Lesions In Breast Cancer Patients Research Articles

Treatment of spinal lesions in breast cancer patients (literature review)

Breast cancer is one of the most significant problems in oncology. This pathology is characterized by increased risk of fractures associated with postmenopausal decrease in bone mineral density, use of hormone therapy, and presence of osteolytic metastases in the spine. All these factors can cause non-traumatic spine fractures decreasing patient mobility and leading to permanent pain syndrome and neurologic deficit.The article presents the modern view on the osteoporosis problem and risk of non-traumatic spine fractures in patients with breast cancer and spine metastases. Literature data on predictors of pathological bone fractures, as well as time and risk of spine metastases in these patients are analyzed. Data of modern studies on the effectiveness of various methods of breast cancer treatment and their combinations, as well as possibilities of minimally invasive surgical interventions, antiresorptive and radiological therapy are considered.

Repeatability of 18F-FDG uptake in metastatic bone lesions of breast cancer patients and implications for accrual to clinical trials

BackgroundStandard measures of response such as Response Evaluation Criteria in Solid Tumors are ineffective for bone lesions, often making breast cancer patients that have bone-dominant metastases ineligible for clinical trials with potentially helpful therapies. In this study we prospectively evaluated the test-retest uptake variability of 2-deoxy-2-[18F]fluoro-D-glucose (18F-FDG) in a cohort of breast cancer patients with bone-dominant metastases to determine response criteria. The thresholds for 95% specificity of change versus no-change were then applied to a second cohort of breast cancer patients with bone-dominant metastases.MethodsFor this study, nine patients with 38 bone lesions were imaged with 18F-FDG in the same calibrated scanner twice within 14 days. Tumor uptake was quantified by the most commonly used PET parameter, the maximum tumor voxel normalized by dose and body weight (SUVmax) and also by the mean of a 1-cc maximal uptake volume normalized by dose and lean-body-mass (SULpeak). The asymmetric repeatability coefficients with confidence intervals for SUVmax and SULpeak were used to determine the limits of 18F-FDG uptake variability. A second cohort of 28 breast cancer patients with bone-dominant metastases that had 146 metastatic bone lesions was imaged with 18F-FDG before and after standard-of-care therapy for response assessment.ResultsThe mean relative difference of SUVmax and SULpeak in 38 bone tumors of the first cohort were 4.3% and 6.7%. The upper and lower asymmetric limits of the repeatability coefficient were 19.4% and − 16.3% for SUVmax, and 21.2% and − 17.5% for SULpeak. 18F-FDG repeatability coefficient confidence intervals resulted in the following patient stratification using SULpeak for the second patient cohort: 11-progressive disease, 5-stable disease, 7-partial response, and 1-complete response with three inevaluable patients. The asymmetric repeatability coefficients response criteria for SULpeak changed the status of 3 patients compared to the standard Positron Emission Tomography Response Criteria in Solid Tumors of ± 30% SULpeak.ConclusionIn evaluating bone tumor response for breast cancer patients with bone-dominant metastases using 18F-FDG SUVmax, the repeatability coefficients from test-retest studies show that reductions of more than 17% and increases of more than 20% are unlikely to be due to measurement variability. Serial 18F-FDG imaging in clinical trials investigating bone lesions in these patients, such as the ECOG-ACRIN EA1183 trial, benefit from confidence limits that allow interpretation of response.

Abstract B038: CD4Th1 cytokine interferon gamma regulates genome profiles and inhibits tumorigenesis of disseminated cancer cells in breast cancer

Abstract Detection and persistence of disseminated cancer cells (DCCs) in the bone marrow (BM) of breast cancer (BC) patients has been identified as a primary source for late recurrence and distant metastasis in multiple organs and the central nervous system. Selective targeting and eradication of DCCs in BM can be of a significant advantage to prevent future recurrence and enhance disease-free survival in BC patients. Unfortunately, no such targeted therapy presently exists. Instead, intense chemotherapy in the adjuvant or neoadjuvant setting are given with the ultimate goal to prevent DCC-driven metastasis in these patients. Clinical studies have confirmed that DCCs have not been effectively eradicated by conventional chemotherapies. DCCs express unique gene signatures that differ from circulating tumor cells (CTC) in BC, but only limited knowledge is available for the genome profiles of DCCs compared to primary and metastatic lesions in BC patients. Here we investigated the detailed gene expression profiles of DCCs compared to primary and metastatic lesions from a murine spontaneous metastasis model and BC patients. Using a two-step immunomagnetic enrichment assay, we were able to successfully isolate highly enriched EpCAM+ DCCs from both the BM aspirates of HER2+ early BC patients and BALB-HER2/neu transgenic (BALB-neuT) spontaneous metastasis mice. RNA sequencing revealed that DCCs from HER2+ BC patients and BALB-neuT mice displayed remarkably similar genomic expression profiles, but both had substantially different profiles when comparing to primary and metastatic lesions. We identified highly enriched signatures in DCCs associated with cancer stemness, epithelial to mesenchymal transition (EMT), cell cycle, cell adhesion, progesterone signaling and cholesterol biosynthesis. Notably, these DCCs showed loss of MHC class I, MHC class II, and CD1d expression leading to a defect in antigen presentation machinery and their subsequent escape from CD4 T, CD8 T, B and NKT-cell mediated clearance. Interestingly, we observed for the first time that anti-tumor CD4Th1 cells, through interferon gamma (IFN-γ) production, upregulated CD1d, MHC class I and II expressions in DCCs leading to high infiltration of CD4Th1, NKT and B cells into the BM to selectively target and eliminate DCC burden. IFN-γ remarkably downregulated stemness, EMT, self-renewing potential and their genome signatures and induced apoptosis and irreversible senescence in DCCs of HER2+ BC patients. Notably, these IFN-γ treated patient DCCs lost their ability to grow into tumors in an immunodeficient NSG mouse model. Collectively, these results provide a detailed genome profile of DCCs from HER2+ BC patients and a novel role for anti-tumor CD4Th1 response in inhibiting DCC-driven tumorigenesis and metastasis. Citation Format: Ganesan Ramamoorthi, Marie Catherine Lee, Krithika Kodumudi, Colin Snyder, Namrata Gautam, Saurabh K. Garg, Shari Pilon-Thomas, Brian Czerniecki. CD4Th1 cytokine interferon gamma regulates genome profiles and inhibits tumorigenesis of disseminated cancer cells in breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Breast Cancer Research; 2023 Oct 19-22; San Diego, California. Philadelphia (PA): AACR; Cancer Res 2024;84(3 Suppl_1):Abstract nr B038.

Multi-center retrospective review of vitiligo-like lesions in breast cancer patients treated with cyclin-dependent kinase 4 and 6 inhibitors.

Cutaneous adverse effects from cyclin-dependent 4 and 6 kinase inhibitors (CDK4/6i) used in metastatic breast cancer are prevalent and well described. Vitiligo-like lesions have been reported and are rare. They can negatively impact patients' quality of life and may be associated with survival benefits. We describe the clinical characteristics of vitiligo-like lesions in an international cohort of patients treated with CDK4/6i to help improve recognition and management. Retrospective review of patients diagnosed with vitiligo-like lesions from CDK4/6i from five academic institutions in the USA and Europe was performed. Ten patients were included in the study. Median age of our patients was 55 (range 37-86). Median progression-free survival was 24months in 5 patients. The median time to rash was 10months. Sun-exposed areas such as the arms and face were the most affected areas. Multiple skin-directed therapies such as topicals, laser, and phototherapy were trialed with minor success. Mild repigmentation was seen in one patient treated with ruxolitinib cream. CDK4/6 treatment was discontinued due to the vitiligo-like lesions in one patient. Clinical characteristics are similar to previously reported findings in case reports and series. We add topical ruxolitinib as a potential treatment option for these patients and include data regarding progression-free survival that should continue to be collected. No definitive conclusions can be made regarding survival benefits from our cohort. Clinicians should refer these patients to dermatologists to aid with management.

Synthesis and Preliminary Study of 99mTc-Labeled HYNIC-FAPi for Imaging of Fibroblast Activation Proteins in Tumors.

Fibroblast activation protein (FAP) is an emerging target for cancer diagnosis. Different types of FAP inhibitor (FAPI)-based radiotracers have been developed and applied for tumor imaging. However, few FAPI tracers for single photon emission computed tomography (SPECT) imaging have been reported. SPECT imaging is less expensive and more widely distributed than positron emission tomography (PET), and thus, 99mTc-labeled FAPIs would be more available to patients in developing regions. Herein, we developed a FAPI-04-derived radiotracer, HYNIC-FAPi-04 (HFAPi), for SPECT imaging. 99mTc-HFAPi, with a radiochemical purity of >98%, was prepared using a kit formula within 30 min. The specificity of 99mTc-HFAPi for FAP was validated by a cell binding assay in vitro and SPECT/CT imaging in vivo. The binding affinity (Kd value) of 99mTc-HFAPi for human FAP and murine FAP was 4.49 and 2.07 nmol/L, respectively. SPECT/CT imaging in HT1080-hFAP tumor-bearing mice showed the specific FAP targeting ability of 99mTc-HFAPi in vivo. In U87MG tumor-bearing mice, 99mTc-HFAPi had a higher tumor uptake compared with that of HT1080-hFAP and 4T1-mFAP tumor models. Interestingly, 99mTc-HFAPi showed a relatively high uptake in some murine joints. 99mTc-HFAPi accumulated in tumor lesions with a high tumor-to-background ratio. A preliminary clinical study was also performed in breast cancer patients. Additionally, 99mTc-HFAPi exhibited an advantage over 18F-FDG in the detection of lymph node metastatic lesions in breast cancer patients, which is helpful in improving treatment strategies. In short, 99mTc-HFAPi showed excellent affinity and specificity for FAP and is a promising SPECT radiotracer for (re)staging and treatment planning of breast cancers.

Abstract 450: Preclinical development of FTX-001: first in class inhibitor of the long non-coding RNA MALAT1

Abstract Long non-coding RNAs (lncRNAs) have emerging roles in many aspects of biology. In the context of cancer, it has been reported that lncRNAs can act as cancer oncogenes and are altered in various cancer types. Among them, MALAT1 is a lncRNA highly expressed in multiple cancer types and associated with disease progression in patients. MALAT1 is highly upregulated in metastatic lesions of breast cancer patients. Both genetic and pharmacologic inhibition of MALAT1 suppressed tumor epithelial to mesenchymal transition, resulted in the differentiation of breast cancers and had a dramatic impact on tumor metastasis. MALAT1 is a nuclear retained lncRNA, and as such MALAT1 is highly sensitive to RNaseH1-dependant Antisense Oligonucleotide (ASO) degradation, because RNaseH1 is also predominantly localized to the nucleus. Thus, MALAT1 represents an attractive novel therapeutic target uniquely tractable to ASOs with the potential to impact metastatic cancer progression. Here, we describe the identification and characterization of FTX-001 leading to its selection as a clinical drug candidate for the treatment of human cancers. Preclinical pharmacology, tolerability, and toxicity studies conducted in rodents and non-human primates demonstrated the safety and potency of FTX-001. FTX-001 ASO contains constrained ethyl (cEt) chemistry Gen 2.5 and was identified by screening over 2700 ASOs against MALAT1. FTX-001 showed a consistent potent inhibition of MALAT1 RNA expression in human cancer cell lines in vitro as well as in human xenograft tumor models in vivo upon systemic delivery. Good exposure, tissue distribution and tolerability profile were observed in mice, rats and non-human primates (NHP) after repeated subcutaneous (sc) administrations. Genotoxicity studies including the bacterial reverse mutation assay and in vivo micronucleus assays demonstrated that FTX-001 did not cause mutagenic or chromosome alterations at doses up to 2000 mg/kg in mice. Preliminary results from 6-weeks nonclinical toxicity testing in mice (sc administration up to 45mg/kg) and NHP (intravenous administration up to 24mg/kg) revealed no significant adverse events observed during dosing and recovery phases. No major variation of blood markers or blood count were observed. Ongoing histopathological evaluation will complete the health hazard evaluation of FTX-001. Taken together, these results demonstrate the high potency and good preclinical safety profile of FTX-001 which supports the potential to achieve good target engagement (MALAT1 RNA knock down in human tumors) at well tolerated clinical doses in cancer patients. Citation Format: Marie-Aline C. Neveu, Alexey Ravenko, Tae-Won Kim, Xiaolin Luo, Youngsoo Kim, Joanna Schmidt, Robert A. MacLeod. Preclinical development of FTX-001: first in class inhibitor of the long non-coding RNA MALAT1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 450.

Abstract 4349: C-C chemokine receptor 2-positive monocytic myeloid-derived suppressor cells predicts chemotherapeutic responses of the metastatic lesions in breast cancer patients

Abstract Anti-tumoral T cell immunity is counterbalanced by several types of immunosuppressive cells such as Myeloid-Derived Suppressor Cells (MDSC). Circulating MDSC levels correlate with poor prognosis and metastatic progression of breast cancer patients. However, the value of MDSC in predicting chemotherapeutic treatment responses in the metastatic lesions is not clearly understood. We performed a prospective cohort clinical study to measure MDSC before and after chemotherapy in metastatic breast cancer patients (N=64). Multicolor flow cytometry was used to quantitate two major subtypes, i.e. monocytic (M-) and polymorphonuclear (PMN-) MDSC, and one additional subtype, C-C chemokine receptor 2 (CCR2)-positive M-MDSC in the fresh peripheral blood mononuclear cells. M-MDSC were defined as HLA-DRlow/−CD45+CD11b+CD15−CD14+ PBMC, and PMN-MDSC were defined as CD45+CD11b+CD33+CD15+ CD14− PBMC. PMN-MDSC and CCR2+ M-MDSC, but not M-MDSC, were significantly increased after chemotherapy. Subsequently, we divided the patients by two groups (therapy-sensitive vs. -resistant groups) by treatment responses. Treatment-resistant patients had significantly increased CCR2+ M-MDSC. Unsupervised clustering of patients based on MDSCs populations dichotomized patients PMN-MDSC high or M-MDSC high groups. M-MDSC high patients had increased bone and lymph node metastasis. In addition, CCR2+ M-MDSC levels correlated with the progression-free survival (P<0.05). Altogether, our results showed that CCR2+ M-MDSC levels potentially predict the therapeutic responses in the metastatic lesions of breast cancer patients. Citation Format: Ju Won Kim, Jason K. Sa, Seung Pil Jung, Kyong Hwa Park, Serk In Park. C-C chemokine receptor 2-positive monocytic myeloid-derived suppressor cells predicts chemotherapeutic responses of the metastatic lesions in breast cancer patients. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4349.

Patient-Derived Breast Cancer Bone Metastasis In Vitro Model Using Bone-Mimetic Nanoclay Scaffolds

The unavailability of reliable models for studying breast cancer bone metastasis is the major challenge associated with poor prognosis in advanced-stage breast cancer patients. Breast cancer cells tend to preferentially disseminate to bone and colonize within the remodeling bone to cause bone metastasis. To improve the outcome of patients with breast cancer bone metastasis, we have previously developed a 3D in vitro breast cancer bone metastasis model using human mesenchymal stem cells (hMSCs) and primary breast cancer cell lines (MCF-7 and MDAMB231), recapitulating late-stage of breast cancer metastasis to bone. In the present study, we have tested our model using hMSCs and patient-derived breast cancer cell lines (NT013 and NT023) exhibiting different characteristics. We investigated the effect of breast cancer metastasis on bone growth using this 3D in vitro model and compared our results with previous studies. The results showed that NT013 and NT023 cells exhibiting hormone-positive and triple-negative characteristics underwent mesenchymal to epithelial transition (MET) and formed tumors in the presence of bone microenvironment, in line with our previous results with MCF-7 and MDAMB231 cell lines. In addition, the results showed upregulation of Wnt-related genes in hMSCs, cultured in the presence of excessive ET-1 cytokine released by NT013 cells, while downregulation of Wnt-related genes in the presence of excessive DKK-1, released by NT023 cells, leading to stimulation and abrogation of the osteogenic pathway, respectively, ultimately mimicking different types of bone lesions in breast cancer patients.

Clinical impact of MRI-detected additional lesions in breast cancer patients with neoadjuvant systemic therapy at the Netherlands cancer institute

In breast cancer patients treated with neoadjuvant systemic therapy (NST), MRI is used pre- and post-NST for response monitoring. The relevance of additional MRI-detected lesions in these patients is unclear. Therefore, we aimed to assess the impact of pre-NST MRI-detected additional lesions on surgical treatment and outcome. We retrospectively selected all early-stage breast cancer patients with MRI pre-NST at our institute from January 2010-2015. MRI-detected lesions were defined as separated from the index tumor and occult at conventional mammography and ultrasound. Outcomes were change in surgical treatment and five-year recurrence-free and overall survival. Overall, MRI detected additional lesions in 206 (31%) of 656 patients: in 160 patients in the ipsilateral breast and in 78 contralateral breasts, including 32 bilateral cases. Ipsilateral lesions were mostly categorized BI-RADS 5 (54 %) and contralateral lesions BI-RADS 3 (64%). Targeted ultrasound was performed in 115 (56%) patients: in 70 ipsilateral and in 64 contralateral cases. Biopsy was obtained in 44 (28% of 160) ipsilateral and 50 (64% of 78) contralateral breasts, containing tumor foci in 20 (13% of 160) and 11 (14% of 78) cases, respectively. Surgical treatment changed in 54 (26% of 206) patients: 19 (9%) had mastectomy, 24 (12%) had wider local excision and 11 (5%) underwent contralateral surgery. Five-year recurrence-free and overall survival did not differ for patients with local excision or mastectomy. Pre-NST MRI-detected additional lesions in 31% of patients, resulting in more extensive surgery in 26% of these patients, including 5% contralateral surgeries.

Risk factors for the development of endometrial lesions in breast cancer patients using tamoxyphen: a retrospective cohort study

RESUMO Introdução: o câncer da mama é o câncer de maior incidência no sexo feminino no Brasil, representando 29,7% de todos os cânceres. Mais de dois terços das mulheres com câncer da mama apresentam expressão para receptores hormonais, estando, nestes casos, indicada a terapia hormonal com tamoxifeno, que pode representar fator de risco para o desenvolvimento do câncer do endométrio (risco relativo quatro vezes maior). Objetivo: este trabalho teve como objetivo avaliar a associação entre o uso de tamoxifeno e o desenvolvimento de distúrbios endometriais bem como eventuais outros fatores associados. Pacientes e método: Estudo de coorte retrospectivo de 364 pacientes com câncer da mama, das quais 286 utilizaram tamoxifeno e 78 não utilizaram esta hormonioterapia. Resultados: pacientes que usaram tamoxifeno tiveram um seguimento médio de 51,42 meses, semelhante àquelas sem terapia hormonal (p=0,081). Um total de 21 (7,3%) mulheres que usaram tamofixeno e nenhuma mulher sem terapia hormonal apresentaram alterações endometriais durante o seguimento (p=0,01). Nas 270 mulheres que tinham informação sobre obesidade, esta se associou significantemente com o desenvolvimento de alterações endometriais (p=0,008). A associação entre tamofixeno e alterações endometriais permaneceu significante (p=0,039) após ajustar para interação com obesidade. Conclusão: o uso de tamoxifeno no tratamento do câncer da mama esteve associado ao maior risco para desenvolvimento de alterações endometriais especialmente quando associado à obesidade.

Importance of Whole-Body Scintigraphy or Positron Emission Tomography for Early Detection of Femoral Lesions in Breast Cancer Patients Treated with Bisphosphonates.

We hypothesized that most of the atypical femoral fractures (AFFs) associated with bisphosphonate treatment for breast cancer (BC) could be found before the fracture event in another radiological examination already performed by breast surgeons, rather than on simple radiographs (SRs). We thoroughly inspected the clinical charts of BC patients treated at our institute between 2008 and 2017. In total, 228 patients were categorized into three groups based on SRs: complete AFF on at least one side (group 1); incomplete fracture on at least one side, but not any complete fracture (group 2); and no suspicious lesion (group X) on either femur. Then, we inspected whole-body scintigraphy (WBS) and positron emission tomography (PET)-computed tomography (CT) images in all groups. For group X, patients with radiological clues from at least one femur were categorized, ultimately, into final group 3 and the rest made up the normal group. About 35% of the patients showed AFFs (complete or incomplete) or suspicious lesions as AFFs, associated with the side effect of Bisphosphonate. In group 1, bilateral lesions (complete or incomplete fractures) were more frequently seen on SRs than unilateral lesions (p = 0.008). The initially identified findings in WBS and PET-CT for the respective complete and incomplete fractures on SRs of groups 1 and 2 were seen at a mean of 7 months previously. SRs did not reveal the lesions in group 3 until 5 months after the initial identification of the lesions in WBS and PET-CT. Even before incomplete AFFs were detectable on SRs, they could be found at check-ups using WBS and PET-CT that had been previously examined by breast surgeons and radiologists for metastasis surveillance. Awareness of the lesions creates an opportunity for prophylactic surgery before complete fractures occur.

Risk factors for the development of endometrial lesions in breast cancer patients using tamoxyphen: a retrospective cohort study.

breast cancer is the cancer with the highest incidence in women in Brazil, representing 29.7% of all cancers. More than two thirds of women with breast cancer show expression for hormone receptors, and in these cases, hormone therapy with tamoxifen is indicated, which may represent a risk factor for the development of endometrial cancer (four-fold greater relative risk). this study aimed to evaluate the association of tamoxifen and the development of endometrial disturbances and to assess possible other associated risk factors. a total of 364 breast cancer patients were evaluated, 286 who used tamoxifen and 78 who did not use this hormone therapy. Results: patients who used tamoxifen had a mean follow-up time of 51.42 months similar to those without hormone therapy (p=0.081). A total of 21 (7.3%) women who used tamofixen and no cases among women without hormone therapy presented endometrial changes during follow-up (p=0.01). Despite information regarding obesity was available for only 270 women, obesity was also significantly associated with the development of endometrial changes (p=0.008). furthermore, the association between tamofixen and endometrial changes remained significant (p=0.039) after adjusting for obesity.

Clinical Significance of Radiologically Detected Small Indeterminate Extra-Mammary Lesions in Breast Cancer Patients.

Patients with breast cancer who have indeterminate extra-mammary lesions, for example in lung, liver or bone, without other metastatic lesions pose a clinical dilemma regarding subsequent management. This study aimed to investigate the prevalence, characteristics and outcomes of such lesions detected on initial staging imaging, and address the clinical significance of these incidental findings. Medical records of patients with newly diagnosed breast cancer who underwent computed tomography scans and bone scintigraphy between January 1, 2015 and June 30, 2021 were reviewed. Patients with indeterminate extra-mammary lesions on imaging were included. Patients with obvious metastatic disease were excluded. Lesion characteristics, breast cancer staging, duration of follow-up and natural history of disease progression were analysed. The study included 52 patients with indeterminate lesions on pre-operative imaging. The median follow-up duration was 14 (range: 6-41) months. The most common site of occurrence of indeterminate lesions was the lung (60.9%) followed by the liver (26.1%). Forty-six had lesions that remained stable (88.5%), while six (11.5%) had progression to metastatic disease. Out of these six, only two (3.8%) developed metastasis in the same site as the original indeterminate lesion, whereas the remaining four developed metastases in other sites. Patients with breast malignancy found to have indeterminate extra-mammary lesions without obvious distant metastasis on initial staging scans are associated with a small risk of subsequently developing metastatic disease. Although most of these lesions remain quiescent, surveillance imaging is recommended because a small but significant proportion of patients with such lesions eventually harbour actual metastatic disease.

Tc-99m-tamoxifen: A novel diagnostic imaging agent for estrogen receptor-expressing breast cancer patients

PURPOSE The aim of the study was to radiolabel, characterize, and perform in vitro and in vivo assessment of Technetium-99m (Tc-99m) tamoxifen for screening ER expressing lesions in breast cancer patients. METHODS In this study, tamoxifen has been radiolabeled with Tc-99m via Tc-99m-tricarbonyl core. The characterization and quality control tests of Tc-99m-tamoxifen were performed. In vitro recep- tor binding and blocking studies were performed in both positive control (MCF-7) and negative control cell lines (MDA-MB-231). Normal biodistribution studies were performed in female Wistar albino rats. The pilot clinical studies were performed in 4 ER-expressing breast cancer patients. Of the 4 patients, 1 was on tamoxifen therapy. All 4 patients had also undergone Fluorine-18 fluorodeoxyglucose (F-18-FDG) positron emission tomography/computed tomography. RESULTS Tamoxifen was radiolabeled with Tc-99m via Tc-99m-tricarbonyl core with more than 95% radio- chemical yield. Mass spectra showed a peak corresponding to the molecular weight of Tc-99m- tricarbonyl and Tc-99m-tamoxifen. The site of binding of Tc-99m-tricarbonyl with tamoxifen was determined by proton nuclear magnetic resonance. The Tc-99m-tamoxifen showed 30% binding with MCF-7 and only 1%-2% receptor binding with MDA-MB-231 cell lines. Also, the percentage of receptor binding was drastically reduced (up to 72%) when ER was saturated with 50 times the excess molar ratio of unlabeled tamoxifen. In a pilot patient study, Tc-99m-tamoxifen uptake was observed in primary and metastatic lesions. However, no uptake was observed in a patient who was on tamoxifen therapy. The uptake of F-18-FDG was noted in all the patients. CONCLUSION Tamoxifen was radiolabeled with an in-house-synthesized Tc-99m-tricarbonyl core. The radio- labeled complex has been characterized and evaluated for receptor specificity in in vitro and in vivo studies. Also, this is the first clinical study using Tc-99m-tamoxifen for imaging ER. More patients need to be evaluated to further explore the role of Tc-99m-tamoxifen in ER-expressing lesions.

Is it sufficient to evaluate metastatic bone involvement in breast cancer using SPECT/CT? A new approach of SPECT/CT-guided targeted bone marrow biopsy

ObjectiveTo investigate the feasibility, safety, and clinical application value of single photon emission computed tomography/computed tomography (SPECT/CT)-guided bone marrow biopsy (BMB) in breast cancer (BC) patients with suspected bone metastases (BM) and compare its diagnostic performance for detection of BM with SPECT/CT.MethodsThe records of breast cancer patients referred for bone scintigraphy (BS), SPECT/CT and SPECT/CT-guided BMB from January of 2018 to June of 2021 in our hospital were retrospectively reviewed. 49 Patients were consecutively included in this study, all 49 specimens were analyzed by pathological and immunohistochemical studies.The biopsy success rate, total examination time, biopsy operation time, complications, CT radiation dose, and pathological and immunohistochemical results were recorded. The diagnostic performance based on SPECT/CT and SPECT/CT-guided BMB were compared with pathological, immunohistochemical examinations and the results of subsequent follow-up.ResultsBone samples of the sites with high uptake were obtained in all 49 patients under BMB. No severe postoperative complications occurred. Among all 49 cases, 34 specimens were positive for metastatic breast cancer (69%, 34/49), and positive for benign tissue in 15 cases (31%, 15/49). 1 case of 15 cases was subsequently diagnosed as metastatic breast cancer according to the follow-up result. SPECT/CT-guided BMB demonstrated significantly higher negative predictive value (NPV) when compared to SPECT/CT (p = 0.021 < 0.05). Patients with differential expression of ER, PR, and HER-2 between primary lesions and metastatic lesions accounted for 12, 17, and 5 cases, respectively, and the changing rates were 35.2% (12/34), 50% (17/34), and 14.7% (5/34), respectively. Molecular subtype changes occurred in 7 patients, accounting for 47% (16/34) of metastatic patients.ConclusionIt is insufficient to evaluate BM in BC patients using SPECT/CT imaging. SPECT/CT-guided BMB provided significantly higher sensitivity and NPV than SPECT/CT for detection of BM in BC patients. Our research redefines a new approach which can confirm diagnosis and potential molecular subtype changes for suspected bone metastatic lesions in BC patients, which can offer important opportunities for precision treatment and improved quality of life of BC patients with BM.

Design of an electronic radiological clip for improved breast cancer imaging with ultrasound

Radiological clips are commonly used to track and identify lesions in breast cancer patients receiving neoadjuvant chemotherapy. Available radiological clips often suffer degradation of visibility in ultrasound during the course of treatment, thus requiring more involved localization procedures to identify regions prior to resection. Furthermore, upon localization, additional markers are placed to aid surgeons during resection. We describe a biocompatible electronic device which transmits a unique identification signal when imaged with ultrasound pulse inversion,i.e., ultrasound identification (USID). The USID clip provides better localization and visualization of the clip compared to passive clips. Furthermore, the ultrasound systems can be programmed to produce an audible indicator of a specific clip’s presence and proximity to the probe, thereby eliminating the need for insertion of additional markers. This concept is tested using a microcontroller and a direct digital synthesis board connected to two sonomicrocrystals, a Verasonics research system, and tissue mimicking phantoms. Clips with six different USID tags were successfully visualized at 10 dB above the background signal. Localization and identification are demonstrated using pulse inversion and image processing techniques.

Abstract P3-02-05: Assessment of repeatability and uptake quantification of 68GaNOTA-anti-HER2 sdAb PET/CT in patients with locally advanced or metastatic breast cancer

Abstract Background: Human epidermal growth factor receptor 2 (HER2) status is an important predictive biomarker in breast cancer (BC). Tumor heterogeneity has been described, with changes in HER2 expression levels between lesions and over the disease course. HER2 expression is assessed on tissue biopsies, at primary diagnosis and in metastatic lesions. A whole-body imaging technique such as PET/CT could help understand expression levels in different lesions. A 68Ga-labeled single domain antibody (sdAb) targeting the HER2 receptor has been developed and proven safe (Keyaerts et al., 2016). Imaging is performed at 90 min post-injection (pi). We report results of a phase II trial to assess the repeatability of the technique in 20 patients and the correlation of tracer uptake with HER2 tissue expression of the lesions present at the time of imaging. Methods: Twenty patients (pts) with a locally advanced or metastatic BC with at least one lesion of minimum 12 mm were included. Pts were injected intravenously with a typical protein mass of 100 µg and a radioactive dose ranging from 98-168 MBq 68GaNOTA-anti-HER2 sdAb. PET/CT images were obtained at 90 min pi. A second tracer injection followed by PET/CT was done with a maximal interval of 8 days. To assess repeatability, up to 5 lesions per pt were selected, with no more than 2 in a single organ. Peak Standard Uptake Values (SUVpeak) of the lesions were measured on both scans and compared with a t-test and Bland-Altman Plots. Images were compared to other available medical or imaging data and interpreted considering the subject’s disease course. Serum and plasma samples were collected before injection and between 60 and 365 days pi and stored for future detection of anti-drug antibodies (ADA) and liquid biopsies analysis for the presence of HER2 amplification. Tissue samples were assessed by central labs using mass spectrometry, immunohistochemistry and in fluorescence situ hybridization. Results: Twenty women with BC (6 HER2+, 14 HER2-) with a mean age of 58.6 y (37-81) were included. Three pts were scanned only once (2 due to withdrawal of consent, 1 due to covid pandemic). Repeatability of the technique was visually scored as excellent. For quantification, 50 lesions were compared on both scans in 17 pts without significant differences between the two measurements (p=0.40). The repeatability coefficient (RC) was 38.2%. The mean absolute percentage difference (MAPD) was 13.6%, comparable to repeat values reported for 18F-FDG. In 3 out of 6 HER2-positive (HER2+) patients, lesions showed high uptake, even better visible than using 18F-FDG in 2 of them. In 2 HER2+ subjects with a negative scan, lesions were confirmed to be true negatives: one patient did not relapse from BC but had tuberculosis; the other was confirmed to have a radiopneumonitis after radiotherapy and no relapse. In 1 HER2+ patient, the uptake was unexpectedly low. However, the HER2 status was also not reconfirmed in the metastatic setting for this subject. In 1 HER2-negative patient, the tumor HER2 status was changed from negative to positive based on a subsequent image-guided biopsy performed in this study. High tracer uptake was also seen in many of the patients presenting with HER2-low BC (IHC 1+ or 2+), indicating the potential of the tracer to detect low-level HER2 expression. Additional correlation to centrally performed tissue and blood analysis is ongoing. Conclusion: 68GaNOTA-Anti-HER2 PET/CT shows high uptake in HER2-expressing BC lesions but also in HER2-low lesions. The technique shows good repeatability and, in some cases, even better sensitivity than 18F-FDG PET/CT. Specificity was confirmed in relapse-free lesions such as tuberculosis and radiopneumonitis. Its sensitivity makes it a promising technique to assess HER2+ and HER2-low lesions in BC patients. Citation Format: Odrade Gondry, Catarina Xavier, Wim Waelput, Omar Al Dabssi, Marian Vanhoeij, Sandrine Aspeslagh, Sofie Joris, Christel Fontaine, Guy Verfaillie, Jacques De Grève, Katrien Glorieus, Ine Luyten, Frederik Vandenbroucke, Sophie Bourgeois, Laurens Raes, Sheeno Thyparambil, Nick Devoogdt, Ilse Vaneycken, Julie Cousaert, Vicky Caveliers, Hendrik Everaert, Tony Lahoutte, Marleen Keyaerts. Assessment of repeatability and uptake quantification of 68GaNOTA-anti-HER2 sdAb PET/CT in patients with locally advanced or metastatic breast cancer [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-02-05.

Comparison of Contrast-Enhanced Spectral Mammography and Contrast-Enhanced MRI in Screening Multifocal and Multicentric Lesions in Breast Cancer Patients.

Objectives We aimed to determine the difference between contrast-enhanced spectral mammography (CESM) and contrast-enhanced magnetic resonance imaging (CE-MRI) in detecting multifocal and multicentric breast cancer (MMBC). Methods: This study was conducted among breast cancer patients between July 1, 2017, and May 30, 2021. The sensitivity, specificity, and accuracy of CESM and CE-MRI in the diagnosis of MMBC were evaluated with pathological results as the gold standard. Results A total of 188 lesions were detected in 54 patients with MMBC, including 177 breast cancer and 11 benign lesions. Based on CESM and CE-MRI, 4 false-positive cases and 3 false-negative cases and 7 false-positive cases and 1 false-negative case, respectively, were found. The accuracy of CESM was higher than that of MRI (96.3% vs 95.7%), and the specificity was higher than that of MRI (63.6% vs 36.4%). There were no significant differences in the sensitivity, specificity, and accuracy for the detection of MMBC between CESM and CE-MRI (p = 0.500; p = 0.250; p = 0.792). Conclusion CESM is an effective method for the detection of MMBC, which is consistent with the sensitivity and accuracy of CE-MRI.

Potential of combination of DCE-MRI and DWI with serum CA125 and CA199 in evaluating effectiveness of neoadjuvant chemotherapy in breast cancer

BackgroundTo determine the potential of the combination of DCE-MRI imaging method with DWI and serum CA125 and CA199 levels in the evaluation of the efficacy of neoadjuvant chemotherapy in breast cancer patients.MethodsSixty-five breast cancer patients who received neoadjuvant chemotherapy in our hospital from April 2016 to April 2017 were selected as research subjects. The patients received 4 courses of neoadjuvant chemotherapy. Lesions were monitored using DCE-MRI and DWI, while ELISA was used to measure the serum expression levels of the tumour markers CA125 and CA199. The patients were divided into the remission group and ineffective group based on pathological diagnosis.ResultsThere were significant differences in Kep, Ktrans, ADCmin, ADCmean, tumour volume, and serum levels of CA125 and CA199 in patients in the remission group, before and after neoadjuvant chemotherapy, and there were significant differences in post-chemotherapy values of these indexes between the remission group and the ineffective group (p < 0.01).ConclusionCombination of DCE-MRI diagnostic imaging with DWI can directly reflect the lesions in breast cancer patients after neoadjuvant chemotherapy. Serum levels of CA125 and CA199 levels are useful for evaluation of the impact of neoadjuvant chemotherapy on breast cancer patients, including risk of cancer cell metastasis and changes in some small lesions.

Superiority of 68Ga-FAPI PET/CT scan in detecting additional lesions compared to 18FDG PET/CT scan in breast cancer.

We compared the ability of 68Ga-FAPI PET//CT with 18FDG PET/CT imaging techniques to detect additional lesions in breast cancer patients that may affect further chemotherapy options. A total of 48 patients with breast cancer underwent concurrent 68Ga-FAPI-04 and 18FDG PET/CT regardless of whether they had received chemotherapy or not in the last month before imaging. Both modalities were compared according to various parameters: clinical/pathological features, number of lesions detected, activity uptake (SUVmax), and the effect on the evaluation of response to treatment in the post-chemotherapy group. This retrospective study included 48 patients with breast cancer (mean age 53.3 ± 11.7years; IDC 89.6%; ILC 10.4%). In the comparison of both modalities, no statistical significance was obtained in terms of the pathological characteristics of the patients. More lesions were demonstrated in all categorized regions in 68Ga-FAPI PET/CT imaging with higher uptake values compared to 18FDG PET/CT in this study. In the treatment response evaluation of the post-chemotherapy group, 12 cases (12/24) who were evaluated as PMR, CMR, or SD according to 18FDG PET/CT results were later accepted as PD due to newly detected lesions in complementary 68Ga-FAPI PET/CT imaging and treatment of patients was managed accordingly by clinicians. It was determined that 68Ga-FAPI PET/CT was superior to 18FDG PET/CT in terms of accuracy and it was thought that 68Ga-FAPI PET/CT could be utilized as an additional complementary imaging to 18FDG PET/CT. Moreover, 68Ga-FAPI PET/CT, with its significant theranostic potential, could become a key element in predicting the pathological response of breast cancer patients in further researches.