Risk Of Metastatic Recurrence Research Articles

Network Pharmacological Analysis and Experimental Validation of the Effects of Silybin on Proliferation, Migration, and Immunotherapy of Papillary Thyroid Cancer.

The study aimed to use network pharmacology research and in vitro experiments to investigate the material basis and molecular mechanisms of silybin in the treatment of papillary thyroid carcinoma. Papillary thyroid cancer (PTC) has a decent prognosis; however, recurrence and metastasis are the leading causes of death in patients with PTC. A key research focus in thyroid cancer treatment is the inhibition of PTC proliferation, invasion, and migration. Silybin, the major active element in the traditional Chinese herb silymarin, has been used to treat a range of diseases, including cancer, but no study has been undertaken to determine whether it can help prevent PTC. In this study, we attempted to determine through network pharmacology and in vitro experiments if silybin inhibits the development of papillary thyroid cancer by inhibiting cell cycle and invasive migration. To predict the probable targets and underlying mechanisms of silybin against PTC, a network pharmacology research was performed. In vitro experiments were conducted to further evaluate silybin's anti-cancer properties and priority targets against PTC. The datasets revealed a total of 489 silybin targets acting on PTC, and functional enrichment analysis suggested that the target genes were enriched in functions and pathways related to PTC development, invasion, migration, and immunotherapy. By constructing these target PPI networks, the seven hub genes, fibronectin 1 (FN1), tissue inhibitor of metalloproteinases 1 (TIMP1), N-cadherin (CDH2), collagen type III alpha 1 chain (COL3A1), cyclin D1 (CCND1), AP-1 transcription factor subunit (JUN), and hepatocyte growth factor receptor (MET) were found. These hub genes were determined to be highly linked to a worse clinicopathological form, a higher risk of metastatic recurrence, and a worse prognosis of PTC. The common immunological checkpoint gene expression levels were positively correlated with the expression levels of the hub genes. Silybin decreased the proliferative and metastatic capacity of PTC cells, according to in vitro investigations. When PTC was treated with silybin, the FN1/AKT signaling pathway was blocked, CCND1 expression was reduced, and CDH2, Vimentin, Snail, Slug and PD-L1 expressions were dramatically reduced, while E-cadherin expression was significantly elevated. These findings provide preliminary evidence that silybin inhibits PTC cell proliferation, metastasis, and invasion by altering the FN1/AKT signaling pathway and inhibiting the EMT process. Silybin can reverse immunosuppression in papillary thyroid cancer by affecting immunological checkpoint gene expression levels. These studies provide a theoretical and experimental scientific basis for the potential anticancer effects of silybin on PTC.

The Risk of Metastatic Recurrence after Non-Curative Endoscopic Resection with Negative Deep Margins for Early Colorectal Cancer: Two-Center Retrospective Cohort Study

Introduction: Non-curative endoscopic resection of T1 colorectal cancer (CRC) carries a substantial risk of recurrence. However, previous studies have reported a significant proportion of cases in which the deep margin of endoscopic resection was positive for cancer due to the technical difficulties of colorectal endoscopic submucosal dissection (ESD). With the advancement of endoscopic technology and techniques resulting in the reduction of positive resection margins, it is important to reassess the long-term prognosis and major risk factors for recurrence in cases of negative deep margins. Methods: We conducted a retrospective cohort study of consecutive patients with T1 CRC who underwent endoscopic resection between January 2006 and December 2021 with negative deep margins. The histological findings of the resected specimens were analyzed to determine the risk factors associated with the primary outcomes of this study, including recurrence and cancer-related deaths. Results: The median age of the 190 patients was 70 years, of which 63% were male, and endoscopic treatment was performed in 64% by endoscopic mucosal resection and 36% by ESD. Eighty-two patients were in the curative resection (CR) group and 108 were in the non-curative resection (NCR) group, wherein the latter comprised 79 patients who underwent additional surgery (AS) and 29 patients who did not receive AS. Five-year recurrence-free survival rates were 98.4% (95% CI: 89.3–99.8) for CR, 98.3% (95% CI: 88.8–99.8) for NCR with AS, and 73.7% (95% CI: 46.5–88.5) for NCR without AS. Lymphatic invasion and budding grade 2/3 were the major risk factors for recurrence, with hazard ratios of 40.7 (p p = 0.007), respectively. Of the patients in the NCR group without AS, the 5-year recurrence-free rate was 85.6% (95% CI: 52.5–96.3) if there were no major risk factors (i.e., no lymphatic invasion or budding grade 2/3) (n = 21), whereas the prognosis was poor in the presence of one or more of the major risk factors, with a median recurrence-free survival and disease-specific survival of 2.5 and 3.1 years, respectively (n = 8). Discussion: In endoscopically resected T1 CRC with negative deep margins, lymphatic invasion or budding grade 2/3 may indicate a higher risk of recurrence when followed up without AS.

Hellebrigenin induces apoptosis by triggering cellular inhibitor of apoptosis 1 and Jun N-terminal kinase pathway in melanoma cells

Abstract Background: Melanoma, the malignancy of melanocytes, is the most fatal form of skin cancer. Although various interventions are currently available, advanced stages of melanoma are still associated with a risk of metastatic recurrence. Objectives: The present study examined the anticancer activity of hellebrigenin, a natural product extracted from toad skin. Methods: Two types of metastatic melanoma cell lines, A2058 and HMY-1, were selected. Results: The findings revealed that hellebrigenin had cytotoxic effects on the two melanoma cell lines by triggering apoptosis: hellebrigenin activated cell arrest during the G2/M phase and downregulated regulators’ expression (e.g., cyclin-dependent kinase [CDK] 1, CDK 4, and cyclins E1, E2, A2, and D3). In intrinsic and extrinsic pathways of apoptosis, hellebrigenin activated the expression of the proapoptotic proteins t-BID, Bak, poly-ADP-ribose polymerase, Fas-associated death domain protein, death receptors 5, and cleaved caspases 3, 8, and 9; it also reduced the expression of the antiapoptotic proteins Bcl-2 and Bcl-xL. Mitochondrial membrane depolarization and cell nucleus condensation were also observed. In addition, human apoptosis arrays revealed that hellebrigenin inhibited the expression of cellular inhibitor of apoptosis 1, which is crucial for blocking cell apoptosis. Regarding upstream signaling activity, hellebrigenin suppressed the phosphorylation of the Jun N-terminal kinase 1/2 pathway in both melanoma cell lines. Conclusion: Overall, hellebrigenin can be used as a potential anticancer agent in clinical settings for treating the advanced stages of melanoma.

Abstract LB_C07: Utilizing a BCL-2 inhibitor (venetoclax) to overcome doxorubicin resistance in triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of the progesterone receptor, estrogen receptor, and human epidermal growth factor-2 over-expression. TNBC comprises 10-15% of all breast cancer cases and compared to other subtypes of breast cancer, TNBC is associated with a higher risk for metastatic recurrence and the chemotherapy agent doxorubicin (dox) remains a mainstay of treatment. Senescence is a cellular phenomenon where cells are committed to an arrested state, however, senescent cells can secrete pro-tumorigenic factors which can help to promote tumor progression and invasion. Senescence is one potential mechanism of resistance to doxorubicin in breast cancer. Avoiding senescence-mediated resistance and promoting apoptosis is one strategy to improve response to dox in TNBC. Venetoclax is an orally bioavailable FDA approved BCL-2 inhibitor with activity in preclinical models of TNBC. The purpose of this study was to investigate venetoclax in combination with dox to overcome senescence-mediated resistance and induce apoptosis. Experimental Procedures: TNBC cell lines were exposed to a no drug, dox, venetoclax or combination at increasing doses for 72 hours and cell viability was assessed via CellTiter-Glo. Synergy scores were calculated from three independent replicates using Synergy Finder+. Apoptosis at 48 hours was analyzed by flow cytometry using Annexin V on cells treated in combination and with single agents. In vitro cell survival following drug treatment for 24 hours was assessed via clonogenic assay. In vitro senescence-associated β-gal was performed after 6 days drug treatment. Athymic nude mice were subcutaneously injected with 5 million MDA-MB-231 cells for in vivo studies. Mice were treated with either no drug, 60 mg/kg venetoclax PO QD, 1.5 mg/kg dox IP QW, or the combination. Results: The combination of venetoclax and dox resulted in synergy based on CellTiter-Glo data, which was used to calculate Bliss scores using Synergy Finder+ in CAL-51, MDA-MB-231, and CAL-120 TNBC cell lines. The dox and venetoclax combination caused a statistically significant increase in apoptosis measured by Annexin V staining when compared to single agents and control in all cell lines. The combination resulted in a decrease in cellular survival in all cell lines tested as measured by the clonogenic assay. Senescence-associated beta-galactosidase showed an increase in senescent cells for both dox and venetoclax treated cells, which was eradicated in combination. Dox and venetoclax were further tested in vivo, where significant tumor growth inhibition was observed in combination compared to doxorubicin (p = 0.0031) and venetoclax alone (p = 0.0038) after 48 days of treatment. Conclusion: The addition of venetoclax to doxorubicin resulted in decreased cellular proliferation, increased apoptosis, and decreased senescence. As a result, venetoclax is a promising combination partner for doxorubicin to overcome doxorubicin resistance and promote apoptosis in TNBC. Citation Format: Evan D Dus, Stephen G Smoots, Anna R Schreiber, Marilyn M Jackson, Stacey M Bagby, Adrian T A Dominguez, Cameron A Binns, Todd M Pitts, Jennifer R Diamond. Utilizing a BCL-2 inhibitor (venetoclax) to overcome doxorubicin resistance in triple-negative breast cancer [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_C07.

Study of gut microbial homeostasis and targeted therapy for hepatocellular carcinoma based on eigenvalue-fitting superiority algorithm

Abstract In this paper, firstly, we propose the eigenvalue-based goodness-of-fit algorithm to evaluate intestinal microorganisms and liver cancer, based on the basic principle of one-sided right-tailed fitting criterion, using the covariance matrix of the signal can capture the correlation between signal samples, and the maximum-minimum eigenvalue-based goodness-of-fit detection algorithm can be obtained. Secondly, based on the eigenvalue goodness-of-fit algorithm, a training set and a test set were tested using the full-dimensional clinical data set of enrolled cases to construct a prediction model for the risk of metastatic recurrence after HCC surgery and to select evaluation indexes for the prediction model. Then, to further clarify the diagnostic role of lgEr/lgFp on hepatocellular carcinoma, its intestinal microorganism lgEr/lgFp was analyzed with the diagnostic role of AFP on hepatocellular carcinoma. The results showed that for lgEr/lgFp ratio, the analysis was compared between the high AFP cirrhosis group and liver cancer group and the low AFP liver cancer group and cirrhosis group, and it was found that there was a highly significant difference P<0.01. This study emphasizes the influence of intestinal homeostasis on the development of liver cancer, and establishes the link between intestinal homeostasis and the development of liver cancer.

Development and validation of time-to-event models to predict metastatic recurrence of localized cutaneous melanoma

The recent expansion of immunotherapy for stage IIB/IIC melanoma highlights a growing clinical need to identify patients at high risk of metastatic recurrence and, therefore, most likely to benefit from this therapeutic modality. To develop time-to-event risk prediction models for melanoma metastatic recurrence. Patients diagnosed with stage I/II primary cutaneous melanoma between 2000 and 2020 at Mass General Brigham and Dana-Farber Cancer Institute were included. Melanoma recurrence date and type were determined by chart review. Thirty clinicopathologic factors were extracted from electronic health records. Three types of time-to-event machine-learning models were evaluated internally and externally in the distant versus locoregional/nonrecurrence prediction. This study included 954 melanomas (155 distant, 163 locoregional, and 636 1:2 matched nonrecurrences). Distant recurrences were associated with worse survival compared to locoregional/nonrecurrences (HR: 6.21, P<.001) and to locoregional recurrences only (HR: 5.79, P<.001). The Gradient Boosting Survival model achieved the best performance (concordance index: 0.816; time-dependent AUC: 0.842; Brier score: 0.103) in the external validation. Retrospective nature and cohort from one geography. These results suggest that time-to-event machine-learning models can reliably predict the metastatic recurrence from localized melanoma and help identify high-risk patients who are most likely to benefit from immunotherapy.

Prediction of Risk of Metastatic Recurrence for Female Breast Cancer Patients in the Presence of Competing Causes of Death.

To estimate risk of recurrence for women diagnosed with nonmetastatic breast cancer considering the risks of other causes mortality. We extend a method based on the diagnosis-metastasis-death pathway to include risks of other causes mortality. We estimate three probabilities as cumulative incidence of: (i) being alive and recurrence-free, (ii) death for other causes before a recurrence, and (iii) recurrence. We apply the method to female breast cancer relative survival from the Surveillance, Epidemiology, and End Results Program registries (2000-2018) data. The cumulative incidence of recurrence shows a higher increase with more advanced cancer stage and is less influenced by age at diagnosis. At 5 years from diagnosis, the cumulative incidence of recurrence is less than 3% for those diagnosed with stage I, 10% to 13% for those diagnosed with stage II, and 37% to 47% for those diagnosed with stage III breast cancer. The estimates of recurrence considering versus ignoring the risks of dying from other causes were generally consistent, except for older women with more advanced stage, and longer time since diagnosis. In these groups, the net probability of recurrence, excluding the risks of dying from other causes, were overestimated. For patients with cancer who are older or long-term survivors, it is important to include the risks of other cause mortality as the crude cumulative incidence of recurrence is a more appropriate measure. These estimates are important in clinical decision making, as higher competing mortality may preclude the benefits of aggressive treatments.

Superficial non-ampullary duodenal epithelial tumors now: endoscopic diagnosis and therapy.

With the recent increase in the frequency of duodenal tumor detection, significant progress has been made in endoscopic diagnosis and treatment. Although the first guidelines were issued in Japan, patient treatment varies widely among institutions. There is a need for improving the quality of endoscopic diagnosis and more curative and safer treatments. Biopsy is the standard diagnostic method; however, the diagnostic accuracy of endoscopic biopsy is not so high. Therefore, the differentiation of superficial non-ampullary duodenal epithelial tumors from non-neoplastic lesions is being developed. The incidence of lymph node and distant metastases of duodenal epithelial tumors is extremely rare in intramucosal carcinomas, and they are considered good candidates for endoscopic treatment if the technical difficulties can be resolved. Adverse events associated with endoscopic treatment are greatly reduced at advanced facilities through novel resection and closure methods, and further improvements are expected in the future. Clarifying the risk of metastatic recurrence may lead to the development of more appropriate treatments and curative resection criteria.

A phase II single-arm, open-label trial of T-DM1 (ado-trastuzumab emtansine) and neratinib for HER2-positive breast cancer with molecular residual disease (KAN-HER2 MRD).

TPS620 Background: HER2-positive breast cancer is a biologically and clinically aggressive subtype that has historically been associated with poor outcomes, but for which there are now multiple effective targeted therapies. Patients who have residual disease following standard neoadjuvant therapy have an elevated risk of metastatic recurrence. In addition, the detection of circulating tumor DNA (ctDNA) in the adjuvant period is strongly associated with relapse and can further stratify patients with residual disease. The ctDNA-based detection of molecular residual disease (MRD) is an emerging strategy to identify patients for treatment intensification, and may enable the development of novel curative treatment strategies for “recurrence interception”. Preclinical and clinical evidence support the investigation of neratinib, an irreversible inhibitor of the HER2 tyrosine kinase, in combination with standard T-DM1 in the adjuvant setting for patients with HER2-positive breast cancer and evidence of MRD. Methods: KAN-HER2 MRD is a multicentre, investigator-initiated, open label, single arm phase II trial to evaluate the addition of neratinib to standard T-DM1 in patients with detected MRD. Participants with HER2-positive breast cancer and residual disease following neoadjuvant therapy are pre-screened (Part A) for MRD using a tumor-informed assay (NeoGenomics RaDaR). Those with ctDNA detected following 2-6 cycles of adjuvant T-DM1 will proceed to the interventional phase (Part B) where neratinib is added to standard T-DM1 at the previously-determined recommended phase 2 combination dose of 160 mg/day, in continuous cycles. The primary endpoint is the rate of ctDNA clearance at 12 weeks after treatment initiation (ctDNAwk12); the study is designed with a 2-stage approach and has sufficient power to detect a clearance rate of 40%. Secondary endpoints include MRD rates and their clinical correlates, invasive disease free survival (iDFS), and safety. Bio-specimens including diagnostic biopsies, residual disease, and peripheral blood are being collected from all participants for additional correlative studies. Enrolment in Part A was initiated at the first trial site (Princess Margaret Cancer Centre) in December 2022. KAN-HER2 represents the first reported MRD-directed interception trial for HER2-positive breast cancer. Clinical trial information: NCT05388149 .

Long-Term Outcomes after Surgery for Pheochromocytoma and Sympathetic Paraganglioma.

The prognosis of pheochromocytoma and sympathetic paraganglioma (PHEO/sPGL) is difficult to predict at the time of diagnosis and long-term follow-up data are scarce, especially for apparently benign and sporadic variants. The aim of the study was to analyze the long-term outcomes in PHEO/sPGL patients. A monocentric series of 170 patients who underwent surgery for PHEO/sPGL was analyzed. The study cohort included 91 female and 79 males with a median age of 48 years (range 6-83). The majority of PHEO/sPGL cases were considered apparently benign at the time of diagnosis; evident malignant behavior was found in 5% of cases. The overall 10-year risk of recurrence was 13%, but it rose up to 33% at 30 years. The risk of new tumor recurrence was higher in patients with hereditary tumors, but the risk was still significant in patients with apparently sporadic variants (20-year risk: 38% vs. 6.5%, respectively; p < 0.0001). The risk of metastatic recurrence was higher in patients with locally aggressive tumors at diagnosis, but the risk was present also in apparently benign variants (5-year risk: 100% vs. 1%, respectively; p < 0.0001). Lifelong follow-up is required not only for hereditary PHEO/sPGL but also for apparently benign and sporadic tumors at diagnosis because of the risk of long-term recurrent disease.

20P Spatial analysis of residual tumor tissue provides new clues for post-neoadjuvant treatment approaches in triple-negative breast cancer

Triple-negative breast cancer (TNBC) is a very heterogeneous disease with high metastatic recurrence risk. We showed (PMID 34535679) that TNBCs relapsing rapidly (RR) after NACT (in ≤ 12 months) are highly proliferative, immune-cold, often with large residual cancer burden (RCB) and fatal outcome. No specific biomarkers or therapeutic targets are known for this clinical category. In this study we performed spatial molecular analysis of the RR and the RCB3 TNBCs, with the aim to help improving treatment of the TNBC patients with the poorest prognosis. We analyzed residual tumor tissue samples of TNBC patients treated by standard NACT from 01/01/2009 to 31/12/2021. The cases were classified into RR, standardly-relapsing (SR, 1-5 years post-NACT) and without recurrences (NR). The amount of tumor-infiltrating lymphocytes (TILs) was determined by optical microscopy (H&E). Tissue protein expression was spatially resolved by GeoMx® Digital Spatial Profiler (NanoString Technology). Sixteen, 17 and 47 RR, SR and NR cases were analyzed, respectively. GeoMx analysis included 216 Region-of-Interest (ROIs) of tumor microenvironment (TME) and 207 of tumor cells (TC), with balanced (∼50/50) numbers of peripheral (P) and central (C) ROIs. Tumors and ROIs were classified into TIL-rich (LR) and TIL-poor (LP) using cut-off of 10% TILs. The RR TNBCs showed higher Ki67, cleaved caspase 9, granzyme B (GZMB), FoxP3 and fibronectin (FBNCT) in TME-P-LR ROIs but higher GADPH, TIM-3, PD-L1 and IDO in TME-P-LP ROIs. Compared to TNBC-SR, the RR had higher GZMB and CD34 in TME-P-LR ROIs. In TME-C-LR ROIs of the RRs, CD8 expression was low, as well as the one of CD45, CD3 and CD8 in TME-C-LP. The RCB3 category contained 9, 8 and 10 RR, SR and NR cases, respectively. Although most RCB3 cases were TIL-poor, the NR cases showed significantly higher expression of CD3, CD8, GZMA, CD4, CD56, CD95, LAG3, HLA-DR, BIM and BCL6 than the RR cases. By this study we revealed several potential therapeutic targets (fibronectin, IDO, TIM-3, CD34 /angiogenesis) in the RR TNBCs. Interestingly, we also showed that some RCB3 cases have immune-activated TME and good prognosis. Spatial tissue analysis was crucial for these discoveries.

Abstract P6-05-05: Patient-reported outcomes, perceptions, and knowledge about recurrence in women with high-risk hormone receptor-positive (HR+) breast cancer (BC)

Abstract Background: Over half of HR+ BC recurrences occur &amp;gt;5 years (y) from diagnosis (dx). While the risk of late recurrence is constant and extends for at least 20y, little is known about concerns, perceptions, knowledge, and interest in risk reduction in longer-term HR+ BC survivors. Methods: From 1/2021-1/2022, we prospectively identified patients (pts) at Dana-Farber Cancer Institute with a history of stage II/III, HR+/HER2- BC, ≥5y from dx, without recurrence. Pts were invited to participate in a study investigating circulating tumor DNA and risk of recurrence as well as a separate, 1-time survey that assessed physical/mental health (PROMIS), dx/treatment concerns (Brief Illness Perception Questionnaire), risk perceptions, knowledge, and interest in risk reduction. “Overestimation” was defined as estimating ≥20% risk based on the response to the question: “If 100 women with HR+ BC are treated according to recommended guidelines, about how many will have BC come back in the 5-10y following completion of active treatment.” Descriptive statistics included medians and proportions. Logistic regression identified factors associated with overestimation of 5-10y metastatic recurrence risk. Results: Among 166 women (of 209 sent surveys, 79%), median age at dx was 51 (range 21-76), 4% were Hispanic and/or Black; 19% did not have a college degree. Approximately 30% had stage III disease, most received chemotherapy (72%) and radiation (81%) and over half (57%) a mastectomy. Median time from dx was 10 y (range: 5-23). Almost all (97%) reported prior (44%) or current hormonal therapy (14% tamoxifen, 39% AI). Median PROMIS anxiety (53; range: 37-73), physical (51, range: 32-68), and mental (51, range: 25-68) scores were similar to population norms (score of 50). On a 0 (not at all)-10 (extremely) scale, the median rating for concern about dx/treatment was 5; for emotional impact of dx/treatment, the median rating was 9. Regarding risk perceptions, participants estimated that on average, a median of 15 and 10 women (of 100 women) would develop a loco-regional or distant recurrence, respectively, in the 5-10y interval; 43% and 40% estimated the risk of loco-regional and distant recurrence as ≥20%, respectively, for this interval. Pts without a college degree were more likely to overestimate 5-10y distant recurrence risk (multivariable OR: 3.66, 95% CI: 1.56, 8.59); age, chemotherapy receipt, surgery type, stage, and grade were not associated with overestimation. When asked, on average, which women have a higher chance of BC returning after 5y, 17% correctly responded HR+; 42% responded triple negative and 41% responded the risk was the same for both. While &amp;gt;1/3 responded they believed alcohol in moderation may decrease the risk of BC coming back, most also responded that having a healthy weight, eating ≥5 fruits/vegetables a day, and exercise may decrease this risk, with over half reporting engagement in these behaviors (Table). Conclusion: While most longer-term stage II/III HR+ BC survivors report mental and physical health commensurate to population norms, inaccurate knowledge and perceptions about recurrence are common. Strategies to effectively communicate risk (e.g., pictograms, decision/conversation aids) and risk reduction information can promote an accurate understanding of risk in the setting of longer-term HR+ BC survivorship, potentially mitigating emotional concerns which are prevalent ≥5y post-dx. The association between lower educational attainment underscores the importance of attention to literacy and numeracy when developing interventions to improve risk communication. Table. Perceived impact of health behaviors on recurrence risk. Citation Format: Shoshana Rosenberg, Yue Zheng, Katheryn Santos, Elizabeth Riley, Hugh Meadows, Craig Snow, Melissa E. Hughes, Elizabeth Frank, Nancy U. Lin, Ann Partridge, Eric Winer, Heather A. Parsons. Patient-reported outcomes, perceptions, and knowledge about recurrence in women with high-risk hormone receptor-positive (HR+) breast cancer (BC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P6-05-05.

Abstract B019: Inflammatory response to dietary carbohydrates contributes to the formation of hepatic metastatic niche

Abstract Mortality from colon and pancreatic cancers arises from cancer metastatic dissemination to the liver. The glycemic load from carbohydrates (carbs) has been specifically linked to the risk of metastatic recurrence of stage 3 colorectal cancer, but the mechanism of how dietary carbs contribute to the formation of liver metastases remains poorly understood. Our analyses now demonstrate that feeding mice a high carb diet (HCD) promotes liver colonization by tumor cells, and supports the survival of these cells, once in the liver. HCD also induces expression of a Type I interferon (IFN) inflammatory gene signatures which may contribute to its ability to promote metastatic seeding of the liver. Notably, this inflammatory phenotype in hepatocytes was completely abolished if animals are fed a diet enriched in fats (75% of calories), indicating a direct link between liver inflammation and consumption of carbohydrates. Specifically, we have discovered that: 1) dietary carbohydrates, but not a high-fat ketogenic diet, activate multiple independent inflammatory cascades in hepatocytes, including Type-I IFN/STAT1, NFkB, and IL6-STAT3 pathways; 2) the inflammatory signaling in hepatocytes is retained in Scid and NSG mice, indicating that it occurs in the absence of adaptive immunity; 3) HCD, but not fasting or ketogenic diet, markedly increases abundance of retained intronic sequences and formation of double-stranded RNA (dsRNAs). We nominate these yet uncharacterized dsRNAs as potential viral mimics which may trigger the Type I IFN signature observed in HCD-fed livers; and (4) a ketogenic diet showed a trend to reduce liver metastatic colonization, but was associated with mild hepatic steatosis. Overall, this study establishes a new paradigm in nutrient sensing by normal hepatocytes and nominates alternative RNA splicing as the potential trigger of inflammatory responses to HCDs via accumulation of dsRNAs. We suggest that a reduction of dietary carbohydrates, by suppressing the diet-induced hepatic inflammation, will improve the survival of cancer patients, and reduce the risk of liver metastases. Citation Format: Aizhan Surumbayeva, Riley Williams, Michael Kotliar, Maryclare Taylor, Débora B. Vendramini Costa, Charline Ogier, Diana Restifo, Kathy Q. Cai, Xueyang He, Paul Boutz, Siddharth Balachandran, Igor Astsaturov. Inflammatory response to dietary carbohydrates contributes to the formation of hepatic metastatic niche [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr B019.

Abstract 1063: Combination strategies to overcome doxorubicin induced senescence in triple-negative breast cancer

Abstract Background: Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor-2 over-expression. Compared to other subtypes of breast cancer, TNBC is associated with a higher risk for metastatic recurrence. While immunotherapy, PARP inhibitors, and sacituzumab govitecan have shown benefit in a subset of TNBC patients, chemotherapy with doxorubicin remains a mainstay of treatment. Senescence is a cellular phenomenon where cells are committed to an arrested state, however, senescent cells are able to secrete pro-tumorigenic factors which can help to promote tumor progression and invasion. It has been suggested that senescence is a potential mechanism of resistance in doxorubicin (dox) treated cells. Transitioning senescence mediated resistance to apoptosis is crucial to the treatment of TNBC. The objective of this study was to evaluate the combination BCL-2 and HDAC inhibitors with dox to overcome resistance and induce apoptosis. Experimental Procedures: TNBC cell lines resistant and sensitive to doxorubicin were identified using a CellTiter-Glo Viability Assay and resistant cell lines were selected for further analysis. To assess proliferation, dox resistant TNBC cell lines were plated in 96-well plates. Cells were exposed to vehicle control, dox, BCL-2 inhibitor, HDAC inhibitor or the combination of dox and BCL-2 inhibitor or HDAC inhibitor for 72 hours. Cellular proliferation was assessed using the BioSpa live cell analysis system. Apoptosis at 24 hours was analyzed by flow cytometry using Annexin V on cells treated in combination and as single agents. Immunoblotting was performed to evaluate the downstream effects of apoptosis and senescence of drugs as single agents and in combination. Results: The addition of a BCL-2 inhibitor and HDAC inhibitor to doxorubicin resulted in decreased proliferation in resistant TNBC cell lines compared to single agents and vehicle control by live cell microscopy. Furthermore, the combination of dox and a BCL-2 inhibitor resulted in increased apoptosis when compared to single agents and control using Annexin V staining. The cyclin dependent kinase inhibitors p21 and p16 were over-expressed in cells exposed to combination treatment. Apoptotic proteins BAD, PUMA, cleaved PARP and the anti-apoptotic protein BCL-2 were upregulated in cells treated with a BCL-2 inhibitor with or without dox. The pro-mitotic protein cyclin-B1 was downregulated in resistant cells treated with single agent BCL-2 inhibitor and in combination with dox. Additional mechanistic studies are ongoing. Conclusion: The combination of doxorubicin with BCL-2 and HDAC inhibitors resulted in decreased cellular proliferation and increased apoptosis. Potential senolytic drugs used with dox represent an exciting potential to overcome dox resistance and warrant further investigation. Citation Format: Anna R. Schreiber, Stephen Smoots, Betelehem W. Yacob, Adrian TA Dominguez, Cecilia Levandowski, Jennifer R. Diamond, Todd M. Pitts. Combination strategies to overcome doxorubicin induced senescence in triple-negative 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 1063.

P-241 Risk factors of recurrence of rectal cancer after neoadjuvant chemoradiotherapy

Treatment of locally advanced rectal cancer is based on concomitant radio-chemotherapy followed by surgery in order to reduce the risk of local recurrence and increase overall survival. In some cases, adjuvant chemotherapy is also recommended to decrease the risk of metastatic recurrence. However, both local and metastatic recurrence have been reported. The aim of this study was to define clinicopathological parameters that could be factors influencing recurrence after perioperative radio-chemotherapy.

Improving outcomes for women aged 70 years or above with early breast cancer: research programme including a cluster RCT

Improving outcomes for women aged 70 years or above with early breast cancer: research programme including a cluster RCT

Risk Estimation of Metastatic Recurrence After Prostatectomy: A Model Using Preoperative Magnetic Resonance Imaging and Targeted Biopsy

BackgroundThe risk of prostate cancer metastatic is correlated with its volume and grade. These parameters are now best estimated preoperatively with magnetic resonance imaging (MRI) and MRI-guided biopsy. ObjectiveTo estimate the risk of metastatic recurrence after radical prostatectomy (RP) in our model versus conventional clinical European Association of Urology (EAU) classification. The secondary objective is biochemical recurrence (BCR). Design, setting, and participantsA retrospective study was conducted of a cohort of 713 patients having undergone MRI-guided biopsies and RP between 2009 and 2018. The preoperative variables included prostate-specific antigen, cT stage, tumor volume (TV) based on the lesion’s largest diameter at MRI, percentage of Gleason pattern 4/5 (%GP4/5) at MRI-guided biopsy, and volume of GP4/5 (VolGP4/5) calculated as TV × %GP4/5. Outcome measurements and statistical analysisThe variables’ ability to predict recurrence was determined in univariable and multivariable Fine-and-Gray models, according to the Akaike information criterion (AIC) and Harrell’s C-index. Results and limitationsOverall, 176 (25%), 430 (60%), and 107 (15%) patients had low, intermediate, and high-risk disease, respectively, according to the EAU classification. During a median follow-up period of 57 mo, metastatic recurrence was observed in 48 patients with a 5-yr probability of 5.6% (95% confidence interval [CI] 3.9–7.7). VolGP4/5 (categories: <0.5, 0.5–1.0, 1.01–3.2, and >3.2 ml) was the parameter with the lowest AIC and the highest C-index for metastatic recurrence of 0.82 (95% CI 0.76–0.88), and for BCR it was 0.73 (95% CI 0.68–0.78). In a multivariable model that included %GP4/5 and TV, C-index values were 0.86 (95% CI 0.79–0.91) for metastatic recurrence and 0.77 (0.72–0.82) for BCR. The same results for EAU classification were 0.74 (0.67–0.80) and 0.67 (0.63–0.72), respectively. Limitations are related to short follow-up and expertise of radiologists and urologists. ConclusionsWe developed a preoperative risk tool integrating the VolGP4/5 based on MRI and MRI-guided biopsies to predict metastatic recurrence after RP. Our model showed higher accuracy than conventional clinical risk models. These findings might enable physicians to provide more personalized patient care. Patient summaryAggressiveness of prostate cancer evaluated before treatment by incorporating magnetic resonance imaging (MRI) and MRI-guided biopsy results gives a better estimate of the risk of metastatic recurrence than previous parameters not based on MRI.

Vertical tumor margin of endoscopic resection for T1 colorectal carcinoma affects the prognosis of patients undergoing additional surgery.

Vertical tumor margin-negative T1 colorectal carcinoma (CRC) is an absolute curative condition following complete endoscopic resection (ER). However, the influence on prognosis in relation to vertical tumor margin is unclear. Therefore, we evaluated the influence of the distance from vertical tumor margin to resected specimen edge (vertical margin distance) of ER for T1b (submucosal invasion depth > 1000μm) CRC on the prognosis of patients undergoing additional surgery after ER. In total, 215 consecutive patients with T1b CRC who underwent additional surgery after ER at Hiroshima University Hospital between February 1992 and June 2019 were enrolled. We assessed 191 patients without lymph node metastases at the additional surgery. The specimens resected by ER were classified into three groups based on the vertical margin distance: patients with a vertical margin distance of ≥ 500μm (Group A); patients with a vertical margin distance of < 500μm (Group B); and patients with a positive vertical tumor margin (Group C). Subsequently, we evaluated the prognosis of the patients in relation to the clinicopathological characteristics among the three groups. There were no significant differences in clinicopathological characteristics among the three groups. Group A had a significantly higher recurrence-free 5-year survival rate than Groups B and C (100%, 84.5%, and 81.8%, respectively). Similarly, Group A had a significantly higher disease-specific 5-year survival rate than Group C (100% vs. 95.5%). Complete en bloc resection with sufficient submucosal layer from the invasive front (vertical margin distance > 500μm) by ER for T1 CRC reduces the risk of metastatic recurrence after additional surgery.

Machine Learning to Discern Interactive Clusters of Risk Factors for Late Recurrence of Metastatic Breast Cancer.

Simple SummaryBreast cancer is the most frequently diagnosed cancer and second leading cause of cancer-related death among women worldwide. After initial tumor resection, breast cancer may recur locally and/or in distant organs within several months to years or even decades. Multiple methods exist to prognosticate disease progression in the early months and years after diagnosis. However, further efforts are needed to identify risk factors that relate to recurrence beyond the initial 5-year window. In this study, we applied machine learning to retrieve single and interactive clinical and pathological risk factors of 5-, 10- and 15-year metastases.Background: Risk of metastatic recurrence of breast cancer after initial diagnosis and treatment depends on the presence of a number of risk factors. Although most univariate risk factors have been identified using classical methods, machine-learning methods are also being used to tease out non-obvious contributors to a patient’s individual risk of developing late distant metastasis. Bayesian-network algorithms can identify not only risk factors but also interactions among these risks, which consequently may increase the risk of developing metastatic breast cancer. We proposed to apply a previously developed machine-learning method to discern risk factors of 5-, 10- and 15-year metastases. Methods: We applied a previously validated algorithm named the Markov Blanket and Interactive Risk Factor Learner (MBIL) to the electronic health record (EHR)-based Lynn Sage Database (LSDB) from the Lynn Sage Comprehensive Breast Center at Northwestern Memorial Hospital. This algorithm provided an output of both single and interactive risk factors of 5-, 10-, and 15-year metastases from the LSDB. We individually examined and interpreted the clinical relevance of these interactions based on years to metastasis and reliance on interactivity between risk factors. Results: We found that, with lower alpha values (low interactivity score), the prevalence of variables with an independent influence on long-term metastasis was higher (i.e., HER2, TNEG). As the value of alpha increased to 480, stronger interactions were needed to define clusters of factors that increased the risk of metastasis (i.e., ER, smoking, race, alcohol usage). Conclusion: MBIL identified single and interacting risk factors of metastatic breast cancer, many of which were supported by clinical evidence. These results strongly recommend the development of further large data studies with different databases to validate the degree to which some of these variables impact metastatic breast cancer in the long term.

PD40-05 NEOADJUVANT IMMUNOTHERAPY IN PATIENTS WITH RENAL CELL CARCINOMA UNDERGOING NEPHRECTOMY

You have accessJournal of UrologyKidney Cancer: Advanced (including Drug Therapy) II (PD40)1 Sep 2021PD40-05 NEOADJUVANT IMMUNOTHERAPY IN PATIENTS WITH RENAL CELL CARCINOMA UNDERGOING NEPHRECTOMY Kyrollis Attalla, Maria Carlo, Sounak Gupta, Sujata Patil, Devon Coskey, Samuel Murray, Ritesh Kotecha, Jonathan Coleman, Robert Motzer, Yingbei Chen, Jeremy Durack, Paul Russo, A Ari Hakimi, and Martin Voss Kyrollis AttallaKyrollis Attalla More articles by this author , Maria CarloMaria Carlo More articles by this author , Sounak GuptaSounak Gupta More articles by this author , Sujata PatilSujata Patil More articles by this author , Devon CoskeyDevon Coskey More articles by this author , Samuel MurraySamuel Murray More articles by this author , Ritesh KotechaRitesh Kotecha More articles by this author , Jonathan ColemanJonathan Coleman More articles by this author , Robert MotzerRobert Motzer More articles by this author , Yingbei ChenYingbei Chen More articles by this author , Jeremy DurackJeremy Durack More articles by this author , Paul RussoPaul Russo More articles by this author , A Ari HakimiA Ari Hakimi More articles by this author , and Martin VossMartin Voss More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002050.05AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Immune checkpoint inhibitor (ICI) therapy improves survival in patients with advanced renal cell carcinoma (RCC), but has not been studied preoperatively in patients with localized RCC who may be at high risk of recurrence, or in patients with metastatic disease who are candidates for cytoreductive nephrectomy. We evaluate the safety and feasibility of neoadjuvant immunotherapy in patients with localized, high-risk RCC. METHODS: Single institution pilot study of neoadjuvant nivolumab in patients with localized, high-risk RCC undergoing nephrectomy. Patients were eligible if their risk of metastatic recurrence within the first 12 years was >20% by nomogram. Nivolumab was administered every 2 weeks for 4 treatments, with a follow-up renal MRI prior to nephrectomy. In addition, we retrospectively assessed a separate cohort of 21 patients with metastatic disease who received preoperative ICI off protocol. RESULTS: In the prospective study cohort, 18 patients (11 men; median age 60) with clear cell RCC were enrolled. All received at least 1 dose of nivolumab; 16/18 patients completed all doses. Two patients had nivolumab discontinued for immune-related adverse events, including grade 3 transaminitis (1) and grade 2 arthralgias (1). All patients had stable disease as the best response prior to surgery. 17/18 (94%) patients completed at least 3 doses and had nephrectomy without delay. 4 patients had surgical complications per Clavien-Dindo classification, including 2 patients with Grade IIIa chylous ascites after lymphadenectomy. The metastatic cohort included 20 patients with ccRCC and one with epithelioid AML. 15 patients received ipilimumab+nivolumab, 6 received single-agent PD-1 or PD-L1 inhibitors. 3 (14%) patients achieved a near or complete pathologic response, including a patient with epithelioid AML. No patient experienced a major intraoperative complication or 30- or 90-day mortality, and one patient was readmitted for pneumonia, metastatic bronchial occlusions requiring bronchoscopy and eventual intubation (Clavien 4a). 5 patients experienced grade 3 or 4 irAEs. CONCLUSIONS: In a pilot study of nivolumab prior to nephrectomy in patients with localized RCC, the approach appeared safe and feasible with no surgical delays and expected rate of immune related adverse events. A retrospective review of patients with metastatic disease who underwent cytoreductive nephrectomy after ICI showed favorable surgical outcomes, with an association of combination CTLA-4 and PD-1 inhibitor with higher grade irAE and pathologic complete responses. Source of Funding: This work was funded in part through the National Institute of Health (NIH)’s Cancer Therapy Evaluation Program (CTEP), and the NIH/NCI Cancer Center Support Grant P30 CA008748 © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e675-e676 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Kyrollis Attalla More articles by this author Maria Carlo More articles by this author Sounak Gupta More articles by this author Sujata Patil More articles by this author Devon Coskey More articles by this author Samuel Murray More articles by this author Ritesh Kotecha More articles by this author Jonathan Coleman More articles by this author Robert Motzer More articles by this author Yingbei Chen More articles by this author Jeremy Durack More articles by this author Paul Russo More articles by this author A Ari Hakimi More articles by this author Martin Voss More articles by this author Expand All Advertisement Loading ...