Small Tumor Burden Research Articles

A Novel Technique to Improve Accuracy of Mohs Mapping for Large Stages with a Small Tumor Burden.

Precision of the Mohs micrographic surgery (MMS) process during orientation, microscopic analysis, tissue mapping, and tumor clearance of specimen margins is essential for MMS to attain high cure rates; however, this elaborate process is subject to error. Large tumor stages with a small tumor burden present an avenue for error during MMS mapping. We present a novel technique to improve the accuracy of MMS mapping using an MMS slide marked for residual tumor superimposed onto a mobile device photograph of the surgical defect. This is taken to better identify location of residual tumor both on the digitalized MMS photomap and surgical defect. This novel technique decreases recurrence rates by decreasing the inevitable subjectivity involved with the superimposition of residual tumor foci from a microscopic view onto the digitalized MMS photomap then onto the surgical defect particularly in larger stages with a small tumor burden.

The characteristics and long-term survival of patients with colorectal liver metastases with pathological complete response after chemotherapy.

Purpose: Preoperative chemotherapy is widely used for colorectal liver metastasis (CRLM). Pathological complete response (PCR) after chemotherapy indicates complete tumor regression and an extremely favorable prognosis. This study aimed to explore the characteristics and long-term survival of CRLM patients with pCR, who underwent surgery after preoperative chemotherapy.Methods: We retrospectively analyzed the clinical data of 494 CRLM patients who underwent hepatectomy after preoperative chemotherapy between January 2006 and January 2019. pCR was defined as the absence of any cancer cells on pathological examination.Results: Thirty (6.07%) patients achieved pCR after preoperative chemotherapy; 70% patients who achieved pCR did not experience recurrence and were cured after hepatectomy. The long-term prognosis of patients with pCR was extremely favorable, with 10-year overall and disease-free survivals of 85.2% and 73.7%, respectively; these were significantly better than those of patients without pCR (31.3% and 15.2%, respectively). Liver metastases <3 cm, preoperative carcinoembryonic antigen level ≤20 ng/mL, primary T stage 1-2, and right-sided primary tumors were independent predictors for pCR.Conclusion: pCR occurred in 6% of patients with CRLM after preoperative chemotherapy. Patients with a smaller tumor burden are more likely to benefit from chemotherapy and achieve pCR.

Extended Real-World Observation of Patients Treated with Sorafenib for Radioactive Iodine-Refractory Differentiated Thyroid Carcinoma and Impact of Lenvatinib Salvage Treatment: A Korean Multicenter Study.

Background: Treatment for patients with radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC) is challenging. Recently, two tyrosine kinase inhibitors (sorafenib and lenvatinib) have been approved and showed benefits for progression-free survival with tolerable adverse events. Methods: This is an extension study of a previous multicenter, retrospective cohort study of real-world experience in treating 98 patients with progressive RAI-refractory DTC with sorafenib. The primary endpoint was overall survival (OS). The efficacy of lenvatinib as salvage therapy after disease progression on first-line sorafenib was evaluated by comparing outcomes in 32 patients who were treated with lenvatinib with 41 patients who were not and therefore served as a no salvage treatment group. Results: The median OS of all 98 patients treated with sorafenib was 41.5 months, and the median progression-free survival was 13.5 months. Patients without disease-related symptoms before sorafenib treatment had better OS than those with symptoms (hazard ratio [HR] = 0.56 [95% confidence interval, CI 0.31-0.99], p = 0.048). Larger tumor size was associated with a minimally increased risk of death (HR = 1.02 [CI 1.00-1.03], p = 0.049). Best tumor response was not associated with OS (p = 0.490). Lenvatinib salvage treatment significantly improved OS in patients receiving it compared with those who did not (HR = 0.28 [CI 0.15-0.53], p < 0.001). The median OS from the time of disease progression after first-line sorafenib treatment was 4.9 months in no salvage treatment group, whereas it was not reached in the lenvatinib salvage group. Conclusions: The absence of disease-related symptoms and smaller tumor burden was associated with survival benefits of first-line sorafenib treatment in patients with progressive RAI-refractory DTC. Lenvatinib salvage therapy was effective in improving OS in patients with disease progression after first-line sorafenib.

1493P - Long-term avelumab treatment in patients with advanced non-small cell lung cancer (NSCLC): Post hoc analyses from JAVELIN solid tumour

1493P - Long-term avelumab treatment in patients with advanced non-small cell lung cancer (NSCLC): Post hoc analyses from JAVELIN solid tumour

Abstract 3681: RAD51AP1 is a novel therapeutic target for cancer prevention and treatment

Abstract Although much progress has been made in recent years in its treatment and prevention, cancer is still the second leading cause of death in the United States. Surgical removal of the tumor is not possible in all cancer types; therefore, chemotherapy and radiation therapy have become the standard course of treatment and are often the only option for more late stage and metastatic tumors. Unfortunately, chemotherapy and radiation therapy resistance are the greatest challenge for physicians trying to eradicate disease, prevent tumor recurrence, and inhibit distant metastasis. This resistance is derived from a heterogeneous population of cells within the tumor known as cancer stem cells (CSCs). CSCs are able to maintain a higher capacity for self-renewal due to a more efficient DNA repair system. CSCs are actively cycling, therefore, the repair mechanism of homologous recombination (HR) plays a significant role in repairing double-stranded DNA breaks that inevitably accumulate. Several studies have examined the link between efficient DNA repair and CSC self-renewal and found that proteins involved in HR repair are elevated in many human cancers. RAD51-associated protein 1 (RAD51AP1), which is responsible for the successful resolution of HR during DNA repair, is overexpressed in wide variety of human cancers. The present study sought to determine the functional role of RAD51AP1 in CSC self-renewal and its relevance to cancer growth and progression and also drug resistance. Our studies provide evidence that RAD51AP1 plays a critical role in CSC self-renewal and maintenance in breast, lung, and colon cancers. To determine the functional role of RAD51AP1 in cancer growth and progression, we generated genetically engineered mouse (GEM) models in breast and lung in WT (Rad51ap1+/+) and Rad51ap1-knockout (KO, Rad51ap1-/-) background and found that Rad51ap1 deletion significantly delayed the time of tumor formation and distant metastasis, which in turn increase the overall survival. Rad51ap1 inactivation in human breast and lung cancer cell lines, significantly reduced tumor growth in xenograft mouse model. This findings are also recapitulated in mouse mammary tumor cell lines (AT3 and 4T1). We also investigated the functional role of RAD51AP1 on colon cancer growth and progression using AOM/DSS and Apcmin/+ models of colon cancer and found that smaller tumor burden in KO mice compared to WT suggesting that Rad51ap1 may have a significant role in tumor growth. Taken together, these data demonstrate that RAD51AP1 plays a critical role in CSC growth and self-renewal in many human cancers and RAD51AP1 could be a novel therapeutic target for cancer prevention and treatment. Citation Format: Allison E. Bridges, Pragya Rajpurohit, Parth Patel, Nagendra Singh, Putter D. Prasad, Muthusamy Thangaraju. RAD51AP1 is a novel therapeutic target for cancer prevention and treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3681.

Abstract A44: No tumor or very small tumor burden in on-treatment biopsies is significantly associated with response to Pembrolizumab

Abstract Background: In phase I clinical trials, baseline and on-treatment biopsies are increasingly performed to investigate biomarkers correlating, e.g., with therapy response. Prior to use these biopsies for expensive analysis, quality control (QC) is performed regarding, e.g., morphology, tumor content. However, studies to correlate the results obtained from QC evaluation with clinical outcomes are lacking. The purpose of this study was to determine if data from the QC process correlate with therapy response. Method: We investigated 64 baseline and 50 on-treatment (C1D15-21) biopsies from 67 patients participating in an ongoing phase I clinical trial receiving pembrolizumab for their rare tumors such as e.g. adrenocortical carcinoma, angiosarcoma, alveolar rhabdomyosarcoma, carcinoma of unknown primary, epithelioid hemangioendothelioma, malignant neoplasm of tunica vaginalis, paraganglioma, penile carcinoma, pituitary tumor, renal medullary carcinoma, teratoma, and others. Baseline and the on-treatment biopsies were taken in &amp;gt;90% from the same amenable tumor lesion. Matched biopsies were available in n= 48 (71.64%) and data on response was available for 54 (80.60%) patients. From all biopsies the tumor content was estimated by a pathologist on an H&amp;E slide. Low tumor burden was defined as 0-10% tumor in the biopsy. If more than one biopsy was available, the average tumor content was calculated and used for analysis. Response was defined as stable disease or partial response. Results: The average tumor content in all biopsies was 39%, 38% baseline and 39% on-treatment. No tumor was detected in 15 (13%) of all biopsies, in 7 baseline (11%) and 8 on-treatment biopsies (16%). Low tumor burden was detected in 29 (25%) of all biopsies, in 17 baseline (27%) and in 12 on-treatment biopsies (24%). In 71% (5/7) of baseline biopsies and in 50% (4/8) of on-treatment biopsies with no tumor, fibrosis or necrosis was present. In 88% (15/17) of baseline biopsies and 67% (8/12) of on-treatment biopsies with low tumor burden fibrosis or necrosis was present. Thirty percent (7/23) of patients with response had no tumor in their on-treatment biopsies. All non-responders had tumor in their on-treatment biopsy. Forty three (10/23) patients with a low tumor burden in their on-treatment biopsies showed response compared to 5% (1/21) of non-responders. Hence, no tumor (0%) or low tumor burden (0-10%) in on-treatment biopsies was significantly associated with response (p=0.006 and p=0.003). Conclusion: Results obtained from the QC of clinical trial biopsies provide valuable information on tissue suitability for further analysis. In addition, we showed that an on-treatment biopsy with no tumor or very little tumor burden may predict partial or stable disease. Further studies to validate the role of tumor content in on-treatment biopsies in predicting response are warranted. Citation Format: Mingxuan Xu, Fengying Ouyang, Anas Alshawa, Joud Hajjar, Lilibeth Castillo, Hung Le, Ravi Murthy, Aung Naing, Coya Tapia. No tumor or very small tumor burden in on-treatment biopsies is significantly associated with response to Pembrolizumab [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2017 Oct 1-4; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2018;6(9 Suppl):Abstract nr A44.

Abstract 5118: Development of new alternative in vivo models to study early metastasic dissemination in breast cancer

Abstract Breast cancer is the first cause of death from female cancer. After the treatments against the primary tumor, a few cells can prevail in a state of quiescence for a long period of time, becoming minimal residual disease. There is a clear need for alternative techniques to enable an early detection of the disease for a better understanding of it and the generation of therapies capable of acting with a smaller tumor burden. Although many models have been developed for the detection of macrometastasis, there is a limitation of in vivo models that allow the identification of disseminated cells, micrometastasis, or analyze another steps of the metastasic cascade, as embolization or cell arrest. The aim of this work is the generation of in vivo models to enable the detection of disseminated tumor cells (DTCs) We began our study by evaluating the presence of disseminated tumor cells in three in vivo models and quantification by FACS. To this end, we generated the F3II murine triple negative mammary carcinoma line expressing the fluorescent protein GFP (F3II GFP); the F3II line was used as control. In s.c heterotopic model, we observed the presence of positive cells in tumors and livers of mice inoculated with F3II GFP (Student's t test) 30 days post inoculation. In the s.c orthotopic model, we detected positive cells in tumors of mice inoculated with F3II GFP (Student's t test). In both models, we did not observe significant differences in the presence of lung DTCs. In experimental metastasis models, we detected DTCs 15 days post inoculation in lungs of mice injected i.v with F3II GFP (Mann Whitney test).We carried out the search for cells disseminated at 24 h in order to obtain an in vivo model that evaluates the establishment capacity of these cells, and we observed that the percentage of GFP positive cells was higher in those mice inoculated iv with F3II GFP (Student´s t test). In addition, the presence of DTCs was detected by fluorescence microscopy in blood smears of these mice, suggesting that at 24 h there are fluorescent tumor cells in both lung and blood. In conclusion, although the established models allowed us to detect DTCs, the experimental metastasis model was more efficient in the detection and quantification of disseminated tumor cells. These models allows the detection and quantification of DTCs in the lung and blood circulation within 24 hours and 15 days after inoculation and could be used to study the mechanisms of metastasic dissemination involved in these cells and to test the capacity of various anti-tumor drugs to the early stage of metastasis Citation Format: Johanna Elena Sidabra, Carla Sabrina Capobianco, Maria Florencia Gottardo, Daniel Fernando Alonso, Hernan Gabriel Farina. Development of new alternative in vivo models to study early metastasic dissemination in breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5118.

Momelotinib decreased cancer stem cell associated tumor burden and prolonged disease-free remission period in a mouse model of human ovarian cancer.

Despite a good initial response to front-line chemotherapy, majority of the ovarian cancer patients relapse with consecutive phases of recurrences; and nearly 60% die within 5 years due to the development of a chemoresistant disease. This study investigated whether inhibition of the Janus kinase 2 (JAK2)-signal transducer and activator of transcription 3 (STAT3) pathway by momelotinib is sufficient in suppressing tumor burden and prolonging the disease-free survival period in a mouse model of ovarian cancer. We demonstrate that paclitaxel treatment enhanced JAK2/STAT3 activation which resulted in the enrichment of cancer stem cell (CSC)-like phenotype in the surviving ovarian cancer cells in vitro and in in vivo mouse xenografts. Combined treatment with paclitaxel and momelotinib inhibited paclitaxel-induced JAK2/STAT3 activation and CSC-like development in mice xenografts, and consequently reduced the tumor burden significantly greater than that achieved by paclitaxel-treatment alone. However, robust recurrent tumor growth with enhanced JAK2/STAT3 activation and CSC-like phenotype was observed in all mice groups after termination of treatments, but was delayed significantly in the paclitaxel and momelotinib treated group compared to other treatment groups. Daily oral gavage of momelotinib after termination of paclitaxel treatment showed sustained inhibition of tumor growth and a prolonged disease-free survival period in 50% of the mice. The other 50% of mice that developed tumors with ongoing momelotinib treatment also showed significantly increased survival benefit and a smaller tumor burden. These preliminary findings may have a profound clinical impact in developing an effective momelotinib-based ‘maintenance-therapy’ in ovarian cancer patients' post-chemotherapy treatment.

Oncoplastic breast reconstruction with omental flap: A retrospective study and systematic review.

The increasing frequency of early breast cancer cases has driven an increasing number of patients to choose immediate reconstruction with an autologous flap. Omentum-flap-based breast reconstruction is a unique strategy that is highly suitable for repairing moderate tissue defects. However, all available evidence comes from individual reports with small numbers of cases, and the overall effectiveness and safety of the procedure have yet to be reported. Here, we reported 7 cases of laparoscopically harvested omental free flap breast reconstruction and performed a systematic review to assess the applicability and safety of this approach. The data were gathered from MEDLINE, Ovid, Google Scholar and the China Knowledge Resource Integrated Database. In total, we combined 15 articles (410 cases) for analysis. The data revealed that almost all patients (87.6%) were reported to have undergone laparoscopy instead of laparotomy; pedicle flaps were used in 90.9% of the cases, while only 5 (37 cases) used free flaps for reconstruction; and 96.6% (396/410) of all reconstruction procedures were immediate. Almost all of these cases had a small tumour burden (T0/Tis/T1 59.8%; T2 36.8%), and the distribution of tumour location was similar among the four quadrants. The cosmetic outcomes were desirable in most cases (83.9%). There were 41 complications identified in the dataset: partial graft necrosis accounted for the largest percentage (41.5%) of all events, followed by skin necrosis (19.5%), haematoma (12.2%) and wound infection (9.8%). During the follow-up period, which had a short median duration, 2 cases of tumour recurrence were reported. Overall, our systematic review found that omentum-flap-based breast reconstruction could achieve a satisfactory aesthetic outcome, especially for small breasts and tissue replacement after breast-conserving surgery, and the safety of the procedure was also acceptable.

Evaluation of a Centyrin-Based Near-Infrared Probe for Fluorescence-Guided Surgery of Epidermal Growth Factor Receptor Positive Tumors.

Tumor-targeted near-infrared fluorescent dyes have the potential to improve cancer surgery by enabling surgeons to locate and resect more malignant lesions where good visualization tools are required to ensure complete removal of malignant tissue. Although the tumor-targeted fluorescent dyes used in humans to date have been either small organic molecules or high molecular weight antibodies, low molecular weight protein scaffolds have attracted significant attention because they penetrate solid tumors almost as efficiently as small molecules, but can be infinitely mutated to bind almost any antigen. Here we describe the use of a 10 kDa protein scaffold, a Centyrin, to target a near-infrared fluorescent dye to tumors that overexpress the epidermal growth factor receptor (EGFR) for fluorescence-guided surgery (FGS). We have developed and optimized the dose and time required for imaging small tumor burdens with minimal background fluorescence in real-time fluorescence-guided surgery of EGFR-expressing tumor xenografts in murine models. We demonstrate that the Centyrin-near-infrared dye conjugate (CNDC) binds selectively to human EGFR+ cancer cells with an EC50 of 2 nM, localizes to EGFR+ tumor xenografts in athymic nude mice and that uptake of the dye in xenografts is significantly reduced when EGFR are blocked by preinjection of excess unlabeled Centyrin. Taken together, these data suggest that CNDCs can be used for intraoperative identification and surgical removal of EGFR-expressing lesions and that Centyrins targeted to other tumor-specific antigens should prove similarly useful in fluorescence guided surgery of cancer. In addition, we demonstrate that the CNDC is detected in the NIR region of the spectrum and can be utilized for fluorescence-guided surgery (FGS). In addition, we propose that with its eventual complete clearance from EGFR-negative tissues and its quantitative retention in the tumor mass for >24 h, a Centyrin-targeted NIR dye should provide excellent tumor contrast when injected at least 6-8 h before initiation of cancer surgery in human patients.

Tumor response assessment: comparison between unstructured free text reporting in routine clinical workflow and computer-aided evaluation based on RECIST 1.1 criteria

Standardized computer-aided tumor response assessment is common in clinical trials. In contrast, unstructured free text reporting (UFTR) is common in daily routine. Therefore, this study aimed to discern and quantify differences between UFTR and computer-aided standardized tumor response evaluation based on RECIST 1.1 criteria (RECIST), serving as gold standard, in clinical workflow. One-hundred consecutive patients with cancer eligible for RECIST 1.1 evaluation, who received five follow-up CTs of the trunk, were retrospectively included. All UFTRs were assigned to RECIST response categories [complete response, partial response (PR), stable disease (SD), progressive disease (PD)]. All CTs were re-evaluated using dedicated software (mint lesion™) applying RECIST 1.1. The accordance in tumor response ratings was analyzed using Cohen's kappa. At the first follow-up, 47 cases were rated differently with an SD underrepresentation and a PR and PD overrepresentation in UFTR. In the subsequent follow-ups, categorical differences were seen in 38, 44, 37, and 44%. Accordance between UFTR and RECIST was fair to moderate (Cohen's kappa: 0.356, 0.477, 0.390, 0.475, 0.376; always p<0.001). Differences were mainly caused by the rating of even small tumor burden changes as PD or PR in UFTR or by comparison to the most recent prior CT scan in UFTR instead of comparison to nadir or baseline. Significant differences in tumor response ratings were detected comparing UFTR and computer-aided standardized evaluation based on RECIST 1.1. Thus, standardized reporting should be implemented in daily routine workflow.

CT volumetric measurement of colorectal cancer helps predict tumor staging and prognosis.

PurposeTo evaluate feasibility of CT colonography (CTC) volumetry of colorectal cancer (CRC) and its correlation with disease stage and patients’ survival.Materials and methodsCTC volumetry was performed for 126 patients who underwent preoperative CTC. Reproducibility of tumor volume (Tvol) between two readers was assessed. One-way ANOVA and ROC analysis evaluated correlation between Tvol and pTNM staging. ROC analysis compared diagnostic performance to predict pTNM staging between Tvol and radiologist. Kaplan-Meier test compared overall survival.ResultsReproducibility among readers was excellent (interclass correlation = 0.9829). Mean Tvol showed an incremental trend with T stage and Tvol of pT4b stage was significantly larger than other stages (P<0.0001). Az value (0.780) of Tvol to predict pT4b stage was significantly larger than that (0.591) of radiologist (P = 0.004). However, Tvol was not significantly different according to pN stage. Az values (0.723~0.857) of Tvol to predict M1 or M1b were comparable to those (0.772~0.690) of radiologist (P>0.05). Smaller tumor burden (≤12.85cm3), ≤T3, N0, M0 stages, and curative surgery were significantly associated with patients’ longer survival (P<0.05).ConclusionCT volumetry has a limited value to predict N stage; however, it may outperform the radiologist’s performance when predicting pT4b and M1b stage and can be a useful prognostic marker.

Abstract NTOC-083: TARGETED APPROACH WITH MOMELOTINIB TREATMENT ATTENUATES PACLITAXEL–INDUCED ENRICHMENT OF CANCER STEM CELLS (CSC)–LIKE AND SUPPRESSES OVARIAN CANCER TUMORIGENESIS AND RECURRENCE

Abstract INTRODUCTION: In the era of personalised medicine, chemotherapy treatment alone is inadequate to treat advanced-stage ovarian cancer patients, given that a steady 75% of patients relapse within five years and die of this disease. We have shown that chemotherapy-treated ovarian cancer cell lines express significantly elevated JAK2/STAT3 activation and CSC-like compared to untreated cells in vitro and in vivo mouse models. We aim to investigate the in vivo significance of targeting paclitaxel-induced ovarian CSC-like and the associated JAK2/STAT3 activation using the JAK2-specific inhibitor, Momelotinib. METHODS: Female Balbc nu/nu mice were injected ip with HEY cells and treated at day 19 with paclitaxel (15mg/kg bodyweight) weekly by ip injection and/or Momelotinib (25mg/kg bodyweight) daily by oral gavage. Study 1: All treatment groups (n=3/group) were sacrificed at the same time as the untreated control group (n=4). Study 2: All treatments were terminated after the endpoint of untreated group groups and were sacrificed at their respective endpoints (n=4). Study 3: Paclitaxel+Momelotinib-treated group was further divided into two groups (n=9/group) after the endpoint of the untreated group: (i) termination of paclitaxel and Momelotinib treatments, and (ii) termination of paclitaxel treatment alone for 13 weeks. One-way ANOVA was used to compare the tumour burden (tumour wt/mice wt), survival period, and immunohistochemistry analysis of the tumour xenograft for the activated JAK2/STAT3 and CSC-like markers (Oct3/4 and c-Kit) expressions between multiple groups. Statistical significance was defined as a p value &amp;lt; 0.05. RESULTS: In Study 1, paclitaxel+Momelotinib-treated group produced the smallest tumour burden compared to all groups, and had tumours that showed a reduction in the activated JAK2/STAT3 pathway and CSC-like markers expressions when compared to the paclitaxel-treated group. In Study 2, paclitaxel+Momelotinib-treated group survived the longest compared to all groups. In Study 3, paclitaxel+(ongoing)Momelotinib-treated group survived substantially longer and produced a significantly smaller tumour burden compared to the untreated and paclitaxel+(terminated) Momelotinib-treated groups. Expressions of the activated JAK2/STAT3 and CSC-like markers were significantly upregulated in the tumours isolated from paclitaxel+Momelotinib-treated group post-Momelotinib termination compared to pre-Momelotinib termination. CONCLUSION: Targeting the paclitaxel-induced JAK2/STAT3 activation and CSC-like using Momelotinib not only enhanced paclitaxel cytotoxicity but also prolonged the survival of HEY-bearing mice. This strongly supports the idea for future clinical testing using Momelotinib (currently in Phase 3 clinical trials for treating myelofibrosis) in combination with paclitaxel for advanced-stage ovarian cancer patients. These results also support the use of Momelotinib as a maintenance treatment for the ongoing suppression of the activated JAK2/STAT3 pathway in an attempt to prevent a relapse in ovarian cancer patients. Citation Format: Chan. E, Findlay. JK, Luwor. R, Hickey. M, Ahmed. N. TARGETED APPROACH WITH MOMELOTINIB TREATMENT ATTENUATES PACLITAXEL–INDUCED ENRICHMENT OF CANCER STEM CELLS (CSC)–LIKE AND SUPPRESSES OVARIAN CANCER TUMORIGENESIS AND RECURRENCE [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr NTOC-083.

Anti-LeY monoclonal antibody (mAb) hu3S193 as consolidation therapy for patients (pts) with relapsing platinum sensitive ovarian cancer (OC) after achieving a second complete response (2CR).

e17039 Background: Lewis-Y (LeY) antigen is a blood group related antigen expressed in 75% of OC. hu3S193 is a humanized anti-LeY IgG1 mAb with strong complement and antibody dependent cytotoxicity with clinical benefit shown in a phase II study in pts with platinum-resistant OC and small tumor burden. Improving progression free survival (PFS) in pts who achieve a 2CR is an unmet need. Methods: This phase II study accrued pts with relapsed OC, LeY expression by IHC, and a KPS ≥ 70% who had achieved a 2CR after 5-8 cycles of platinum doublet chemotherapy (chemoRx). Patients received intravenous infusions of hu3S193, 30mg/m2every 2 weeks starting ≤ 8 weeks after the last dose of chemoRx and continuing for 12 doses (24 weeks) or until disease progression or unacceptable toxicity. Primary endpoint was PFS with a sample size calculated to detect a 50% increase in PFS, compared to a historical value of 10.8 months. Secondary objectives were safety and pharmacokinetics (PK). Results: 29 pts were enrolled. Median age: 55 yrs (range 29-67); Median KPS: 90% (range 80-100); LeY expression by IHC (N): strong (20), weak (9); stage at initial diagnosis: I/II (2), III/IV (27); median CA-125 prior to 2CR chemoRx: 104 (range 9-514); chemoRx agents to achieve 2CR: paclitaxel/platin (21), liposomal doxo/carboplatin (8); median cycles of prior chemoRx to achieve a 2CR:6; median doses of hu3S193 delivered: 10 (range 10-12). Evaluable pts: 28 (1 pt did not have 2CR); median PFS: 11.8 months (95% CI: 10.6-13.9) while 3 pts achieved PFS of 25+ months. Grade 4 toxicities observed: none. Most frequent toxicities (any grade/grade 3): Nausea (16/2), Vomiting (15/3), Hypersensitivity (9/0). PK data will be presented. Conclusions: Despite the good tolerance and the longer PFS compared to historical control, this trial did not show a significant improvement with hu3S193 as a consolidative strategy in patients with 2CR in platinum-sensitive OC. Tumor molecular analysis of patients with long PFS may provide insight for future studies. Clinical trial information: NCT01137071.

Abstract B01: Enhancing radiotherapy by targeting inflammatory monocytes

Abstract Approximately 50% of cancer patients receive radiotherapy (RT) at some point throughout their treatment. Nevertheless, RT alone does not often result in cures, making it necessary to develop new ways to enhance this treatment modality. It is now understood that the efficacy of RT relies in large part on the anti-tumor immune response that it elicits. However, we believe that RT acts as a double-edged sword as it results in the infiltration of anti-tumor effector cells as well as myeloid cells associated with immunosuppression. One type of these myeloid cells, known as inflammatory monocytes (IM), are precursors for many immunosuppressive cells and have been shown to promote the progression of cancer in various models. However, the role these cells play in modulating the immune response following RT is unknown. To explore this, we focused on the specific chemokine receptors CCR2 and CCR5 and the primary ligands for these receptors, CCL2 and CCL5 respectively, which are present on IM and have been shown to play a role in the recruitment of myeloid cells into tissues and tumors alike. Here, we locally treat syngeneic tumors in C57BL/6 mice with 15Gy RT in order to study the role of CCL2+CCR5+ IM after RT. We show that RT upregulates the expression of intratumoral CCL2 and CCL5 by tumor cells. We also demonstrate that RT subsequently induces the increase of CCR2+ CCR5+ monocytes in circulation as well as their increased infiltration intratumorally. Therefore, we hypothesized that inhibiting the CCL2/CCR2 and CCL5/CCR5 axes and therefore blocking the infiltration of this potentially immunosuppressive cell population could improve the efficacy of RT. Administering a dual CCR2/CCR5 inhibitor (CCR2/CCR5i) daily beginning two days before RT, we demonstrate that inhibition of IM, both intratumorally and in circulation, results in smaller tumor burden and sustained tumor free survival in radioresponsive tumors. Furthermore, the anti-tumor effects of RT and the enhanced response afforded by CCR2/CCR5i is dependent on CD8+ T cells. These data suggest that inhibiting specific chemokine axes augments the anti-tumor effects of the adaptive arm of the immune system. Future studies will address the mechanism and clinical significance of targeting immunosuppressive myeloid cells as a means to enhance the effector functions of anti-tumor T-cells and further augment the efficacy of RT. Citation Format: Kelli Connolly, David Linehan, Scott Gerber. Enhancing radiotherapy by targeting inflammatory monocytes. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr B01.

Nationwide analysis: Changes in the natural history of low risk localized prostate cancer.

12 Background: Increased use of prostate-specific antigen (PSA) has introduced an increase in PCa incidence and a lead time and stage migration at diagnosis, altering the natural history of PCa. Contemporary PCa patients are likely younger and have smaller tumor burden at diagnosis. We investigated if changes in the PCa landscape have altered the course of low-risk localized PCa. Methods: In the Danish Prostate Cancer Registry (DaPCaR), patients diagnosed from 1995 to 2011 with localized (T1-2, N0/X, M0) PCa with Gleason score ≤ 6 were identified. Patients were stratified into three periods of diagnosis; 1995-2000 (period 1), 2001-2005 (period 2) and 2006-2011 (period 3). Competing risk analysis treating PCa and other-cause death as competing events was performed. Results: Of the 5,660 patients identified, 35.9% had undergone radical prostatectomy (RP). From period 1 to period 3, the median age at diagnosis decreased from 72.2 to 66.0 years and the median PSA decreased from 16.2 to 8.6 ng/mL. From period 1 to period 3, the 5-year risk of PCa-death decreased from 14.3% (95% CI: 12.1-16.4%) to 1.3% (95% CI: 0.83-1.7%), p &lt; .0.0001 and the risk of other cause death decreased from 18.1% (95% CI: 15.8-20.5%) to 7.2% (95% CI: 6.2-8.2), p = 0.0001. In patients undergoing RP, the 5-year risk of PCa-death decreased from 0.67% (95% CI: 0.67-2.0%) for patients diagnosed in period 1 to 0.45% (95% CI: 0.0055-0.84), for patients diagnosed in period 3, p = 0.92. For patients not undergoing RP, the 5-year risk of PCa death decreased from 16.6% (95% CI: 14.1-19.1) to 2.0% (95% CI: 1.2-2.7%), p &lt; 0.0001. Conclusions: In a nationwide cohort of patients with low risk localized PCa, the 5-year risk of PCa-death significantly decreased when comparing patients diagnosed during 2006-2011 to those diagnosed during 1995-2000. This was mainly driven by patients not undergoing RP. In the most recently diagnosed group, the difference in 5-year PCa-death between patients undergoing RP and not undergoing RP was small (0.45% vs. 2.0%). Our data demonstrate that the impact of PSA induced lead-time and stage migration has diminished the absolute effect of RP on the risk of 5-year PCa-death because contemporary low-risk localized patients have a significantly better prognosis.

Effect of N-Wasp knockout on tumour burden and survival in murine models of intestinal tumorigenesis and its potential as a prognostic biomarker in human colorectal cancer

BackgroundAPC loss is a common initiating event in colorectal cancer but additional mutations are required for progression along the adenoma–carcinoma pathway. The Neural Wiskott–Aldrich syndrome protein (N-WASP) is crucial for invasion in a variety of cancers. Its role in colorectal cancer has not been investigated; however, it is implicated in Wnt signalling (the pathway affected when APC function is lost). The aim of this project was to investigate the role of N-WASP in intestinal tumorigenesis and its potential as a prognostic biomarker. MethodsThe effect of N-Wasp knockout (N-Waspfl/fl) on survival and tumour burden was investigated using two established murine models of intestinal tumorigenesis (Apcfl/+ and Apcfl/+ KrasG12D/+). Immunohistochemistry for N-WASP was performed on two human tissue microarrays—namely, colorectal cancers with linked clinicopathological data and long-term follow-up, and early cancers diagnosed via bowel screening. N-WASP expression was assessed by weighted histoscore, and correlation with survival was tested. FindingsN-Wasp knockout decreased survival in the Apcfl/+ model (median survival 143 days [IQR 127·3–167·0] vs 269 [228·8–304·5], p<0·0001) and developed more small intestinal tumours (mean 39·7 tumours [SD 14·24] vs 8 [4·34], p<0·0001). Interestingly, although mean tumour size was decreased in Apcfl/+ N-Waspfl/fl mice compared with Apcfl/+ mice (0·538 mm2 [SD 0·238] vs 1·547 [0·609], p=0·0317), there was no difference in mean size of the largest tumour. There was no effect of N-Wasp knockout on survival or small intestinal tumour burden in the Apcfl/+ KrasG12D/+ model. However, they developed fewer colonic tumours (mean 16·8 [SD 10·2] vs 35·4 [11·5], p=0·0018). In the human tissue microarray studies, there was no difference in overall or cancer-specific survival between tumours with high and low N-WASP expression. InterpretationWe found that loss of N-Wasp promotes early tumorigenesis in Apc-deficient intestinal epithelium in mice. N-WASP stabilises epithelial cell–cell junctions and might be a regulator of Wnt signalling. Further research is required to ascertain whether either of these roles explains the effects seen here and whether it promotes invasion and metastasis in more advanced intestinal cancers, as seen in other tissues. FundingFunded by a Medical Research Council grant via the Scottish Clinical Pharmacology and Pathology Programme (SCP3).

Cell Adhesion Molecule CD166 Drives Malignant Progression and Osteolytic Disease in Multiple Myeloma.

Multiple myeloma is incurable once osteolytic lesions have seeded at skeletal sites, but factors mediating this deadly pathogenic advance remain poorly understood. Here, we report evidence of a major role for the cell adhesion molecule CD166, which we discovered to be highly expressed in multiple myeloma cell lines and primary bone marrow cells from patients. CD166+ multiple myeloma cells homed more efficiently than CD166- cells to the bone marrow of engrafted immunodeficient NSG mice. CD166 silencing in multiple myeloma cells enabled longer survival, a smaller tumor burden, and less osteolytic lesions, as compared with mice bearing control cells. CD166 deficiency in multiple myeloma cell lines or CD138+ bone marrow cells from multiple myeloma patients compromised their ability to induce bone resorption in an ex vivo organ culture system. Furthermore, CD166 deficiency in multiple myeloma cells also reduced the formation of osteolytic disease in vivo after intratibial engraftment. Mechanistic investigation revealed that CD166 expression in multiple myeloma cells inhibited osteoblastogenesis of bone marrow-derived osteoblast progenitors by suppressing Runx2 gene expression. Conversely, CD166 expression in multiple myeloma cells promoted osteoclastogenesis by activating TRAF6-dependent signaling pathways in osteoclast progenitors. Overall, our results define CD166 as a pivotal director in multiple myeloma cell homing to the bone marrow and multiple myeloma progression, rationalizing its further study as a candidate therapeutic target for multiple myeloma treatment. Cancer Res; 76(23); 6901-10. ©2016 AACR.

Physical activity induced protection against breast cancer risk associated with delayed parity

Epidemiological evidence indicates that physical activity between menarche and first pregnancy is associated with a lower risk of breast cancer among women with at least 20years between these reproductive events. The mechanism by which physical activity during this interval confers protection is unknown. This study used a novel animal model to assess potentially protective effects of physical activity on tumor development in delayed parity. Thirty-six female Sprague Dawley rats received an i.p. injection of 50mg/kg N-methyl-N-nitrosourea (MNU) at 5weeks of age. Estrogen and progesterone pellets were implanted subcutaneously 1week (early parity, EP, n=8) or 4weeks (delayed parity, DP, n=11) following MNU injection. An additional group of DP rats were progressively exercise trained (Ex+DP, n=9) on a treadmill following MNU injection for 7weeks (up to 20m/min at 15% incline for 30min). We observed the greatest tumor latency and smallest tumor burden in Ex+DP animals. Ductal hyperplasia and inflammation of non-tumor bearing mammary glands were only found in DP, and we detected a significant increase in collagen for DP and Ex+DP compared to EP. Exercise induced differential gene expression of cyclin-dependent kinase-inhibitor 1C (Cdkn1c) and urokinase-plasminogen activator (Plau) in mammary tissue of Ex+DP animals compared to DP alone. While there are delayed parity-induced changes in mammary gland collagen and gene expression levels, Ex+DP animals had longer tumor latency, smaller tumor burden, and glandular tissue resistant to ductal hyperplasia. Exercise may induce protection through beneficial regulation of gene expression profiles.

Management of Hepatocellular Carcinoma (HCC)

Hepatocellular carcinoma (HCC) is the fifth most common malignancy worldwide and the third leading cause of cancer-related death. Historically, HCC has been a problem mostly faced by patients from Asian countries due to the high prevalence of hepatitis B (HBV). Increasing global rates of HBV, hepatitis C, and obesity-related non-alcoholic steatohepatitis has caused a global increased incidence in HCC. Potentially curative therapies for HCC include liver resection, liver transplant, and radiofrequency ablation. More advanced HCC may be palliated with transarterial chemoembolization, transcatheter radioembolization, and sorafenib. Appropriate surveillance for those at risk and accurate clinical staging allows for earlier diagnosis and improved chance for cure. Hepatic resection remains the preferred primary therapy for HCC in the setting of relatively preserved liver function, while liver transplantation is the preferred curative therapy in the setting of small tumor burden with underlying liver disease. The application of locoregional therapies can also cure small lesions and maximize the utility of the limited donor pool by temporizing HCC and reserving livers for those who succumb to their underlying chronic liver disease.