Higher Rate Of Metastatic Disease Research Articles

Abstract 459: Exosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysisExosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysis

Abstract Over 80% of the patients with pancreatic ductal adenocarcinoma (PDAC) have cachexia, which is associated with reduced survival, decreased quality of life, and higher rates of metastatic disease. To date, the diagnostic and therapeutic options of PDAC-associated cachexia remain limited due to the lack of a complete understanding of the underlying pathological mechanism. Here, we demonstrate that fat loss is the earliest feature of cachexia induced by PDAC through its secreted exosomes. By analyzing exosomal components of normal and cancer-derived exosomes through small RNA-seq, we identify miR-16-5p, miR-21-5p, miR-29a-3p and miR-125b-5p enriched in pancreatic cancer-derived exosomes and in the exosomes from sera of mice or patients with pancreatic tumor. Among these, miR-16-5p and miR-29a-3p play a key role in fat loss by inhibiting adipogenesis through decreasing Erlin2 and CMPK1 expression leading to C/EBPβ and PPARγ downregulation. Synergistically, miR-29a-3p increases ATGL expression to facilitate lipolysis by suppressing MCT1 expression. Furthermore, PDAC-derived exosomes deprived of miR-16-5p and miR-29a-3p fail to induce fat loss, suggesting that these two exosomal miRs are required for PDAC-induced fat loss. These findings unravel a precise mechanism of how PDAC causes adipose atrophy via exosomal miRs and may provide new diagnostic and therapeutic strategies for PDAC-induced cachexia. Citation Format: Sui-Chih Tien, Chin-Chun Chang, I-Chih Chen, Ching-Hsuan Huang, Hsuan-Yu Peng, Yu-Ting Chang, Ming-Chu Chang, Chun-Mei Hu, Wen-Hwa Lee. Exosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysisExosomal miRNA 16-5p/29a-3p secreted from pancreatic cancer induce adipose atrophy by inhibiting adipogenesis and promoting lipolysis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 459.

Migration, invasion, and metastasis are mediated by P-Rex1 in neuroblastoma.

Neuroblastoma accounts for approximately 15% of pediatric cancer-related deaths despite intensive multimodal therapy. This is due, in part, to high rates of metastatic disease at diagnosis and disease relapse. A better understanding of tumor biology of aggressive, pro-metastatic phenotypes is necessary to develop novel, more effective therapeutics against neuroblastoma. Phosphatidylinositol 3,4,5-trisphosphate-dependent Rac exchanger 1 (P-Rex1) has been found to stimulate migration, invasion, and metastasis in several adult malignancies. However, its role in neuroblastoma is currently unknown. In the present study, we found that P-Rex1 is upregulated in pro-metastatic murine models of neuroblastoma, as well as human neuroblastoma metastases. Correspondingly, silencing of P-Rex1 was associated with decreased migration and invasion in vitro. This was associated with decreased AKT-mTOR and ERK2 activity, dysregulation of Rac, and diminished secretion of matrix metalloproteinases. Furthermore, increased P-Rex1 expression was associated with inferior relapse-free and overall survival via tissue microarray and Kaplan-Meier survival analysis of a publicly available clinical database. Together, these findings suggest that P-Rex1 may be a novel therapeutic target and potential prognostic factor in neuroblastoma.

Fungating Soft Tissue Sarcoma: A Complex Treatment Dilemma.

Fungating soft tissue sarcoma (STS) occurs in up to 3.7% of STS cases, ulcerate or protrude directly from the skin. Several studies have examined past treatments and outcomes of patients with such tumors and suggest that management can be especially challenging. Considering this, it is plausible that fungating extremity tumors may warrant an individualized treatment approach that differs from standard treatment for non-fungating STS. We sought to examine treatment and outcome trends for fungating extremity STS to guide future treatment considerations. A comprehensive literature review of the PubMed database identified 1515 articles. Inclusion criteria included human subjects, adult population, extremity tumors and fungating tumors. Studies published prior to 1982 were excluded. 10 articles were relevant and met all criteria. Outcomes compare fungating STS with non-fungating STS. Patients with fungating STS are more likely to receive amputations as primary or secondary treatment (23-35 vs. 7.8-12%). Metastatic disease is more common among patients with fungating STS (20-33% vs. 9-15%). Patients with fungating STS have been found to have a higher likelihood of local recurrence (LR) (20.0% vs. 16.5%). 5-year overall survival (OS) is significantly decreased in patients with fungating STS (18.0-26.0% vs. 56.8-71.3%).Patients with fungating STS who receive limb sparing surgery (LSS) are more likely to require plastic surgical intervention (65% vs. 25%). Fungating STS is strongly associated with decreased mean time to death (13.8-16.2 months vs 29.0-30.4 months). Complication rates following surgical treatment of fungating STS are as high at 75% following amputation and 43% following LSS with up to 17% of those requiring reoperation. Infection and flap necrosis are the most common complications described. Though limited, current literature persistently reveals fungation as a poor prognostic factor for patients with soft tissue sarcoma. Expedient primarysurgical treatment may be appropriate given the higher metastatic potential and increased rate of complications associated with fungating STS. Limb salvage surgery is appropriate for primary, non-metastatic surgical treatment, though fungating tumors are treated with primary amputation more often than non-fungating STS, which may reduce postoperative complications in high-risk patients. Fungation is well established as an indication for palliative amputation. Increased rates of primary amputation in fungating STS may correspond to higher rates of metastatic disease at time of initial presentation for fungating STS. Timing of XRT should be carefully considered, as neoadjuvant XRTcoupled with a fungating tumor may result in a higher incidence of pre and postoperative complications and increased need for plastic surgical closure techniques. Adjuvant XRT is appropriate though used less often in patients with fungating STS.

Machine learning identification of patient clusters for cutaneous melanoma.

Cutaneous melanoma is a cancer arising in melanocyte skin cells and is the deadliest form of skin cancer worldwide. Although some risk factors are known, accurate prediction of disease progression and probability for metastasis are difficult to ascertain, given the complexity of the disease and the absence of reliable predictive markers. Since early detection and treatment are essential to enhance survival, this study utilizing machine learning (ML) aims to further delineate additional risk factors associated with cutaneous melanoma. A Bayesian Gaussian Mixture ML model was created with data from 2056 patients diagnosed with cutaneous melanoma and then used to group the patients into six Clusters based on a Silhouette Score analysis. A t-distributed stochastic neighbor embedding (t-SNE) model was used to visualize the six Clusters. Statistical analysis revealed that Cluster 4 showed a significantly higher rate of metastatic disease, as well as higher Breslow depth at diagnosis, compared to the other five Clusters. Compared to the other five Clusters, patients represented in Cluster 4 also had lower healthcare utilization, fewer dermatology clinic visits, fewer primary care providers, and less frequent colonoscopies and mammograms, and were more likely to smoke and less likely to have a prior diagnosis of basal cell carcinoma. This study uncovers gaps in healthcare utilization of services among patient groups with cutaneous melanoma as well as possible implications for management of disease progression. Data-driven analyses emphasize the importance of routine clinic visits to dermatologists and/or primary care physicians (PCPs) for early detection and management of cutaneous melanoma. The findings from this study demonstrate that unsupervised ML methodology may serve to define the best candidate patients to benefit from enhanced dermatology/primary care which, in turn, is expected to improve outcomes for cutaneous melanoma.

Clinical-pathological features and treatment outcomes in Hispanic/Latino patients with advanced renal cell carcinoma at a single institution.

e16554 Background: Annually, there are over 400,000 new renal cell carcinoma (RCC) cases and more than 170,000 deaths worldwide. RCC is one of the top ten more prevalent malignancies in the United States, with 76,000 new cases each year and almost 14,000 deaths. Over the past half-century, RCC has more than doubled in incidence. Studies demonstrate histologic differences and outcome disparities among Hispanic and Latino patients diagnosed with RCC. Research to date describes earlier and more advanced diseases at diagnosis, higher rates of obesity at presentation, and higher mortality among these cohorts. However, there is limited data on clinical, pathological, molecular, and treatment outcomes in this patient population. This study aims to characterize clinical features and treatment outcomes in this patient population in South Florida. Methods: We conducted a retrospective cohort study to describe the characteristics and rates of recurrence of RCC among patients treated at Sylvester Comprehensive Cancer Center in Miami (which serves four counties in South Florida) between June 2010 to June 2022. An IRB-approved advanced RCC database was developed on RedCap, where clinical, laboratory, pathological, treatment, and response information were captured. Ethnicity was determined as Hispanic/Latino (HL) or non-Hispanic/Latino (NHL). Clinical groups were classified based on the last encounter as local RCC after nephrectomy, recurrent metastatic RCC after nephrectomy, and metastatic RCC at diagnosis/de novo. Results: We analyzed a total of 2048 patients aged 18 and older diagnosed with RCC, from which 1008 patients (47.70%) were identified as NHL and 963 (47.92%) as HL. RCC was in over a 2:1 ratio of men to women in both HLs and NHLs. A subtotal of 435 patients (22.87%) had metastatic RCC at diagnosis/de novo, from which 245 (55.59%) were NHL, and 175 (40.32%) were HL. A subtotal of 1613 patients (78.76%) were diagnosed with local RCC and underwent nephrectomy, from which 763 (45.46%) were identified as NHL and 788 (50.15%) as HL. From the NHL group that underwent nephrectomy, 222 patients (28.21%) had recurrent disease, and 541 patients (71.79%) did not. From the HL group, 175 patients (21.69%) had recurrent disease, and 613 (78.31%) did not. Overall, 408 patients had metastasis after nephrectomy, of which 175 (44.31%) were HL, and 203 (52.24%) were NHL. Conclusions: In this cohort of patients with RCC, over 40% of patients diagnosed with metastasis were HL. NHL appeared to have more disease recurrence after nephrectomy and higher rates of metastatic disease at diagnosis compared to Hispanics. Further histopathological differences, clinical outcomes, genomic characterization, and rates of clinical trial participation between the NHL and HL cohorts will be presented at the meeting, along with comparisons between US and foreign-born HLs.

Prognostic and predictive factors in undifferentiated pleomorphic sarcoma: A long-term study from a large tertiary care urban center.

Undifferentiated pleomorphic sarcoma (UPS) is an aggressive type of soft tissue sarcoma (STS) with high rates of metastatic disease and local recurrence. We sought to identify risk factors for local recurrence, metastasis, and overall death, and assess their impact on overall survival (OS), local recurrence-free survival (LRFS), and metastasis-free survival (MFS). A total of 386 cases of UPS treated at our institution from 1980 to 2020 were included. Coxproportional hazards regression was used to identifying risk factors for death, local recurrence, and/or metastasis. Using the Kaplan-Meier method, we assessed OS, LRFS, and MFS. Sixty-six (17%) and 121 (30%) patients with UPS developed local recurrence or metastasis, respectively. Lymph node(LN) involvement was present in 13.5% of patients. The most affected organ in patients with metastatic disease was the lungs (76.9%). Age ≥ 60 (hazard ratio [HR] = 2.42) and size ≥7 cm (HR = 1.52) were some of the significant risk factors for overall death. LN involvement was an important risk factor for both LR (HR = 2.79) and distant metastasis (HR = 5.73). UPSdisplays high rates of metastatic disease and local recurrence. Using a tumor size cutoff value of 7 cm yields superior prognostic value than the standard STS T-score thresholds. Lymphovascular invasion is an important risk factor for the development of metastasis.

Abstract 722: Epidemiological characterization of renal cell carcinoma in Hispanics: A single US center cohort study

Abstract Background: Annually, there are over 400,000 new cases of renal cell carcinoma (RCC) and more than 170,000 deaths worldwide. RCC is one of the top ten more prevalent malignancies in the United States, with 76,000 new cases each year and almost 14,000 deaths. Over the past half-century, RCC has more than doubled in incidence. RCC seems to have a greater incidence among Hispanics with a nearly three-fold increase. The epidemiology of RCC in the Caucasian population has been previously studied. However, there is a knowledge gap on disparities in RCC on minority populations. Studying the epidemiology of RCC in Hispanics is integral to our community where Hispanics make up 70%. Methods: We conducted a retrospective cohort study to describe the characteristics and rates of recurrence of RCC among patients treated at Sylvester Comprehensive Cancer Center in Miami (which serves four counties in South Florida) between June 2010 to June 2022. We identified ethnicity as Hispanic/Latino (HL) or non-Hispanic/Latino (NHL). Clinical presentation was classified based on the last encounter as local RCC without recurrence, metastatic RCC after nephrectomy, and metastatic RCC at diagnosis/de novo. Results: We analyzed a total of 2049 patients aged 18 and older diagnosed with RCC, from which 1014 patients (47.90%) were identified as NHL and 933 (48.02%) as HL. A subtotal of 435 patients (22.86%) had metastatic RCC at diagnosis/de novo, from which 245 (55.60%) were NHL, and 176 (40.57%) were HL. A subtotal of 1614 patients (77.14%) were diagnosed with local RCC and underwent nephrectomy, from which 769 (45.61%) were identified as NHL and 787 (50.22%) as HL. From the NHL group that underwent nephrectomy, 223 patients (28.28%) had recurrent disease, and 546 patients (71.72%) did not. From the HL group, 176 patients (21.81%) had recurrent disease, and 611 (78.19%) did not. Overall, 409 patients had metastasis after nephrectomy, of which 176 (44.5%) were HL, and 203 (52.42%) were NHL. Conclusions: In this cohort of patients with RCC, almost 50% of patients diagnosed with metastasis were HL. NHL appeared to have more disease recurrence after nephrectomy and higher rates of metastatic disease at diagnosis compared to Hispanics. Further histopathological differences, clinical outcomes, genomic characterization, and rates of clinical trial participation between the NHL and HL cohorts will be presented at the meeting, along with comparisons between US and foreign-born HLs. Citation Format: Abner A. Murray, Jesus A. Ocejo Gallegos, Sandra Jones, Jose Noy, Rosa L. Frias, Leticia E. Campoverde, Jaime R. Merchan. Epidemiological characterization of renal cell carcinoma in Hispanics: A single US center cohort study [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 722.

Prognostic Value of the Intermediate-risk Feature in Men with Favorable Intermediate-risk Prostate Cancer: Implications for Active Surveillance

BackgroundGuidelines suggest that active surveillance (AS) may be considered for select patients with favorable intermediate-risk (fIR) prostate cancer. ObjectiveTo compare the outcomes between fIR prostate cancer patients included by Gleason score (GS) or prostate-specific antigen (PSA). Most patients are classified with fIR disease due to either a 3 + 4 = 7 GS (fIR-GS) or a PSA level of 10–20 ng/ml (fIR-PSA). Previous research suggests that inclusion by GS 7 may be associated with worse outcomes. Design, setting, and participantsWe conducted a retrospective cohort study of US veterans diagnosed with fIR prostate cancer from 2001 to 2015. Outcome measurements and statistical analysisWe compared the incidence of metastatic disease, prostate cancer–specific mortality (PCSM), all-cause mortality (ACM), and receipt of definitive treatment between fIR-PSA and fIR-GS patients managed with AS. Outcomes were compared with those of a previously published cohort of patients with unfavorable intermediate-risk disease using cumulative incidence function and Gray’s test for statistical significance. Results and limitationsThe cohort included 663 men; 404 had fIR-GS (61%) and 249 fIR-PSA (39%). There was no evidence of difference in the incidence of metastatic disease (8.6% vs 5.8%, p = 0.77), receipt of definitive treatment (77.6% vs 81.5%, p = 0.43), PCSM (5.7% vs 2.5%, p = 0.274), and ACM (16.8% vs 19.1%, p = 0.14) between the fIR-PSA and fIR-GS groups at 10 yr. On multivariate regression, unfavorable intermediate-risk disease was associated with higher rates of metastatic disease, PCSM, and ACM. Limitations included varying surveillance protocols. ConclusionsThere is no evidence of difference in oncological and survival outcomes between men with fIR-PSA and fIR-GS prostate cancer undergoing AS. Thus, presence of GS 7 disease alone should not exclude patients from consideration of AS. Shared decision-making should be utilized to optimize management for each patient. Patient summaryIn this report, we compared the outcomes of men with favorable intermediate-risk prostate cancer in the Veterans Health Administration. We found no significant difference between survival and oncological outcomes.

Results of the c-TRAK TN trial: a clinical trial utilising ctDNA mutation tracking to detect molecular residual disease and trigger intervention in patients with moderate- and high-risk early-stage triple-negative breast cancer

Post-treatment detection of circulating tumour DNA (ctDNA) in early-stage triple-negative breast cancer (TNBC) patients predicts high risk of relapse. c-TRAK TN assessed the utility of prospective ctDNA surveillance in TNBC and the activity of pembrolizumab in patients with ctDNA detected [ctDNA positive (ctDNA+)]. c-TRAK TN, a multicentre phase II trial, with integrated prospective ctDNA surveillance by digital PCR, enrolled patients with early-stage TNBC and residual disease following neoadjuvant chemotherapy, or stage II/III with adjuvant chemotherapy. ctDNA surveillance comprised three-monthly blood sampling to 12 months (18 months if samples were missed due to coronavirus disease), and ctDNA+ patients were randomised 2 : 1 to intervention : observation. ctDNA results were blinded unless patients were allocated to intervention, when staging scans were done and those free of recurrence were offered pembrolizumab. A protocol amendment (16 September 2020) closed the observation group; all subsequent ctDNA+ patients were allocated to intervention. Co-primary endpoints were (i) ctDNA detection rate and (ii) sustained ctDNA clearance rate on pembrolizumab (NCT03145961). Two hundred and eight patients registered between 30 January 2018 and 06 December 2019, 185 had tumour sequenced, 171 (92.4%) had trackable mutations, and 161 entered ctDNA surveillance. Rate of ctDNA detection by 12 months was 27.3% (44/161, 95% confidence interval 20.6% to 34.9%). Seven patients relapsed without prior ctDNA detection. Forty-five patients entered the therapeutic component (intervention n= 31; observation n= 14; one observation patient was re-allocated to intervention following protocol amendment). Of patients allocated to intervention, 72% (23/32) had metastases on staging at the time of ctDNA+, and 4 patients declined pembrolizumab. Of the five patients who commenced pembrolizumab, none achieved sustained ctDNA clearance. c-TRAK TN is the first prospective study to assess whether ctDNA assays have clinical utility in guiding therapy in TNBC. Patients had a high rate of metastatic disease on ctDNA detection. Findings have implications for future trial design, emphasising the importance of commencing ctDNA testing early, with more sensitive and/or frequent ctDNA testing regimes.

Ductal prostate cancer: Clinical features and outcomes from a multicenter retrospective analysis and overview of the current literature.

The aim of the study is to evaluate clinical features and outcomes after different therapeutic strategies for ductal prostate adenocarcinoma (DPC), a rare but aggressive subtype of invasive prostate cancer (PCa) accounting for, in the pure and mixed form, 1% or less and 5% or less, respectively, of all the newly diagnosed PCa. Patients with a proven diagnosis of DPC undergoing surgery, radiotherapy, and androgen deprivation therapy, alone or in combination, were considered for this multicenter, retrospective study. The study assessed overall survival (OS), disease-free survival (DFS), and age-related disease-specific survival. Eighty-one patients met the study inclusion criteria. Pure DPC was found in 29 patients (36%) and mixed ductal-acinar-PCa in 52 patients (64%). After a median follow-up of 63 months (range, 3-206 months), 3- and 5-year OS rates were 84% and 67%, respectively, and 3- and 5-year DFS rates were 54% and 34%, respectively. There were no significant differences in OS or DFS between the pure and mixed DPC groups. Pure DPC was associated with a higher rate of metastatic disease at onset. Patients 74 years or younger had better disease-specific survival (p=0.0019). A subgroup analysis favored radiotherapy as the primary treatment for nonmetastatic, organ-confined DPC (3- and 5-year DFS of 80% and 50%, respectively, compared with 5-year DFS of 35% for surgical patients; p = 0.023). Our study found DPC to be rarer, more aggressive, more likely to metastasize, and have a worse prognosis than the common acinar variant, especially in its pure form. Multicenter series are encouraged to obtain large data sets, or propensity score matching analyses with patients with conventional PCa are desirable to understand the best therapeutic approach and improve outcomes.

Ewing sarcoma of the pelvis: Clinical features and overall survival,

IntroductionPrimary Ewing Sarcoma of Bone is a malignancy whose treatment requires both systemic chemotherapy and local control through surgical resection and/or radiation. Ewing Sarcoma of the pelvis has been noted to confer a worse prognosis relative to other anatomic sites of Ewing Sarcoma. This study explores the presenting features, treatment modalities for local control, and overall survival of primary Ewing sarcoma of the pelvis in comparison to other commonly affected anatomic sites. MethodsThe National Cancer Institute Surveillance, Epidemiology, and End-Results (SEER) database was used to identify cases of pelvic Ewing sarcoma diagnosed between years 2004 and 2015. Demographic variables including sex, race, and age at diagnosis were described for each case, as well as therapeutic modalities including surgery and radiation. Bone-specific Collaborative Staging variables, including tumor size, tumor extension, and metastasis at diagnosis, were described for the same cohort. Univariate and multivariate assessments were performed for statistical comparison between presenting factors, treatment modalities, and between anatomic locations of presentation. ResultsWithin the database, 296 patients with Ewing sarcoma of the pelvic bones were available for review, which represented 25.7% of the 1152 cases surveyed across all anatomic sites. In the subset of patients with Ewing Sarcoma of the pelvis, 63.5% were male; the median age of diagnosis was 17 years; extra-compartmental tumor extension was noted in 82.1%; average tumor size was 9.7 cm; and metastasis at diagnosis was noted in 46.1% of the cohort. Only 28.6% of the pelvis sarcoma patients received surgical resection as part or all of their local control treatment, while 67.6% received some form of radiation therapy. When compared to the presenting features of Ewing Sarcoma from other anatomic sites, patients with pelvic tumors had larger tumors at time of diagnosis, higher rates of metastatic disease, and were less likely to undergo surgical intervention. The 2-, 5-, and 10-year overall survival rates for the patients presenting with Ewing Sarcoma of the pelvis was 70.3%, 49.7%, and 41.9%, respectively, which were significantly lower across all time-points than any other anatomic site. Discussion and ConclusionEwing Sarcoma of the pelvis is an aggressive malignancy that presents with relatively large tumors and a high rate of metastatic dissemination. Surgical intervention is less frequent when Ewing Sarcoma presents in the pelvis than when it presents in other anatomic locations. These factors may contribute to the worse overall survival of Ewing Sarcoma when compared to the same diagnosis originating in other anatomic sites. Prospective, randomized study is required to determine the true causal effects of these factors on survival.

Osteosarcoma of the Pelvis: Clinical Presentation and Overall Survival.

Introduction Osteosarcoma is the most common sarcoma of bone. Pelvic osteosarcoma presents a significant therapeutic challenge due to potential late symptom onset, metastatic dissemination at diagnosis, and inherent difficulties of wide surgical resection secondary to the complex and critical anatomy of the pelvis. The rates of survival are well reported for osteosarcoma of the appendicular skeleton, but specific details regarding presentation and survival are less known for osteosarcoma of the pelvis. Methods The Surveillance, Epidemiology, and End Results (SEER) program was queried for primary osteosarcoma of the bony pelvis from 2004 to 2015. Cases with Collaborative Staging variables (available after 2004) were analyzed by grade, histologic subtype, surgical intervention, tumor size, tumor extension, and presence of metastasis at diagnosis. The 2-, 5-, and 10-year survival rates were assessed with respect to these variables. The SEER database was then queried for age, tumor size, surgical intervention, metastasis at time of presentation, and survivorship data for patients with primary osteosarcoma of the upper extremity, lower extremity, vertebrae, thorax, and face/skull, and rates for all anatomic locations were then compared to patients with primary pelvic osteosarcoma. Results A total of 292 cases of pelvic osteosarcoma were identified from 2004 to 2015 within the database, representing 9.8% of cases among all surveyed primary sites. The most common histologic subtype was osteoblastic osteosarcoma (69.9%), followed by chondroblastic osteosarcoma (22.3%). The majority of cases were high-grade tumors (94.3%), of size >8 cm (72.0%), and with extension beyond the originating bone (74.0%). For the entire pelvic osteosarcoma group, the 2-, 5-, 10-year survival rates were 45.6%, 26.5%, and 21.4%, respectively, which were the poorest among surveyed anatomic sites. The 5-year overall survival was an abysmal 5.3% for patients with metastatic disease at diagnosis, and 37.0% for non-metastatic pelvic osteosarcoma treated with surgery and chemotherapy. When compared to other locations, pelvic osteosarcoma had higher rates of metastatic disease at presentation (33.5%), larger median tumor size (11.0 cm), and older median age at diagnosis (47.5 years). While over 85% of patients with tumors at the extremities received surgery, only 47.4% of pelvic osteosarcomas in this cohort received surgical resection—likely influenced by larger tumor size, sacral involvement, frequency of metastasis, older age, or delayed referral to a sarcoma center. Conclusion This study clarifies presenting features and clinical outcomes of pelvic osteosarcomas, which often present with large, high-grade tumors with extracompartmental extension, high likelihood of metastatic disease at diagnosis, and a potential limited ability to be addressed surgically. The survival rates of primary osteosarcoma of the pelvis are poor and are lower than osteosarcomas from other anatomic locations. While acknowledging the influence of metastasis, tumor characteristics, and advanced age on the decision to undergo surgical excision of a pelvic osteosarcoma, the rates of surgical resection are low and highlight the importance of understanding appropriate conditions for oncologic resection of pelvic sarcomas.

PSMA PET Validates Higher Rates of Metastatic Disease for European Association of Urology Biochemical Recurrence Risk Groups: An International Multicenter Study.

The European Association of Urology (EAU) prostate cancer guidelines panel recommends risk groups for biochemical recurrence (BCR) of prostate cancer to identify men at high risk of progression or metastatic disease. The rapidly growing availability of PSMA-directed PET imaging will impact prostate cancer staging. We determined the rates of local and metastatic disease in BCR and biochemical persistence (BCP) of prostate cancer stratified by EAU BCR risk groups and BCP. Methods: Patients with BCR or BCP were enrolled under the same prospective clinical trial protocol conducted at 3 sites (n = 1,777 [91%]: UCLA, n = 662 [NCT02940262]; University of California San Francisco, n = 508 [NCT03353740]; University of Michigan, n = 607 [NCT03396874]); 183 patients with BCP from the Universities of Essen, Bologna, and Munich were included retrospectively. Patients with BCR had to have sufficient data to determine the EAU risk score. Multivariate, binomial logistic regression models were applied to assess independent predictors of M1 disease. Results: In total, 1,960 patients were included. Post-radical prostatectomy EAU BCR low-risk, EAU BCR high-risk, and BCP groups yielded distant metastatic (M1) detection in 43 of 176 (24%), 342 of 931 (37%), and 154 of 386 (40%) patients. For postradiotherapy EAU BCR low-risk and EAU BCR high-risk groups, the M1 detection rate was 113 of 309 (37%) and 110 of 158 (70%), respectively. BCP, high-risk BCR, and higher levels of serum prostate-specific antigen were significantly associated with PSMA PET M1 disease in multivariate regression analysis. PSMA PET revealed no disease in 25% and locoregional-only disease in 33% of patients with post-radical prostatectomy or postradiotherapy EAU BCR high risk. Conclusion: Our findings support the new EAU classification; EAU BCR high-risk groups have higher rates of metastatic disease on PSMA PET than do the low-risk groups. Discordant subgroups, including metastatic disease in low-risk patients and no disease in high-risk patients, warrant inclusion of PSMA PET stage to refine risk assessment.

Hormone receptor-positive breast cancer and black race: does sex matter?

Black breast cancer patients have worse clinical outcomes than their White counterparts. There are few studies comparing clinical outcomes between Black male breast cancer (MBC) and female breast cancer (FBC) patients. The objective of this study is to examine differences in presentation, treatment, and mortality between Black MBC and FBC. The National Cancer Database was queried for all Black MBC and FBC patients, ages 18-90, with hormone receptor-positive breast cancer diagnosed between 2010 and 2016. Hormone receptor positivity was defined as estrogen receptor-positive, progesterone-positive and HER 2-negative cancer. Sociodemographic and clinical variables were compared between MBC and FBC patients on bivariable analysis. After propensity score matching, overall survival was evaluated using the log-rank test and Cox proportional hazards. Compared to FBC patients, MBC patients had higher rates of metastatic disease (stage 4, MBC 4.4% vs. FBC 2.6%, p < 0.001), larger tumors (tumor size < 2cm, MBC 32.1 vs. FBC 49.1%, p < 0.001) and a higher percentage of poorly differentiated tumors (grade 3, MBC 28.5% vs. FBC 21.4%, p < 0.001). MBC patients had lower rates of hormone therapy (MBC 66.4% vs. FBC 80.7%, p < 0.001) and neoadjuvant chemotherapy (MBC 5.8% vs. FBC 7.5%, p = 0.05) than FBC. On propensity score matched analysis, Black MBC patients had a higher overall mortality (p25 of 60months vs. 74months) compared to FBC patients (p = 0.0260). Among hormone receptor-positive Black MBC and FBC patients, there are sex-based disparities in stage, hormone therapy use and overall survival.

Optimizing Loco Regional Management of Oligometastatic Colorectal Cancer: Technical Aspects and Biomarkers, Two Sides of the Same Coin.

Simple SummaryThe treatments for patients with oligometastatic colorectal carcinoma are rapidly evolving. The present review focuses on the role of minimally invasive techniques since they can now be used as an alternative to surgical management in selected cases in association with systemic therapies according to ESMO and NCCN guidelines. In recent years, biomarkers (both at molecular and imaging level) have emerged as a relevant and potential criteria for treatment strategy decision and will be crucial in the future for patients selection. Tumor molecular profile impacts on local outcome of image guide ablation as well as metabolic imaging which predicts the outcome of both percutaneous and trans-arterial treatments. Oncologists should be aware of advantages and disadvantages of those treatments options as well as the potential role of molecular profile for a better patient selection.Colorectal cancer (CRC) is the third most common cancer worldwide and has a high rate of metastatic disease which is the main cause of CRC-related death. Oligometastatic disease is a clinical condition recently included in ESMO guidelines that can benefit from a more aggressive locoregional approach. This review focuses the attention on colorectal liver metastases (CRLM) and highlights recommendations and therapeutic locoregional strategies drawn from the current literature and consensus conferences. The different percutaneous therapies (radiofrequency ablation, microwave ablation, irreversible electroporation) as well as trans-arterial approaches (chemoembolization and radioembolization) are discussed. Ablation margins, the choice of the imaging guidance as well as characteristics of the different ablation techniques and other technical aspects are analyzed. A specific attention is then paid to the increasing role of biomarkers (in particular molecular profiling) and their role in the selection of the proper treatment for the right patient. In conclusion, in this review an up-to-date state of the art of the application of locoregional treatments on CRLM is provided, highlighting both technical aspects and the role of biomarkers, two sides of the same coin.

Treatment of Osteosarcoma Patients in the Philippine General Hospital during the COVID-19 Outbreak

Objectives. The ongoing Coronavirus disease 2019 (COVID-19) pandemic has disrupted healthcare systems worldwide. This study aimed to document the effect of COVID-19 on osteosarcoma treatment pathways in the Philippine General Hospital (PGH) and determine if there were any delays.&#x0D; Method. A retrospective review of osteosarcoma patients treated at the PGH from January 1, 2019 – January 1, 2020 (pre-COVID-19) was compared to those treated during the COVID-19 pandemic from March 1, 2020 – September 1, 2020. Rates of diagnosed osteosarcoma, admission for chemotherapy, admission for surgery, treatment abandonment, metastatic disease on presentation, 1-year mortality, and amputation were calculated and compared between the two groups.&#x0D; Results. From March to September 2020, 11 newly diagnosed osteosarcoma patients sought consult at the PGH. Only one patient sought consult during the initial 3-4 months of the study, suggesting that patients delayed seeking healthcare during the period of enhanced community quarantine. Patients seen during the pandemic had a higher rate of metastatic disease on presentation, reflecting the delay in diagnosis. Due to COVID-19 restrictions early in the pandemic, osteosarcoma patients were coordinated and referred to outside hospitals for intravenous chemotherapy and surgery. Normalization of services (hospital admissions, limb salvage surgeries) were seen at the later stages of the study, corresponding to the loosening of the quarantine.&#x0D; Conclusions. Osteosarcoma patients experienced delays in seeking consult, diagnosis, and treatment at the PGH due to the COVID-19 pandemic. Early indicators suggest worse outcomes for these patients due to the delays. Strategies employed during the pandemic, such as networking of care and telemedicine, may help in future outbreaks.

Signet Ring Carcinoma of the Pancreas: A Rare and Deadly Disease

Introduction: Compared to pancreatic ductal adenocarcinoma (PDAC), signet ring carcinoma of the pancreas (SRC) is a rare mucin-producing exocrine malignancy, comprising less than 1% of all cases. Clinical information regarding this disease is scant. Method: Data on 103,341 patients with pancreatic cancer from the Surveillance Epidemiology and End Result (SEER) database (1973-2017) was analyzed. Results: SRC comprised 0.6% of all pancreatic cancers (621 cases). Both SRC and PDAC were more common in men, Caucasians and in the pancreatic head. SRC was more often poorly differentiated (81.3%) and had metastatic disease (68.1%). The majority of SRC were untreated (70%), while 14% had surgery and chemotherapy. Mean survival for SRC was significantly lower (0.47 years vs. 0.85 years), even with resection. However, SRC patients benefited more from primary radiotherapy than PDAC (1.05 vs. 0.93 years, p< 0.001). Multivariate analysis identified SRC size >4cm (OR 1.4), distant disease (OR 1.8), and poor differentiation (OR 1.6) as independent risk factors for mortality, p< 0.005. Survival advantage was seen with pancreatic body (OR 0.7) or tail location (OR 0.7), and radiation therapy (OR 0.36), p< 0.005 Conclusions: SRC presents with larger size, poor differentiation, and a higher rate of metastatic disease than PDAC, resulting in worse survival. Despite this, SRC patients amenable to radiation therapy derive greater survival advantage than PDAC. Resection was associated with the longest survival compared to other treatment modalities for SRC. These results suggest that combination surgery and radiotherapy may have an important role in improving survival for SRC patients. Data On 103,341 Patients With Pancreatic Cancer from the SEER Database (1973-2017)

MBRS-71. ATAXIA TELANGIECTASIA AND RAD3-RELATED PROTEIN ATTENUATES DNA DAMAGE AND IS A THERAPEUTIC TARGET IN Myc-DRIVEN MEDULLOBLASTOMA

Group 3 medulloblastoma tumors (Myc-MB), and particularly the 3γ subtype, have the worst prognosis and show a 5-year overall survival of less than 40%. Group 3 tumors are often accompanied by Myc amplification and have a higher rate of metastatic disease and relapse. Unfortunately, therapeutic strategies to target Mychave remained elusive. Further, the relapse of the MB has been linked to DNA replication stress. Ataxia telangiectasia and Rad3-related protein (ATR) senses persistent DNA damage, which arises due to replication stress, and activates damage checkpoints, thereby leading to increased cell survival. ATR is highly expressed in MB and is thought to contribute to undisturbed DNA replication to protect genomic integrity. Yet, the exact underlying mechanisms involving ATR are still unclear in MB. Inhibition of ATR (ATRi) using the ATR inhibitor, AZD6738, suppressed clonogenicity and cell self-renewal in Myc-MB. ATRi in Myc-MB cell lines downregulated Chk1 and upregulated P21. ATRi also induced cell cycle arrest and increased apoptosis in Myc-MB cell lines. Further, mice with orthotopic xenografts treated with ATR inhibitor survived significantly longer than control mice. High-throughput drug screening showed ATRi to be synergistic with chemotherapeutic agents including gemcitabine, cisplatin and topotecan. The treatment of Myc-MB cells with ATR inhibitor in combination with gemcitabine and with radiation increased in expression of DNA damage markers. These findings emphasize the role of ATR in alleviating DNA replication stress and that its inhibition is critical to the treatment of Myc-MB.

MBRS-65. FBXW7 ACTS A TUMOR SUPPRESSOR IN MYC-DRIVEN MEDULLOBLASTOMA BY CONTROLLING A FEED-FORWARD REGULATORY LOOP OF PLK1 AND MYC

Group 3 medulloblastoma (MB) is often accompanied by MYC amplification and has a higher rate of metastatic disease. So, it is critical to have more effective therapies for high MYC expressing sub-groups. Here we report that FBXW7, a substrate recognition component of the SKP1-CUL1-Fbox (SCF) E3 ligase, interacts with and targets c-MYC for polyubiquitination and proteasomal degradation. FBXW7 shows lower expression level in MYC-driven MB compared with other MB subgroups suggesting activity as a tumor suppressor. Genomic deletion or mutation of Fbxw7 has frequently been identified in many human cancers but not in MB. We demonstrate that overexpression of Fbxw7 in MB cells induces apoptosis and suppresses proliferation in vitro and in vivo. Both phospho-deficient (T205A) and phosphomimetic aspartic acid (T205D) mutants deactivate its tumor suppressor function suggesting a conformational change of its protein structure. Mechanistically, PLK1 kinase specifically phosphorylates FBXW7 and promotes its auto-polyubiquitination and proteasomal degradation, counteracting FBXW7-mediated degradation of oncogene substrates, including c-MYC and PLK1. Chip-Seq results show stabilized c-MYC in turn directly activates PLK1 and FBXW7 transcription, constituting a feedforward regulatory loop. Co-immunoprecipitation demonstrates that FBXW7 directly binds to PLK1 and c-MYC, facilitating their protein degradation by promoting the ubiquitination of both proteins. Furthermore, we show that FBXW7 protein can be stabilized by various kinase inhibitors, proposing a mechanism of kinase-targeted agents to treat MYC-driven MB. These results collectively demonstrate how kinase inhibition stabilizes the tumor suppressor FBXW7 in MYC-driven MB, thus revealing an important function of FBXW7 in suppressing MB progression.

Definitive High-Dose, Proton-Based Radiation for Unresected Mobile Spine and Sacral Chordomas

Spine chordoma is treated primarily by surgical resection. However, the local recurrence rate is high. Adjuvant radiotherapy to adequate dose improves local control. In certain locations, such as high sacrum, resection may result in significant neurological dysfunction, so definitive radiation has been used as an alternative to surgery. The purpose of this study is to report the results of high-dose, proton-based definitive radiotherapy for unresected spinal and sacral chordomas. We retrospectively reviewed 67 patients with newly diagnosed, previously untreated spinal chordomas (biopsy only; no prior resection) treated with high-dose definitive, proton-based radiotherapy at our center from 1975 to 2019. Reasons for radiotherapy alone included medical inoperability and/or concern for neurological dysfunction based on spine level or patient choice. Median age at diagnosis was 66.6 years. Male 53.7 %; female 46.3%. Tumor locations included cervical (n = 10), thoracic (n = 1), lumbar (n = 4) spine, and sacrum (n = 52). Median maximal tumor diameter was 7.4 cm (range 1.8- 25 cm). Most patients were irradiated in daily fraction sizes of 1.8-2 GyRBE, although some patients were irradiated with daily doses as high as 2.5 GyRBE per fraction, so doses were normalized to daily dose of 1.8 GyRBE daily (using an alpha/beta ratio of 3). Median total dose was 77.4 GyRBE. Analysis with median follow-up of 48.7 months (maximum 22 years) showed overall survival of 88.1 % (95%CI:73.2-95.0%) and 69.3% (95%CI: 47.0-83.7%), chordoma-free survival of 58.3% (95%CI: 40.7 – 72.3 and 40.3%(95%CI: 22.4 – 57.7%), local control of 78% (95%CI: 59.2-88.8%) and 62.9%(95%CI: 40.7 – 78.7%), and distant control of 78.6% (95%CI: 63.2-88.1%) and 72.5%( 95%CI: 52.8 – 85.1%) at 5 and 8 years respectively. In Cox model for local control (Likelihood Ratio Statistic), total dose: HR 0.73 (95%CI: 0.48-1.03) p = 0.079. LC at 5 years with dose 73.8-77.42 GyRBE was 76.0% (95%CI: 52.2-89.1) compared to 84.0% (95%CI: 46.8-96.0) with 78.0-85.9 GyRBE. LC at 8 years with dose = 73.8-77.42 GyRBE was 53.7% (95%CI: 27.1-74.4) compared to 84.0%% (95%CI: 46.8-96.0) with 78.0-85.9 GyRBE, p = 0.3492. In Cox model for distant control, size: HR 1.10 (95%CI: 1.01-1.20), p = 0.0318 and site, HR:3.65 (95% CI:0.71-66.7) p = 0.1389. Distant control for tumors ≤ 7.4 cm at 8 years was 81.2% (95%CI: 56.3-92.7%) compared to only 56.4% (95%CI: 18.9-82.1%) for tumors > 7.4 cm, p = 0.2041. Distant control at 8 years for sacral tumors was 56.5% (95%CI: 28.1-77.4%) vs. 87.5% (95%CI: 38.7-98.1%) for other sites, p = 0.1833. The most common late side effect was insufficiency fracture. These results support the use of high-dose definitive radiotherapy for patients with medically inoperable or otherwise unresected mobile spine or sacrococcygeal chordomas. There is a trend towards better local control with doses >78.GyRBE. There is a trend towards higher rates of metastatic disease with large and sacral tumors.