Metastatic Soft Tissue Research Articles

Modular Design of High-Brightness pH-Activatable Near-Infrared BODIPY Probes for Noninvasive Fluorescence Detection of Deep-Seated Early Breast Cancer Bone Metastasis: Remarkable Axial Substituent Effect on Performance.

We herein report a series of high-brightness pH-activatable near-infrared (NIR) BODIPY probes for high-contrast intravital imaging of deep-seated early breast cancer bone metastasis by harnessing the axial substituent effect. These probes exhibit tunable pKa, higher brightness, and antiquenching capabilities in aqueous solution, which can be simultaneously adjusted by axial steric substituents. The optimized probe BODO-3 bearing axial dimethyl substituents exhibited a higher pKa value of 5.6 and a brighter NIR fluorescence under tumor acidic pH, showing 10.3-fold and 6.5-fold enhanced brightness (εΦ) at pH 5.5 and 6.5, respectively. Due to the higher brightness, BODO-3 with a brilliant NIR emission at 700 nm allows for deep optical penetrations of 5 and 8 mm at pH 6.5 and 4.5, respectively. Meanwhile, covalent functionalization with glucose (BODO-3-Glu) could further enhance breast cancer and its soft tissue metastasis imaging in vivo. Notably, covalent functionalization with bisphosphonate (BODO-3-PO3H2) allowed the successful targeting and visualization of deep-seated bone metastases of breast cancer with a high tumor to normal contrast of 8/1, outperforming X-rays in early detection. This strategy may provide insights for designing high-brightness activatable NIR probes for detecting deep-seated tumors and metastases.

Dosimetric comparison between carbon, proton and photon radiation for renal retroperitoneal soft tissue sarcoma recurrence or metastasis after radical nephrectomy

Objective To compare the dosimetric difference between various modalities in the radiation treatment for renal retroperitoneal soft tissue sarcoma recurrence or metastasis (RRSTSRM) after radical nephrectomy, and assess the dosimetric advantage on protecting the organs at risk (OARs) in the carbon and proton radiotherapy for the patients with a single kidney. Methods A total of 12 patients with RRSTSRM who underwent radical nephrectomy were enrolled in this study. Carbon, proton, and photon radiotherapy were implemented for treatment planning. The prescription dose was fulfilled by simultaneously integrated boosting technique, with giving the planning target volume-1 (PTV-1) 51Gy (RBE) and planning target volume-2 (PTV-2) 60 Gy (RBE). Doses in the patient’s spinal cord, stomach, duodenum, bowel, colon, and contralateral kidney were evaluated. The normal tissue complication probability (NTCP) of the duodenum, bowel, colon, and contralateral kidney was derived under Lyman-Kutcher-Burman (LKB) estimation. Results In the carbon plans, the percentage volume of 95% prescription dose (V95%) covering PTV-1 (PTV-2) was 95.93% ± 3.42% (95.61% ± 4.26%). No significant dosimetric difference on the target was obtained between the four radiation modalities (P > .05). The percentage volume of receiving 40 Gy (RBE) [V40Gy (RBE)] in the duodenum could be reduced from 12.94% ± 15.99% in the IMRT plans to 6.36% ± 8.79% (8.44% ± 12.35%) in the carbon (proton) plans (P < .05). The V40Gy (RBE) in the bowel could be reduced from 13.48% ± 13.12% in the IMRT plans to 7.04% ± 9.32% (7.34% ± 9.89%) in the carbon (proton) plans (P < .05). The mean value of NTCP for the duodenum was 0.43 ± 0.47 (0.45 ± 0.48) by using carbon (proton) radiation. The value was 0.05 (0.03) lower than the IMRT plans on average, with a reduction of 0.20 (0.13) for the patients with lesions <5 mm away from the duodenum. The mean doses of the contralateral kidney were 0.28 ± 0.37 Gy (RBE) [0.28 ± 0.40 Gy (RBE)] in the IMCT (IMPT) plans, which was 92.43% (92.43%) lower than the value in the IMRT plans respectively (P < .05). Conclusion Compared to the conventional radiation techniques, particle radiotherapy of carbon and proton could significantly spare more OARs in the treatment for RRSTSRM after radical nephrectomy. Patients, especially those whose residuals are close to the duodenum would potentially benefit from the particle radiation therapy for RRSTSRM on the decrease in radiation-related side-effect.

Fluorodeoxyglucose positron emission tomography/CT for primary malignant intraosseous neoplasms of the mandible.

Primary intraosseous malignant neoplasm of the mandible is a very rare entity. There are few publications regarding fluorodeoxyglucose (FDG) positron emission tomography (PET)/CT for primary intraosseous neoplasms of the mandible. FDG PET/CT scans from 10 patients with primary malignant neoplasm of the mandible were retrieved from the Picture Archiving and Communication System database, and image findings were analyzed with correlation to contrast-enhanced diagnostic CT and surgical pathology. Accuracy of the FDG PET/CT findings was evaluated with respect to uptake intensity, lesion extension to adjacent soft tissue, lymph node and distant metastasis. All untreated primary mandible neoplasms demonstrated high FDG avidity on PET imaging. Most mandible lesions extended beyond the bones and involved perimandibular soft tissue. FDG PET/CT imaging showed improved sensitivity and specificity compared with that for CT for lymph node staging in 3 cases, with discordant findings between diagnostic CT and PET/CT. FDG PET/CT identified 4 distant metastases, which were not documented prior to PET/CT. The results suggested that FDG PET/CT was a valuable image modality to demonstrate all primary and metastatic lesions of primary malignant neoplasm of the mandible, to define perimandibular soft tissue involvement, and more accurately stage/restage the disease than diagnostic CT.

68Ga-PSMA PET in prostate cancer: a systematic review andmeta-analysisof theobserver agreement.

The performance of 68Ga-PSMA PET/CT-MR has been evaluated in prostate cancer (PCa), showing significant results. However, even a technically accurate imaging procedure requires a high interobserver agreement in its interpretation to implement in patients' management. This study aims to perform a systematic review and meta-analysis on the interobserver variability in 68Ga-PSMA PET/CT-MR imaging in PCa patients. We conducted a systematic review and meta-analysis on the interobserver variability, including studies: (1) providing Kappa (K) as the inter-observer agreement test or the essential data to calculate it, (2) providing the K confidence interval or the essential crude data to calculate it, (3) measuring K statistic based on the appropriate use criteria for the inter-observer agreement. Twelve studies, providing 1585 68Ga-PSMA PET/CT-MR studies reviewed by 62 independent readers, were included. In general, the pooled inter-observer agreement was interpreted as substantial for all analyzed groups, including tumoral lesions in the prostate bed, lymphadenopathies, bone metastasis, and soft-tissue metastasis (all between 0.6 and 0.8). The regional lymphadenopathy group (0.74) obtained the highest agreement, while the lowest was for soft tissue metastasis (0.65). This study showed a substantial interobserver agreement in the overall interpretation and detecting locoregional and distant involvement with 68Ga-PSMA PET/CT-MR in PCa patients.

99mTc]Tc-DB15 in GRPR-Targeted Tumor Imaging with SPECT: From Preclinical Evaluation to the First Clinical Outcomes.

Simple SummaryRadiolabeled gastrin-releasing peptide receptor (GRPR)-antagonists have been proposed for diagnostic imaging and radionuclide therapy—theranostics—of human tumors, including prostate (PC) and breast cancer (BC). We herein present [99mTc]Tc-DB15, a SPECT radiotracer based on the potent GRPR-antagonist [DPhe6,LeuNHEt13]BBN(6-13). After Sar11/Gly11-replacement an acyclic tetraamine was coupled at the N-terminus via a spacer allowing for stable binding of the diagnostic radiometal Tc-99m. The forming [99mTc]Tc-DB15 radiotracer displayed high in vitro uptake in GRPR-expressing mammary (T-47D) and prostate cancer (PC-3) cells. Furthermore, it showed an attractive biodistribution profile in mice bearing T-47D or PC-3 xenografts. A pilot proof-of-principle study of [99mTc]Tc-DB15 in PC and BC patients applying SPECT is currently under way. Promising results from the first two BC patients are presented herein.Diagnostic imaging and radionuclide therapy of prostate (PC) and breast cancer (BC) using radiolabeled gastrin-releasing peptide receptor (GRPR)-antagonists represents a promising approach. We herein propose the GRPR-antagonist based radiotracer [99mTc]Tc-DB15 ([99mTc]Tc-N4-AMA-DGA-DPhe6,Sar11,LeuNHEt13]BBN(6-13); N4: 6-carboxy-1,4,8,11-tetraazaundecane, AMA: aminomethyl-aniline, DGA: diglycolic acid) as a new diagnostic tool for GRPR-positive tumors applying SPECT/CT. The uptake of [99mTc]Tc-DB15 was tested in vitro in mammary (T-47D) and prostate cancer (PC-3) cells and in vivo in T-47D or PC-3 xenograft-bearing mice as well as in BC patients. DB15 showed high GRPR-affinity (IC50 = 0.37 ± 0.03 nM) and [99mTc]Tc-DB15 strongly bound to the cell-membrane of T-47D and PC-3 cells, according to a radiolabeled antagonist profile. In mice, the radiotracer showed high and prolonged GRPR-specific uptake in PC-3 (e.g., 25.56 ± 2.78 %IA/g vs. 0.72 ± 0.12 %IA/g in block; 4 h pi) and T-47D (e.g., 15.82 ± 3.20 %IA/g vs. 3.82 ± 0.30 %IA/g in block; 4 h pi) tumors, while rapidly clearing from background. In patients with advanced BC, the tracer could reveal several bone and soft tissue metastases on SPECT/CT. The attractive pharmacokinetic profile of [99mTc]DB15 in mice and its capability to target GRPR-positive BC lesions in patients highlight its prospects for a broader clinical use, an option currently being explored by ongoing clinical studies.

Effect of palliative microwave ablation on metastatic osseous pain: a single-center retrospective study.

Bone is among the most common metastasis sites in patients with advanced cancer. Approximately two-thirds of bone metastasis results in pain, the majority of which is moderate to unbearable pain, which seriously affects the quality of life of patients. With the development of ablation techniques, microwave ablation (MWA) has great potential to eliminate the pain caused by bone metastasis. This study aimed to evaluate the efficacy and safety of image-guided (computed tomography-guided) percutaneous MWA for metastatic osseous pain. This is a retrospective study involving 18 patients with cancer-related pain caused by osseous or soft tissue metastasis in the First Affiliated Hospital of Soochow University from June 2015 to October 2020. All patients (14 men and 4 women; mean age 60.2 years) underwent image-guided percutaneous palliative MWA. A paired-sample t-test was used to compare the changes in Numeric Rating Scale (NRS) score and dosage of morphine preoperatively and postoperatively (at 24 h, 3 days, and 14 days after MWA). In addition, we assessed the level of pain relief according to the patients' subjective feelings. The paired-samples t-test showed that the NRS score (6.83±0.92 vs. 1.67±0.97, P<0.05) and dosage of morphine (85.56±17.23 vs. 32.78±4.61, P<0.05) were significantly decreased at 3 days after MWA. At 14 days after MWA, the NRS score (6.83±0.92 vs. 0.94±0.87, P<0.05) and dosage of morphine (85.56±17.23 vs. 10.56±8.73, P<0.05) were also markedly decreased. Moreover, according to the patients' subjective feeling, 88.89% patients had pain relief postoperatively, while the remaining patients had no progress. Image-guided (Computed Tomography-guided) percutaneous MWA can effectively relieve pain, thus improving the quality of life in patients with osseous metastasis. MWA is a feasible, safe, and effective treatment for pain caused by bone metastasis.

Prognostic role of docetaxel-induced suppression of free testosterone serum levels in metastatic prostate cancer patients

To date, only few data concerning the biologically active, free form of testosterone (FT) are available in metastatic prostate cancer (mPC) and the impact of FT on disease, therapy and outcome is largely unknown. We retrospectively studied the effect of docetaxel on FT and total testosterone (TT) serum levels in 67 mPC patients monitored between April 2008 and November 2020. FT and TT levels were measured before and weekly during therapy. The primary endpoint was overall survival (OS). Secondary endpoints were prostate-specific antigen response and radiographic response (PSAR, RR), progression-free survival (PFS), FT/TT levels and safety. Median FT and TT serum levels were completely suppressed to below the detection limit during docetaxel treatment (FT: from 0.32 to < 0.18 pg/mL and TT: from 0.12 to < 0.05 ng/mL, respectively). Multivariate Cox regression analyses identified requirement of non-narcotics, PSAR, complete FT suppression and FT nadir values < 0.18 pg/mL as independent parameters for PFS. Prior androgen-receptor targeted therapy (ART), soft tissue metastasis and complete FT suppression were independent prognostic factors for OS. FT was not predictive for treatment outcome in mPC patients with a history of ART.

Initial Clinical Experience with 90Y-FAPI-46 Radioligand Therapy for Advanced-Stage Solid Tumors: A Case Series of 9 Patients.

Fibroblast activation protein (FAP) is overexpressed in several solid tumors and therefore represents an attractive target for radiotheranostic applications. Recent investigations demonstrated rapid and high uptake of small-molecule inhibitors of FAP (68Ga-FAPI-46) for PET imaging. Here, we report our initial experience of the feasibility and safety of 90Y-FAPI-46 for radioligand therapy of extensively pretreated patients with solid tumors. Methods: Patients were considered for 90Y-FAPI-46 therapy if they showed both an exhaustion of all approved therapies based on multidisciplinary tumor board decision, and high FAP expression, defined as SUVmax greater than or equal to 10 in more than 50% of all lesions. If tolerated, 90Y-FAPI-46 bremsstrahlung scintigraphy was performed after therapy to confirm systemic distribution and focal tumor uptake, and 90Y-FAPI-46 PET scans were performed at multiple time points to determine absorbed dose. Blood-based dosimetry was used to determine bone marrow absorbed dose. Adverse events were graded using Common Terminology Criteria for Adverse Events (version 5.0). Results: Nine patients either with metastatic soft-tissue or bone sarcoma (n = 6) or with pancreatic cancer (n = 3) were treated between June 2020 and March 2021. Patients received a median of 3.8 GBq (interquartile range [IQR], 3.25-5.40 GBq) for the first cycle, and 3 patients received subsequent cycles with a median of 7.4 GBq (IQR, 7.3-7.5 GBq). Posttreatment 90Y-FAPI-46 bremsstrahlung scintigraphy demonstrated sufficient 90Y-FAPI-46 uptake in tumor lesions in 7 of 9 patients (78%). Mean absorbed dose was 0.52 Gy/GBq (IQR, 0.41-0.65 Gy/GBq) in the kidney, 0.04 Gy/GBq (IQR, 0.03-0.06 Gy/GBq) in bone marrow, and less than 0.26 Gy/GBq in the lung and liver. Measured tumor lesions received up to 2.28 Gy/GBq (median, 1.28 Gy/GBq). New laboratory G3 or G4 toxicities were noted in 4 patients (44%, n = 2 patients with thrombocytopenia only, n = 2 patients with new onset of thrombocytopenia and anemia). Other G3 or G4 laboratory-based adverse events occurred in 2 patients or fewer. No acute toxicities attributed to 90Y-FAPI-46 were noted. Radiographic disease control was noted in 4 patients (50%). Conclusion: FAP-targeted radioligand therapy with 90Y-FAPI-46 was well tolerated, with a low rate of attributable adverse events. Low radiation doses to at-risk organs suggest feasibility of repeat cycles of 90Y-FAPI-46. We observed signs of tumor response, but further studies are warranted to determine efficacy and the toxicity profile in a larger cohort.

Stereotactic radiotherapy is a useful treatment option for patients with medullary thyroid cancer

The role of radiotherapy in advanced medullary thyroid carcinoma (MTC) is confined to patients in whom surgical treatment or the administration of tyrosine kinase inhibitors are not possible or contraindicated. High fractionated radiation doses during radiosurgery or fractionated stereotactic radiotherapy are applied to reduce cancer-related symptoms and stabilize irradiated lesions. This study aimed to retrospectively evaluate the therapeutic effect of stereotactic radiotherapy in MTC patients.Material and methodsThe study group involved 11 MTC patients, treated due to 16 cancer lesions, mainly bone metastases (10 lesions), lymph node (2 lesions) metastases, or liver metastases (2 lesions), one primary thyroid tumor, and one MTC recurrence in the thyroid bed. The fractionated and total radiation doses ranged between 5 and 12 Gy and 8–44 Gy, respectively. Six lesions were treated with a single radiation fraction, three lesions with 2 fractions, another 6 lesions with 3 fractions, whereas the remaining one metastatic lesion with 9 fractions of stereotactic radiosurgery.ResultsThe beneficial effect of stereotactic radiosurgery was obtained in all treated lesions. None of treated lesions progressed in the further disease course. Fourteen lesions were stable (87.5 %), including eight lesions showing progression before radiosurgery (good response). Disease control was obtained in all soft-tissue metastases. Regarding bone metastases, partial regression was achieved in 20 % lesions, whereas in 30 % lesions progressive before radiotherapy, the treatment led to disease stabilization.ConclusionsOur data pointed to the effectiveness of high-dose fractionated radiotherapy in MTC. However, an observation of a larger group of patients is required to confirm it.

Abstract 2718: Digital spatial profiling in HER2 positive breast cancer: The road to precision medicine

Abstract Background: Breast cancer (BC) has been considered immunologically quiescent, this could be explained by tumor and tumor immune microenvironment (TIME) characteristics. We aimed to characterize the TIME of human epidermal growth factor 2 positive (HER2+) BC using GeoMx Digital spatial profiling (DSP) in primary and metastatic samples. Methods: DSP was performed on 15 primary and metastatic FFPE samples from 8 patients; including 2 brain metastases. Visualization markers for Pan-Cytokeratin (PanCK, tumor), CD45 (immune), CD3 (T cells) were used to guide selection of immune cold, warm and hot regions of interest (ROI). Each ROI segmented tumor (PanCK+) or stroma (PanCK-) based on PanCK tumor + or - areas of illumination (AOI). For each AOI 71 protein targets were tested. Gene expression profiling for PAM50 subtypes and Tumor Inflammation Score (TIS) was done using NanoString's nCounter PanCancer IO360 assay with PAM50 spike. TIS was determined by threshold of 6.5. Results: Primary HER2+ samples had the highest amount of tumor infiltrating lymphocytes (CD3) and overall immune cells (CD45) compared to all metastatic disease in tumor and stroma (Table 1). Brain metastases had lowest TIS. Stroma of primary tumors had higher protein expression of immune activation and checkpoint markers CD27, ICOS, 41BB and TIM3 compared to brain and soft tissue metastases. HER2 protein expression most correlated with metastases. Metastatic tumor had higher proliferation by Ki67. Patient 2 had archival primary tumor (n=2) and soft tissue metastasis (ST) (n=1). TIS was obtained from immune hot, warm and cold ROI of each sample. Primary tumor stroma had highest expression of STING and Granzyme B compared to ST, suggesting that the tumor underwent immune escape. Conclusions: Primary tumors had a higher number of immune cells than metastatic sites. These findings suggest that immunotherapy in early stage BC could be more effective than in the advanced BC. This project will be part of the GeoMx Breast Cancer Consortium. Table 1.Summary of patient, tissue, diagnosis, ER/PR/HER2 status, PAM50 subtype and TIS statusPatientTissueDiagnosisER(%)/PR(%)/HER2(+)PAM50 SubtypeTIS Status1BreastIDC, DCIS2/0/3Luminal AHigh1BreastTumor emboliN/ALuminal AHigh1LungMetastatic0/0/3HER2 enrichedHigh2BreastICD, DCIS0/0/3HER2 enrichedLow2BreastResidual IDC0/0/N/AHER2 enrichedHigh2Soft tissueLocal recurrence0/0/3HER2 enrichedLow3BrainMetastatic15/0/3HER2 enrichedLow4BreastIDC0/0/3Basal likeHigh4BreastLocal recurrenceN/ALuminal AHigh5BrainMetastatic0/0/3Basal likeLow6BreastIDC, DCIS80/70/2*Luminal AHigh7BreastIDC, DCIS0/0/3HER2 enrichedHigh7BreastLocal recurrenceN/ABasal likeHigh8BreastIDC, DCIS10/15/1Luminal ALow8Soft tissueLocal recurrence0/0/3Basal likeLowAbbreviations: ER: estrogen receptor; PR: progesterone receptor; HER2: human epidermal growth factor 2; TIS: tumor inflammation score; IDC: invasive ductal carcinoma; DCIS: ductal carcinoma in situ*HER2/CEP17 ratio: 2.13 Citation Format: Ilana Schlam, Sarah E. Church, Krysta Chaldekas, Brent T. Harris, Briana M. Hudson, Andrew M. White, Sandra M. Swain. Digital spatial profiling in HER2 positive breast cancer: The road to precision medicine [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2718.

Different prognostic implications of hepatic metastasis according to front-line treatment in non-small cell lung cancer: a real-world retrospective study.

BackgroundAlthough liver metastasis occurs in approximately 15% of metastatic non-small cell lung cancer (NSCLC) patients with poor prognosis, its prognostic effect in patients who receive immunotherapy is unclear. This study aimed to verify the effects of liver metastasis on the prognosis of metastatic NSCLC patients according to their first-line treatment.MethodsPatients who were initially diagnosed with stage 4 NSCLC from January 2015 to December 2019 were analyzed in this retrospective real-world data-based study. The patients were divided into three groups according to the type of first-line chemotherapy they received: cytotoxic, targeted, and immunotherapy. Prognosis was then compared depending on the presence of liver metastasis in each treatment group.ResultsAmong the 1,470 patients, 723 (49.2%) received cytotoxic chemotherapy, 678 (46.1%) received targeted therapy, and 69 (4.7%) received immunotherapy as their first-line chemotherapy. A total of 234 (15.9%) patients had liver metastasis at the initial diagnosis. The mean patient age was 63.7 years, and 59.1% were male. There was no difference in overall survival (OS) in the immunotherapy group in patients with or without liver metastasis (11.7 vs. 13.0 months, P=0.968); however, patients with liver metastasis had worse outcomes in the cytotoxic and targeted therapy groups compared to patients without liver metastasis. Furthermore, in patients with liver metastasis, the immunotherapy group had a longer OS than the cytotoxic chemotherapy group (11.7 vs. 4.4 months, P<0.001). Liver metastasis was associated with poor outcomes (hazard ratio of 1.438), as were age, male sex, bone, adrenal gland, or soft tissue metastasis, and three or more metastatic sites; however, lymph node, brain, collateral lung, and pleura metastasis did not affect prognosis.ConclusionsAlthough liver metastasis was associated with poor outcomes, it did not affect prognosis in patients who received immunotherapy.

VERU-111, an oral cytoskeleton disruptor, to treat men with metastatic castration-resistant prostate cancer (mCRPC) who failed an androgen receptor targeting agent.

5056 Background: VERU-111 is an oral cytoskeletal disruptor that disrupts microtubules supporting the cytoskeleton and has no affinity for multidrug resistance proteins. A phase 1b/2 clinical study has been conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with mCRPC also resistant to androgen receptor targeting agents. Methods: In the phase 1b component of the study, a 3+3 design with escalating oral dosing of 4.5 mg to 81 mg (7 days on drug/14 days off per 21-day cycle) was utilized. The schedule was also expanded to continuous dosing/cycle. The phase 2 portion utilized 63 mg daily dosing to evaluate efficacy in approximately 40 taxane-naïve men with mCRPC that have failed at least one androgen receptor targeting agent. Results: In the phase 1b portion of the study, 30 taxane-naïve men with mCRPC and a median age of 76 (61-92) were enrolled. 8 had received prior enzalutamide, 12 abiraterone and 10 both. 8 men had bone mets, 5 lymph node, 5 mixed and 1 had soft tissue metastases at study entry. The MTD of VERU-111 is 72mg (3/11 men had grade 3 diarrhea) and the recommended phase 2 dose is 63mg. Grade 3 diarrhea was not observed at doses ≤ 63mg per day and the most common non-dose limiting AEs were mild to moderate nausea, vomiting, diarrhea, and fatigue, with no observed neurotoxicity or neutropenia. Efficacy was assessed by PSA and bone/CT scans. In men treated for ≥ 4 continuous 21-day cycles, 6/10 (60%) had PSA declines, 4(40%) men had ≥ 30% declines and 2(20%) ≥ 50% declines compared to their 21-day cycle baseline PSA. Median PFS is currently 12 months (6-23+ months) with 3 patients continuing on study, 2 of which have been on study for approximately 2 years. In patients receiving at least a single dose of ≥ 63 mg daily (n=19), objective tumor responses were seen in 3 men (16%). The median rPFS in these patients is currently 12.4 months. In the phase 2 portion of the study, 55% of the patients had bone only metastases, 11% had nodal only, 32% had mixed bone and nodal disease and 3% had visceral disease at study entry. 6/32 (19%) were previously treated with abiraterone alone, 12/32 (38%) with enzalutamide alone, and 14/32 (44%) had abiraterone in combination with enzalutamide, proxalutamide or apalutamide. The phase 2 portion of the study is ongoing and objective tumor responses have been observed including a CR and PRs and PSA decreases &gt;50%. Patients have been on study as long as 9 months. Conclusions: This phase 1b/2 clinical trial, demonstrates that oral daily dosing of VERU-111 has a favorable safety profile and that chronic dosing is feasible. The recommended phase 2 dose of 63mg daily has significant durable antitumor activity. These data support a potential prominent role of VERU 111 for the treatment of men with mCRPC who previously failed an androgen receptor targeting agent and prior to the administration of intravenous chemotherapy. Clinical trial information: NCT03752099.

Leptomeningeal Metastasis in ER + HER2- Advanced Breast Cancer Patients: A Review of the Cases in a Single Institute Over a 15-year Period.

While leptomeningeal metastasis (LM) from estrogen receptor-positive, HER2-negative advanced breast cancer (ER + HER2-ABC) has a poor prognosis, the details of ER + HER2-LM are unclear. We therefore retrospectively investigated patients with LM from ER + HER2-ABC. ER + HER2-ABC patients who received any therapy at Shizuoka Cancer Center between October 2002 and December 2017 were retrospectively analyzed. Patients with central nervous system (CNS) metastases were divided into three groups: brain metastasis (BM) only (B group); BM with LM (BL group); and LM only (L group). Among 369 patients, 102 developed CNS metastases: 70 (68.6%), 13 (12.8%), and 19 (18.6%) in the B, BL, and L groups, respectively. The L group showed a later onset, poorer performance status, more symptoms, and more skull metastasis than the other groups. Radiotherapy as the initial treatment was introduced to 13/13 (100%) and 15/19 (78.9%) in the BL and L groups, respectively. Subsequent systemic therapy excluding best supportive care was introduced to 5/13 (38.5%) and 5/19 (26.3%) in the BL and L groups, respectively. The median overall survival from the diagnosis of CNS lesions was 295.0, 146.0, and 99.0 days in the B, BL, and L groups, respectively, and worsening of CNS lesions was the major cause of death in the BL and L groups. Multivariate analyses showed that concurrent soft tissue metastasis (hazard ratio, 4.620) and subsequent systemic therapy (hazard ratio, 0.063) were prognostic for the L group. Management of LM from ER + HER2-ABC remains challenging, so a multimodal approach with novel systemic therapy is warranted.

338 Biceps Metastasis Presenting as A Presumed Abscess in Patient with An Undiagnosed Non-Small Cell Lung Cancer - An Unusual Presentation

Abstract Lung cancer is the most common cancer worldwide and has highest cancer mortality. Around 50% of cases present with metastasis, however skeletal muscle metastasis is rarely reported. In this case we describe a fifty-nine-year-old male patient who presented complaining of fever and a mass on the distal biceps and proximal forearm over a five-month period, with no reported improvement despite debridement and antibiotics spanning three presentations to the emergency department. Subsequent biopsy at various anatomical sites showed adenocarcinoma, later identified as metastatic from a primary non squamous-cell lung cancer (NSCLC). Metastases from lung cancer are more commonly limited to liver and adrenal glands. Presentation of such a mass in skeletal muscle would raise suspicion for the more-commonly seen soft-tissue sarcoma or hemangiomas. This case illustrates a rare example of lung cancer metastatic to skeletal muscle, more specifically, the biceps. Presentation of the mass was also unique in its morphology of an abscess with purulent discharge, raising the importance of cytology and suspicion for malignancy in an abscess unresponsive to antibiotics. Non-small cell lung cancer can present with skeletal metastasis. A work-up of a mass or abscess of the muscle should include the possibility of soft tissue metastasis.

From Good to Bad: The Opposing Effects of PTHrP on Tumor Growth, Dormancy, and Metastasis Throughout Cancer Progression.

Parathyroid hormone related protein (PTHrP) is a multifaceted protein with several biologically active domains that regulate its many roles in normal physiology and human disease. PTHrP causes humoral hypercalcemia of malignancy (HHM) through its endocrine actions and tumor-induced bone destruction through its paracrine actions. PTHrP has more recently been investigated as a regulator of tumor dormancy owing to its roles in regulating tumor cell proliferation, apoptosis, and survival through autocrine/paracrine and intracrine signaling. Tumor expression of PTHrP in late stages of cancer progression has been shown to promote distant metastasis formation, especially in bone by promoting tumor-induced osteolysis and exit from dormancy. In contrast, PTHrP may protect against further tumor progression and improve patient survival in early disease stages. This review highlights current knowledge from preclinical and clinical studies examining the role of PTHrP in promoting tumor progression as well as skeletal and soft tissue metastasis, especially with regards to the protein as a regulator of tumor dormancy. The discussion will also provide perspectives on PTHrP as a prognostic factor and therapeutic target to inhibit tumor progression, prevent tumor recurrence, and improve patient survival.

Unusual pattern of recurrence and atypical visceral metastases in extremity soft tissue sarcoma: a case report

: Soft-tissue sarcomas (STS) are a rare group of tumors, commonly arising in the extremities. For extremity STS, the main treatment strategy is limb sparing surgery followed by neoadjuvant radiotherapy. Patterns of disease relapse after multimodal treatment have been analyzed in the past decades, being the lung the first recurrence site. Non-pulmonary metastases are uncommon and are associated with worse prognosis. Local recurrences are less frequent and usually develop after a longer period of time. Local control depends on tumor grade and size, surgical margins and adjuvant radiotherapy. Here, we describe the case of an extremity STS fibrosarcoma in a 30-year-old male that in the course of the disease developed multiple marginal recurrences followed by gastric, lung and soft-tissue metastases. All local recurrences where identified by the patient himself and confirmed by magnetic resonance imaging (MRI). Limb marginal recurrences were treated with a multidisciplinary approach consisting of radical surgery and radiotherapy. Metastatic lesions were initially resected and adjuvant chemotherapy was considered after the last distant failure. STS can have an unpredictable pattern of recurrence, therefore follow-up protocols should be tailored to individual risk. Multimodal management for primary site is the key to achieve higher local control rates, and it should also be considered as an approach for secondary sites in selected patients.

The prognostic impact of bone metastasis in urothelial carcinoma treated with first-line platinum-based chemotherapy.

415 Background: Metastatic urothelial carcinoma (mUC) is an aggressive disease with a median overall survival (OS) of ≈ 15 months. In the first-line setting, key prognostic factors include ECOG performance status, white blood cell count, and response to treatment per the Galsky nomogram. Bone metastases (BM) in mUC are associated with morbidity and mortality but are grouped with visceral disease; hence, their impact on prognosis is not well established. We aimed to assess the survival impact of BM in mUC patients treated with first-line platinum-based chemotherapy (PBC). Methods: A retrospective collection of patient and tumor characteristics, with clinical response to treatment (complete response [CR], partial response [PR]; stable disease [SD] or progressive disease [PD]) for patients treated at Princess Margaret Cancer Centre, Tom Baker Cancer Centre, and Cross Cancer Institute from 2005-2018 was performed. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method. Univariate (UVA) followed by multivariate analysis (MVA) of patient variables [Cox] using PFS and OS was performed. Results: Overall 376 mUC patients were included; 222 (59%) had soft-tissue metastases (STM) only, 70 (19%) had bone-only metastases, and 84 (22%) had both STM and BM. Overall, 35% had PR or CR, 19% had SD, and 39% had PD (7%: unknown response). The median PFS and OS for the whole cohort were 5.6 months (95%CI: 4.8-6.4) and 9.7 months (95% CI: 8.8-10.8) respectively. Select UVA by metastatic site showed inferior PFS for bone-only (p=0.03) and combination STM and BM (p=0.017). Only combination STM and BM were significant on UVA for OS (p=0.002). MVA showed that bone-only metastases (p=0.03) and ECOG 3-4 (p&lt;0.0001) were associated with worse PFS (Table). Predictors of worse OS were the combination of STM and BM (p=0.02), ECOG 3-4 (p=0.001), and WBCs ≥ULN (p=0.02), (Table). Conclusions: BM are a significant predictor of worse outcomes for mUC patients treated with first-line PBC. Consideration as a treatment stratification factor for future studies is suggested. Strategies for the treatment of mUC patients with BM (ie: bone targeted agents) in the first-line setting should be addressed in future trials. [Table: see text]

Pretherapeutic first-in-human targeting trial of anti-hK2 antibody h11B6: A potential molecular vector for alpha-particle radioimmunotherapy.

122 Background: Radioligand therapy for metastatic castration resistant prostate cancer (mCRPC) has focused to date on targeting prostate specific membrane antigen, an approach associated with salivary gland toxicity and variable lesion expression. New targets are needed. Human kallikrein-2 (hK2) is overexpressed in most prostate cancer, with minimal normal tissue expression or serum secretion. Humanized monoclonal antibody (mAb) h11B6 exclusively targets hK2 in pre-clinical studies. This phase 0 study (NCT04116164) is a first-in-human trial of [111In]-DOTA-h11B6 to determine the hk2-targeting potential of h11B6. Objective: The purpose of this ongoing protocol is to characterize the biodistribution of [111In]-DOTA-h11B6 and determine a suitable mAb mass that targets mCRPC with minimal non-tumor targeting. Methods: Patients with progressive mCRPC were enrolled. A single slow bolus infusion of 2 mg [111In]-DOTA-h11B6 (nominally 185 MBq [111In]), was administered IV with or without 8 mg h11B6. Patients were observed for adverse events (AE) for at least 2 weeks. Serial gamma camera imaging including at least one SPECT/CT scan was performed up to 8 days post-administration. Serial blood samples were obtained over 2 weeks to determine serum radioactivity and h11B6 protein levels. Dosimetry for normal organs was estimated using OLINDA-EXM. Results: Results for the first 6 patients are summarized in Table. Treatment was tolerated in all patients with no AEs and no evidence of enhanced accumulation in any organ including salivary glands. Initial volume of distribution appeared confined to the vascular compartment. Slow clearance of radioactivity from the vascular compartment was observed with gradual targeting to skeletal and non-skeletal lesions in all patients. Conclusions: h11B6 is a novel mAb that targets hK2, localizes to bone and soft tissue metastases, has no significant normal tissue uptake, and spares salivary glands. An IND for a phase I therapeutic study using [225Ac] has been secured. Clinical trial information: NCT04116164. [Table: see text]

Clinical study of VERU-111, an oral cytoskeletal disruptor, in metastatic castration-resistant prostate cancer (mCRPC) who failed an androgen receptor targeting agent.

131 Background: VERU-111 is an oral, cytoskeletal disruptor that crosslinks α &amp; ß tubulin and inhibits microtubule polymerization with no affinity for multidrug resistance proteins. A Phase 1b/2 clinical study has been conducted to establish the maximum tolerated dose (MTD) and evaluate the preliminary efficacy in men with progressive mCRPC resistant to androgen receptor targeting agent (ARTA). Methods: In the Phase 1b portion of the study, a 3+3 design with escalating oral dosing of 4.5 - 81 mg (7 days on drug/14 days off per 21 day cycle) was utilized. After no dose limiting toxicity was observed, the dose was increased in the next cohort. The schedule was also expanded in those completing the 7 days on/14 days off cycle to continuous dosing/cycle. The recommended Phase 2 study dose is 63 mg daily and the trial is fully enrolled with 40 taxane-naiive men with mCRPC that have failed at least one ARTA. Results: In the Phase 1 portion of the study, 30 taxane-naïve mCRPC men with a median age of 76 (61-92) were enrolled. 8 received prior enzalutamide, 12 abiraterone and 10 both. 8 men had bone mets, 5 lymph node, 5 mixed and 1 had soft tissue metastases. The MTD of VERU-111 is 72mg (3 /11 men had Grade 3 diarrhea). No Grade 3 diarrhea was observed at doses &lt; 72 mg per day. At doses &lt; 72mg/d, the most common AEs were mild to moderate nausea, vomiting, diarrhea, and fatigue, with no observed neurotoxicity or neutropenia. In the Phase 1b, antitumor activity was assessed by PSA and bone/CT scans in men that were treated for ≥ 4 continuous 21-day cycles. 6/10 (60%) had PSA declines: 4 (40%) men had ≥ 30% and 2(20%) ≥ 50% declines compared to their 21 day cycle baseline. Based on PCWG3/RECIST 1.1 criteria, objective tumor responses were seen in 2 men (soft tissue and bone). Median duration of response is 11 months (6-18+ months). In the Phase 2 portion of the study, 49% had bone only metastases, 54% have bone only metastases, 11% have nodal disease, 32% had mixed bone and nodal disease and 3% had visceral disease. This portion of the study is ongoing and results will be reported. 9/29 (31%) had previously abiraterone, 10/29 (34%)( enzalutmide, 7/29 (24%) both enzalutmide and abiraterone and 4/29 (14%) apalutamide. Conclusions: Based upon this Phase 1b/2 clinical trial, oral VERU-111 has a favorable safety profile allowing for chronic administration and significant and durable antitumor activity. The daily dose of 63mg is being tested in the fully enrolled Phase 2 portion. Oral administration, safe long-term treatment and evidence of antitumor activity highlight a potential prominent role of VERU 111 for the treatment of men with mCRPC who failed an androgen receptor targeting agent. Clinical trial information: NCT03752099.

Patient-derived xenografts and organoids model therapy response in prostate cancer

Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.