Independent Prognostic Factor For Recurrence Research Articles

Abstract PO5-18-06: On-going phase 1A clinical trial of A01, a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88) in patients with advanced malignancy

Abstract Progranulin (PGRN/GP88) is an 88 kDa glycoprotein characterized by seven and a half double cysteine rich repeats which is the largest member of the granulin-epithelin protein family. PGRN/GP88 has been demonstrated as a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC), lung prostate, ovarian and digestive cancers. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence in breast, lung cancers while elevated serum PGRN/GP88 level in metastatic breast, lung, ovarian and prostate cancer patients. Elevated PGRN/GP88 levels are associated with poor outcomes such as progression and shortened survival. An anti-human PGRN/GP88 monoclonal antibody able to inhibit the the in vitro and in vivo action of human PGRN/GP88 has been developed, chimerized and expressed in CHO cells. All IND enabling activities including pharmacology, GMP manufacturing, formulation and GLP toxicology studies have been conducted. The IND application has been filed and cleared by the Food and Drug Administration. A first-in-human, first-in-class phase 1 safety and efficacy clinical study of AG01 in patients with solid tumors and advanced disease with special focus on patients with breast, lung and ovarian cancers has been initiated and is on-going at the University of Maryland Greenebaum Cancer Center. The trial is registered as NCT05627960 to clinicaltrials.gov site. The presentation will provide an update on the number of patients enrolled in this on-going phase 1A trial. Supported by grants R44CA162629 and R44CA224718 from the National Cancer Institute to GS. Citation Format: Katherine Tkaczuk, Paula Rosenblatt, Ranee Mehra, Katherine Scilla, Nancy Tait, Binbin Yue, Ginette Serrero. On-going phase 1A clinical trial of A01, a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88) in patients with advanced malignancy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-18-06.

Abstract PO4-06-11: Development of fully human anti-progranulin monoclonal antibodies as inhibitors of triple negative breast cancer cell growth and tumor formation

Abstract Triple negative breast cancer (TNBC) is characterized by invasiveness and poor survival. Identifying novel TNBC targeted therapies to potentiate standard of care (SOC) therapy, is an unmet need. In the past 4 years, several targeted therapies for TNBC have been approved by the Food and Drug Administration (FDA). However, the identification of targeted therapies against other biological drivers of TNBC remains important. Progranulin (PGRN/GP88) is a biological driver of tumorigenesis, survival, and drug resistance in breast cancer. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence while elevated serum PGRN/GP88 level is associated with poor outcomes such as progression of disease and shortened survival. PGRN/GP88 expression is elevated in 30% TNBC. The importance of inhibiting PGRN/GP88 effect on the proliferation and tumor growth of triple negative breast cancer cells was previously established. In the current study, in association with Precision Antibody, we developed anti-PGRN/GP88 fully human monoclonal antibodies by immunizing TC transgenic humanized mice with recombinant human progranulin. Within 60 days since the start of immunization, several fully human monoclonal antibodies were successfully developed, characterized by several functional assays including neutralization, inhibition of PGRN/GP88 cell surface binding, proliferation, migration in MDA-MB-231 cells in vitro and in vivo. Results: The inhibition of PGRN/GP88 action by fully human monoclonal antibodies inhibited proliferation and migration in a dose-and time-dependent fashion in TNBC cells. Octet analysis determined Kd in the range of 10−11 M to 10−10 M. Transwell assay showed that anti-PGRN treatment inhibited migration In vivo xenograft studies with MDA-MB-231 cells injected in athymic nude mice showed that several fully human anti-PGRN antibodies inhibited tumor growth when compared to antibody control treated mice. In vivo dose response of AG01 in MDAMB-231 tumor bearing mice will be provided. Conclusion: PGRN/GP88 represents a therapeutic target for TNBC with two companion diagnostics (tissue test and ELISA to measure GP88 circulating levels). The use of the TC transgenic mice allows for the rapid development of fully human high affinity monoclonal antibodies bypassing the need for chimerization or humanization of mouse monoclonal antibodies. The development of fully human anti-progranulin antibodies provides novel targeted therapeutic option for TNBC. This work is supported by a an SBIR grant 5R44 CA 224718 from the National Cancer Institute to GS. Citation Format: Ginette Serrero, Jianping Dong, Jun Hayashi, Chun Dong. Development of fully human anti-progranulin monoclonal antibodies as inhibitors of triple negative breast cancer cell growth and tumor formation [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-06-11.

Abstract 1864: New generation of fully human anti-progranulin monoclonal antibodies inhibiting migration and tumor formation of non-small cell carcinoma cells

Abstract Advanced carcinomas of the lung or the breast are characterized by invasiveness and poor survival. Identifying novel targeted therapies to potentiate standard of care (SOC) therapy, remains an unmet need. In the past 4 years, numerous targeted therapies in Oncology have been approved by the Food and Drug Administration (FDA). However, the identification of targeted therapies against direct tumor biological drivers remains important. Progranulin (PGRN/GP88) is a biological driver of tumorigenesis, survival, and drug resistance in multiple cancers including breast and lung cancers. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence and mortality while elevated serum PGRN/GP88 level is associated with poor outcomes such as progression of disease and shortened survival. The importance of inhibiting PGRN/GP88 expression or action effect on the proliferation and tumor growth of several cancers has been established by several laboratories including ours. In the current study, in association with Precision Antibody, we developed anti-PGRN/GP88 fully human monoclonal antibodies by immunizing TC transgenic humanized mice with recombinant human progranulin. Within 60 days following the start of immunization, several fully human anti-progranulin monoclonal antibodies were developed, characterized by several functional assays including neutralization, inhibition of PGRN/GP88 cell surface binding, proliferation, migration in vitro and tumor formation in vivo. Results: The inhibition of PGRN/GP88 action by fully human monoclonal antibodies inhibited cell proliferation and migration in a dose-and time-dependent fashion. Octet analysis determined Kd in the range of 10−11 M to 10−10 M. Transwell assay showed that anti-PGRN treatment inhibited migration of non-small cell lung cancer cells such as H1299 and A549 cells. In vivo xenograft studies with H1299 cells injected in athymic nude mice showed that fully human anti-PGRN antibodies inhibited tumor growth when compared to antibody control treated mice. Conclusion: PGRN/GP88 represents a therapeutic target for non-small cell carcinoma with two companion diagnostics (tissue test and ELISA to measure GP88 circulating levels). The use of the TC transgenic mice allows for the rapid development of fully human high affinity monoclonal antibodies bypassing the need for chimerization or humanization and affinity maturation of monoclonal antibodies raised in mice or other humanized systems. This work is supported by SBIR grants R44 CA 224718 and R44CA162729 from the National Cancer Institute to GS. Citation Format: Ginette Serrero, Jianping Dong, Binbin Yue, Mitsuo Oshimura, Chun Dong, Jun Hayashi. New generation of fully human anti-progranulin monoclonal antibodies inhibiting migration and tumor formation of non-small cell carcinoma cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1864.

Abstract 6520: Clinical verification oftherelationship betweenserum lipid metabolism andtumor immune microenvironment inpostmenopausal hormone receptor-positive/HER2-negative breast cancer patients

Abstract Background: Recently, some basic research has reported that the tumor immune microenvironment (TIME) is related to the therapeutic efficacy and prognosis of breast cancer patients, and that the regulation of metabolism can affect TIME and enhance antitumor immunity. Suppression of aromatase expression from adipose tissue is the standard adjuvant endocrine therapy for postmenopausal hormone receptor (HR)-positive/human epidermal growth factor receptor 2 (HER2)-negative breast cancer, but few studies have examined the impact of controlling lipid metabolism on TIME and cancer prognosis. Materials and Methods: Except for patients with ductal carcinoma in situ, 531 postmenopausal HR-positive/HER2-negative breast cancer patients treated with curative surgery between 2011 and 2017 were examined. Serum lipid levels and systemic immune-related markers were evaluated by blood samples, and tumor-infiltrating lymphocytes (TILs) in cancer tissue samples were investigated by immunohistochemistry. We also examined the relationship between lipid metabolism, TIME, and prognosis, respectively. Results: Good serum lipid control group was significantly correlated with low neutrophil- to-lymphocyte ratio (NLR) (p = 0.024) and high TILs (p = 0.039). The median follow-up time for the assessment of prognosis was 5.5 years, and 67 patients had recurrence. Only patients treated with aromatase inhibitor as adjuvant endocrine therapy showed significantly better recurrence-free survival (RFS) in the good lipid control group (p = 0.025, log-rank). Also, multivariate analyses showed that good serum lipid control was an independent prognostic factor for recurrence (HRs = 4.722, 95%CI: 1.006-22.161, p = 0.049). Patients with high CD8/FOXP3 ratio (CFR) had significantly better RFS (p=0.027, log-rank) and tended to have good lipid control. Conclusions: Good control of serum lipid metabolism may inhibit the acquisition of resistance to endocrine therapy by improving TIME and induce favorable outcome in postmenopausal HR-positive/HER2-negative breast cancer patients. Citation Format: Wataru Goto, Hanae Matsuda, Saeko Henmi, Mariko Nishikawa, Asuka Kouchi, Rika Kouhashi, Akimichi Yabumoto, Koji Takada, Yukie Tauchi, Kana Ogisawa, Tamami Morisaki, Shinichiro Kashiwagi. Clinical verification oftherelationship betweenserum lipid metabolism andtumor immune microenvironment inpostmenopausal hormone receptor-positive/HER2-negative breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6520.

Immunohistochemical markers Ki67 and P16 help predict prognosis in locally advanced cervical cancer

ObjectiveTo investigate the relationship between Ki-67 and P16 expression levels after neoadjuvant chemotherapy, and the clinicopathological characteristics and prognosis of patients with locally advanced cervical cancer. MethodsPatients with FIGO 2009 stage IB2 or IIA2 cervical cancer, who underwent neoadjuvant chemotherapy combined with radical hysterectomy at the First Affiliated Hospital of Chongqing Medical University between January 2015 and December 2019, were identified retrospectively to correlate postoperative Ki-67 and P16 expression levels with clinicopathological factors. The optimal threshold for predicting recurrence was analysed using receiver operating characteristic (ROC) curves for the Ki-67 index, and univariate and multi-factorial Cox regression analysis were used to investigate the association between clinicpathological features including Ki-67 and P16 and recurrence-free survival. ResultsIn total, 334 patients were included after screening. The cut-off value of Ki-67 for determining recurrence was 67.5 % according to the ROC curve. On multi-factorial Cox analysis, lymphatic vascular space (p = 0.003) and Ki-67 index (p = 0.005) were shown to increase the risk of recurrence, and were independent prognostic factors for recurrence, while the expression of P16 was not significantly associated with the risk of recurrence (p = 0.097, odds ratio = 0.319). Patients with cervical cancer in the high Ki-67 expression group (Ki-67 ≥ 67.5 %) had lower recurrence-free survival and overall survival than patients in the low Ki-67 expression group (Ki-67 < 67.5 %) (p = 0.001 and 0.036, respectively). ConclusionThe expression levels of Ki-67 and P16 after neoadjuvant chemotherapy for locally advanced cervical cancer correlated with tumour differentiation. High expression of Ki-67 (Ki-67 ≥ 67.5 %) may indicate poorer recurrence-free survival and overall survival.

Correlation between urine cytology results on the day after overnight continuous saline irrigation following transurethral resection of bladder tumor and bladder tumor recurrence.

To investigate the relationship between urine cytology results after overnight continuous saline irrigation (OCSI) following transurethral resection of bladder tumor (TURBT) and bladder tumor recurrence in non-muscle invasive bladder cancer (NMIBC). A retrospective study was conducted on patients diagnosed with NMIBC between 2016 and 2020 after undergoing TURBT at our hospital. All patients received OCSI following TURBT and had urine cytology test at postoperative 1 day. Urine cytology was classified into three groups: Negative, low-grade urothelial neoplasm (LGUN)+atypical urothelial cells (AUC), and suspicious for high-grade urothelial carcinoma (SHGUC)+high-grade urothelial carcinoma (HGUC). Recurrence-free survival (RFS) in each group was compared using the Kaplan-Meier method. Univariable and multivariable Cox regression analyses were performed to evaluate independent prognostic factors. A total of 172 patients were included in this study. Based on urine cytology group (after OCSI), RFS did not reach the median value in the Negative group. In the LGUN+AUC group, the median RFS was 615.00 days. In the SHGUC+HGUC group, the median RFS was 377.00 days. In survival analysis, the Negative group had a longer RFS than the SHGUC+HGUC group (p=0.013). However, Cox regression analysis showed that SHGUC+HGUC was not an independent prognostic factor for recurrence. Urine cytology results after OCSI following TURBT in NMIBC were associated with bladder tumor recurrence. Specifically, SHGUC or HGUC in urine cytology after OCSI showed earlier recurrence than negative cases. However, further research is needed to accurately determine whether it is an independent prognostic factor.

Prognostic analysis of surgical treatment for T3 glottic laryngeal cancer based on different tumor extension patterns.

To investigate the prognostic impact of different tumor invasion patterns in the surgical treatment of T3 glottic laryngeal cancer. We conducted a retrospective analysis of clinical data of 91 patients with T3 glottic laryngeal cancer. We found that the posterior invasion being significantly associated with involvement of the lamina of cricoid cartilage (P < 0.001), arytenoid cartilage (P = 0.001), and subglottic (P = 0.001). There was no statistical difference in survival outcomes between the total laryngectomy (TL) group and the partial laryngectomy(PL) group, but in the PL group, tumors with anterior invasion were associated with a better 5-year DFS than tumors with posterior invasion (HR: 4.681, 95% CI: 1.337-16.393, P = 0.016), and subglottic involvement was associated with worse LRRFS (HR: 3.931, 95% CI: 1.054-14.658, P = 0.041). At the same time, we found that involvement of the lamina of cricoid cartilage was an independent risk factor for postoperative laryngeal stenosis in PL patients (HR: 11.67, 95% CI: 1.89-71.98, P = 0.008). Selectively performed PL can also achieve favorable oncological outcomes comparable to those of TL. Posterior invasion and subglottic involvement are independent prognostic factors for recurrence after PL in T3 glottic laryngeal cancer, and involvement of the lamina of cricoid cartilage is associated with postoperative laryngeal stenosis. The tumor invasion pattern of patients with laryngeal cancer should be further subdivided to allow for selection of a more individualized treatment plan.

Prognostic impact of different tumor invasion patterns in the surgical treatment of T3 glottic laryngeal cancer

Objective:To investigate the prognostic impact of different tumor invasion patterns in the surgical treatment of T3 glottic laryngeal cancer. Methods:A retrospective analysis was conducted on the clinical data of 91 patients with T3 glottic laryngeal cancer. Results:Among the 91 patients, 58 cases （63.7%） had anterior invasion and 33 cases （36.3%） had posterior invasion. The posterior invasion was significantly correlated with invasions of the dorsal plate of cricoid cartilage （P<0.001）, arytenoid cartilage （P= 0.001）, and subglottic region（P = 0.001）. There was no statistical difference in survival outcomes between the total laryngectomy group and the partial laryngectomy group. But in the partial laryngectomy group, the 5-year disease-free survival（DFS） of patients with anterior invasive tumors was better than that of patients with posterior invasion tumors （HR: 4.681, 95%CI 1.337-16.393, P=0.016）, and subglottic invasion was associated with worse loco-regional recurrence-free survival（LRRFS）（HR: 3.931, 95%CI 1.054-14.658, P=0.041）. At the same time, we found that involvement of the dorsal plate of cricoid cartilage was an independent risk factor for postoperative laryngeal stenosis in partial laryngectomy patients （HR:11.67, 95%CI 1.89-71.98,P=0.008）. Conclusion:Compared with total laryngectomy, selected partial laryngectomy can also achieve favorable oncological outcomes. Posterior invasion and subglottic extension are independent prognostic factors for recurrence of partial laryngectomy in T3 glottic laryngeal cancer, and the involvement of the dorsal plate of cricoid cartilage is associated with postoperative laryngeal stenosis. The tumor invasion pattern of laryngeal cancer should be further subdivided in order to select a more individualized treatment plan.

Imaging-Derived Biomarkers Integrated with Clinical and Laboratory Values Predict Recurrence of Hepatocellular Carcinoma After Liver Transplantation.

To investigate the prognostic value of computed tomography (CT) derived imaging biomarkers in hepatocellular carcinoma (HCC) recurrence after liver transplantation (LT) and develop a predictive nomogram model. This retrospective study included 178 patients with histopathologically confirmed HCC who underwent liver transplantation between 2007 and 2021 at the two academic liver centers. We evaluated dedicated imaging features from baseline multiphase contrast-enhanced CT supplemented by several clinical findings and laboratory parameters. Time-to-recurrence was estimated by Kaplan-Meier analysis. Univariable Cox proportional hazard regression and multivariable Least Absolute Shrinkage and Selection Operator (LASSO) regression were used to assess independent prognostic factors for recurrence. A nomogram model was then built based on the independent factors selected through LASSO regression, to predict the probabilities of HCC recurrence at one, three, and five years. The rate of HCC recurrence after LT was 17.4% (31 of 178). The LASSO analysis revealed six independent predictors associated with an elevated risk of tumor recurrence. These predictors included the presence of peritumoral enhancement, the presence of over three tumor lesions, the largest tumor diameter greater than 3 cm, serum alpha-fetoprotein (AFP) levels exceeding 400 ng/mL, and the presence of a tumor capsule. Conversely, a history of bridging therapies was found to be correlated with a reduced risk of HCC recurrence. In addition, Kaplan-Meier curves showed patients with irregular margin, satellite nodules, or small lesions displayed shorter time-to-recurrence. Our nomogram demonstrated good performance, yielding a C-index of 0.835 and AUC values of 0.86, 0.88, and 0.85 for the predictions of 1-year, 3-year, and 5-year TTR, respectively. Imaging parameters derived from baseline contrast-enhanced CT showing malignant behavior and aggressive growth patterns, along with serum AFP and history of bridging therapies, show potential as biomarkers for predicting HCC recurrence after transplantation.

Role of Adjuvant Radiotherapy in Patients with Cervical Cancer Undergoing Radical Hysterectomy.

The benefit of adjuvant radiotherapy (RT) after radical hysterectomy in patients with cervical cancer remains controversial. The aim of this study was to determine adjuvant RT's impact on survival in accordance with Sedlis criteria. Patients with early-stage cervical cancer undergoing radical hysterectomy between 2005 and 2022 at a single tertiary care institution were included. A multivariate analysis was performed to determinate if RT was an independent prognostic factor for recurrence or death. We also analysed whether there was a statistically significant difference in overall survival (OS) between patients who met only one or two Sedlis criteria, depending on whether they received adjuvant RT or not. 121 patients were included in this retrospective study, of whom 48 (39.7%) received adjuvant RT due to the presence of unfavourable pathological findings. In multivariate analysis, RT was not found to be a statistically significant prognostic factor for OS (p = 0.584) or disease-free survival (DFS) (p = 0.559). When comparing patients who met one or two Sedlis criteria, there were no statistically significant differences in OS between RT and no adjuvant treatment in either group. Since the selection of patients with cervical cancer eligible for surgery is becoming more accurate, adjuvant RT might not be necessary for patients with intermediate risk factors.

Lymph Node Ratio Predicts Recurrence in Patients with Papillary Thyroid Carcinoma with Low Lymph Node Yield.

The American Thyroid Association risk stratification system suggests that having >5 metastatic lymph nodes (LNs) increase the recurrence risk in patients with papillary thyroid carcinoma (PTC). However, little is known about PTC with <5 harvested LNs. This study aimed to stratify patients with low-LN-yield (low-LNY) PTC based on lymph node ratios (LNRs). From 2007 to 2017, 6317 patients who underwent thyroidectomies were diagnosed with PTC at Seoul St. Mary's Hospital, and 909 patients with low LNYs were included in the study. Tumor recurrence was compared based on LNR. The LNR cutoff was determined using a receiver operating characteristic curve. Forty-six patients (5.1%) experienced recurrences over a mean follow-up period of 127.24 ± 33.6 months (range, 5-190 months). The cutoff for the low-LNR (n = 675) and high-LNR (n = 234) groups was 0.29 (AUC = 0.676, 95% CI = 0.591-0.761, p < 0.001). The recurrence rate was significantly higher in the high-LNR group compared to the rate in the low-LNR group (12.4% vs. 2.5%, p < 0.001). Multivariate analysis using Cox regression revealed that tumor size and LNR ≥ 0.29 were independent prognostic factors for recurrence. Therefore, LNR can be utilized to stratify the risk of recurrence in patients with low-LNY PTC.

Adjuvant TACE may not improve recurrence-free or overall survival in HCC patients with low risk of recurrence after hepatectomy.

To identify whether adjuvant transarterial chemoembolization (TACE) can improve prognosis in HCC patients with a low risk of recurrence (tumor size ≤ 5 cm, single nodule, no satellites, and no microvascular or macrovascular invasions) after hepatectomy. The data of 489 HCC patients with a low risk of recurrence after hepatectomy from Shanghai Cancer Center (SHCC) and Eastern Hepatobiliary Surgery Hospital (EHBH) were retrospectively reviewed. Recurrence-free survival (RFS) and overall survival (OS) were analyzed with Kaplan-Meier curves and Cox proportional hazards regression models. The effects of selection bias and confounding factors were balanced using propensity score matching (PSM). In the SHCC cohort, 40 patients (19.9%, 40/201) received adjuvant TACE, and in the EHBH cohort, 113 patients (46.2%, 133/288) received adjuvant TACE. Compared to the patients without adjuvant TACE after hepatectomy, patients receiving adjuvant TACE had significantly shorter RFS (P=0.022; P=0.014) in both cohorts before PSM. However, no significant difference existed in OS (P=0.568; P=0.082). Multivariate analysis revealed that serum alkaline phosphatase and adjuvant TACE were independent prognostic factors for recurrence in both cohorts. Furthermore, significant differences existed in tumor size between the adjuvant TACE and non-adjuvant TACE groups in the SHCC cohort. There were differences in transfusion, Barcelona Clinic Liver Cancer stage and tumor-node-metastasis stage in the EHBH cohort. These factors were balanced by PSM. After PSM, patients with adjuvant TACE after hepatectomy still had significantly shorter RFS than those without (P=0.035; P=0.035) in both cohorts, but there was no difference in OS (P=0.638; P=0.159). Adjuvant TACE was the only independent prognostic factor for recurrence in multivariate analysis, with hazard ratios of 1.95 and 1.57. Adjuvant TACE may not improve long-term survival and might promote postoperative recurrence in HCC patients with a low risk of recurrence after hepatectomy.

Diffuse Sclerosing Papillary Thyroid Carcinoma: Clinicopathological Characteristics and Prognostic Implications Compared with Classic and Tall Cell Papillary Thyroid Cancer.

The clinical behaviour and oncologic outcome of diffuse sclerosing papillary thyroid carcinoma (DS-PTC) is poorly understood. The objectives of this study were to compare the clinicopathological characteristics and oncological outcomes of DS-PTC to classic PTC (cPTC) and tall cell PTC (TC-PTC). After institutional review board approval, 86 DS-PTC, 2,080 cPTC, and 701 TC-PTC patients treated at MSKCC between 1986 and 2021 were identified. Clinicopathological characteristics were compared by using chi-squaretest. Kaplan-Meier and log rank were used to compare recurrence-free survival (RFS), disease-specific survival (DSS), and overall survival (OS). DS-PTC patients were propensity matched to cPTC and TC-PTC patients for further comparison. DS-PTC patients were younger with more advanced disease than cPTC and TC-PTC (p < 0.05). Lymphovascular invasion (LVI), extranodal extension, and positive margins were more common in DS-PTC (p < 0.02). Propensity matching confirmed more aggressive histopathological features in DS-PTC. The median number of metastatic lymph nodes was significantly greater and DS-PTC metastases were RAI avid. DS-PTC 5-year RFS was 50.4% compared with 92.4% in cPTC and 88.4% in TC-PTC (p < 0.001). Multivariate analysis confirmed DS-PTC as an independent prognostic factor of recurrence. Ten-year DSS for DS-PTC was 100% compared with 97.1% in cPTC and 91.1% in TC-PTC. Differentiated high-grade, thyroid carcinoma DS had more advanced T-stage and worse 5-year RFS than DS-PTC. DS-PTC presents with more advanced clinicopathological features than cPTC and TC-PTC. Large-volume nodal metastases and LVI are characteristic features. Almost half of patients develop recurrence despite aggressive initial management. Despite this, with successful salvage surgery DSS is excellent.

Results of dose-dense neoadjuvant chemotherapy in the treatment of stages IB2—IIB cervical cancer

Background. Applied standard methods of cervical cancer (CC) treatment have several disadvantages in terms of local and systemic toxicity and the risks of local recurrence. Our study proposed the use of neoadjuvant chemotherapy (NACT) in a dose-dense mode, followed by radical hysterectomy, in order to improve the results of treatment of locally advanced CC (IB2-IIB stages) (FIGO)/T1b2-2bN0M0 (TNM).Aim. Improvement of immediate and long-term results in treatment of locally advanced CC IB2-IIB stages (FIGO), determining the immediate effectiveness of dose-dense NACT, based on magnetic resonance imaging (MRI) data, and the identification of prognostic factors for tumor response to chemotherapy.Materials and methods. Between April 2016 to November 2019 120 women with IB2-IIB stages (FIGO) were included in this study. Of these, 58 patients underwent 3 cycles of intensified NACT according to the AP scheme (cisplatin 75 mg/m2, doxorubicin 35 mg/m2) and 62 patients underwent NACT according to the TR scheme (cisplatin 60 mg/m2, paclitaxel 60 mg/m2). The assessment of the effect of intensified NACT was performed according to the RECIST 1.1 criteria according to MRI data. Also 2 retrospective groups of patients were recruited: group I - surgical treatment without preoperative chemotherapy (25 patients with IB2-IB3 stages (FIGO) from November 2009 to August 2019), group II - concurrent chemoradiotherapy (44 patients with stage IIB cervical cancer (FIGO) from January 2013 to June 2018).Results. Complete clinical response was detected in 12 (10.0 %) patients, partial response - in 69 (57.5 %) patients, stable disease - in 35 (29.2 %) patients, progression was observed in 4 cases (3.3 %). After NACT in a dose dense mode, due to an objective clinical response (complete response, partial response and stable disease for stage IIA according to RECIST 1.1 criteria), 99 (82.5 %) patients underwent surgical treatment. For 21 (17.5 %) patients due to the absence achievement of objective clinical response (stable disease for stage IIB according to RECIST 1.1 criteria or progression), performed concurrent chemoradiotherapy. During the observation period, 113 (94.2 %) patients remained alive. Mortality for the first year was 1.7 % (2 cases). There was a coincidence of the results of a complete response according to MRI in 11 (91.7 %) cases out of 12 cases with the pathology data. According to multivariate analysis, it was revealed that parametrial invasion, according to the histological examination of the surgical material, is an independent prognostic factor for recurrence. According to comparative evaluation of disease-free survival curves between groups of IB2-IIB stages (FIGO) patients who received and did not receive dose-dense chemotherapy, it was found that disease- free survival in the group with NACT was higher compared to the group without NACT (p = 0.03, the log-rank criterion).Conclusions. The use of dose-dense NACT is an effective treatment mode for patients with IB2-IIB CC (FIGO), which in most cases allows achieving a tumor response with subsequent improvement in immediate and long-term results and can be considered as an alternative to standard treatment for locally advanced CC.

Synthetic miR-26a mimics delivered by tumor exosomes repress hepatocellular carcinoma through downregulating lymphoid enhancer factor 1.

The dysregulation of exosomal microRNAs plays an important role in the progression of hepatocarcinogenesis. In this study, we investigated the therapeutic potential of synthetic exosomal miR-26a against HCC cells and explored the feasibility of tumor-derived exosomes as drug delivery vehicles. Proliferation and migration assays were performed to examine the effects of miR-26a on HCC in vitro. The direct target gene of miR-26a was identified through miRecords analysis and target validation. The transferringefficiency and anti-HCC effect of exosomes with different origin were studied and the optimal miR-26a delivery method was established and verified in vitro and in vivo. In addition, the relationships between prognosis of HCC patients and miR-26a expression in HCC serum and exosomes were retrospectively analyzed. Here, we found that tumor cell-derived exosomes were taken in preferentially by HCC cells and promoted HCC progression through Wnt pathway by low-density lipoprotein receptor-related protein 6 (LRP6). HCC cells with vacuolar protein sorting-associated protein 35 knocked down were adopted to generate engineered LRP6-exosomes. The engineered HCC-derived exosomes loading miR-26a inhibited HCC progression in vitro and in vivo effectively. Overexpression of miR-26a impaired the growth and migration of HCC by targeting lymphoid enhancer factor 1 (LEF1). Moreover, low expression of exosomal miR-26a was an independent prognostic factor for recurrence and survival in HCC patients. Our findings suggested the exosomal miR-26a could serve as a non-invasive prognostic marker for HCC patients. Genetically modified tumor-derived exosomes showed preferable transfection efficiency but reduced Wnt activity, which provides a novel therapeutic strategy for HCC.

Prognostic value of TLR from FDG PET/CT in patients with margin-negative stage IB and IIA non-small cell lung cancer.

To evaluate the prognostic value of TLR from PET/CT in patients with resection margin-negative stage IB and IIA non-small cell lung cancer (NSCLC) and compare high-risk factors necessitating adjuvant treatment (AT). Consecutive FDG PET/CT scans performed for the initial staging of NSCLC stage IB and IIA were retrospectively reviewed. The maximum standardized uptake value (SUVmax) of the primary tumor and mean SUV of the liver were acquired. The tumor-to-liver SUV ratio (TLR) was also calculated. Charts were reviewed for basic patient characteristics and high-risk factors for considering AT (poor differentiation, visceral pleura invasion, vascular invasion, tumors > 4cm, and wedge resection). Statistical analysis was performed using Cox regression analysis and the Kaplan-Meier method. Of the 112 patients included, 15 (13.4%) died, with a median overall survival (OS) of 43.8months. Twenty-two patients (19.6%) exhibited recurrence, with median disease-free survival (DFS) of 36.0months. In univariable analysis, pathology, poor differentiation, and TLR were associated with shorter DFS and OS. In multivariable analysis, TLR (hazard ratio [HR] = 1.263, p = 0.008) and differentiation (HR = 3.087, p = 0.012) were associated with shorter DFS. Also, TLR (HR = 1.422, p < 0.001) was associated with shorter OS. TLR from FDG PET/CT was an independent prognostic factor for recurrence and survival. PET parameters constitute risk factors for consideration in the decision-making for AT in margin-negative stage IB and IIA NSCLC. In this study, TLR from FDG PET/CT was an independent prognostic factor in stage IB-IIA non-small cell cancer patients. Although additional validation studies are warranted, TLR has the potential to be used to determine the need for adjuvant therapy. • High TLR is an independent poor prognostic factor in stage IB-IIA NSCLC. • Adjuvant treatment should be considered in patients with high TLR following complete tumor resection.

Abstract CT240: On-going phase 1A clinical trial for AG01 an first-in-class anti-progranulin (GP88) monoclonal antibody in patients with advanced malignancies

Abstract Progranulin (PGRN/GP88) is an 88 kDa glycoprotein characterized by seven and a half double cysteine rich repeats which is the largest member of the granulin-epithelin protein family. PGRN/GP88 has been demonstrated as a biological driver of tumorigenesis, survival, and drug resistance in several cancers including breast cancer (BC), lung prostate, ovarian and digestive cancers. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence in breast, lung cancers while elevated serum PGRN/GP88 level in metastatic breast, lung, ovarian and prostate cancer patients. Elevated PGRN/GP88 levels are associated with poor outcomes such as progression and shortened survival. An anti-human PGRN/GP88 monoclonal antibody able to inhibit PGRN/GP88 action in vitro and in vivo has been developed, chimerized and expressed in CHO cells. All IND enabling activities including pharmacology, GMP manufacturing, formulation and GLP toxicology studies have been conducted. The IND application has been filed and cleared by the Food and Drug Administration. A first-in-human, first-in-class phase 1 safety and efficacy clinical study of AG01 in patients with solid tumors and advanced disease with special focus on patients with breast, lung and ovarian cancers has been initiated and is on-going at the University of Maryland Greenebaum Cancer Center. The trial is registered as NCT05627960 to clinicaltrials.gov site. Supported by grants R44CA162629 and R44CA224718 from the National Cancer Institute to GS. Citation Format: Katherine R. Tkaczuk, Paula Rosenblatt, Ranee Mehra, Katherine A. Scilla, Nancy Tait, Katerra Caple, Binbin Yue, Ginette Serrero. On-going phase 1A clinical trial for AG01 an first-in-class anti-progranulin (GP88) monoclonal antibody in patients with advanced malignancies [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT240.

Abstract OT3-13-01: First in Human Study of AG01 a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88)

Abstract Progranulin (PGRN/GP88) is an 88 kDa glycoprotein characterized by seven and a half double cysteine rich repeats in the granulin-epithelin family. PGRN/GP88 is an autocrine biological driver of tumorigenesis, survival &amp; drug resistance in several cancers including breast, ovarian, multiple myeloma, prostate cancers, non-small cell lung carcinoma (NSCLCA) &amp; digestive cancers. PGRN/GP88 tissue expression is an independent prognostic factor of recurrence while elevated serum PGRN/GP88 level in metastatic breast, lung &amp; prostate cancer patients is associated with poor outcomes such as progression &amp; shortened survival. An anti-human PGRN/GP88 monoclonal antibody inhibiting PGRN/GP88 action has been developed &amp; expressed as recombinant antibody in CHO cells. Activities including pharmacology, manufacturing, formulation &amp; GLP toxicology studies have been carried out. The IND application has been cleared by the Food and Drug Administration to proceed with the first-in-human AG01 clinical study in adult patients ((pts) with advanced solid tumors. We present an ongoing First in Human Phase 1A (dose escalation,1+(3+3) &amp; IB (expansion cohorts) study of AG01 in pts advanced solid tumor malignancies (1A) with 4 expansion cohorts (1B) in pts with advanced Triple Negative Breast Cancer (TNBC), Hormone Resistant ER+/Her2- BC, advanced NSCLC &amp; mesothelioma. Study Design: This is an open-label, dose escalation study of AG01 antibody administered intravenously (IV) over 90 minutes every 14 days +/- 1 day (1A), followed by 4 predefined expansion cohorts, which will be treated at the RP2D determined in the phase 1A of this study. In the 1A part, initially accelerated titration design will be utilized to guide dose progression &amp; estimation of the maximum tolerated dose (MTD and/or maximum administered dose (MAD). In the 1A portion of the study pts with advanced relapsed/refractory solid tumor malignancies who failed 1 or more standard of care (SOC) therapies (tx) or for whom no SOC tx exists will be accrued. The primary objective of the 1A part is to determine the MTD and/or MAD of AG01. Secondary objectives are to determine the RP2D, assess the safety/tolerability, the pharmacokinetics (PKs) &amp; immunogenicity of AG01 &amp; the preliminary anti-tumor activity of AG01 via RECIST 1.1. The exploratory objectives are to determine PGRN/GP88 expression in tumor tissue and PGRN/GP88 blood levels using A&amp;G’s ELISA test. In the 1B Cohort Expansion phase, 4 separate cohorts of pts with PGRN/GP88 tissue expression of 1+, 2+, 3+ by IHC will be enrolled. Cohort 1- TNBC: ER and/or PR &amp;lt; 1% by IHC, HER2 &amp;lt; 3+ by IHC and/or FISH negative, pts must have failed 1 or more SOC tx for metastatic BC. Cohort 2- Hormone-resistant BC: ER and/or PR &amp;gt;1%, HER2 &amp;lt; 3+ by IHC and/or FISH negative, failed 1 or more prior hormonal tx (HT) or HT/CD4/6 kinase inhibitor tx or other targeted tx. Cohort 3- NSCLCA: metastatic/recurrent NSCLCA failed 2 or more SOC tx. Cohort 4 -Mesothelioma- failed 1 or more SOC tx for metastatic/recurrent mesothelioma or not a candidate for SOC tx. The primary objective of 1B part is to evaluate the antitumor efficacy of AG01 by overall response rate (ORR) defined as completed response (CR), partial response (PR), stable disease &amp;gt;=24 weeks (SD) (CR+PR+ SD) based on RECIST v1.1 in the 4 cohorts with each cohort assessed separately for response. Secondary objectives are to evaluate progression free survival (PFS), duration of response (DOR) &amp; overall survival (OS) of pts in cohorts 1-4, &amp; to evaluate the ORR, DOR &amp; PFS based on GP88 tissue expression, to further characterize the PKs &amp; the safety/tolerability of AG01. Exploratory objectives in 1B part will assess AG01 effect on circulating PGRN/GP88 levels in plasma or other potential biomarkers in the 4 cohorts. The estimated study sample is approximately 77 pts; 17 pts for the 1A part &amp; 60 pts for 1B part. The study is open to accrual at the UMGCCC. Supported by NCI grants R44CA224718 and R44CA162629 Citation Format: KATHERINE TKACZUK, Paula Rosenblatt, Ranee Mehra, Katherine Scilla, Nancy Tait, Binbin Yue, Ginette Serrero. First in Human Study of AG01 a chimerized monoclonal antibody to Progranulin/Glycoprotein 88 (GP88) [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 OT3-13-01.

Prognostic value of tumor budding in patients with stage II and III colon cancer: A single-institution experience.

247 Background: Tumor budding has recently been recognized as one important prognostic factor for recurrence in patients with localized colon cancer. Nevertheless, not all guidelines consider tumor budding in the decision-making process for selecting patients for adjuvant chemotherapy. We aim to assess the prognostic value of tumor budding in a cohort of patients with stage II and III colon cancer. Methods: We included patients with pathologically confirmed diagnosis of stage II and III colon cancer at Hospital Universitario La Paz and tumor budding assessment available, from October 2016 to August 2021. Tumor budding was reported following the recommendations from the 2016 International Tumour Budding Consensus Conference. Results: A total of 390 patients were included. Patients were predominantly men (55%) and had a median age of 75 (35-95). Fifty percent of the patients were stage II and 50% were localized in the right colon. Tumor budding was reported as low, intermediate, and high in 186 (48%), 110 (28%), and 94 (24%) patients, respectively. After a median follow up of 18 months, 63 recurrences and 73 deaths were observed. Time to recurrence was significantly worse for patients with high tumor budding. At 24 months, 91%, 79%, and 67% of patients with low, intermediate and high budding were recurrence-free. Median TTR was not reached in any of the three cohort (P &lt;0.001). Comparing high vs low or intermediate budding, the hazard ratio (HR) for recurrence was 0.13 [confidence interval (CI)95%: 0.05 to 0.32; P &lt; 0.001]. We performed a univariate analysis with the most relevant clinic-pathological features. T4, N2, R1, bowel obstruction or perforation, positive resection margins (R1), lymphovascular or perineural invasion, and mismatch repair protein status were found to be statistically associated with TTR and entered the multivariate analysis. T4, N2, R1 and high tumor budding (HR: 0.48 [CI95%: 0.28 to 0.84], P = 0.011) were independent prognostic factors for recurrence at the multivariate analysis. Conclusions: High tumor budding is an adverse independent prognostic factor for recurrence in patients with stage II and III colon cancer and should be acknowledge when considering adjuvant chemotherapy.

Combining γ-GT, PIVKA-II, and AFP to predict long-term prognosis in patients with hepatocellular carcinoma after hepatectomy.

Hepatocellular carcinoma (HCC) is one of the top five contributors to the cancer burden in China, with a poor prognosis and heavy disability-adjusted life year burden. The criteria used for HCC prognosis are complicated and therefore restricted in routine clinical practice. Multiple factors influence HCC malignancy and progression. In this study, we retrospectively evaluated 173 patients with HCC who underwent curative resection for 9 years to evaluate the correlation of a combination of γ-glutamyl transferase (γ-GT), protein induced by vitamin K absence or antagonist-II (PIVKA-II), and α-fetoprotein (AFP) with the long-term survival of patients with HCC. Multivariate analysis revealed that the γ-GT level was an independent prognostic factor for recurrence. The prediction rate of early recurrence with γ-GT, PIVKA-II, and AFP levels individually was 63.5%, 79.4%, and 39.7%, respectively, whereas the prediction rate of early recurrence was 95.2% with the combination of γ-GT, PIVKA-II, and AFP levels as a composite indicator. Our long-term retrospective study revealed that γ-GT, PIVKA-II, and AFP can aid in predicting long-term prognosis of HCC recurrence. The combination of γ-GT, PIVKA-II, and AFP can further aid in identifying patients with early recurrence. Together, γ-GT, PIVKA-II, and AFP may a be used to develop a new prediction method to improve the prognosis of patients with HCC, and our results indicate the requirement of more active HCC treatment strategies.