in HER2-positive and HER2-negative mouse models. Subsequently, 124I-trastuzumab was applied in human clinic trial. Six gastric cancer patients with metastases underwent 124I-trastuzumab PET imaging, with 18F-FDG PET/CT in each to compare. In animal studies, PET imaging of 124I-trastuzumab showed significant higher tumor uptake than that of 124I-IgG1 in HER2-positive PDX mouse models at 24h. The low tumor uptake of 124I-trastuzumab in HER2-negative PDX models further confirmed the specificity. In human clinical studies, 18 HER2-positive lesions and 11 HER2-negative lesions were evaluated in PET imaging analysis. The detection sensitivity of 124I-trastuzumab was 100% (18/18) at 24h. The PET images showed significant difference in tumor uptake between HER2-positive and HER2-negative lesions at 24h (SUVmax 7.83 ± 0.55 vs. 1.75 ± 0.29, p < 0.0001). Quite striking difference in tumor uptake was observed between 124I-trastuzumab and 18F-FDG (SUVmax 1.75 ± 0.29 vs. 6.46 ± 0.44, p < 0.0001) in HER2-negative lesions, further confirming the specific binding of 124I-trastuzumab in HER2-positive lesions. The radiation-absorbed dose was calculated to be 0.3011 ± 0.005mSv/MBq. No toxicities or adverse effects were observed in any of the patients. The findings described here demonstrated that 124I-trastuzumab was feasible to detect HER2-positive lesions in primary and metastatic gastric cancer patients and to differentiate HER2-positive and HER2-negative lesions quantitatively.

Peptide Based Imaging Agents for HER2 Imaging in Oncology.

Breast cancer continues to be the most lethal cancer type in women and one of the most diagnosed. Understanding Breast cancer receptor status is one of the most vital processes for determining treatment options. One type of breast cancer, human epidermal growth factor receptor 2 (HER2) positive, has approved receptor-based therapies including trastuzumab and pertuzumab that can significantly increase the likelihood of survival. Current methods to determine HER2 status include biopsies with immunohistochemical staining and/or fluorescence in situ hybridization. However, positron emission tomography (PET) imaging techniques using 89Zr-trastuzumab or 89Zr-pertuzumab are currently in clinical trials for a non-invasive, full body diagnostic approach. Although the antibodies have strong specificity to the HER2 positive lesions, challenges involving long post-injection time for imaging due to the blood circulation of the antibodies and matching of long-live isotopes leading to increased dose to the patient leave opportunities for alternative PET imaging probes. Peptides have been shown to allow for shorter injection-to-imaging time and can be used with shorter lived isotopes. HER2 specific peptides under development will help improve the diagnosis and potentially therapy options for HER2 positive breast cancer. Peptides showing specificity for HER2 could start widespread development of molecular imaging techniques for HER2 positive cancers.

Histogram Analysis and Visual Heterogeneity of Diffusion-Weighted Imaging with Apparent Diffusion Coefficient Mapping in the Prediction of Molecular Subtypes of Invasive Breast Cancers.

Objective To investigate if histogram analysis and visually assessed heterogeneity of diffusion-weighted imaging (DWI) with apparent diffusion coefficient (ADC) mapping can predict molecular subtypes of invasive breast cancers. Materials and Methods In this retrospective study, 91 patients with invasive breast carcinoma who underwent preoperative magnetic resonance imaging (MRI) with DWI at our institution were included. Two radiologists delineated a 2-D region of interest (ROI) on ADC maps in consensus. Tumors were also independently classified into low and high heterogeneity based on visual assessment of DWI. First-order statistics extracted through histogram analysis within the ROI of the ADC maps (mean, 10th percentile, 50th percentile, 90th percentile, standard deviation, kurtosis, and skewness) and visually assessed heterogeneity were evaluated for associations with tumor receptor status (ER, PR, and HER2 status) as well as molecular subtype. Results HER2-positive lesions demonstrated significantly higher mean (p=0.034), Perc50 (p=0.046), and Perc90 (p=0.040), with AUCs of 0.605, 0.592, and 0.652, respectively, than HER2-negative lesions. No significant differences were found in the histogram values for ER and PR statuses. Neither quantitative histogram analysis based on ADC maps nor qualitative visual heterogeneity assessment of DWI images was able to significantly differentiate between molecular subtypes, i.e., luminal A versus all other subtypes (luminal B, HER2-enriched, and triple negative) combined, luminal A and B combined versus HER2-enriched and triple negative combined, and triple negative versus all other types combined. Conclusion Histogram analysis and visual heterogeneity assessment cannot be used to differentiate molecular subtypes of invasive breast cancer.