Aggressive Tumor Biology Research Articles

Is a R0 Resection Always the Aim in Resection of Colorectal Liver Metastasis?

Introduction: Colorectal cancer is the 3rdmost common cancer in the UK, with up to 50% developing colorectal liver metastases (CRLM). When suitable, surgical resection of CRLM offers a five year survival of 35%-58%. Evidence remains equivocal regarding a superior surgical technique for resection or if synchronous colon and liver resections show more favourable results. Resection margin status is important, with recent evidence suggesting that an R1 resection often reflects more aggressive tumour biology.

Hepatic Stem Cell-like Subtypes of Hepatocellular Carcinoma Revealed from the Integrative Multi-omics Analysis Using Developmental Hierarchies of the Liver

Background: Hepatocellular carcinoma (HCC) is lethal malignancy showing high relapse rates after curative resection in early-stage. Aggressive tumor biology in resectable HCC remains unclear. Methods: Using human fetal liver signatures, multi-omics dataset from multiple clinical HCC cohorts were analyzed comprehensively to reveal molecular mechanisms for HCC stemness as well as potential biomarkers to enhance therapeutic efficacy for molecular targeted therapy or immunotherapy in stem cell-like HCC subtypes. Results: The patients predicted to the hepatic stem cell (HS) subtype showed aggressive tumor features including large tumor size, high AFP, vascular invasion, and extrahepatic metastasis as well as worst prognosis with early recurrence even in early-stage. The oncogenic pathways in terms of cell cycle, epithelial-mesenchymal transition, and TGF-beta pathway were highly upregulated in the HS subtype. Higher mutations of TP53, RB1 with PTEN deletion were significantly identified in the HS subtype. We also identified subtype-specific tissue and serum biomarkers. Predicted responders for immunotherapy were significantly lower in stem cell-like subtypes due to higher accumulation of TAM and MDSC. The HS subtype showed potential higher response to multi-tyrosine kinase inhibitors, especially sorafenib and lenvatinib. Conclusion: Stem cell-like HCC is not only associated with significantly higher relapse rate after curative resection but also with molecular biology for the aggressive subtype of HCC. We identified subtype-specific serum and tissue biomarkers for stem cell-like subtypes and precise therapeutic strategies for each subtype regarding immunotherapy and molecular-targeted treatment. Our findings may offer theoretical foundation of biomarker-based clinical trials for new therapeutic approaches to resectable early-stage HCC patients.

L1CAM is not a reliable predictor for lymph node metastases in endometrial cancer, but L1CAM positive patients benefit from radiotherapy.

Purpose: Several studies evidenced the potential of L1CAM as a prognostic marker in endometrial cancer. The aim of this study was to investigate whether L1CAM can predict lymph node metastasis and could therefore be used preoperatively to identify patients with low to high-intermediate risk endometrial cancer who would profit from a lymphadenectomy and an adjuvant treatment. To avoid unnecessary morbidity, de-escalating strategies are still required.Methods: Immunohistochemistry for L1CAM was performed on curettage or hysterectomy specimens from 212 patients diagnosed with endometrial cancer who were treated at the University Hospital Basel during 2011-2019. L1CAM expression was correlated with clinicopathological features such as histological subtype, FIGO stage, lymph node metastasis, lymphadenectomy, adjuvant treatment and outcome.Results: Using a cut off ≥10%, L1CAM was positive in 41/212 patients (19.3%) and negative in 171/212 patients (80.7%). L1CAM was associated with high-risk features such as non-endometrioid histology, high tumour grade, and high FIGO stage. There was no significant correlation between L1CAM expression and lymph node metastasis. However, patients with L1CAM positive tumours showed improved disease-specific survival if treated with adjuvant radiotherapy.Conclusion: Although L1CAM expression pointed towards aggressive tumour biology, preoperative L1CAM analysis did not add any substantial predictive information regarding lymph node metastasis in low to high-intermediate risk groups. Therefore, L1CAM status is not suitable to tailor the surgical algorithm for lymph node staging. Nevertheless, our results suggest that L1CAM could be used as a predictive biomarker to select patients who may benefit the most from adjuvant radiotherapy.

Prognosis of first-line tumor directed therapy for hepatocellular carcinoma using a combination of AFP, AFP-L3, and DCP

Presenter: Paul Thevenot PhD | Ochsner Health System Background: The expanded biomarker panel consisting of α-fetoprotein (AFP), AFP-L3%, and des-γ-carboxy prothrombin (DCP) has improved surveillance and early detection of hepatocellular carcinoma (HCC). The biomarkers individually, when elevated, have also been linked to aggressive tumor biology including vascular invasion and advanced staging. With increased clinical utilization on the horizon, we investigated the role of using biomarker combinations at the time of diagnosis and correlating the outcomes at the time of liver transplantation. Methods: This prospective study was conducted at a single-center in HCC patients presenting to a multi-disciplinary tumor board for liver-directed therapy (LDT) and evaluation for bridge to liver transplantation (8/30/16 – 10/16/20). AFP, AFP-L3%, and DCP were assayed on the day of first line LDT using the μTASWako i30 instrument. Additional analyzed parameters were also obtained prior to first-line LDT and monitored for bridge to transplant outcome as the primary study endpoint. Results: Consented for analysis were 140 treatment naïve HCC patients undergoing first line LDT with transarterial chemoembolization, Ytrrium-90, or microwave ablation. The median cohort age was 61 years with majority demographics of male (74%) and hepatitis C etiology (59%). Tumor burden was 82% within Milan with a median MELD-Na prioritization score of 11. Study endpoint breakdown was 29% transplanted, 29% dropout due to tumor progression, 24% censored from study endpoint, and 18% remaining waitlist active at the time of analysis. Median biomarker values were 10 ng/mL AFP, 7% AFP-L3, and 3.1 ng/mL DCP. Forty-four percent of cohort was negative for all three biomarkers while 14% were triple positive. Univariate analysis for each biomarker at threshold were associated with tumor progression (OR 5.6 – AFP > 20 ng/mL, 4.8 – AFP-L3 >10%, 8.8 – DCP >7.5 ng/mL). Analysis of cohort based on biomarker status (triple negative, AFP only, or positive for AFP-L3% and/or DCP) revealed an association between biomarker positivity and largest lesion size (P < 0.001). Univariate analysis showed largest lesion, and each individual biomarker, along with 2 positive biomarkers was associated with bridge to transplant survival. Controlling for tumor burden in separate multivariate analyses, AFP (HR 4.8), and DCP (HR 2.2), or having 2 positive biomarkers (HR 6.0) remained associated with bridge to transplant survival. In endpoint analysis, patients with more than 2 positive biomarkers had significant lower bridge to transplant survival. Biomarker positivity was also associated with response to first line LDT (OR 3.2). Conclusion: The expanded biomarker panel (AFP, AFP-L3%, and DCP) prior to LDT in bridge to transplant HCC can identify patients at high risk of tumor progression following LDT. The expanded biomarker panel may provide an opportunity to optimize treatment modality with outcome based on profile independent of radiographic tumor burden.

The Impact of Molecular Subtyping on Pathological Staging of Pancreatic Cancer

Purpose: The long-term outcomes following surgical resection for Pancreatic Ductal Adenocarcinoma (PDAC) remains poor, with only 20% of patients surviving 5 years after pancreatectomy. Patient selection for surgery remains sub-optimal largely due to the absence of consideration of aggressive tumour biology. Molecular subtyping has demonstrated 2 broad subtypes in PDAC, called Classical Pancreatic and Squamous.

Interface between obesity with dysfunctional metabolism and inflammation, and the triple-negative breast cancer in African American women.

Obesity has dramatically increased over the past fifty years. In the last decade, it has been noted that augmented body mass, metabolic abnormalities, and the relevant “obese” tumor microenvironment (TME) are connected with signaling molecular networks, which in turn, may contribute to aggressive tumor biology in some patients with breast malignancies. This article presents the associations between obesity, metabolic derangements, inflammatory processes in the adipose tissue or TME, and aggressive behavior of triple-negative breast cancer (TNBC) in African American (AA) women. It also describes some abnormal molecular signaling patterns in the “obese” TME with relevance to TNBC biology. Ethnic disparities in TNBC can be due to a variety of biological features (e.g., genetic mutations and tumor heterogeneity), comorbidities (e.g., cardio-metabolic diseases, including diabetes mellitus), and reproductive factors (e.g., multiparty or short breastfeeding period). Such a constellation of biological variables potentially leads to the association between obesity, metabolic derangements, inflammatory processes in the adipose tissue or TME, and aggressive behavior of TNBC in AA women. Since the TNBC and its TME can display very aggressive behavior, it is crucial that the afflicted AA women make efforts to maintain healthy body weight, “flexible” metabolism, and a well-functioning immune system. Further studies are merited to explore the multi-disciplinary factors that can affect TNBC prevention, management, and outcomes to optimize treatment strategies and survival among AA women.

Taking tumour budding to the next frontier - a post International Tumour Budding Consensus Conference (ITBCC) 2016 review.

Tumour budding in colorectal cancer, defined as single tumour cells or small clusters containing four or fewer tumour cells, is a robust and independent biomarker of aggressive tumour biology. On the basis of published data in the literature, the evidence is certainly in favour of reporting tumour budding in routine practice. One important aspect of implementing tumour budding has been to establish a standardised and evidence-based scoring method, as was recommended by the International Tumour Budding Consensus Conference (ITBCC) in 2016. Further developments have aimed at establishing methods for automated tumour budding assessment. A digital approach to scoring tumour buds has great potential to assist in performing an objective budding count but, like the manual consensus method, must be validated and standardised. The aim of the present review is to present general considerations behind the ITBCC scoring method, and a broad overview of the current situation and challenges regarding automated tumour budding detection methods.

Impact of intraoperative margin clearance on survival following pancreatoduodenectomy for pancreatic cancer: a systematic review and meta-analysis

The use of intraoperative margin revision to achieve margin clearance in patients undergoing pancreatoduodenectomy for pancreatic cancer is controversial. We performed a systematic review and meta-analysis to summarize the evidence of intraoperative margin revisions of the pancreatic neck and its impact on overall survival (OS). Nine studies with 4501 patients were included. Patient cohort was stratified in an R0R0-group (negative margin on frozen and permanent section), R1R0-group (revised positive margin on frozen section which turned negative on permanent section), and R1R1-group (positive margin on frozen and permanent section despite margin revision). OS was higher in the R1R0-group (HR 0.83, 95% CI 0.72–0.96, P = 0.01) compared to the R1R1-group but lower compared to the R0R0-group (HR 1.20; 95% CI 1.05–1.37, P = 0.008), respectively. Subgroup analyses on the use of different margin clearance definitions confirmed an OS benefit in the R1R0-group compared to the R1R1-group (HR 0.81; 95% CI 0.65–0.99, P = 0.04). In conclusion, intraoperative margin clearance of the pancreatic neck margin is associated with improved OS while residual tumor indicates aggressive tumor biology. Consensus definitions on margin terminologies, clearance, and surgical techniques are required.

Abstract PO-221: Racial disparities in breast cancer characteristics and outcomes among Hispanic and White patients

Abstract Background: Therapeutic advances in breast cancer (BC) have led to an improved prognosis. However, significant differences in survival outcomes across diverse ethnicities exist. We aim to investigate the differences in demographics, tumor characteristics (cts) and survival outcomes among Hispanic patients (pts) as compared to Non-Hispanic White (NHW) pts. Methods: BC pts diagnosed between 1975-2016 were identified using the Surveillance, Epidemiology, and End Results (SEER) database, and demographic and clinical cts were analyzed. Cox regression models were used for univariate (UV) and multivariable (MV) analyses to evaluate the associations of race with disease-specific survival (DSS) and overall survival (OS) Results: A total of 806,704 (n=720,144 NHW, n=86,560 Hispanic) pts were analyzed. At the time of diagnosis, Hispanic pts were younger [median age 55 years (yrs) vs. 62 yrs], had a higher stage (III/IV=21.3% vs. 16.3%) and a higher grade (grade III/IV=43.3% vs. 35.3%) as compared to NHW pts (p&amp;lt;0.001). Hispanic pts were more likely to present with triple-negative BC (TNBC) (14.2% vs. 11.1%) and Her-2 receptor + BC (6.7% vs. 4.7%) than NHW pts (p&amp;lt;0.001). Hispanic pts were more likely to live in urban areas (95.6% vs. 87.9%) but had similar access to hospitals with oncology services/million population (4.1 vs 4.6) than NHW pts (p&amp;lt;0.001). Hispanic pts were more likely to be uninsured (4% vs.1.1%) with lower odds of undergoing BC surgery (92.8% vs. 95.4%) than NHW pts (p&amp;lt;0.001). On UV analysis, Hispanic pts had a slightly worse DSS [Hazard Ratio (HR) 1.05, 95% CI 1.03-1.07)], but had a better OS (HR 0.84, 95% CI=0.83-0.85) as compared to NHW pts (p&amp;lt;0.0001). On MV analysis controlling for demographic, tumor acts, and disparities in health care access, no significant differences were noted in DSS (HR 0.98, 95% CI=0.96-0.99) and OS (HR 0.99, 95% CI=0.98-1.01) between both groups. However, in pts age&amp;lt;50 yrs, Hispanic pts had a worse DSS (HR 1.17, 95% CI 1.13, 1.20) and OS (HR 1.16, 95% CI 1.13-1.19) than NHW pts. Additionally, worse DSS but not OS was noted in Hispanic pts with hormone receptor+/HER2- BC, pts who received chemotherapy and or surgery and married pts. Conclusions: Our study highlights that Hispanic BC pts appear to have a more aggressive tumor biology than NHW pts with younger age at onset, higher stage, and predominance of TNBC and Her 2+ BC. Although both ethnicities had similar access to health care services, lack of insurance might be a barrier for adequate health care utilization. Despite differences in disease biology, we observed similar survival rates in Hispanic and NHW pts. Interestingly, in pts age&amp;lt;50 yrs, Hispanic pts had a worse DSS and OS than NHW pts. Our findings suggest that racial disparities in outcomes could be related to differences in tumor biology, social status, treatment, and healthcare utilization patterns, especially in younger pts. Further studies are needed to elucidate the causes of racial disparities especially among the younger pt population and develop strategies to mitigate them. Citation Format: Medhavi Gupta, Rohit Gosain, Maithreyi Sarma, Stuthi Perimbeti, Attwood Kristopher, Wenyan Ji, Shipra Gandhi, Yara Abdou. Racial disparities in breast cancer characteristics and outcomes among Hispanic and White patients [abstract]. In: Proceedings of the AACR Virtual Conference: Thirteenth AACR Conference on the Science of Cancer Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; 2020 Oct 2-4. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2020;29(12 Suppl):Abstract nr PO-221.

Disulfiram as a Therapeutic Agent for Metastatic Malignant Melanoma-Old Myth or New Logos?

Simple SummaryIn recent years, disulfiram has gained in attention as an anticancer drug due to its broad activity against various cancers, and its mechanisms and molecular targets have been deciphered in vitro and in vivo. One of these cancers is melanoma. Initial data from human studies show some benefit, but do not confirm its broad efficacy as a monotherapy. However, combination approaches could pave the way for exploiting the beneficial effects of disulfiram for cancer patients, including those with melanoma. New therapeutic concepts such as anti-PD-1-based immunotherapy or targeted therapy with BRAF and MEK inhibitors have significantly improved the survival of melanoma patients. However, about 20% of patients with targeted therapy and up to 50% with immunotherapies do not respond to their first-line treatment or rapidly develop resistance. In addition, there is no approved targeted therapy for certain subgroups, namely BRAF wild-type melanomas, although they often bear aggressive tumor biology. A repurposing of already approved drugs is a promising strategy to fill this gap, as it will result in comparatively low costs, lower risks and time savings. Disulfiram (DSF), the first drug to treat alcoholism, which received approval from the US Food and Drug Administration more than 60 years ago, is such a drug candidate. There is growing evidence that DSF has great potential for the treatment of various human cancers, including melanoma. Several mechanisms of its antitumor activity have been identified, amongst them the inhibition of the ubiquitin-proteasome system, the induction of reactive oxygen species and various death signaling pathways. This article provides an overview of the application of DSF in humans, its molecular mechanisms and targets in cancer therapy with a focus on melanoma. The results of clinical studies and experimental combination approaches of DSF with various cancer therapies are discussed, with the aim of exploring the potential of DSF in melanoma therapy.

Astragaloside IVinhibits cell proliferation and metastasis of breast cancer via promoting thelong noncoding RNATRHDE-AS1.

Astragaloside IV (ASV), which has several pharmacological abilities, shows potential therapeutic effects on certain cancers by regulating the expression of long noncoding RNA (lncRNA). However, the anticancer role that ASV plays by regulating lncRNAs in breast cancer remains unknown. In this study, we first demonstrated that the lncRNA of TRHDE antisense RNA 1 (TRHDE-AS1) was downregulated in breast cancer tissues and cells. Low TRHDE-AS1 expression is associated with poor outcomes in patients with breast cancer and potentially contributes to the aggressive tumor biology of breast cancer. Furthermore, ASV significantly increased TRHDE-AS1 expression in a dose- and time-dependent manner in breast cancer cells. By upregulating TRHDE-AS1, ASV repressed breast cancer cell growth and metastasis both in vitro and in vivo. Taken together, our data indicated that TRHDE-AS1 participates in the anticancer role of ASV in breast cancer, which provides evidence for the application of ASV for breast cancer therapy.

A novel waitlist dropout score for hepatocellular carcinoma – identifying a threshold that predicts worse post-transplant survival

It has been suggested that patients with hepatocellular carcinoma (HCC) at high risk of wait-list dropout would have done poorly after liver transplantation (LT) because of tumour aggressiveness. To test this hypothesis, we analysed risk of wait-list dropout among patients with HCC in long-wait regions (LWRs) to create a dropout risk score, and applied this score in short (SWRs) and mid-wait regions (MWRs) to evaluate post-LT outcomes. We sought to identify a threshold in dropout risk that predicts worse post-LT outcome. Using the United Network for Organ Sharing database, including all patients with T2 HCC receiving priority listing from 2010 to 2014, a dropout risk score was created from a developmental cohort of 2,092 patients in LWRs, and tested in a validation cohort of 1,735 patients in SWRs and 2,894 patients in MWRs. On multivariable analysis, 1 tumour (3.1-5 cm) or 2-3 tumours, alpha-fetoprotein (AFP) >20 ng/ml, and increasing Child-Pugh and model for end-stage liver disease-sodium scores significantly predicted wait-list dropout. A dropout risk score using these 4 variables (C-statistic 0.74) was able to stratify 1-year cumulative incidence of dropout from 7.1% with a score ≤7 to 39.5% with a score >23. Patients with a dropout risk score >30 had 5-year post-LT survival of 60.1% vs. 71.8% for those with a score ≤30 (p= 0.004). There were no significant differences in post-LT survival below this threshold. This study provided evidence that patients with HCC with the highest dropout risk have aggressive tumour biology that would also result in poor post-LT outcomes when transplanted quickly. Below this threshold risk score of ≤30, priority status for organ allocation could be stratified based on the predicted risks of wait-list dropout without significant differences in post-LT survival. Prioritising patients with hepatocellular carcinoma for liver transplant based on risk of wait-list dropout has been considered but may lead to inferior post-transplant survival. In this study of nearly 7,000 patients, we created a threshold dropout risk score based on tumour and liver-related factors beyond which patients with hepatocellular carcinoma will likely have poor post-liver transplant outcomes (60% at 5 years). For patients below this risk score threshold, priority status could be stratified based on the predicted risk of wait-list dropout without compromising post-transplant survival.

CYP27A1 expression is associated with risk of late lethal estrogen receptor-positive breast cancer in postmenopausal patients

Background27-Hydroxycholesterol (27HC) stimulates estrogen receptor-positive (ER+) breast cancer (BC) progression. Inhibiting the sterol 27-hydroxylase (CYP27A1) abrogates these growth-promoting effects of 27HC in mice. However, the significance of CYP27A1 expression on BC biology and prognosis is unclear.MethodsIntratumoral CYP27A1 expression in invasive BC was measured by immunohistochemistry in two Swedish population-based cohorts (n = 645 and n = 813, respectively). Cox proportional hazards models were used to evaluate the association between CYP27A1 expression and prognosis.ResultsCYP27A1 was highly expressed in less than 1/3 of the tumors. High CYP27A1 expression was more frequent among high-grade tumors lacking hormone receptor expression and with larger tumor sizes. Over a median of 12.2 years follow-up in cohort 1, high CYP27A1 expression was associated with impaired survival, specifically after 5 years from diagnosis among all patients [overall survival (OS), HRadjusted = 1.93, 95%CI = 1.26–2.97, P = 0.003; breast cancer-specific survival (BCSS), HRadjusted = 2.33, 95%CI = 1.28–4.23, P = 0.006] and among patients ≥ 55 years presenting with ER+ tumors [OS, HRadjusted = 1.99, 95%CI = 1.24–3.21, P = 0.004; BCSS, HRadjusted = 2.78, 95%CI = 1.41–5.51, P = 0.003].Among all patients in cohort 2 (median follow-up of 7.0 years), CYP27A1 expression was significantly associated with shorter OS and RFS in univariable analyses across the full follow-up period. However after adjusting for tumor characteristics and treatments, the association with survival after 5 years from diagnosis was non-significant among all patients [OS, HRadjusted = 1.08, 95%CI = 0.05–2.35, P = 0.83 and RFS, HRadjusted = 1.22, 95%CI = 0.68–2.18, P = 0.50] as well as among patients ≥ 55 years presenting with ER+ tumors [OS, HRadjusted = 0.46 95% CI = 0.11–1.98, P = 0.30 and RFS, HRadjusted = 0.97 95% CI = 0.44–2.10, P = 0.93].ConclusionCYP27A1 demonstrated great potentials as a biomarker of aggressive tumor biology and late lethal disease in postmenopausal patients with ER+ BC. Future studies should investigate if the benefits of prolonged endocrine therapy and cholesterol-lowering medication in BC are modified by CYP27A1 expression.

153P Mutational landscape of gastric cancer (GC) in adolescents and young adults (AYA) in Asia from 2015-2019

Gastric cancer (GC) is an aggressive cancer and it is thought that they have a worse prognosis in AYA due to delayed diagnosis and a more aggressive tumour biology. There is an increasing trend to adopt next-generation sequence (NGS) to identify tumour genomic alterations for precision medicine in AYA. We aim to study the differences in the mutational landscape of GC in AYA and how it correlates to outcomes in a single-centre high-volume Asian institution. Patients diagnosed between 16-39 years old with GC between 2015 to 2019 in our centre, National Cancer Centre Singapore, were included in this study. A total of 50 AYA GC patients were referred to NCCS between 1st January 2015 and 31st December 2019. 7 patients were excluded from this analysis (3 due to incomplete data and 4 were neuroendocrine tumours). The median age (n=43) was 35(22-39) with 22 males (51.2%) and majority (53.5%, n=23) having signet ring cell carcinoma. 28 patients (65.1%) had metastatic disease at diagnosis. Out of the 43 patients, only 60.5%(n=26) and 58.1%(n=25) were tested for programmed death-ligand 1(PD-L1) and DNA mismatch repair (MMR) respectively. 1 patient (3.8%) had MLH 1 loss and 1 patient (4.5%) had PD-L1 percentage of more than 50% by using combined positive score (CPS). 32 patients (74.4%) had the human epidermal growth factor receptor 2(HER2) tested, of which 5 were HER2 positive (15.6%). With a median follow-up of 11 months, median OS was 16.0 months (range 0.5- 111.3 months). There was no significant differences between subgroups with regards to age(p=0.931), presence of signet-ring histology (p=0.135), histology grade (p=0.384) and HER2 positivity (p=0.66). Gastric cancer in the young behaves differently and generally seem more aggressive in the young regardless of gender. Further studies to evaluate how the differences in the mutational landscape of gastric cancer in the adolescents and young adults impact prognosis and treatment paradigm.

Patterns Of Failure After Adjuvant Radiation For Meningioma, Radiologic Assessment To Inform Target Delineation And Treatment Planning

Adjuvant radiotherapy is increasingly used for intermediate and high-risk meningioma, and although short-term results from prospective trials demonstrate good rates of local control, long-term failures remain common. Moreover, the optimal expansions for postoperative radiotherapy target delineation for meningioma are unknown. We sought to elucidate the patterns of failure after adjuvant radiotherapy for meningioma to inform target delineation and treatment planning. Patients undergoing surgical resection for meningioma at a single institution were retrospectively reviewed for treatment with adjuvant radiation therapy, including external beam radiation therapy (EBRT), stereotactic radiosurgery (SRS), or brachytherapy. Patients treated with EBRT were evaluated for patterns of failure based on MRI review, and were classified as resection cavity, dural margin, osseous craniotomy tract, and intraparenchymal brain. Analysis was performed to evaluate factors associated with each failure type, and to identify the radiologic distance from the resection cavity margin to the furthest margin of each site of recurrent disease. From 1991 to 2015, 71 patients with 86 lesions were treated with adjuvant radiation therapy after resection of meningioma. The median follow-up was 4.2 years (IQR: 1.5-8.4 years). There were 14 (16%) grade 1, 49 (57%) grade II, and 23 (27%) grade III meningiomas, and gross total resection was achieved in 53 (61.6%) of cases. There were 22 local failures after EBRT, 16 (72.7%) were in-field, 11 (50%) were at the dural margin, 2 (9.1%) were along a craniotomy track, and 2 (9.1%) were intraparenchymal. In patients with dural marginal failure, the median distance from the edge of the resection cavity to the distal extent of the recurrence was 15 mm (IQR: 13-24 mm). Of the resection cavity recurrences, 5 (31.2%) occurred within 10 mm of the apex of the orbit or the cavernous sinus. The median MIB1 labeling index in meningioma with either intraparenchymal or craniotomy tract failure was 31.0%, compared to 11.3% (p = 0.018) in patients with infield or dural margin failure. Local failure along the dural margin after adjuvant radiation therapy for meningiomas occurred a median of 15 mm from the resection cavity. Failure along the craniotomy tract or parenchymal brain was uncommon, and was associated with a significantly higher MIB1, likely reflecting more aggressive tumor biology. These data may help to inform target delineation and margin expansion for patients receiving adjuvant radiotherapy for meningioma.

Assessment of Clinical Radiosensitivity in Patients with Head-Neck Squamous Cell Carcinoma using Pre-treatment Quantitative Ultrasound Texture-Derivatives and Machine Learning Classifiers

Quantititative ultrasound (QUS) provides information related to the tumor microstructure based on the tissue organization and elastic properties. To assess the efficacy of QUS in predicting recurrence risk and radiotherapy (RT) response at 3 months in patients with head-neck squamous cell carcinoma (HNSCC) treated with curative intent RT. Fifty-one patients with HNSCC with cervical lymph node (LN) were treated with 70 Gy/33 fractions (+/- chemotherapy) to the high-risk volumes according to standard institutional practice. The largest LN was scanned using a 6 MHz transducer before initiation of RT. QUS-parametric maps were generated from the radiofrequency data, from which texture features were extracted using grey-level co-occurrence matrices (GLCM). Further processing of texture images led to the generation of higher-order texture derivatives leading to a total of 105 parameters. After treatment completion, response assessment and follow up was done according to standard practice with clinical examination and imaging. Response at 3 months (primary and LN) and recurrence at any time period were considered as the end-points for this analysis. Machine learning algorithms based on linear discriminant (FLD), k-nearest-neighbors (KNN), support vector machine (SVM) were tested for developing classifier models with leave one out cross-validation. To avoid overfitting, we used a maximum of 3 features in model generation. The primary sites were oropharynx (34), hypopharynx (8), larynx (4), unknown primary (4), and oral cavity (1). Staining with p16 was positive in 35, negative in 2, and unknown in 13. Cisplatin was given concurrently in 37, Carboplatin in 5; and Cetuximab in 1. There were 21 complete responders (CR) and 30 partial responders (PR) at 3 months following RT completion. The best classifier performance was obtained using KNN (k = 2) with sensitivity, specificity, accuracy, and area under curve (AUC) values of 94%, 100%, 96% and 0.95 respectively. The inclusion of texture-derivatives led to significant improvement of the classifier accuracy compared to texture parameters alone (96% vs 86%). All the 3 selected features used in model construction were selected from higher-order texture-derivatives. With a median follow up of 30 months, recurrence was seen in 13 patients. The sensitivity, specificity, accuracy, and AUC were 82%, 85%, 83%, and 0.84 respectively, using SVM classifier to differentiate between the 2 groups (rec vs. no recurrence). This study shows QUS-texture derivatives coupled with machine learning can lead to the non-invasive determination of radiation response even before the initiation of RT with high accuracy. Similarly, patients with aggressive tumor biology with a higher risk of recurrent disease can be identified from pre-treatment QUS-radiomic signatures. Being an easily available, inexpensive, and portable imaging, QUS-radiomics can be potentially used to guide personalized RT in the future.

Prognostic Impact of Intra-Ampullary Papillary-Tubular Neoplasm versus Flat Dysplasia as Precursor Lesions of Ampullary Adenocarcinoma

Background: The aim of this study is to compare the prognostic impact of 2 precursor lesions of ampullary adenocarcinoma, intra-ampullary papillary-tubular neoplasm (IAPN) and flat dysplasia (FD). Methods: From December 1994 to December 2012, a total of 359 patients underwent curative surgery for ampullary adenocarcinoma. Results: The precursor lesions were IAPNs in 134 (37.3%) patients and FD in the other 225 (62.7%) patients. The FD group had more aggressive tumor biology with advanced T stage (p = 0.002), nodal involvement (p < 0.001), poor differentiation (p < 0.001), perineural and lymphovascular invasion (p < 0.001), and pancreatobiliary or mixed subtype (p < 0.001). Five-year overall survival rates were 71.1% in the IAPN group and 51.4% in the FD group (p = 0.002), respectively. Five-year disease-free survival rates were 69.7% in the IAPN group and 49.6% in the FD group (p < 0.001), respectively. The recurrence rate was also higher in the FD group (49.8 vs. 30.6%; p < 0.001). On multivariate analysis, higher levels of tumor markers including CEA and CA19-9, lymph node metastasis, poorly differentiated histology, and perineural invasion were negative predictive factors for survival. Higher levels of CEA and CA19-9, lymphovascular invasion, and FD were independent prognostic factors for recurrence. Conclusion: FD was significantly associated with worse prognosis and a greater tendency toward advanced disease. Further studies are needed to clarify the impacts of these precursor lesions.

Impact of KRAS status on tumor response and survival after neoadjuvant treatment of locally advanced rectal cancer.

Mutation of the KRAS oncogene (mKRAS) in colorectal cancer has been associated with aggressive tumor biology, resistance to epidermal growth factor inhibitors, anddecreased overall survival (OS). The aim of the current study was to analyze the association of mKRAS with pathologic complete response (pCR) and neoadjuvant rectal (NAR) score, and its impact on the survival of patients with locally advanced rectal cancer who were managed with multimodality therapy. The National Cancer Database was queried for stage II-III rectal cancer patients with a known KRAS status who underwent neoadjuvant chemoradiation therapy (nCRT) and proctectomy between 2004 and 2015. In total, 1886 patients were identified; 12% had pCR and 36% had mKRAS. Patients with mKRAS were more likely to have advanced pathologic T stage, tumor deposits, perineural invasion, and elevated carcinoembryonic antigen levels (all p ≤ .05). After adjustment for available confounders, mKRAS status was not associated with pCR or NAR score. In multivariable analysis, patients with pCR and lower NAR score had better OS, whereas mKRAS was independently associated with a worse prognosis. In this cohort of locally advanced rectal cancer patients who underwent proctectomy after nCRT, mKRAS was not associated with lower pCR rates or NAR scores;however,these patients experienced worse survival.

Real-World Data Analysis of Pregnancy-Associated Breast Cancer at a Tertiary-Level Hospital in Romania

Background and objectives: Breast cancer is among the most common cancer types encountered during pregnancy. Here, we aimed to describe the characteristics, management, and outcomes of women with pregnancy-associated breast cancer at a tertiary-level hospital in Romania. Material and Methods: We retrospectively and prospectively collected demographic, oncological, and obstetrical data for women diagnosed with cancer during pregnancy, and who elected to continue their pregnancy, between June 2012 and June 2020. Complete data were obtained regarding family and personal medical history and risks factors, cancer diagnosis and staging, clinical and pathological features (including histology and immunohistochemistry), multimodal cancer treatment, pregnancy management (fetal ultrasounds, childbirth, and postpartum data), and infant development and clinical evolution up to 2020. Cancer therapy was administered following national guidelines and institutional protocols and regimens developed for non-pregnant patients, including surgery and chemotherapy, while avoiding radiotherapy during pregnancy. Results: At diagnosis, 16.67% of patients were in an advanced/metastatic stage, while 75% were in early operable stages. However, the latter patients underwent neoadjuvant chemotherapy rather than up-front surgery due to aggressive tumor biology (triple negative, multifocal, or HER2+). No patient achieved complete pathological remission, but only one patient relapsed. No recurrence was recorded within 12 months among early-stage patients. Conclusions: In this contemporary assessment of real-world treatment patterns and outcomes among patients with pregnancy-associated breast cancer, our findings were generally consistent with globally observed treatment outcomes, underscoring the need for a multidisciplinary team and reference centers.

994P Stem cell-like subtypes revealed by integrative multi-omics analysis in early-stage hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is lethal malignancy with second highest worldwide cancer mortality. Cancer stem cell in HCC has been regarded as a major cause of cancer progression. However, molecular and clinical features of stem cell-like HCC contributing aggressive tumor biology and therapeutic resistance remain unclear.