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Background The TARGIT-A trial reported risk-adapted targeted intraoperative radiotherapy (TARGIT-IORT) during lumpectomy for breast cancer to be as effective as whole-breast external beam radiotherapy (EBRT). Here, we present further detailed analyses. Methods In total, 2298 women (≥45 years, invasive ductal carcinoma ≤3.5 cm, cN0–N1) were randomised. We investigated the impact of tumour size, grade, ER, PgR, HER2 and lymph node status on local recurrence-free survival, and of local recurrence on distant relapse and mortality. We analysed the predictive factors for recommending supplemental EBRT after TARGIT-IORT as part of the risk-adapted approach, using regression modelling. Non-breast cancer mortality was compared between TARGIT-IORT plus EBRT vs. EBRT. Results Local recurrence-free survival was no different between TARGIT-IORT and EBRT, in every tumour subgroup. Unlike in the EBRT arm, local recurrence in the TARGIT-IORT arm was not a predictor of a higher risk of distant relapse or death. Our new predictive tool for recommending supplemental EBRT after TARGIT-IORT is at https://targit.org.uk/addrt. Non-breast cancer mortality was significantly lower in the TARGIT-IORT arm, even when patients received supplemental EBRT, HR 0.38 (95% CI 0.17–0.88) P = 0.0091. Conclusion TARGIT-IORT is as effective as EBRT in all subgroups. Local recurrence after TARGIT-IORT, unlike after EBRT, has a good prognosis. TARGIT-IORT might have a beneficial abscopal effect. Trial registration ISRCTN34086741 (21/7/2004), NCT00983684 (24/9/2009).

Introduction: Metastatic breast cancer (MBC) is the 2nd leading cause of cancer-related deaths in American women. While improvements in local and systemic therapies have significantly improved survival, 43,250 MBC patients are expected to succumb to their disease in the United States in 2022 alone. Triple-negative breast cancer (TNBC) represents 15% of all breast cancer and is defined by the lack of expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2). TNBC is the most aggressive subtype of breast cancer, known for its early relapse rate, chemo-resistance, and reduced survival. TNBC is also nearly twice as common in African American (AA) than in White women. In this study, we aim to ascertain the cancer disparity in a large cohort of Black/AA TNBC patients compared to their White counterparts in Hampton Roads, Virginia, as well as to the national SEER database. Methods: A retrospective chart review and survival study of 554 TNBC patients who received standard of care (SOC) treatment at Sentara-EVMS-VOA was performed. Kaplan-Meier survival curves were generated. Statistical analyses were conducted to determine if any clinicopathologic parameters, chemotherapy regimens, insurance, or socioeconomic status could be used to predict patient survival and risk stratify Black/AA and White TNBC patients in this Sentara cohort. Results: According to the national SEER TNBC database, 5-year survival rates for Black/AA and Whites are reported as 71.65% and 78.98%, respectively, compared to 70.33% and 75.53% within our local TNBC cohort. The Kaplan-Meier curve, which stratified our TNBC patients by race, predicted significant reduction in breast cancer-specific survival among Black/AA patients as compared to their White counterparts at all TNBC stages, especially in advanced and metastatic settings. This disparity is notably pronounced at stages II and III, as the Black/AA survival curves trend below that of the White TNBC patients for years following surgical intervention. A higher percentage of Black/AA patients were uninsured or under Medicaid coverage and did not receive standard AC-T regimens, particularly for TNBC patients with stage II disease, likely contributing to a reduced 5-year survival in the Black/AA TNBC cohort. We detected racial disparity in prescription of monotherapy or combination chemotherapy that might have also linked to reduced survival in the Black/AA patients from the Sentara catchment areas. Conclusion: Low socioeconomic status is a major impediment for access to health care. Multipronged combination chemotherapy regimens are critical in treating high-risk and high-grade TNBC patients. Therefore, it is imperative that Medicaid coverage includes AC-T regimens to improve TNBC survival, especially in our Black/AA patients in Hampton Roads, Virginia. Citation Format: Taylor N. Drake, Brandon Euker, Angela M. Tang-Tan, Caroline Dasom Lee, Emily L. Breeding, Janet S. Winston, Billur Samli, Rick J. Jansen, Michael Danso, Mary L. Guye, Richard A. Hoefer, Amy H. Tang. Stratifying high-risk patients, quantifying therapy efficacy, and detecting treatment/racial disparity in triple-negative breast cancer (TNBC) at Sentara-EVMS-VOA [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 1961.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype and disproportionately affects BRCA1 mutation carriers and young black women. Black/African American (AA) patients with TNBC have the highest mortality rate and the shortest survival of any racial/ethnic group in the United States. TNBC challenges our ability to personalize effective therapy. Neoadjuvant chemotherapy (NACT) is the standard-of-care (SOC) to treat T2 or LN+ TNBC. The addition of immune checkpoint blockade (ICB) has revolutionized treatment for these high-risk patients. Pembrolizumab plus chemotherapy is the new SOC for neoadjuvant systemic therapy (NST) in TNBC. Pathologic complete response (pCR) is a reliable indicator that correlates with improved long-term survival. However, clinical uncertainties remain in those who have an incomplete pathologic response (pIR) since many similarly treated TNBC patients with identical stage and comparable residual cancer burden (RCB) demonstrate disparate clinical outcomes. Current methods fall short in predicting tumor recurrence and treatment resistance in the clinic. Supported by ample evidence in developmental, evolutionary, and cancer biology, we proposed that EGFR-K-RAS-SIAH pathway activation is a major driving force in TNBC and that its most downstream gatekeeper, SIAH, is a tumor-specific, therapy-responsive, and prognostic biomarker for patient risk stratification in TNBC. The persistent high expression of SIAH in residual tumors after neoadjuvant therapy reflects EGFR/K-RAS pathway activation (ON) and resistance to treatment. The loss of expression of SIAH in residual tumors reflects EGFR/K-RAS pathway inactivation (OFF) and response to treatment (i.e. treatment efficacy). Here we propose to establish the power of SIAH as a prognostic biomarker to differentiate high-risk from low-risk tumors and predict “real-time” therapy response, in both pre- and post-neoadjuvant (NACT/NST) setting. Breast cancer mortality rates in Hampton Roads Virginia and Richmond Virginia are among the worst in the U.S. and demonstrate a major cancer health disparity. Black patients in our region have a 60-70% higher mortality rate than white patients according to CDC/SEER databases. Using a large cohort of 525 racially diverse TNBC patients (246 black and 279 white patients) at Sentara Cancer Network, we conducted Kaplan-Meier survival analyses and detected a major racial disparity, with significantly lower survival among the Black/AA TNBC cohort, compared to national databases. We will expand this TNBC disparity study by using 2 large racially-diverse cohorts of 981 TNBC patients (459 Black and 493 white patients) from the Sentara Cancer Network and VCU Massey Cancer Center to analyze the prognosis of SIAH expression. By focusing on this tumor-driving EGFR-K-RAS-SIAH pathway, we aim to delineate the underlying molecular basis of treatment resistance and racial disparity in high-risk TNBC. Citation Format: Amy H. Tang, Richard A. Hoefer, Dasom Lee, Emily L. Breeding, Mary L. Guye, Janet S. Winston, Billur Samli, Jennifer Koblinski, Valentina Robila, Michael O. Idowu, Rick J. Jansen, Harry D. Bear. Early detection of cancer disparity and treatment resistance in TNBC. [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 5531.

Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype. It disproportionately affects BRCA mutation carriers and young women, especially African American (AA) women. Chemoresistant TNBC is a heterogeneous and molecularly unstable disease that challenges our ability to apply personalized therapies. With the approval of immune checkpoint blockade (ICB) for TNBC, the addition of pembrolizumab to systemic chemotherapy has become standard of care (SOC) in neoadjuvant systemic therapy (NST) for high-risk early-stage TNBC. Pembrolizumab plus chemotherapy significantly increased the pathologic complete response (pCR) and improved event-free survival in TNBC. However, clinical uncertainties remain because similarly treated TNBC partial responders with comparable tumor responses to neoadjuvant therapy often experience disparate clinical outcomes. Current methods fall short in accurately predicting which high-risk patients will develop chemo-resistance and tumor relapse. Therefore, novel treatment strategies and innovative new research initiatives are needed. We propose that the EGFR-K-RAS-SIAH pathway activation is a major tumor driver in chemoresistant TNBC. Persistent high expression of SIAH in residual tumors following NACT/NST reflects that the EGFR/K-RAS pathway remains activated (ON), indicating an ineffective response to treatment. These chemoresistant tumor clones persist in expressing SIAH (SIAHHigh/ON) and are linked to early tumor relapse and poorer prognosis. Conversely, the loss of SIAH expression (SIAHLow/OFF) in residual tumors post-NACT/NST reflects EGFR/K-RAS pathway inactivation (OFF), indicating effective therapy and chemo-sensitive tumor cells. SIAHLow/OFF signal is linked to tumor remission and better prognosis post-NACT/NST. Therefore, SIAH is well-positioned to become a novel tumor-specific, therapy-responsive, and prognostic biomarker. Potentially, this new biomarker (SIAHHigh/ON) could be used to quantify therapy response, predict chemo-resistance, and identify those patients at the highest risk for tumor relapse and poor survival in TNBC.

Introduction A BRCA-2 mutation carrier with a metachronous pancreatic adenocarcinoma (PC) and established peritoneal metastases is presented. Combined modality therapy including Cytoreductive Surgery (CS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) was associated with long-term disease-free survival. Case presentation A 62-yr. old female underwent successful treatment for stage IIIa carcinoma of the right breast at age 48. 11 years later a cystic adenocarcinoma of the tail of the pancreas with peritoneal metastases was diagnosed. Platin based neoadjuvant chemotherapy followed by definitive resection of the pancreatic mass with cytoreductive surgery (CS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) with mitomycin C was performed. Postoperatively, a retro-gastric fluid collection developed from a pancreatic duct leak, successfully managed non-operatively. Maintenance poly ADP ribose polymerase (PARP) inhibitor therapy was initiated after recovery from surgery. The patient experienced a 30-month disease free survival and was subsequently found to have oligometastases to the brain. Discussion CR and HIPEC have not been reported to be efficacious in patients with pancreatic carcinomatosis. However, PC arising in BRCA-2 carriers has a DNA repair defect, which is sensitive to platin based chemotherapy and mitomycin C. HIPEC has more severe postoperative complications following distal pancreatectomy. Isolated brain metastases from PC are rare. BRCA-2 mutation carriers are at significantly increased risk for PC. Conclusion Leveraging the DNA Repair defect in BRCA-2 pancreatic adenocarcinoma, including CS and HIPEC, led to long-term disease-free survival and good locoregional control in this patient. Complications from HIPEC are more severe. BRCA-2 carriers should undergo annual pancreatic cancer screening., Highlights • BRCA-2 females should be considered for screening for pancreatic cancer. • Pancreatic cancer in BRCA-2 mutation carrier has a defect in DNA repair. • Accurate staging of pancreatic cancer is essential. • CS and HIPEC can lead to good long-term control of abdominal disease. • Complications from CS and HIPEC can be more severe but are manageable.

Microcalcifications are an important mammographic feature of ductal carcinoma in situ (DCIS) and are detected in 85-90% of abnormal mammograms. Calcium transport and calcium channels regulate microcalcifications and are essential for breast cancer proliferation. The breast duct intraductal lumen, which is the origin of ductal carcinomas, has been shown to be a non-sterile environment. We hypothesize that the intraductal microbiome influences calcium handling and mineral deposition in breast cancer. Bacteria have been known to enhance the formation of mineral deposits, including calcium salts, in various non mammalian microenvironments via secreted factors or extracellular vesicle mediated nucleation. We performed a clinical study on a cohort of 150 women who received a suspicious mammogram and were subjected to a follow up biopsy, and we identified differences in calcium handling microbiota between patients who harbored a malignant disease with respect to benign controls. To mechanistically study the role of microbiota in breast cancer calcium handling, we developed a 3D spheroid model of ductal carcinoma in situ using the BT-474 cell line. When exposed to high concentrations of calcium in the culture medium (from 1.75 mM to 2.05 mM), spheroids developed calcium mineral deposits in a calcium dose dependent manner; deposits were identified in internal regions of the spheroid, which correspond to hypoxic areas of DCIS in vivo. Extracellular calcium deposition correlated with cell survival in face of a toxic calcium level. Spheroids were cultured under a continuous flow of Lactobacillus rhamnosus LMS2-1-derived EVs over the course of two weeks. EVs were isolated by sequential ultracentrifugation; the 100K fraction was retained and characterized in terms of size, concentration, and protein content. EV treatment induced increased calcium export and mineral deposition in a dose dependent manner. Our findings support the hypothesis that L. rhamnosus-derived extracellular vesicles influence calcium regulation and mineral deposition in the hypoxic breast cancer milieu. More studies will be undertaken in the future to unveil molecular mechanisms that underlie this interaction, both at the cancer cell and the microbiota level. Citation Format: Ngoc Bao Vuong, Melany Alomia, Intisar Alruwaili, Fahad Alsaab, James L. Erickson, Weidong Zhou, Alessandra Luchini, Monique Van Hoek, Virginia Espina, Richard A. Hoefer, Lance Liotta. Evaluating the influence of Lactobacillus rhamnosus-derived extracellular vesicles on calcium deposition in early breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 189.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), became a pandemic in early 2020. Lateral flow immunoassays for antibody testing have been viewed as a cheap and rapidly deployable method for determining previous infection with SARS-CoV-2; however, these assays have shown unacceptably low sensitivity. We report on nine lateral flow immunoassays currently available and compare their titer sensitivity in serum to a best-practice enzyme-linked immunosorbent assay (ELISA) and viral neutralization assay. For a small group of PCR-positive, we found two lateral flow immunoassay devices with titer sensitivity roughly equal to the ELISA; these devices were positive for all PCR-positive patients harboring SARS-CoV-2 neutralizing antibodies. One of these devices was deployed in Northern Italy to test its sensitivity and specificity in a real-world clinical setting. Using the device with fingerstick blood on a cohort of 27 hospitalized PCR-positive patients and seven hospitalized controls, ROC curve analysis gave AUC values of 0.7646 for IgG. For comparison, this assay was also tested with saliva from the same patient population and showed reduced discrimination between cases and controls with AUC values of 0.6841 for IgG. Furthermore, during viral neutralization testing, one patient was discovered to harbor autoantibodies to ACE2, with implications for how immune responses are profiled. We show here through a proof-of-concept study that these lateral flow devices can be as analytically sensitive as ELISAs and adopted into hospital protocols; however, additional improvements to these devices remain necessary before their clinical deployment.

Triple-negative breast cancer (TNBC), characterized by the absence or low expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor (HER2), is the most aggressive subtype of breast cancer. TNBC accounts for about 15% of breast cancer cases in the U.S., and is known for high relapse rates and poor overall survival (OS). Chemo-resistant TNBC is a genetically diverse, highly heterogeneous, and rapidly evolving disease that challenges our ability to individualize treatment for incomplete responders and relapsed patients. Currently, the frontline standard chemotherapy, composed of anthracyclines, alkylating agents, and taxanes, is commonly used to treat high-risk and locally advanced TNBC. Several FDA-approved drugs that target programmed cell death protein-1 (Keytruda) and programmed death ligand-1 (Tecentriq), poly ADP-ribose polymerase (PARP), and/or antibody drug conjugates (Trodelvy) have shown promise in improving clinical outcomes for a subset of TNBC. These inhibitors that target key genetic mutations and specific molecular signaling pathways that drive malignant tumor growth have been used as single agents and/or in combination with standard chemotherapy regimens. Here, we review the current TNBC treatment options, unmet clinical needs, and actionable drug targets, including epidermal growth factor (EGFR), vascular endothelial growth factor (VEGF), androgen receptor (AR), estrogen receptor beta (ERβ), phosphoinositide-3 kinase (PI3K), mammalian target of rapamycin (mTOR), and protein kinase B (PKB or AKT) activation in TNBC. Supported by strong evidence in developmental, evolutionary, and cancer biology, we propose that the K-RAS/SIAH pathway activation is a major tumor driver, and SIAH is a new drug target, a therapy-responsive prognostic biomarker, and a major tumor vulnerability in TNBC. Since persistent K-RAS/SIAH/EGFR pathway activation endows TNBC tumor cells with chemo-resistance, aggressive dissemination, and early relapse, we hope to design an anti-SIAH-centered anti-K-RAS/EGFR targeted therapy as a novel therapeutic strategy to control and eradicate incurable TNBC in the future.

Chemo-resistant breast cancer is a major barrier to curative treatment for a significant number of women with breast cancer. Neoadjuvant chemotherapy (NACT) is standard first- line treatment for most women diagnosed with high-risk TNBC, HER2+, and locally advanced ER+ breast cancer. Current clinical prognostic tools evaluate four clinicopathological factors: Tumor size, LN status, pathological stage, and tumor molecular subtype. However, many similarly treated patients with identical residual cancer burden (RCB) following NACT experience distinctly different tumor relapse rates, clinical outcomes and survival. This problem is particularly apparent for incomplete responders with a high-risk RCB classification following NACT. Therefore, there is a pressing need to identify new prognostic and predictive biomarkers, and develop novel curative therapies to augment current standard of care (SOC) treatment regimens to save more lives. Here, we will discuss these unmet needs and clinical challenges that stand in the way of precision medicine and personalized cancer therapy.

Intraoperative radiation therapy (IORT) has been investigated for patients with low-risk, early-stage breast cancer. The The North American experience was evaluated by TARGIT-R (retrospective) to provide outcomes for patients treated in “real-world” clinical practice with breast IORT. This analysis presents a 5-year follow-up assessment. TARGIT-R is a multi-institutional retrospective registry of patients who underwent lumpectomy and IORT between the years 2007 and 2013. The primary outcome of the evaluation was ipsilateral breast tumor recurrence (IBTR). The evaluation included 667 patients with a median follow-up period of 5.1 years. Primary IORT (IORT at the time of lumpectomy) was performed for 72%, delayed IORT (after lumpectomy) for 3%, intended boost for 8%, and unintended boost (primary IORT followed by whole-breast radiation) for 17% of the patients. At 5 years, IBTR was 6.6% for all the patients, with 8% for the primary IORT cohort and 1.7% for the unintended-boost cohort. No recurrences were identified in the delayed IORT or intended-boost cohorts. Noncompliance with endocrine therapy (ET) was associated with higher IBTR risk (hazard ratio [HR], 3.67). Patients treated with primary IORT who were complaint with ET had a 5-year IBTR rate of 3.9%. The local recurrence rates in this series differ slightly from recent results of randomized IORT trials and are notably higher than in previous published studies using whole-breast radiotherapy for similar patients with early-stage breast cancer. Understanding differences in this retrospective series and the prospective trials will be critical to optimizing patient selection and outcomes going forward.

Key Points Question For early breast cancer, is 5-year local control with delayed second-procedure targeted intraoperative radiotherapy (TARGIT-IORT) noninferior to whole-breast postoperative external beam radiotherapy (EBRT), and how do long-term outcomes compare? Findings In this randomized clinical trial including 1153 participants, delayed second-procedure TARGIT-IORT was not noninferior to EBRT at 5-year complete follow-up; however, long-term (median 9 years) mastectomy-free survival, distant disease-free survival, and overall survival were not different. Meaning For early breast cancer, delayed second-procedure single-dose TARGIT-IORT given by reopening the lumpectomy wound had similar long-term mastectomy-free and overall survival compared with EBRT despite higher local recurrence., This secondary analysis of the TARGIT-A randomized clinical trial compares the effect of delayed second-procedure targeted intraoperative radiotherapy (TARGIT-IORT) with whole-breast external beam radiotherapy (ERBT) on local recurrence at 5 years and long-term survival outcomes among women with early breast cancer., Importance Conventional adjuvant radiotherapy for breast cancer given daily for several weeks is onerous and expensive. Some patients may be obliged to choose a mastectomy instead, and some may forgo radiotherapy altogether. We proposed a clinical trial to test whether radiotherapy could be safely limited to the tumor bed. Objective To determine whether delayed second-procedure targeted intraoperative radiotherapy (TARGIT-IORT) is noninferior to whole-breast external beam radiotherapy (EBRT) in terms of local control. Design, Setting, and Participants In this prospective, randomized (1:1 ratio) noninferiority trial, 1153 patients aged 45 years or older with invasive ductal breast carcinoma smaller than 3.5 cm treated with breast conservation were enrolled from 28 centers in 9 countries. Data were locked in on July 3, 2019. Interventions The TARGIT-A trial was started in March 2000; patients were randomized after needle biopsy to receive TARGIT-IORT immediately after lumpectomy under the same anesthetic vs EBRT and results have been shown to be noninferior. A parallel study, described in this article, was initiated in 2004; patients who had their cancer excised were randomly allocated using separate randomization tables to receive EBRT or delayed TARGIT-IORT given as a second procedure by reopening the lumpectomy wound. Main Outcomes and Measures A noninferiority margin for local recurrence rate of 2.5% at 5 years, and long-term survival outcomes. Results Overall, 581 women (mean [SD] age, 63 [7] years) were randomized to delayed TARGIT-IORT and 572 patients (mean [SD] age, 63 [8] years) were randomized to EBRT. Sixty patients (5%) had tumors larger than 2 cm, or had positive nodes and only 32 (2.7%) were younger than 50 years. Delayed TARGIT-IORT was not noninferior to EBRT. The local recurrence rates at 5-year complete follow-up were: delayed TARGIT-IORT vs EBRT (23/581 [3.96%] vs 6/572 [1.05%], respectively; difference, 2.91%; upper 90% CI, 4.4%). With long-term follow-up (median [IQR], 9.0 [7.5-10.5] years), there was no statistically significant difference in local recurrence-free survival (HR, 0.75; 95% CI, 0.57-1.003; P = .052), mastectomy-free survival (HR, 0.88; 95% CI, 0.65-1.18; P = .38), distant disease-free survival (HR, 1.00; 95% CI, 0.72-1.39; P = .98), or overall survival (HR, 0.96; 95% CI, 0.68-1.35; P = .80). Conclusions and Relevance These long-term data show that despite an increase in the number of local recurrences with delayed TARGIT-IORT, there was no statistically significant decrease in mastectomy-free survival, distant disease-free survival, or overall survival. Trial Registration ISRCTN34086741, ClinicalTrials.gov Identifier: NCT00983684

Background Metastatic breast cancer exhibits diverse and rapidly evolving intra- and inter-tumor heterogeneity. Patients with similar clinical presentations often display distinct tumor responses to standard of care (SOC) therapies. Genome landscape studies indicate that EGFR/HER2/RAS “pathway” activation is highly prevalent in malignant breast cancers. The identification of therapy-responsive and prognostic biomarkers is paramount important to stratify patients and guide therapies in clinical oncology and personalized medicine. Methods In this study, we analyzed matched pairs of tumor specimens collected from 182 patients who received neoadjuvant systemic therapies (NST). Statistical analyses were conducted to determine whether EGFR/HER2/RAS pathway biomarkers and clinicopathological predictors, alone and in combination, are prognostic in breast cancer. Findings SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two logical, sensitive and prognostic biomarkers in metastatic breast cancer. We found that increased SIAH and EGFR expression correlated with advanced pathological stage and aggressive molecular subtypes. Both SIAH expression post-NST and NST-induced changes in EGFR expression in invasive mammary tumors are associated with tumor regression and increased survival, whereas ER, PR, and HER2 were not. These results suggest that SIAH and EGFR are two prognostic biomarkers in breast cancer with lymph node metastases. Interpretation The discovery of incorporating tumor heterogeneity-independent and growth-sensitive RAS pathway biomarkers, SIAH and EGFR, whose altered expression can be used to estimate therapeutic efficacy, detect emergence of resistant clones, forecast tumor regression, differentiate among partial responders, and predict patient survival in the neoadjuvant setting, has a clear clinical implication in personalizing breast cancer therapy. Funding This work was supported by the Dorothy G. Hoefer Foundation for Breast Cancer Research (A.H. Tang); Center for Innovative Technology (CIT)-Commonwealth Research Commercialization Fund (CRCF) (MF14S-009-LS to A.H. Tang), and National Cancer Institute (CA140550 to A.H. Tang)., Graphical abstract Image 1, Highlights • EGFR/RAS pathway activation is prevalent in breast cancer with poor prognosis. • The two RAS pathway biomarkers, SIAH and EGFR, are prognostic in breast cancer. • The RAS pathway biomarkers can be used to stratify patients and guide therapies. • The RAS pathway biomarkers can be used to identify resistant tumor clones post NST. • SIAH and EGFR outperform ER, PR, HER2 and Ki67 in predicting patient survival. The prognostic power of SIAH/EGFR is comparable to that of clinical predictors Early stage breast cancer is amenable to standard of care therapies with excellent long-tern survival. Locally advanced and metastatic breast cancer has a much worse prognosis despite intense systemic and locoregional therapies. This disparity in prognosis underlines the acute need to identify resistant breast cancer cells, and administer and select effective therapies to eradicate resistant mammary tumors. We report that the activation of the EGFR/RAS/SIAH pathway can be used to identify resistant tumor clones and differentiate effective from ineffective therapies, and therefore predict tumor relapse and patient survival in human breast cancer during first-line neoadjuvant systemic therapy in clinic.

e15533 Background: Biomarker identification for early breast cancer diagnosis is confounded by comparing healthy control patients to patients undergoing surgical procedures and stress of a potential cancer diagnosis. We implemented a clinical research protocol that combines biomarker harvesting and identification with Breast Imaging-Reporting and Data System (BIRADS) results, within a cohort of women with a suspicious mammogram who donated samples prior to biopsy. The primary goals were to discover candidate novel plasma markers for stage I breast cancer versus benign lesions, and validate the markers by mass spectrometry and immunohistochemistry. Methods: 150 women found on screening mammography to have a BIRADS IV or V mammographic abnormality were enrolled in the IRB approved study, with one year follow-up. After informed consent, serum, plasma, and saliva specimens were obtained and frozen. The patient underwent image guided biopsy of the mammographic abnormality. Hydrogel nanoparticles were used to harvest and concentrate low abundance protein biomarkers from plasma. Proteins were identified by mass spectrometry. The BIRADS score and biopsy outcome were blinded to the laboratory researchers. Results: 37/150 women (median age 64, 73% ER+, 70% PR+) were diagnosed with biopsy-proven breast cancer. 15/37 had a family history of breast cancer. Within the context of stress of an abnormal mammogram and invasive biopsy, we identified 5478 plasma peptides. A model to predict endpoints that discriminate cancer vs no cancer was developed using cross-validation and lasso shrinkage method. The best fit multi-analyte ROC/AUC model of peptide spectral matches revealed 10 candidate peptides, including PLAA, TRAPPC9, PROS1, DDX41, ANKRD63, EGFLAM (AUC = 0.81), that discriminated cancer versus no cancer. The functional mechanisms of these proteins are calcium metabolism, GPI anchor biosynthesis, neural-immune crosstalk, DNA repair, and ubiquitin-mediated protein trafficking. Conclusions: Molecular profiling of blood can potentially complement imaging to improve diagnostic specificity in the setting of a suspicious mammogram. This unique trial design, enhanced by nanotechnology protein harvesting, identified potential novel cancer biomarkers in the presence of a suspicious mammogram. A confirmation trial is underway.

Sentinel-lymph-node biopsy is associated with increased melanoma-specific survival (i.e., survival until death from melanoma) among patients with node-positive intermediate-thickness melanomas (1.2 to 3.5 mm). The value of completion lymph-node dissection for patients with sentinel-node metastases is not clear. In an international trial, we randomly assigned patients with sentinel-node metastases detected by means of standard pathological assessment or a multimarker molecular assay to immediate completion lymph-node dissection (dissection group) or nodal observation with ultrasonography (observation group). The primary end point was melanoma-specific survival. Secondary end points included disease-free survival and the cumulative rate of nonsentinel-node metastasis. Immediate completion lymph-node dissection was not associated with increased melanoma-specific survival among 1934 patients with data that could be evaluated in an intention-to-treat analysis or among 1755 patients in the per-protocol analysis. In the per-protocol analysis, the mean (±SE) 3-year rate of melanoma-specific survival was similar in the dissection group and the observation group (86±1.3% and 86±1.2%, respectively; P=0.42 by the log-rank test) at a median follow-up of 43 months. The rate of disease-free survival was slightly higher in the dissection group than in the observation group (68±1.7% and 63±1.7%, respectively; P=0.05 by the log-rank test) at 3 years, based on an increased rate of disease control in the regional nodes at 3 years (92±1.0% vs. 77±1.5%; P

Chemotherapy resistant breast cancer is a major health challenge, resulting in high relapse rates and poor survival. Neoadjuvant chemotherapy (NACT) is a standard treatment for women with high-risk TNBC, HER2+, and locally advanced ER+ breast cancer. A completed course of NACT results in two possible outcomes: pathologic complete response (pCR) or residual disease. While pCR is a reliable clinical prognostic biomarker associated with excellent outcomes and prolonged survival, especially for TNBC and HER2+ cancers, patients with residual disease have a higher risk of recurrence. Patients with residual disease can be further stratified clinically using the Residual Cancer Burden (RCB) classification; however, patients with similar RCB classes may experience dramatically different clinical outcomes. Thus, additional precision biomarkers to stratify patients with residual disease after NACT are needed to identify patients at highest risk of recurrence, and to develop new therapeutic strategies to eradicate multidrug-resistant tumors. Supported by strong evidence in developmental, evolutionary and cancer biology, we found that K-RAS-SIAH pathway activation is a major tumor driver, and SIAH represents a key tumor vulnerability in breast cancer. Normal K-RAS/SIAH signaling pathway activation is indispensable for proper cell-cell communication, cell proliferation and tissue homeostasis in multicellular organisms. However, abnormal K-RAS/SIAH pathway activation is highly prevalent in high-risk and locally advanced breast cancer, and may confer chemo-resistance to these high-risk mammary tumors. Based on its evolutionary conservation and significance as the most downstream signaling module indispensable for K-RAS signal transduction, SIAHON/OFF expression is a reliable readout of K-RAS/EGFR/HER2 pathway activation/inactivation. We showed that SIAHON/OFF expression is a binary code in residual mammary tumors that can be used to stratify patients, augment RCB classification, forecast tumor relapse, and predict patient survival after 1st line NACT in a pilot retrospective study. Multidrug-resistant high-grade breast cancer is a genetically diverse, highly heterogeneous disease that challenges our ability to individualize and optimize precision therapy. Persistent K-RAS-SIAH-EGFR pathway activation endows TNBC with therapy resistance, and increases the risk of metastasis and early relapse. As such, we developed a K-RAS/SIAH-centered biomarker discovery program and a new anti-SIAH research initiative with the intended goal of designing novel and potentially life-saving anti-K-RAS targeted strategies to control and eradicate multidrug-resistant and intractable mammary tumors. Citation Format: Amy H. Tang, Lauren L. Siewertsz van Reesema, Vasilena P. Zheleva, Janet S. Winston, Rick J. Jansen, Emanuel F. Petricoin, Matthew P. Goetz, Matthew P. Goetz, Harry D. Bear, Richard A. Hoefer. Detect early tumor relapse in high-risk breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2145.

The American Society of Peritoneal Surface Malignancies (ASPSM) is a consortium of cancer centers performing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC). This is a position paper from the ASPSM on the standardization of the delivery of HIPEC.A survey was conducted of all cancer centers performing HIPEC in the United States. We attempted to obtain consensus by the modified method of Delphi on seven key HIPEC parameters: (1) method, (2) inflow temperature, (3) perfusate volume, (4) drug, (5) dosage, (6) timing of drug delivery, and (7) total perfusion time. Statistical analysis was performed using nonparametric tests.Response rates for ASPSM members (n = 45) and non-ASPSM members (n = 24) were 89 and 33 %, respectively. Of the responders from ASPSM members, 95 % agreed with implementing the proposal. Majority of the surgical oncologists favored the closed method of delivery with a standardized dual dose of mitomycin for a 90-min chemoperfusion for patients undergoing cytoreductive surgery for peritoneal carcinomatosis of colorectal origin.This recommendation on a standardized delivery of HIPEC in patients with colorectal cancer represents an important first step in enhancing research in this field. Studies directed at maximizing the efficacy of each of the seven key elements will need to follow.

Single-dose intraoperative radiotherapy (IORT) is an emerging treatment for women with early stage breast cancer. The objective of this study was to define the frequency of IORT use, patient selection, and outcomes of patients treated in North America.A multi-institutional retrospective registry was created, and 19 institutions using low-kilovoltage IORT for the treatment of breast cancer entered data on patients treated at their institution before July 31, 2013. Patient selection, IORT treatment details, complications, and recurrences were analyzed.From 2007 to July 31, 2013, a total of 935 women were identified and treated with lumpectomy and IORT. A total of 822 patients had at least 6 months' follow-up documented and were included in the analysis. The number of IORT cases performed increased significantly over time (p 0.001). The median patient age was 66.8 years. Most patients had disease that was2 cm in size (90 %) and was estrogen positive (91 %); most patients had invasive ductal cancer (68 %). Of those who had a sentinel lymph node procedure performed, 89 % had negative sentinel lymph nodes. The types of IORT performed were primary IORT in 79 %, secondary IORT in 7 %, or planned boost in 14 %. Complications were low. At a median follow-up of 23.3 months, crude in-breast recurrence was 2.3 % for all patients treated.IORT use for the treatment of breast cancer is significantly increasing in North America, and physicians are selecting low-risk patients for this treatment option. Low complication and local recurrence rates support IORT as a treatment option for selected women with early stage breast cancer.

BACKGROUND Targeted intraoperative radiation therapy (IORT) as an alternative to whole breast irradiation (WBI) has been described for patients with early-stage breast cancer. The randomized phase III TARGiT trial demonstrated similar recurrence rates to WBI and a lower overall toxicity profile on short-term follow-up. We report on our early North American surgical experience using the Intrabeam radiotherapy delivery system and review the current literature. METHODS Prospectively gathered estrogen receptor-positive, clinically node-negative patients with invasive breast cancer < 3 cm receiving IORT using the Intrabeam system were reviewed. IORT-related effects and early postoperative outcome were assessed. A literature review was also performed. RESULTS Forty-two patients (median age 71 years) underwent lumpectomy, sentinel lymph node (SLN) biopsy, and concurrent IORT from January 2011 to July 2011. Ninety-one percent of patients had invasive ductal histology with a median tumor size of 1.0 cm. This review highlights the patient selection criteria, describes commercially available accelerated partial breast irradiation (APBI) treatment options, and discusses outcomes for the variety of APBI techniques currently utilized in clinical practice as well as an institutional review of our early surgical experience using the Intrabeam radiotherapy delivery system. CONCLUSIONS While a variety of APBI techniques are currently available for clinical use, our early North American operative experience with IORT shows it is well tolerated with low morbidity. Delivery of IORT adds moderate operative time and may require creating subcutaneous tissue fl aps. The addition of WBI may be necessary in situations for positive residual margins or microscopic nodal disease in patients who do not undergo additional surgery.

SIAH is a new and potent anti-K-RAS drug target in human cancer. The oncogenic EGFR/HER2/K-RAS pathway activation is pivotal in driving uncontrolled tumor growth and systemic metastasis. Thus, counteracting ERBB/K-RAS hyperactivation in attempt to reverse malignant transformation and inhibit latent tumor growth is an important area for new therapy development against late-stage and metastatic cancer. Guided by Drosophila studies, we found that SIAH (Seven-In-Absentia Homologue) is the most downstream “gatekeeper” required for proper K-RAS signaling. Based on its extraordinarily evolutionary conservation, SIAH E3 ligase is well positioned to serve as an ideal drug target for developing new anti-K-RAS and anticancer therapy. We have shown that anti-SIAH-based therapy is indeed effective in inhibiting tumorigenesis and metastasis of pancreatic, lung and breast cancer cells in xenograft models. Importantly, we have shown that anti-SIAH-based anti-K-RAS strategy is effective against well-established, super-large and late-stage pancreatic and triple-negative breast tumors in a xenograft model in vivo. Through these studies, we have successfully identified a new oncogenic K-RAS "vulnerability," SIAH, in high-grade metastatic cancer. We aim to design and develop potent SIAH inhibitor, and translate these findings to the clinic to benefit more cancer patients with therapy-refractory, relapsed and metastatic diseases in the future. SIAH is a therapy-responsive and prognostic biomarker in human cancer: SIAH expression can be used to monitor tumor responses, and identify resistant tumor clones post-NST. SIAH and EGFR outperform ER, PR, HER2 and Ki67 as two robust, sensitive and prognostic biomarkers to predict survival in breast cancer patients with lymph node metastases. The prognostic power of SIAH and EGFR, alone or in combination, is comparable to the clinical gold standards of clinical predictors (LN positivity, mammary tumor size, grade, stage and molecular subtypes in combination), and imaging-guided technology. A marked reduction in SIAH/EGFR expression post-NST would indicate effective therapy and increased survival, while persistent high SIAH/EGFR expression post-NST would indicate ineffective therapy and decreased survival. The therapy-induced changes in SIAH expression are prognostic in quantifying effective/ineffective therapies, differentiating partial responders, identifying resistant tumor clones, and predicting remission/relapse in breast cancer at neoadjuvant settings. The identification of therapy-responsive and prognostic biomarkers is of paramount importance to stratify patients and guide therapies in clinical oncology and personalized medicine. By validating the RAS/SIAH pathway-centered prognostic biomarkers, we hope to guide standard therapies and improve patient survival in the future. Citation Format: Amy H. Tang, Robert E. Van Sciver, Elizaveta Svyatova, Kevin Kanda, Michael P. Lee, Caroline Dasom Lee, Lauren L. Siewertsz Van Reesema, Alex C, Lafever, Amber L. Collier, Apoorva S. Iyer, L.D. Britt, Janet S. Winston, Cynthia A. Allen, David Z. Chang, Gloria M. Petersen, Richard A. Hoefer. Conquering undruggable oncogenic K-RAS-driven incurable metastatic cancer, and delivering precision medicine at neoadjuvant settings [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 584.

Introduction: An analysis of experience of surgical and gynecologic oncologists in the United States with the use of hyperthermic intraperitoneal chemotherapy for women with invasive epithelial ovarian cancer (EOC). Methods: An Internet-based registry (HYPER-O) collected data from collaborating institutions. Eligibility included women with EOC treated with hyperthermic intraperitoneal chemotherapy. Borderline and nonepithelial cancers were excluded. Results: As of July 1, 2008, 141 women were eligible for analysis treated at the following time points: frontline (n = 26), interval debulking (n = 19), consolidation (n = 12), and recurrence (n = 83). The mean perfusion temperatures were 38.5 to 43.6°C (median, 41.9°C) for inflow and 36.9 to 42.9°C (median, 41°C) for outflow for 30 to 120 minutes. Treatment was with a platinum agent (n = 72), mitomycin (n = 53), or a combination (n = 14). Median follow-up was 18 months (range, 0.3-140.5 months) and median overall survival 30.3 months (95% confidence interval, 23.0-37.6) with 2-, 5-, and 10-year overall survival probabilities of 49.1%, 25.4%, and 14.3%, respectively. Of the 141 patients, 110 (78%) experienced recurrence of ovarian cancer and 87 died, 3 (0.5%) dying within 30 days of surgery. In the multivariable analysis, the factors significant for increased survival were sensitivity to platinum response (P = 0.048), completeness of cytoreduction scores of 1 or 0 (P = 0.025), carboplatin alone or a combination of 2 or more chemotherapy agents used (P = 0.011), and duration of hospital stays of 10 days or less (P = 0.021). Conclusions: Hyperthermic intraperitoneal chemotherapy is a viable additional treatment option for patients with invasive EOC and may extend life in selected groups. It warrants further study in randomized controlled trials.

Hyperactive K-RAS signaling is a major menace that drives aggressive cancer cell dissemination, tumor progression and metastasis in human pancreatic cancer. Currently, there are no effective therapies to control human pancreatic cancers that have metastasized and oncogenic K-RAS mutations reman “undruggable” in the clinics. Therefore, counteracting K-RAS hyperactivation in attempt to reverse malignant transformation and inhibit latent tumor spread is an important goal in pancreatic cancer biology and major challenge in targeted therapy development in pancreatic cancer. Instead of targeting an upstream signaling module such as EGFR/K-RAS/B-RAF/MEK/MAPK/ERK/AKT/mTOR, we targeted the most downstream signaling module in the K-RAS signaling pathway called the SIAH-dependent proteolytic machinery. SIAHs are the human homologs of Seven-In-Absentia (SINA), an evolutionarily conserved RING E3 ligase, an essential downstream signaling module and a critical “gatekeeper” required for proper K-RAS signal transduction. Guided by studies in Drosophila, SIAH (seven-in-absentia homologue), the most downstream gatekeeper required for proper RAS signaling and tumor cell survival, was identified as a suitable and new drug target for anti-K-RAS and anticancer therapy. We found that inhibiting SIAH function is highly effective to abolish well-established and late-stage pancreatic tumor growth and metastasis in our pre-clinical studies. Thus, we have identified a new vulnerability, SIAH E3 ligase, in the oncogenic K-RAS signaling pathway in pancreatic cancer. These findings demonstrate that SIAH is indeed an attractive, logical and potent anti-K-RAS therapeutic target for us to develop new and effective anticancer strategy against human pancreatic cancer. Through our work, SIAH has emerged as a new and effective drug target against oncogenic K-RAS hyperactivation in human pancreatic cancer. As one of the most evolutionarily conserved E3 ligases, SIAH is ideally and logically positioned to become a next-generation anti-K-RAS drug target in human pancreatic cancer. Our preclinical results have demonstrated that “SIAH-dependent proteolysis” is indeed an Achilles’ heel for human pancreatic cancer cells. Hence, anti-SIAH-based small molecule inhibitors may aid in expanding our arsenal of novel anticancer therapies in pancreatic cancer. By attacking the most downstream “gatekeeper” critical for the proper oncogenic K-RAS signaling transmission, we may be in a position to halt the genesis, progression and metastasis of the most aggressive and the deadliest forms of human pancreatic cancer in the future. We aim to translate these exciting findings to the cancer clinics to benefit our pancreatic cancer patients with metastatic diseases in the future. Citation Format: Amy H. Tang, Minglei Bian, Vasilena Zheleva, Monicah M. Njogu, Justin J. Odanga, Roger R. Perry, Richard A. Hoefer, Bruce E. Knudsen.{Authors}. An effective new strategy to control and inhibit the “undruggable” oncogenic K-RAS hyperactivation in human pancreatic cancer. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2016 May 12-15; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(24 Suppl):Abstract nr B63.

The oncogenic EGFR/HER2/K-RAS “pathway” activation is pivotal in driving uncontrolled cell proliferation, aggressive tumor growth and systemic metastasis. Guided by studies in Drosophila, SIAH (seven-in-absentia homologue), the most downstream gatekeeper required for proper RAS signaling and tumor cell survival, was identified as a suitable target for anti-neoplastic therapy. We have shown that anti-SIAH-based therapy leads to the complete blockade of tumorigenesis in highly aggressive pancreatic, lung and breast cancer cells expressing a proteolysis deficient mutant protein, SIAHPD, at the onset of tumor initiation. In this study, we aim to determine if this anti-SIAH strategy is effective against well-established and late-stage pancreatic and triple negative breast (TNBC) tumors in a xenograft mouse model in vivo. We established stable cancer cell lines with doxycycline (DOX)-inducible SIAH2PD expression. One million MiaPaCa-SIAH2PD or MDA-MB-231-SIAH2PD cells were injected subcutaneously bilaterally in the dorsal scapular areas or bilaterally into the mammary fat pads, respectively, in 4-week-old female athymic nude mice. Tumor growth was monitored 3 times per week. Once tumors reached certain volume, SIAH2PD expression was induced via oral DOX treatment. Tumor growth in these mice was compared to control. Immunohistochemical (IHC) and immunofluorescence (IF) staining for endogenous SIAH and FLAG-tagged exogenous SIAH2PD were performed on formalin-fixed, paraffin-embedded sections of tumor tissue. Expression of SIAH2PD blocks oncogenic K-RAS signaling and K-RAS-mediated tumor growth in established pancreatic (MiaPaCa) and triple negative breast (MDA-MB-231) tumors in athymic nude mice. The immunohistochemical (IHC) and immunofluorescent (IF) staining reveals that in control tumors there is high expression of endogenous SIAH and none of SIAH2PD, while in tumors responding to treatment there is pronounced SIAH2PD and diminished endogenous SIAH expression. Oncogenic HER2/EGFR/K-RAS activation promote neoplastic transformation and tumorigenesis. In this study, we have identified a new vulnerability in the oncogenic K-RAS signaling pathway and we have demonstrated a novel and effective way to block K-RAS-driven tumor growth in well-established pancreatic adenocarcinoma and TNBC tumors in a xenograft model. In the follow-up studies, we hope to develop a small molecule inhibitor against SIAH, test their efficacy against patient-derived stage IV and II tumors in our “xenopatient” models. In the future, we aim to translate these exciting findings to the cancer clinics to benefit our cancer patients with metastatic diseases in VA. Citation Format: Minglei Bian, Vasilena Zheleva, Xiaofei Gao, Justin Odanga, Monica Njogu, Zena Urban, Bruce Knudsen, Richard A. Hoefer, Roger R. Perry, Amy H. Tang. Inhibition of late-stage tumor growth of human pancreatic and triple-negative breast cancer by blocking the most downstream “gatekeeper” signaling module, SIAH E3 ligase, in the oncogenic ERBB/ K-RAS signaling pathway. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4366. doi:10.1158/1538-7445.AM2015-4366

Hyperactive K-RAS signaling is a major menace that drives aggressive cancer cell dissemination, tumor progression and metastasis in human pancreatic cancer. Currently, there are no effective therapies to control human pancreatic cancers that have oncogenic K-RAS mutations that confer drug resistance, aggressive tumor growth, systemic metastasis and poor clinical outcome. Therefore, finding novel approaches and new drug targets to inhibit oncogenic K-RAS activation is an urgent goal and major challenge in targeted therapy development in pancreatic cancer. Instead of targeting an upstream signaling module such as EGFR/K-RAS/B-RAF/MEK/MAPK/ERK/AKT/mTOR, we targeted the most downstream signaling module in the K-RAS signaling pathway called the SIAH-dependent proteolytic machinery. SIAHs are the human homologs of Seven-In-Absentia (SINA), an evolutionarily conserved RING E3 ligase, an essential downstream signaling module and a critical “gatekeeper” required for proper K-RAS signal transduction. Guided by the insights and principles learned from Drosophila RAS signaling pathway, we have conducted preclinical studies to dissect SIAH function in the context of K-RAS-mediated tumorigenesis and metastasis in human pancreatic cancer cells and tumor specimens. We found that inhibiting SIAH function is highly effective to abolish well-established and late-stage pancreatic tumor growth and metastasis in our pre-clinical studies. These findings demonstrate that SIAH is indeed an attractive, logical and potent anti-K-RAS therapeutic target for us to develop new and effective anticancer strategy against human pancreatic cancer. Through our work, SIAH has emerged as a new and effective drug target against oncogenic K-RAS hyperactivation in human pancreatic cancer. As one of the most evolutionarily conserved E3 ligases, SIAH is ideally and logically positioned to become a next-generation anti-K-RAS drug target in human cancer. Our preclinical studies have demonstrated that “SIAH-dependent proteolysis” is indeed an Achilles’ heel for human pancreatic cancer cells. Hence, anti-SIAH-based small molecule inhibitors may aid in expanding our arsenal of novel anticancer therapies in pancreatic cancer. By attacking the most downstream “gatekeeper” critical for the proper oncogenic ERBB/K-RAS signaling transmission, we may be in a position to halt the genesis, progression and metastasis of the most aggressive and the deadliest forms of human pancreatic cancer in the future. Citation Format: Vasilena Zheleva, Minglei Bian, Xiaofei Gao, Justin J. Odanga, Monicah M. Njogu, Zena M. Urban, Bruce E. Knudsen, Richard A. Hoefer, Roger R. Perry, Amy H. Tang. Developing a new and potent anti-K-RAS strategy by inhibiting SIAH E3 ligase, the most downstream “gatekeeper” in the oncogenic K-RAS signal pathway, to block well-established pancreatic tumor growth. [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Innovations in Research and Treatment; May 18-21, 2014; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2015;75(13 Suppl):Abstract nr B70.

Oncogenic K-RAS activation is a major menace that drives aggressive tumor progression and metastasis in 30% of all human cancer. Currently, there are no effective therapies to treat stage III and IV metastatic human cancers with oncogenic K-RAS hyperactivation that often confer drug resistance, aggressive tumor growth, systemic metastasis, and poor clinical outcome. Therefore, finding novel approaches and new drug targets to inhibit oncogenic K-RAS pathway activation is an urgent goal and the major challenge in cancer therapy and anti-K-RAS-based drug development. Instead of targeting an upstream signaling module such as EGFR/HER2/K-RAS/B-RAF, we targeted the most downstream signaling module in the oncogenic K-RAS signaling pathway called the SIAH-dependent proteolytic machinery. SIAHs are the human homologs of Seven-In-Absentia (SINA), an evolutionarily conserved RING E3 ligase - the most downstream signaling module and a critical “gatekeeper” required for proper RAS signal transduction. Guided by the insights and fundamental principles learned from the Drosophila RAS signal transduction, we conducted preclinical studies to dissect SIAH function in promoting the oncogenic K-RAS-driven tumorigenesis and metastasis in human cancer. We found that (1) SIAH is a new biomarker reflective of oncogenic K-RAS activation in human cancer, and (2) SIAH loss-of-function is highly effective to block tumorigenesis and metastasis against the well-established, end-stage and metastatic pancreatic cancer and triple negative breast cancer (TNBC). These findings demonstrate that SIAH is an attractive and logical new therapeutic target for developing novel and effective anti-K-RAS and anticancer therapy against metastatic human cancer. Through our work, SIAH has emerged as a promising new drug target against oncogenic K-RAS hyperactivation in metastatic human cancer cells. Using anti-SIAH molecules to block oncogenic K-RAS signaling in human cancer is an excellent example of science going “from the bench (basic research in fruit flies) to the bedside (preclinical studies and ultimately clinical trials)”. As a highly evolutionarily conserved E3 ligase that is the most downstream and the most conserved “signaling gatekeeper” in the oncogenic K-RAS signaling network, SIAH is uniquely and strategically positioned to become a great and logical anti-K-RAS drug target. Our preclinical studies have demonstrated that “SIAH-dependent proteolysis” is indeed an Achilles' heel in metastatic human cancer cells. Knowledge gained from our preclinical study has promising translational values. Anti-SIAH-based small molecule inhibitors are likely to aid in expanding our limited arsenal of novel anti-K-RAS-based anticancer therapies. By attacking the oncogenic K-RAS pathway using multi-pronged synergistic inhibitions at upstream (EGFR/HER2 membrane receptors), midstream (K-RAS/B-RAF/MEK/mTOR) and downstream (SIAH E3 ligase) signaling modules in parallel, we will be in a position to control the late-stage, relapsed and metastatic human cancers by shutting down the hyperactivated K-RAS signaling transduction cascades in cancer cells in the future. Citation Format: Minglei Bian, Yang Liao, Vasilena Zheleva, Zena Urban, Monicah Njogu, Justin J. Odanga, Andrew J. Isbell, Roger R. Perry, Richard A. Hoefer, Thomas C. Smyrk, Gloria M. Petersen, Amy H. Tang. Attacking the most downstream “gatekeeper,” the SIAH-dependent proteolytic machinery, in the oncogenic ERBB/K-RAS signaling pathway to block tumorigenesis and control metastasis in human cancer. [abstract]. In: Proceedings of the AACR Special Conference on RAS Oncogenes: From Biology to Therapy; Feb 24-27, 2014; Lake Buena Vista, FL. Philadelphia (PA): AACR; Mol Cancer Res 2014;12(12 Suppl):Abstract nr A26. doi: 10.1158/1557-3125.RASONC14-A26

The Persian Gulf War necessitated the activation of many Army Reserve and National Guard physicians, including a number in residency training. No prototype existed for the continued training of resident surgeons in a combat setting. The 159th Mobile Army Surgical Hospital (MASH) deployed in support of the Allied invasion of Iraq. A structured training program for two general surgery residents attached to the 159th MASH was developed and implemented. This program combined supervised operating room experience, perioperative management, morbidity and mortality conferences, and orthopedic grand rounds, all with careful professional documentation. A planned reading program could not be realized, due to the physical setting of wartime. Residents and attending staff interacted positively and the residents were able to continue their formal training as an integral part of the hospital. The model developed by the 159th MASH is a practical method of continuing structured resident training in a combat setting.

Hyperactive ERBB/K-RAS signaling is a major menace that drives aggressive tumor growth and metastasis in human cancer. Currently, there are no effective ways to treat late-stage and relapsed human cancers that have oncogenic ERBB/K-RAS mutations that often confer drug resistance, aggressive tumor growth, systemic metastasis, and poor clinical outcome. Therefore, finding novel approaches and new drug targets to inhibit oncogenic ERBB/K-RAS activation is an urgent goal and the major challenge in cancer therapy and treatment. Instead of targeting an upstream signaling module such as EGFR/HER2/KRAS/B-RAF, we targeted the most downstream signaling module in the EGFR/HER2/K-RAS pathway called the SIAH-dependent proteolytic machinery. SIAHs are the human homologs of Seven-In-Absentia (SINA), an evolutionarily conserved RING E3 ligase, an essential downstream signaling module and a critical “gatekeeper” required for proper EGFR/HER2/K-RAS/B-RAF signal transduction. Guided by the insights and fundamental principles learned from the Drosophila RAS signaling pathway, we conducted preclinical studies to dissect SIAH function in the context of ERBB/K-RAS-mediated tumorigenesis and metastasis in human cancer cells and human cancer biospecimens. We found that (1) SIAH is a great prognostic and predictive biomarker for human cancer, and (2) inhibiting SIAH function is highly effective to block tumorigenesis and metastasis against the well-established, late-stage and metastatic pancreatic cancer and triple negative breast cancer (TNBC). These findings demonstrate that SIAH is an attractive and logical new therapeutic target for novel anti-ERBB/oncogenic K-RAS and anticancer therapy in human cancer. Through our work, SIAH has emerged as a new and effective drug target against oncogenic ERBB/K-RAS activation in human cancer cells. Using anti-SIAH molecules to block K-RAS signaling in human cancer is an excellent example of science going “from the bench (basic research in fruit flies) to the bedside (preclinical studies and ultimately clinical trials)”. As a highly evolutionarily conserved E3 ligase and the most downstream “gatekeeper” of EGFR/HER2/K-RAS/B-RAF signaling pathway, SIAH is uniquely and logically positioned to become a next-generation anti-ERBB/anti-K-RAS drug target. Our preclinical studies have demonstrated that “SIAH-dependent proteolysis” is indeed an Achilles' heel in human cancer. Knowledge gained from our study has great promise and immediate translational values. Anti-SIAH-based small molecule inhibitors may aid in expanding our arsenal of novel anticancer therapies. By attacking the oncogenic ERBB/K-RAS/B-RAF pathway using multi-pronged synergistic inhibitions at upstream (EGFR/HER2 membrane receptors), midstream (K-RAS/B-RAF/MEK/mTOR) and downstream (SIAH E3 ligase) signaling modules in parallel, we will be in a position to control the late-stage, relapsed and metastatic human cancers. If successful, we hope to develop anti-SIAH-based therapy and translate our findings to the cancer clinics to treat cancer patients with metastatic diseases in the near future. Citation Format: Minglei Bian, Yang Liao, Vasilena Zheleva, Xiaofei Gao, Zena M. Urban, Monicah M. Njogu, Justin J. Odanga, Andrew J. Isbell, Rebecca L. Schmidt, Rie Takahashi, Roger R. Perry, Richard A. Hoefer, Thomas C. Smyrk, Gloria M. Petersen, Amy H. Tang. Attacking the most downstream “gatekeeper” signaling module in the oncogenic ERBB/K-RAS signaling pathway to block tumorigenesis and metastasis in human cancer. [abstract]. In: Proceedings of the Third AACR International Conference on Frontiers in Basic Cancer Research; Sep 18-22, 2013; National Harbor, MD. Philadelphia (PA): AACR; Cancer Res 2013;73(19 Suppl):Abstract nr C62.

The dismal prognosis of patients diagnosed with metastatic cancer points to our limited arsenal of effective anticancer and anti-metastasis therapies. Chemotherapy, radiation and targeted therapies are largely ineffective against metastatic cancer, resulting in the deaths of more than half million cancer patients each year. Oncogenic EGFR/HER2/K-RAS/B-RAF pathway activation is a major menace that drives aggressive cancer cell dissemination, tumor invasion and systemic metastasis. Therefore, finding novel approaches and new drug targets to inhibit hyperactive EGFR/HER2/K-RAS/B-RAF signaling is an urgent goal and major challenge in the struggle against metastatic diseases. Guided by the insights and principles learned from the evolutionarily conserved RAS signal transduction cascade in Drosophila, we targeted the most downstream signaling module in the EGFR/HER2/K-RAS/B-RAF signaling pathway, the SIAH-dependent proteolytic machinery. SIAHs are the human homologs of Seven-In-Absentia (SINA), a highly conserved RING E3 ligase, an essential downstream signaling module and a critical “gatekeeper” required for proper EGFR/HER2/K-RAS/B-RAF signal transduction. We found that inhibiting SIAH function is highly effective in halting cancer cell dissemination, altering cell adhesion and motility, inhibiting tumor invasion and cancer metastasis of human cancer cells. Importantly, our anti-SIAH-based anticancer strategy is effective in reducing tumor burdens in the late-stage and aggressive tumor growth and metastasis in the preclinical models. These exciting results and new findings demonstrate that SIAH is a highly attractive, mechanistically logical and great therapeutic target for developing novel anti-ERBB/K-RAS/B-RAF and anticancer therapies against invasive and metastatic cancer. Through our work, SIAH has emerged as a new, potent and promising drug target against metastatic diseases. As a highly evolutionarily conserved E3 ligase and the most downstream “gatekeeper” of EGFR/HER2/K-RAS/B-RAF signaling pathway, SIAH is ideally and logically positioned to become a next-generation anticancer and anti-metastasis drug target in the clinic. By simultaneously attacking the tumor-driving and metastasis-promoting ERBB/K-RAS signaling pathway using multi-pronged synergistic inhibitions at upstream (EGFR/HER2 membrane receptors), midstream (K-RAS/B-RAF/MEK/mTOR) and downstream (SIAH E3 ligase) signaling modules, we aim to make a difference and save lives from the deadliest forms of human metastatic cancers in the future. Citation Format: Amy H. Tang, Yang Liao, Minglei Bian, Vasilena Zheleva, Zena M. Urban, Monicah M. Njogu, Xiaofei Gao, Oscar A. Gonzalez, Justin J. Odanga, Bruce E. Knudsen, Roger R. Perry, Richard A. Hoefer, Thomas C. Smyrk, Gloria M. Petersen. Make a difference and save lives in human metastatic cancer by attacking the Achilles heel in the oncogenic ERBB/K-RAS signaling pathway. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Invasion and Metastasis; Jan 20-23, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;73(3 Suppl):Abstract nr A88.

Eosinophilic gastroenteritis, an inflammatory bowel disease of unknown etiology, occurs in one of 10,000 admissions to this Children's Hospital. We have added 4 cases to the 11 retrieved from a literature review. The inflammation is characterized by mature eosinophils predominating a transmural process which may produce pain, obstruction, perforation, bleeding, or fistulae. All levels of the gastrointestinal tract are involved, but stomach (25.9%) and small bowel (66.7%) lesions are most common. Eosinophilia occurs in 61% of children and allergy in 13%. X-rays may demonstrate a diffuse or localized process. Operative intervention may be necessary to exclude tumors or regional enteritis, and at times to extirpate complications of local disease, but conservative therapy is the treatment of choice for this exacerbating-remitting disease.