Risk Of Disease Recurrence Research Articles

Meta-analysis of Randomized Clinical Trials on Long-term Outcomes of Surgical Treatment of Perforated Diverticulitis.

To assess long-term outcomes of patients with perforated diverticulitis treated with resection or laparoscopic lavage (LL). Surgical treatment of perforated diverticulitis has changed in the last few decades. LL and increasing evidence that primary anastomosis (PRA) is feasible in certain patients have broadened surgical options. However, debate about the optimal surgical strategy lingers. PubMed, Scopus, and Web of Science were searched for randomized clinical trials (RCT) on surgical treatment of perforated diverticulitis from inception to October 2022. Long-term reports of RCT comparing surgical interventions for the treatment of perforated diverticulitis were selected. The main outcome measures were long-term ostomy, long-term complications, recurrence, and reintervention rates. After screening 2431 studies, 5 long-term follow-up studies of RCT comprising 499 patients were included. Three studies, excluding patients with fecal peritonitis, compared LL and colonic resection, and 2 compared PRA and Hartmann procedures. LL had lower odds of long-term ostomy [odds ratio (OR) = 0.133, 95% CI: 0.278-0.579; P < 0.001] and reoperation (OR = 0.585, 95% CI: 0.365-0.937; P = 0.02) compared with colonic resection but higher odds of diverticular disease recurrence (OR = 5.8, 95% CI: 2.33-14.42; P < 0.001). Colonic resection with PRA had lower odds of long-term ostomy (OR = 0.02, 95% CI: 0.003-0.195; P < 0.001), long-term complications (OR = 0.195, 95% CI: 0.113-0.335; P < 0.001), reoperation (OR = 0.2, 95% CI: 0.108-0.384; P < 0.001), and incisional hernia (OR = 0.184, 95% CI: 0.102-0.333; P < 0.001). There was no significant difference in odds of mortality among the procedures. Long-term follow-up of patients who underwent emergency surgery for perforated diverticulitis showed that LL had lower odds of long-term ostomy and reoperation, but more risk for disease recurrence when compared with resection in purulent peritonitis. Colonic resection with PRA had better long-term outcomes than the Hartmann procedure for fecal peritonitis.

Predictive Role of Serum Thyroglobulin after Surgery and before Radioactive Iodine Therapy in Patients with Thyroid Carcinoma.

Thyroidectomy followed by radioactive iodine therapy (RAI) is the treatment of choice for differentiated thyroid carcinoma (DTC). Serum thyroglobulin (Tg) measurement has proved to be useful for predicting persistent and/or recurrent disease during follow-up of DTC patients. In our study, we evaluated the risk of disease recurrence in patients with papillary thyroid carcinoma (PTC), who were treated with thyroidectomy and RAI, by measuring serum Tg at different time-points: at least 40 days after surgery, in euthyroidism with TSH < 1.5 and usually 30 days before RAI (Tg-30), on the day of RAI (Tg0), and seven days after RAI (Tg+7). One hundred and twenty-nine patients with PTC were enrolled in this retrospective study. All patients were treated with 131I for thyroid remnant ablation. Disease relapse (nodal disease or distant disease) during at least 36 months follow-up was evaluated by serum measurements of Tg, TSH, AbTg at different time points and by imaging techniques (neck ultrasonography, 131I-whole body scan (WBS) after Thyrogen® stimulation). Typically, patients were assessed at 3, 6, 12, 18, 24, and 36 months after RAI. We classified patients in five groups: (i) those who developed nodal disease (ND), (ii) those who developed distant disease (DD), (iii) those with biochemical indeterminate response and minimal residual thyroid tissue (R), (iv) those with no evidence of structural or biochemical disease + intermediate ATA risk (NED-I), and (v) those with no evidence of structural or biochemical disease + low ATA risk (NED-L). ROC curves for Tg were generated to find potential discriminating cutoffs of Tg values in all patients' groups. A total of 15 out of 129 patients (11.63%) developed nodal disease and 5 (3.88%) distant metastases, during the follow-up. We found that Tg-30 (with suppressed TSH) has the same sensitivity and specificity than Tg0 (with stimulated TSH), and it is slightly better than Tg+7, which can be influenced by the size of the residual thyroid tissue. Serum Tg-30 value, measured in euthyroidism 30 days before RAI, is a reliable prognostic factor to predict future nodal or distant disease, thus allowing to plan the most appropriate therapy and follow-up.

Abstract CT003: IMbrave050: Phase 3 study of adjuvant atezolizumab + bevacizumab versus active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following resection or ablation

Abstract Background: The risk of HCC recurrence after liver resection or ablation with curative intent is 70-80% within 5 years, indicating an unmet need for effective adjuvant therapies. Atezolizumab (atezo) with bevacizumab (bev) is the standard of care for unresectable HCC based on the IMbrave150 study, which demonstrated statistically significant and clinically meaningful improvements in overall survival (OS), progression-free survival, and objective response rate versus sorafenib (Finn NEJM 2020, Cheng J Hepatol 2022). On the basis of the antitumor activity of atezo + bev and its capacity to positively modulate the tumor microenvironment, IMbrave050 was designed to evaluate the efficacy of adjuvant atezo + bev in delaying or preventing recurrence in patients (pts) with high-risk HCC. Methods: IMbrave050 (NCT04102098) enrolled pts with HCC at high risk of recurrence following resection or ablation. High-risk criteria were based on tumor burden (tumor size and number), vascular invasion, and tumor differentiation. Pts were randomized to Arm A (atezo + bev) or Arm B (active surveillance). Stratification factors included geographic region (Asia-Pacific excluding Japan vs rest of world) and a composite factor encompassing the number of high-risk features, curative procedure, and use of optional adjuvant TACE (allowed for one cycle following resection). Pts in Arm A received atezo 1200 mg + bev 15 mg/kg IV q3w for a period of one year or 17 cycles. Pts in Arm B underwent active surveillance for one year and were eligible to crossover to atezo + bev following independent review facility (IRF) confirmation of recurrence. The primary endpoint was IRF-assessed recurrence-free survival (RFS). Secondary efficacy endpoints included OS; investigator-assessed (INV) RFS; RFS and OS according to PD-L1 status; and time to extrahepatic spread and/or macrovascular invasion. Results: The ITT population included 334 pts each in Arms A and B. Baseline demographics were well balanced between arms. At interim analysis, with a median follow-up of 17.4 mo (cut off date: Oct 21, 2022), the primary endpoint was met with an IRF-RFS HR of 0.72 (95% CI, 0.56, 0.93; P=0.0120), and results were generally consistent across clinical subgroups. INV-RFS was similar (HR, 0.70; 95% CI, 0.54, 0.91). The safety of atezo + bev was generally manageable and consistent with the well-established safety profile of each therapeutic agent and with the underlying disease. Conclusions: Atezo + bev is the first adjuvant regimen to demonstrate a statistically significant and clinically meaningful improvement in RFS vs active surveillance in pts at high risk of disease recurrence following resection or ablation. The benefit:risk profile of atezo + bev favors the use of this regimen as an adjuvant therapy and has potential to set a new standard of care in adjuvant HCC. Citation Format: Pierce Chow, Minshan Chen, Ann-Lii Cheng, Ahmed O. Kaseb, Masatoshi Kudo, Han Chu Lee, Adam Yopp, Jian Zhou, Lu Wang, Xiaoyu Wen, Jeong Heo, Won Young Tak, Shinichiro Nakamura, Kazushi Numata, Thomas Uguen, David Hsiehchen, Edward Cha, Stephen P. Hack, Qinshu Lian, Jessica Spahn, Chun Wu, Shukui Qin. IMbrave050: Phase 3 study of adjuvant atezolizumab + bevacizumab versus active surveillance in patients with hepatocellular carcinoma (HCC) at high risk of disease recurrence following resection or ablation [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 CT003.

Cost-Effectiveness Analysis of MammaPrint® to Guide the Use of Endocrine Therapy in Patients with Early-Stage Breast Cancer.

Gene expression profiling tests can predict the risk of disease recurrence and select patients who are expected to benefit from therapy, while allowing other patients to forgo therapy. For breast cancers, these tests were initially designed to tailor chemotherapy decisions, but recent evidence suggests that they may also guide the use of endocrine therapy. This study evaluated the cost effectiveness of a prognostic test, MammaPrint®, to guide the use of adjuvant endocrine therapy in patients eligible according to Dutch treatment guidelines. We constructed a Markov decision model to calculate the lifetime costs (in 2020 Euros) and effects (survival and quality-adjusted life-years) of MammaPrint® testing versus usual care (endocrine therapy for all patients) in a simulated cohort of patients. The population of interest includes patients for whom MammaPrint® testing is currently not indicated, but for whom it may be possible to safely omit endocrine therapy. We applied both a health care perspective and a societal perspective and discounted costs (4%) and effects (1.5%). Model inputs were obtained from published research (including randomized controlled trials), nationwide cancer registry data, cohort data and publicly available data sources. Scenario and sensitivity analyses were conducted to explore the impact of uncertainty around input parameters. Additionally, threshold analyses were performed to identify under which circumstances MammaPrint® testing would be cost effective. Adjuvant endocrine therapy guided by MammaPrint® resulted in fewer side effects, more (quality-adjusted) life-years (0.10 and 0.07 incremental QALYS and LYs, respectively) and higher costs (€18,323 incremental costs) compared with the usual care strategy in which all patients receive endocrine therapy. While costs for hospital visits, medication costs and productivity costs were somewhat higher in the usual care strategy, these did not outweigh costs of testing in the MammaPrint® strategy. The incremental cost-effectiveness ratio was €185,644 per QALY gained from a healthcare perspective and €180,617 from a societal perspective. Sensitivity and scenario analyses showed that the conclusions remained the same under changed input parameters and assumptions. Our results show that MammaPrint® can become a cost-effective strategy when either the price of the test is reduced (>50%), or the proportion of patients for which treatment is altered (i.e. those with ultra-low risk) increases to >26%. Standard MammaPrint® testing to guide the use of endocrine therapy in our simulated patient population appears not to be a cost-effective strategy compared with usual care. The cost effectiveness of the test can be improved by reducing the price or preselecting a population more likely to benefit from the test.

KRAS G12C mutation and risk of disease recurrence in stage I surgically resected lung adenocarcinoma

KRAS G12C mutations are found in about 12–13% of LUAD samples and it is unclear whether they are associated with worse survival outcomes in resected, stage I LUAD. We assessed whether KRAS-G12C mutated tumours had worse DFS when compared to KRAS-nonG12C mutated tumours and to KRAS wild-type tumours in a cohort of resected, stage I LUAD (IRE cohort). We then leveraged on publicly available datasets (TCGA-LUAD, MSK-LUAD604) to further test the hypothesis in external cohorts. In the stage I IRE cohort we found a significant association between the KRAS-G12C mutation and worse DFS in multivariable analysis (HR: 2.47). In the TCGA-LUAD stage I cohort we did not find statistically significant associations between the KRAS-G12C mutation and DFS. In the MSK-LUAD604 stage I cohort we found that KRAS-G12C mutated tumours had worse RFS when compared to KRAS-nonG12C mutated tumours in univariable analysis (HR 3.5). In the pooled stage I cohort we found that KRAS-G12C mutated tumours had worse DFS when compared to KRAS-nonG12C mutated tumours (HR 2.6), to KRAS wild-type tumours (HR 1.6) and to any other tumours (HR 1.8); in multivariable analysis, the KRAS-G12C mutation was associated with worse DFS (HR 1.61). Our results suggest that patients with resected, stage I LUAD with a KRAS-G12C mutation may have inferior survival outcomes..

Impact of sex on the efficacy of immune checkpoint inhibitors in kidney and urothelial cancers: a systematic review and meta-analysis

PurposeTo analyze and summarize the efficacy of immune checkpoint inhibitor (ICI) alone or in combination therapy for renal cell carcinoma (RCC) and urothelial carcinoma (UC) stratified by sex.MethodsThree databases were queried in October 2022 for randomized controlled trials (RCTs) analyzing RCC and UC patients treated with ICIs. We analyzed the association between sex and the efficacy of ICIs in RCC and UC patients across several clinical settings. The outcomes of interest were overall survival (OS) and progression-free survival for the metastatic setting and disease-free survival (DFS) for the adjuvant setting.ResultsOverall, 16 RCTs were included for meta-analyses and network meta-analyses. In the first-line treatment of metastatic RCC (mRCC) and UC (mUC) patients, ICI-based combination therapies significantly improved OS compared to the current standard of care, regardless of sex. Adjuvant ICI monotherapy reduced the risk of disease recurrence in female patients with locally advanced RCC (pooled hazard ratio [HR]: 0.71, 95% confidence interval [CI] 0.55–0.93) but not in male patients, and, conversely, in male patients with muscle-invasive UC (pooled HR: 0.80, 95%CI 0.68–0.94) but not in female patients. Treatment ranking analyses in the first-line treatment of mRCC and mUC showed different results between sexes. Of note, regarding adjuvant treatment for RCC, pembrolizumab (99%) had the highest likelihood of improved DFS in males, whereas atezolizumab (84%) in females.ConclusionsOS benefit of first-line ICI-based combination therapy was seen in mRCC and mUC patients regardless of sex. Sex-based recommendations for ICI-based regimens according to the clinical setting may help guide clinical decision-making.

Recurrent genital endometriosis: risk factors and possible prevention strategy

Endometriosis is one of the most common gynecological diseases in women of reproductive age, which is characterized by a relapsing course. The recurrence rate varies greatly among literary sources. This review covers symptoms and types of endometriosis, laboratory tests, options for hormonal therapy, as well as features of surgical approaches that may be associated with the disease recurrence risk. The aim of this article was to analyze and summarize current literature on the definition of endometriosis recurrence, risk factors and prevention strategy. Despite advances in the study of various mechanisms for the development of endometriosis and the use of combined treatment, a high recurrence rate remains an unsolved problem for this disease. All of this underscores the need to develop new methods for early diagnosis and treatment, taking into account the risk group and a personalized approach.

A-269 IMPACT OF THE COVID-19 PANDEMIC ON SURGERY FOR INDETERMINATE THYROID NODULES: RESULTS FROM A LARGE MULTICENTRIC INTERNATIONAL (THE THYCOVID) STUDY

Abstract Background During the COVID-19 pandemic, planned surgery was ubiquitously suspended or slowed down. We focused our attention on surgery for indeterminate thyroid nodules (ITNs). Methods This was a retrospective multicentric study. Patients with ITNs were included in the study and were divided into three groups based on when they were submitted to thyroidectomy: The main aims of the THYCOVID study were: Results We included 22974 patients with ITNs from 157 centers, mainly located in Europe (76.5%) and Asia (11.8%). The median monthly operations per center were 2 (IQR: 0.9-3.7) in P1, 1.4 (IQR: 0.6-3.4) in P2, and 2.3 (IQR: 1-5) in P3; the differences among the phases were all significant (p&amp;lt;0.001). At pathological examination, the incidence of lymph node metastases was significantly higher in P2 (11.7%) and in P3 (12.2%) than in P1 (9.3%; p&amp;lt;0.0001). Considering the ATA classification for risk of disease recurrence, the incidence of high-risk tumours increased over time from 203 (5.7%) patients in P1, to 198 (6.2%) in P2, and to 155 (7.7%) in P3; the difference between P1 and P3 was significant (p=0.0072). Conclusion Surgical activity for ITNs decreased significantly during the pandemic. In the last phase, an increased incidence of aggressive tumours was found.

Clinical factors of the risk of hyperplastic endometry processes on tamoxifen therapy with breast cancer: Retrospective population study

Background. One of the main stages of the treatment of breast cancer (BC) is endocrine therapy with tamoxifen or aromatase inhibitors. Five years of adjuvant tamoxifen therapy reduces the risk of disease recurrence by 39%. Tamoxifen was approved by the U.S. Food and Drug Administration in 1977 as a treatment for ER-positive BC. However, sometime after the start of tamoxifen's wide use, reports have been published on its long-term adverse effects. Most common were hot flashes, gynecological symptoms (vaginal dryness, vaginal discharge), depression, forgetfulness, sleep changes, weight gain, and decreased libido. However, more serious adverse events such as venous thromboembolic disease and endometrial hyperplasia or cancer are the most clinically significant. The article presents the results of a retrospective population-based study on assessing hyperplastic processes of the endometrium (HPE) in patients with breast cancer during TAM therapy, conducted in 2017, approved by the Ethics Committee of the Scientific Research of the Russian Medical Academy of Continuing Professional Education. Aim. To identify clinical factors that may increase the risk of HPE during tamoxifen therapy in patients with a history of breast cancer living in the Moscow region. Materials and methods. We retrospectively reviewed 230 case histories of patients with breast cancer. Of these, 120 patients who received TAM therapy had the following HPE risk factors: average age, menopausal status, body mass index, and duration of TAM therapy. Results. It was found that patients with HPE taking TAM were older (p=0.017), more likely to be postmenopausal (p=0.035), overweight (p=0.023), and received TAM for a longer period (p=0.028) than patients without HPE. Conclusion. The data obtained indicate the need for continuous monitoring by gynecologists of patients with breast cancer taking tamoxifen, paying particular attention to women from high-risk groups, namely older postmenopausal women with high body mass index receiving TAM for more than 1.52 years.

Metastatic neuroblastoma in fertility preservation biopsy of clinically normal testis: a case report

Research questionIs there potential for the detection of neuroblastoma malignancy in testicular tissue extracted for fertility preservation for prepubertal boys at the time of tissue freezing? DesignThis is a case report. ResultsA boy was diagnosed with primary localized left adrenal neuroblastoma, with complete resection of the tumour. During 6 months’ surveillance, he developed a relapse in the left para-renal region with progression of molecular and chromosomal features into undifferentiated neuroblastoma. Before highly gonadotoxic treatment, testicular biopsy for fertility preservation was taken, from a clinically normal testis. Histopathological examination of the testicular biopsy revealed metastatic neuroblastoma. ConclusionsMetastatic neuroblastoma detected histologically in a clinically normal testis highlights the importance of routine histological examination at the time of testicular cryopreservation. The histological evaluation of gonadal tissue for potential malignant contamination before freezing should be mandatory, regardless of the malignancy diagnosis. Advances in sensitive molecular detection and in-vitro maturation are critically required to decrease future risk of disease recurrence in both solid and haematological malignancies.

106P Perceptions, attitudes, and behaviors towards the risk of disease recurrence among women with HER2+ early breast cancer (eBC): ASKHER2 survey French cohort analysis

106P Perceptions, attitudes, and behaviors towards the risk of disease recurrence among women with HER2+ early breast cancer (eBC): ASKHER2 survey French cohort analysis

Multifokal Papiller Tiroid Karsinomlu Hastalarda Total Tiroidektominin Sonuçları ve Patolojik Özellikleri

Aim: The incidence of thyroid cancer has increased dramatically in recent decades. Multifocality is considered a poor prognostic factor for papillary thyroid carcinoma (PTC). Patients with multifocal PTC (MPTC) are at high risk for local recurrence, as well as lymphatic and distal metastases. This study examined the features and outcomes of MPTC. Material and Methods: This retrospective study was conducted on 300 patients with PTC. Patients were classified into a multifocal group and a unifocal group. The pathological features of the PTC and the patients’ outcomes were analyzed and compared. Results: The multifocal group included 146 patients (48.7%), while the unifocal group included 154 patients (51.3%). The occurrence of multifocality was higher in females than in males (Odds ratio, OR: 2.37, 95% confidence interval, CI: 1.20-4.67, p=0.015). Tumor size of &amp;gt;1 cm in the multifocal group was larger than in the unifocal group (2.5 and 2.2 cm, respectively, p=0.021). Moreover, in multifocal group higher moderate risk of recurrence was detected than in the unifocal group (OR: 1.63, 95% CI: 1.01-2.60, p=0.044). At follow-up after treatment, MPTC patients had higher lymph node metastasis (OR: 2.89, 95% CI: 1.23-6.80, p=0.014). In addition, significantly higher thyroglobulin plasma levels (p=0.026) and disease recurrence (OR: 2.41, 95% CI: 1.05-5.52, p=0.037) were found in the multifocal group compared to the unifocal group. Conclusion: Patients with MPTC had a higher risk of disease recurrence, and multifocality was concluded to be an independent prognostic factor for overall disease recurrence.

Effect of the COVID-19 pandemic on surgery for indeterminate thyroid nodules (THYCOVID): a retrospective, international, multicentre, cross-sectional study

Since its outbreak in early 2020, the COVID-19 pandemic has diverted resources from non-urgent and elective procedures, leading to diagnosis and treatment delays, with an increased number of neoplasms at advanced stages worldwide. The aims of this study were to quantify the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic; and to evaluate whether delays in surgery led to an increased occurrence of aggressive tumours. In this retrospective, international, cross-sectional study, centres were invited to participate in June 22, 2022; each centre joining the study was asked to provide data from medical records on all surgical thyroidectomies consecutively performed from Jan 1, 2019, to Dec 31, 2021. Patients with indeterminate thyroid nodules were divided into three groups according to when they underwent surgery: from Jan 1, 2019, to Feb 29, 2020 (global prepandemic phase), from March 1, 2020, to May 31, 2021 (pandemic escalation phase), and from June 1 to Dec 31, 2021 (pandemic decrease phase). The main outcomes were, for each phase, the number of surgeries for indeterminate thyroid nodules, and in patients with a postoperative diagnosis of thyroid cancers, the occurrence of tumours larger than 10 mm, extrathyroidal extension, lymph node metastases, vascular invasion, distant metastases, and tumours at high risk of structural disease recurrence. Univariate analysis was used to compare the probability of aggressive thyroid features between the first and third study phases. The study was registered on ClinicalTrials.gov, NCT05178186. Data from 157 centres (n=49 countries) on 87 467 patients who underwent surgery for benign and malignant thyroid disease were collected, of whom 22 974 patients (18 052 [78·6%] female patients and 4922 [21·4%] male patients) received surgery for indeterminate thyroid nodules. We observed a significant reduction in surgery for indeterminate thyroid nodules during the pandemic escalation phase (median monthly surgeries per centre, 1·4 [IQR 0·6-3·4]) compared with the prepandemic phase (2·0 [0·9-3·7]; p<0·0001) and pandemic decrease phase (2·3 [1·0-5·0]; p<0·0001). Compared with the prepandemic phase, in the pandemic decrease phase we observed an increased occurrence of thyroid tumours larger than 10 mm (2554 [69·0%] of 3704 vs 1515 [71·5%] of 2119; OR 1·1 [95% CI 1·0-1·3]; p=0·042), lymph node metastases (343 [9·3%] vs 264 [12·5%]; OR 1·4 [1·2-1·7]; p=0·0001), and tumours at high risk of structural disease recurrence (203 [5·7%] of 3584 vs 155 [7·7%] of 2006; OR 1·4 [1·1-1·7]; p=0·0039). Our study suggests that the reduction in surgical activity for indeterminate thyroid nodules during the COVID-19 pandemic period could have led to an increased occurrence of aggressive thyroid tumours. However, other compelling hypotheses, including increased selection of patients with aggressive malignancies during this period, should be considered. We suggest that surgery for indeterminate thyroid nodules should no longer be postponed even in future instances of pandemic escalation. None.

Machine learning-based immune phenotypes correlate with STK11/KEAP1 co-mutations and prognosis in resectable NSCLC: a sub-study of the TNM-I trial

We aim to implement an immune cell score model in routine clinical practice for resected non-small-cell lung cancer (NSCLC) patients (NCT03299478). Molecular and genomic features associated with immune phenotypes in NSCLC have not been explored in detail. We developed a machine learning (ML)-based model to classify tumors into one of three categories: inflamed, altered, and desert, based on the spatial distribution of CD8+ T cells in two prospective (n= 453; TNM-I trial) and retrospective (n= 481) stage I-IIIA NSCLC surgical cohorts. NanoString assays and targeted gene panel sequencing were used to evaluate the association of gene expression and mutations with immune phenotypes. Among the total of 934 patients, 24.4% of tumors were classified as inflamed, 51.3% as altered, and 24.3% as desert. There were significant associations between ML-derived immune phenotypes and adaptive immunity gene expression signatures. We identified a strong association of the nuclear factor-κB pathway and CD8+ T-cell exclusion through a positive enrichment in the desert phenotype. KEAP1 [odds ratio (OR) 0.27, Q= 0.02] and STK11 (OR 0.39, Q= 0.04) were significantly co-mutated in non-inflamed lung adenocarcinoma (LUAD) compared to the inflamed phenotype. In the retrospective cohort, the inflamed phenotype was an independent prognostic factor for prolonged disease-specific survival and time to recurrence (hazard ratio 0.61, P= 0.01 and 0.65, P= 0.02, respectively). ML-based immune phenotyping by spatial distribution of T cells in resected NSCLC is able to identify patients at greater risk of disease recurrence after surgical resection. LUADs with concurrent KEAP1 and STK11 mutations are enriched for altered and desert immune phenotypes.

Systemic LRG1 Expression in Melanoma is Associated with Disease Progression and Recurrence.

LRG1 could serve as a potential target and as a biomarker to identify patients with high risk for disease recurrence, and consequently benefit from additional therapies and intensive follow-up.

MRNA Vaccine Slows Melanoma Recurrence.

Findings from the phase IIb KEYNOTE-942 trial indicate that the investigational vaccine mRNA-4157/V940 plus pembrolizumab is a potential adjuvant therapy for high-risk melanoma. Following surgery, patients who received the combination experienced a significant reduction in disease recurrence risk, compared with those given just PD-1 inhibitor.

Imaging and photodynamic therapy of prostate cancer using a theranostic PSMA-targeting ligand

PurposeIncomplete resection of prostate cancer (PCa) results in increased risk of disease recurrence. Combined fluorescence-guided surgery with tumor-targeted photodynamic therapy (tPDT) may help to achieve complete tumor eradication. We developed a prostate-specific membrane antigen (PSMA) ligand consisting of a DOTA chelator for 111In labeling and a fluorophore/photosensitizer IRDye700DX (PSMA-N064). We evaluated the efficacy of PSMA-tPDT using PSMA-N064 in cell viability assays, a mouse xenograft model and in an ex vivo incubation study on fresh human PCa tissue.MethodsIn vitro, therapeutic efficacy of PSMA-N064 was evaluated using PSMA-positive LS174T cells and LS174T wild-type cells. In vivo, PSMA-N064-mediated tPDT was tested in immunodeficient BALB/c mice-bearing PSMA-positive LS174T xenografts. Tumor growth and survival were compared to control mice that received either NIR light or ligand injection only. Ex vivo tPDT efficacy was evaluated in excised fresh human PCa tissue incubated with PSMA-N064.ResultsIn vitro, tPDT led to a PSMA-specific light- and ligand dose-dependent loss in cell viability. In vivo, tPDT-induced tumor cell apoptosis, delayed tumor growth, and significantly improved survival (p = 0.004) of the treated PSMA-positive tumor-bearing mice compared with the controls. In fresh ex vivo human PCa tissue, apoptosis was significantly increased in PSMA-tPDT-treated samples compared to non-treated control samples (p = 0.037).ConclusionThis study showed the feasibility of PSMA-N064-mediated tPDT in cell assays, a xenograft model and excised fresh human PCa tissue. This paves the way to investigate the impact of in vivo PSMA-tPDT on surgical outcome in PCa patients.

Abstract CT270: Immunogenicity of PGV_001 neoantigen vaccine in a Phase-I clinical trial, across various types of cancers in adjuvant setting

Abstract Introduction: Immunotherapies such as checkpoint blockade, have demonstrated remarkable clinical efficacy yet a large percentage of patients do not respond, potentially due to a paucity of pre-existing immune priming against neoantigens. We developed a personalized genome vaccine (PGV_001) platform to generate neoantigen vaccines targeting each patient’s unique mutanome. Primary objectives of the study were to determine 1) the safety and tolerability; 2) the feasibility of PGV_001 production and administration; and 3) the immunogenicity of PGV_001. Secondary objectives included immunophenotyping vaccine driven cellular and soluble immune milieu in peripheral blood. We previously reported on the clinical efficacy, and here we report, analysis of vaccine-driven immune responses in all treated patients. Methods: The study (Trial Registration NCT02721043) enrolled patients with resected malignancies, including Head and neck squamous cell carcinomas, breast cancer and bladder cancer, or, in the case of multiple myeloma treated with autologous stem cell transplant; all patients determined to have a high risk of disease recurrence (&amp;gt;30% over 5 years). Tumor-derived and germline RNA and DNA was sequenced to predict neoantigens utilizing our custom computation pipeline, OpenVax. Approximately 10 peptides were synthesized per patient, and a mixture of these peptides was administered as 10 subcutaneous and intradermal vaccines over 27 weeks in combination with poly-ICLC and helper Tetanus peptide as adjuvants. Immune responses were analyzed utilizing assays including IFN-gamma ELISPOT, antigen specific T cell expansion followed by flow cytometry, etc. Results: In total 148 neoantigen peptides were manufactured for 15 patients. Overall, 136 PGV_001 doses were administered to 13 patients. Vaccine-specific T cell immunity was observed against multiple vaccine neoepitopes in all 13 subjects. Of the peptides administered, 45% of vaccine antigens (57/126) induced de novo immunity, starting as early as Week8 and often sustaining past last vaccination. Notably, while the vaccine driven T cell immunity was CD4 T cell dominant, most evaluated subjects also displayed vaccine induced polyfunctional CD8-T cell responses. Additional studies are ongoing to define qualities of reactive T cells, evaluate vaccine-induced humoral responses and probe the circulating inflammatory immune milieu. These will be presented. Conclusions: We have established a platform for generating personalized neoantigen vaccines. 100% of the vaccinated patients developed an immune response specific to the vaccine neoantigens predicted by OpenVax. Subjects who received treatment experienced mild Grade 1 or 2 adverse reactions as per the CTEP v 4.0 NCI CTCAE. This vaccine trial reached the primary endpoint of safety, tolerability, feasibility and immunogenicity. Based on the PGV_001 platform two clinical trials, one in patients with glioblastoma multiforme (NCT03223103) in combination with TT fields and second in patients with urothelial carcinoma (NCT03359239) in combination with Atezolizumab have been performed. Data from these trials is under evaluation. Citation Format: Mansi Saxena, Thomas Marron, Julia Kodysh, Alex Rubinsteyn, John Finnigan, Ana Blasquez, Marcia Meseck, Tim O'Donnell, Daniela Delbeau, Mathew Galsky, Deborah Doroshow, Brett Miles, Krzysztof Misiukiewicz, Hanna Irie, Amy Tiersten, Samir Parekh, Marshall Posner, Andrea Wolf, John Mandeli, Rachel Brody, Sacha Gnjatic, Eric Schadt, Philip Friedlander, Nina Bhardwaj. Immunogenicity of PGV_001 neoantigen vaccine in a Phase-I clinical trial, across various types of cancers in adjuvant setting [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 CT270.

Abstract LB293: The evolution of MRD assays: Moving beyond the tumor-Informed bespoke NGS panel

Abstract The non-invasive detection of circulating tumor DNA (ctDNA) from plasma has been shown to have clinical value for detection of minimal residual disease (MRD), identification of emerging resistance to treatment, and predicting treatment response. The ability to detect MRD following curative treatment allows for the stratification of patients with higher risk of disease recurrence. Multiple studies, across hundreds of patients in different indications, including lung and colon cancer, have shown that tumor-informed personalized assays have high sensitivity to detect recurrence. The tumor-informed bespoke panels utilize sequencing of the tumor tissue to identify clonal somatic variants, which are then used to generate a personalized panel to track the variants in patient plasma. Next-generation MRD technologies are aiming to provide greater sensitivity by expanding methods beyond the small, personalized panels. Utilization of increased numbers of somatic variants is predicted to achieve a greater level of sensitivity for detection of MRD. Here we describe, C2I Genomics which provides a novel platform that exploits whole genome sequencing of the tumor tissue and plasma to define a somatic variant signature. An important difference of this method is that it develops a personalized bioinformatic signature rather than a personalized NGS panel. To understand the potential of this novel methodology, we utilized a set of 54 contrived clinical sample dilutions from three indications, with an expected (or engineered) VAF range of 0.2-0.002%, that have commutability to the intended use population. We found that C2I Genomics technology is highly sensitive, where for all returned samples, the assay routinely achieved detection down to the lowest dilution of 0.002% allelic frequency. Overall, the assay resulted in an average detection rate of 93% across all dilutions (n = 54). The aggregate detection rate of several tumor-informed assays, examining the same dilutions, yielded a detection rate of 68%. In summary, the C2I Genomics assay showed robust detection from contrived samples which are representative of clinical trial samples in both cfDNA yields and allele frequency. Citation Format: Paul Labrousse, Daniel Stetson, James Hadfield, Chris Abbosh, Ahmet Zehir, Carl Barrett, Brian Dougherty, Darren Hodgson. The evolution of MRD assays: Moving beyond the tumor-Informed bespoke NGS panel [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 LB293.

Abstract 5594: Association of circulating cell-free DNA and prostate cancer risk groups in patients undergoing proton therapy

Abstract Even after radiation treatment, prostate cancer (PCa) patients receiving radiotherapy (RT) are still at risk for disease progression and recurrence. Predicting outcomes associated with cancer treatment is critical to PCa survivorship given that the 5-year survival rates for local and regional stage PCa is nearly 100%. Radiogenomics is a promising field of research focused on identifying genomic markers that can provide clinically useful prognostic predictions regarding radiation response and can potentially serve as the basis for personalized RT where cancer management is tailored to fit each individual patient. Circulating cell-free (ccfDNA) DNA has been found to 1) be associated with radiation sensitivity or toxicity, 2) relapse or recurrence, and 3) risk for the development of metastases before, during or following photon RT. Proton therapy, alternative to photon therapy, is a promising treatment that can reduce excess radiation dose and, in turn, the risk for adverse events. However, few studies have been done to determine if ccfDNA can predict response in proton radiation, which purports superior dose distribution, avoiding healthy tissues, minimizing the exit dose, and potentially reducing overall toxicity. The overall aim of this study is to determine if the quantity of ccfDNA is associated with PCa risk groups. We hypothesized that PCa patients within the highest risk group have quantitatively increased levels of ccfDNA compared to those in low and intermediate risk groups. This study leveraged the University of Florida Health Proton Therapy Institute Outcomes Tracking Protocol biobank of PCa patients with plasma and serum collected before, during and after proton RT. Isolation of ccfDNA at baseline, during treatment, and following treatment was undertaken and ccfDNA quantities were compared among patients in the low, intermediate and high risk groups using ANOVA. Our results indicate that the quantity difference between baseline and day 14 of treatment (p=0.055), 2 weeks post-treatment (p=0.54), and 4 weeks post-treatment (p=0.002) was associated with risk group. There was trend towards increasing ccfDNA quantity, as risk group increased; however, there was no correlation between risk group and treatment times using the Pearson correlation. Our results were consistent in that high ccfDNA quantity was associated with PCa risk. This is the first study determining the application of ccfDNA quantity on prostate cancer outcomes in patients undergoing proton RT. Identifying the determinants of radiation-related adverse outcomes will help inform impending predictive genomic technologies and improve cancer-related outcomes and survivorship. Citation Format: Andrew Bass, Johnny Velasquez, Moein Rajaei, Curtis Bryant, Nancy Mendenhall, Luisel J. Ricks-Santi. Association of circulating cell-free DNA and prostate cancer risk groups in patients undergoing proton therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5594.