High Risk Of Distant Metastasis Research Articles

Prediction of distant metastasis in esophageal cancer using a radiomics–clinical model

BackgroundDistant metastasis, which occurs at a rate of 25% in patients with esophageal cancer (EC), has a poor prognosis, with previous studies reporting an overall survival of only 3–10 months. However, few studies have been conducted to predict distant metastasis in EC, owing to a dearth of reliable biomarkers. The purpose of this study was to develop and validate an accurate model for predicting distant metastasis in patients with EC.MethodsA total of 299 EC patients were enrolled and randomly assigned to a training cohort (n = 207) and a validation cohort (n = 92). Logistic univariate and multivariate regression analyses were used to identify clinical independent predictors and create a clinical nomogram. Radiomic features were extracted from contrast-enhanced computed tomography (CT) images taken prior to treatment, and least absolute shrinkage and selection operator (Lasso) regression was used to screen the associated features, which were then used to develop a radiomic signature. Based on the screened features, four machine learning algorithms were used to build radiomics models. The joint nomogram with radiomic signature and clinically independent risk factors was developed using the logical regression algorithm. All models were validated and compared by discrimination, calibration, reclassification, and clinical benefit.ResultsMultivariable analyses revealed that age, N stage, and degree of pathological differentiation were independent predictors of distant metastasis, and a clinical nomogram incorporating these factors was established. A radiomic signature was developed by a set of sixteen features chosen from 851 radiomic features. The joint nomogram incorporating clinical factors and radiomic signature performed better [AUC(95% CI) 0.827(0.742–0.912)] than the clinical nomogram [AUC(95% CI) 0.731(0.626–0.836)] and radiomics predictive models [AUC(95% CI) 0.754(0.652–0.855), LR algorithms]. Calibration and decision curve analyses revealed that the radiomics–clinical nomogram outperformed the other models. In comparison with the clinical nomogram, the joint nomogram's NRI was 0.114 (95% CI 0.075–0.345), and its IDI was 0.071 (95% CI 0.030–0.112), P = 0.001.ConclusionsWe developed and validated the first radiomics–clinical nomogram for distant metastasis in EC which may aid clinicians in identifying patients at high risk of distant metastasis.

Aspirin Use is Associated with Improvement in Distant Metastases Outcome in Patients with Residual Disease after Neoadjuvant Chemotherapy

<h3>Purpose/Objective(s)</h3> Previous data has suggested that aspirin (ASA) use may be associated with improved outcomes in patients at higher risk for distant metastases after completion of curative therapy. Patients with breast cancer (BC) that do not obtain a pathologic complete response (pCR), particularly those with residual nodal disease (ypN+) after neoadjuvant chemotherapy (NAC) are at higher risk of worse outcomes. To date, there are no reported studies of potential benefit of ASA use within this subgroup. Our hypothesis is that ASA use can reduce the risk of distant metastases and improve outcome in ypN+ patients after NAC. <h3>Materials/Methods</h3> Patients at two institutions with BC treated with NAC who did not achieve pCR between 2005-2018 were reviewed (IRB protocol STU- 052012-019). Pertinent data, including evidence of ASA use (initiated during remission period), and clinico-pathologic parameters were analyzed. Overall survival (OS), disease free survival (DFS), and distant metastases free survival (DMFS) were obtained using Kaplan Meier analysis. Univariate and multivariate (MVA) logistic regression models were constructed and analyzed. <h3>Results</h3> 637 patients were evaluated, of which 138 were ASA users. Median follow-up for the control group was 3.8 (IQR 2.2-6.3) years and 3.8 (IQR 2.5-6.4) years for the ASA group. Nearly all patients had stage II or III disease (IIA: 75, IIB: 171, IIIA: 120, IIIB: 72, IIIC: 43). 416 patients underwent mastectomy, and 221 patients underwent partial mastectomy. 387 patients were HR+ (hormone receptor positive), 194 HER2+, and 157 were triple negative. 422 patients remained ypN+. The aspirin and non-aspirin groups did not show significant differences in patient characteristics analyzed. Clinico-pathologic characteristics analyzed for association with outcome included age, race, ASA use, molecular profile, pathologic and clinical stage, LVI, and clinical grade. On univariate analysis, ASA use, PR status, ypT, ypN, and clinical stage showed significance for improvements in DMFS, while ASA use, ER/PR status, ypT, ypN, and clinical stage showed significance for improvements in DFS. On MVA, ASA use remained significantly associated with improvements in 5-year DFS (p=.02, 87.0% vs 79.6%) and trended for 5-year DMFS improvement (p=.08, 92.8% vs 89.2%). In the ypN+ patients, ASA use was significantly associated with improvement in 5-year DMFS (p=.03, 85.7% vs 70.7%) on MVA. <h3>Conclusion</h3> Patients at higher risk for worse outcome, particularly those that are unable to achieve nodal clearance after NAC, demonstrated significant outcome benefits with ASA use initiated during remission period. These hypotheses-generating results suggest consideration for development of prospective clinical trials of augmented ASA use in these high-risk BC patients.

Investigating the clinical significance of EGFR expression using machine learning in a series of Iraqi patients with triple-negative breast cancer.

Breast cancer is a heterogeneous disease with a distinct profile of the expression of each tumor. Triple-negative breast cancer (TNBC) is a molecular subtype of breast cancer characterized by an aggressive clinical behavior linked to loss or reduced expression of estrogen, progesterone, and Her2/neu receptors. The study's main objective was to investigate the clinical significance of epidermal growth factor receptor (EGFR) overexpression in a series of Iraqi patients with TNBC. The sectional analytic study involved immunohistochemical analysis of EGFR expression in randomly selected 53 formalin fixed paraffin embedded tissue blocks of TNBC cases out of 127 Iraqi patients with TNBC and correlated expression data with clinicopathological parameters including survival time. Machine learning (statistical tests and principal component analysis (PCA)) was used to predict the outcome of the patients using EGFR expression data together with clinicopathological parameters. EGFR was expressed in approximately 28% of TNBC cases. We estimated the risk of mortality and distant metastasis based on EGFR expression and clinicopathologic factors using the principal component analysis (PCA) model. We found a substantial positive correlation between clinical stage and distant metastasis, clinical stage and death, death and distant metastasis, and death and positive EGFR expression. Overall, EGFR expression was linked to a poor prognosis and increased mortality. A higher risk of distant metastasis and death was associated with an advanced clinical stage of the tumor. Furthermore, the existence of distant metastases increased the risk of death. These findings raise the possibility of using EGFR expression data with other clinicopathological parameters to predict the outcome of patients with TNBC.

Can granulysin provide prognostic value in primary breast cancer?

BackgroundGranulysin (GNLY) is a cytolytic and proinflammatory molecule which also acts as an immune alarmin. The multifunctional nature of this molecule has made it challenging to define its full potential as a biomarker in breast cancer. AimTo evaluate the prognostic value of intratumoral GNLY in primary breast cancer patients and its association with established clinicopathological parameters. Patients and methodsThe study included 69 node-negative breast cancer patients with known clinicopathological parameters, all of whom had not received any prior hormonal or chemotherapeutic systemic therapy that would interfere with the course of disease. The median follow-up period was 144 months. Steroid hormone receptor status was determined by ligand-binding assay and HER2 status by chromogenic in situ hybridisation (CISH). Intratumoral GNLY mRNA levels were determined by RT-qPCR. Prognostic performance was evaluated by the receiver operating characteristic (ROC), Cox proportional hazards regression and Kaplan-Meier analysis. Classification of patients into GNLYlow and GNLYhigh subgroups was performed by the use of the outcome-oriented cut-off point categorisation approach. ResultsThere was a significant difference between GNLY values of patients without any recurrences and those with local or distant recurrences (Mann-Whitney test, p = 0.05 and p = 0.02, respectively). None of the tested parameters showed prognostic significance for local and distant recurrences when combined. When distant metastases and local recurrences were separated as events, the best prognostic performance was observed for GNLY as compared with any clinicopathological parameter (AUC=0.24 and p = 0.04 for local events; AUC=0.71 and p = 0.03 for distant events). Local recurrence incidence was 0% for the GNLYhigh subgroup and 19% for the GNLYlow subgroup; however distant recurrence incidence was 24% for the GNLYhigh subgroup but only 3% for the GNLYlow subgroup (Kaplan–Meier analysis). A significant positive correlation was found between intratumoral ER and GNLY levels, and a significant negative correlation between tumour grade and GNLY levels. ConclusionHigh levels of granulysin prognosticate low risk of local recurrence but a high risk of distant metastasis in primary, untreated, breast cancer patients.

A decision support framework for postoperative radiotherapy in patients with pathological N2 non-small cell lung cancer

IntroductionPostoperative radiotherapy (PORT) plays a highly controversial role in pathological N2 (pN2) non-small cell lung cancer (NSCLC) disease. Recent studies reveal that not all patients can benefit from PORT. Further research is needed to identify predictors of PORT. MethodsA total of 1044 pathologic stage T1-3N2M0 NSCLC patients were analyzed. Risk factors of distant metastasis were identified by the log-rank tests and the multivariable Cox models. We integrated risk factors of distant metastasis and our previously published loco-regional recurrence (LRR) related prognostic index into a decision support framework (DSF) to predict the outcomes of PORT. An independent cohort was used to validate the DSF. ResultsWe defined patients with more than two of three identified LRR-related features (heavy cigarette smoking history, clinical N2 status, and more than four positive lymph nodes) as a high LRR risk group. We found the high-intermediate-risk histological type (with micropapillary and/or solid components) was associated with a higher risk of distant metastasis (HR = 1.207, 95 % CI 1.062 to 1.371, P = 0.0038), but not LRR. We built the DSF by combining these two types of features. Patients were stratified into four groups by using the DSF. PORT significantly improved OS only in the subgroup without high-risk histological features (without micropapillary or solid components) and with a high risk for LRR (three-year OS: 66.7 % in the PORT group vs 50.2 % in the non-PORT group; P = 0.023). ConclusionsA particular pN2 subgroup with a high risk of LRR and without micropapillary or solid components could benefit from PORT.

The Value of Volumetric Indicators of PET/CT &lt;sup&gt;18&lt;/sup&gt;F-Fluorodeoxyglucose of Patients with Synovial Sarcoma: Two Clinical Cases

Synovial sarcoma (SS) is a rare malignant soft tissue tumor that is associated with a high risk of distant metastasis, which significantly reduces patients` life expectancy. The analysis of volume indicators of PET/ CT)with 18F-fluorodeoxyglucose (FDG) was performed in two patients with the same grade of SS malignancy. The presented clinical cases demonstrate that in different patients with similar values 18F- FDG of the standardized uptake value (SUVmax) PET/CT volume indicators such as Metabolic Tumor Volume (MTV) and Total Lesion Glycolysis (TLG) can vary significantly, and therefore they can be additional prognostic factors for overall survival.

Abstract 6123: High-fat diets promote lung metastasis of breast cancer by activating lung fibroblasts

Abstract Metastasis is the main cause of patient death among many tumor types including breast cancer and breast cancer patients with obesity have higher risk of distant metastases during 10-year follow-up. Diet is one of the main and manageable factors that cause obesity and regular intake of high-fat diets can induce obesity. In addition, fibroblasts, as the most abundant stromal cell type in tumor microenvironment, are involved in cancer metastasis. However, the role of fibroblasts and the downstream mechanism in metastasis of patients with high-fat diet remains unclear. In this study, we fed MMTV-PyMT transgenic mice with high-fat diet to obtain a high-fat tumorigenesis model, and isolate primary lung fibroblasts and then coculture them with breast cancer cells to explore the interaction. We found that a high-fat diet can significantly promote progression of primary breast cancer and lung metastasis, and that before weight difference shows, there is a different chemotactic influence of lung fibroblasts on breast cancer cell between high-fat diet and normal diet group. And we observed increased chemotactic function of primary lung fibroblasts in high-fat diet group. Moreover, tumor cells treated with primary lung fibroblasts in high-fat diet group show increased ability of adhesion, suggesting that high-fat diet chemoattracts breast cancer cell colonization by activating lung fibroblasts. Collectively, we explored the functional differences of lung fibroblast and the key factors for the lung colonization of recruited breast cancer cells. Our findings suggest that dietary patterns are associated with the risk of breast cancer metastasis and targeting activated fibroblasts in pre-metastatic microenvironment may serve as potential early therapeutic strategy to reduce breast cancer lung metastasis. Citation Format: Huiping Chen, Penghan Huang, Jianing Chen, Erwei Song. High-fat diets promote lung metastasis of breast cancer by activating lung fibroblasts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 6123.

Outcomes in pleomorphic liposarcoma of the extremity and trunk: Is multimodality therapy indicated?

e23545 Background: In comparison to the more common histologic subtypes of liposarcoma (e.g., well differentiated/dedifferentiated; myxoid round cell), pleomorphic liposarcoma (PLPS) is poorly understood but generally regarded as more aggressive, with a high risk of distant metastasis. In this study, we sought to 1) assess outcomes after surgery for primary, non-metastatic PLPS and 2) explore indications for multimodality therapy (e.g., perioperative chemotherapy, radiation therapy) in this ultra-rare malignancy. Methods: Clinicopathologic data were retrospectively collected for eligible adult patients treated from 2002-2019 at our sarcoma referral center. Descriptive data was summarized and Kaplan-Meier plots were constructed for overall survival (OS) and crude cumulative incidences (CCI) of disease-specific death (DSD), local recurrence (LR) and distant metastasis (DM). Univariable models were performed to assess the association of specific variables of interest (e.g., tumor size) on outcome. Results: In total, 51 PLPS patients were included in this study. Mean tumor size was 9.7 cm. Tumors originated mostly in the extremity (67%), were deep in location (73%), and high grade (FNCLCC 3/3, 78%). All patients underwent complete (R0/R1) resection. Chemotherapy was given in 33% of patients and radiation therapy in 69%. With a median follow-up of 62 months, OS was 76% at 5 years. CCI of DSD, LR and DM at 5 years was 16%, 2% and 26%. Greater tumor size was observed to be strongly associated with worse OS (p = 0.002) and DSD (p = 0.006). Survival did not seem to be affected by pre-referral inadequate excision once patients (n = 18) underwent re-excision at our center. A separate subgroup of patients (n = 14) was identified with smaller (mean: 5.4 cm), superficial, lower grade tumors who underwent surgery alone without any DSD. Conclusions: In primary, non-metastatic PLPS, adequate surgery combined with perioperative chemotherapy and radiation therapy, when appropriate, is associated with favorable outcomes. Subgroups with potentially better clinical outcomes likely exist suggesting heterogeneity within PLPS. Multidisciplinary collaborative efforts across sarcoma centers are needed to better characterize these subgroups and determine the optimal strategies for management.

Evaluating the impact of the degree of extranodal extension on outcomes in locally advanced oral cavity cancer.

e18058 Background: The presence of extranodal extension (ENE) in oral cavity cancer is associated with a higher risk of distant metastasis and worse overall survival (OS). Trials show that patients with locally advanced head and neck cancer and ENE benefit from concurrent chemoradiation over radiation therapy alone.We explored whether degree of ENE impacts survival outcomes in individuals with oral cavity cancer. Methods: From an IRB-approved database of 303 pts with locally advanced oral cavity cancer treated with surgical resection between 2001-2020, patients with pathologic ENE who received adjuvant treatment were included. Patient demographics, tumor staging, treatment information, disease recurrence, and survival were collected. Surgical slides were reviewed to confirm the extent of ENE. All staging was updated to AJCC 8th edition. Cox proportional hazards regression was used to relate patient, tumor, or treatment characteristics with either disease-free survival (DFS, composite of disease recurrence and death) or OS, from the time of radiation therapy completion. ENE was analyzed as both a dichotomous variable (major if &gt; 2 mm, minor if ≤2 mm) and as a continuous variable in the subset of patients for whom exact ENE extent could be confirmed. Results: A total of 113 patients were identified who underwent surgery and adjuvant therapy for advanced oral cavity cancer with ENE, with 35 having major ENE and 78 having minor ENE. Forty-one patients had T1-T2 disease while 72 had T3-T4 disease. Additionally, 24 had N2a disease and 89 had N3b disease. Of these, 78 received concurrent chemoradiation while 35 received radiation therapy alone. Ninety-nine patients had pathologic slides available for review to determine exact ENE extent. Median ENE distance was 1 mm (IQR 1-2, range 0.1-10). With a median follow up time of 22.3 months, there were 48 recurrences and 67 deaths. Median DFS was 21.3 months (95%CI 11.1-33.2) and median OS was 29.9 months (95%CI 20.6-66.6). Between major vs minor ENE, there was no statistically significant difference in DFS (HR 1.18, 95%CI 0.72-1.92, p = 0.51) or OS (HR 1.17, 95%CI 0.70-1.96, p = 0.55). Furthermore, there was no statistically significant association between ENE as a continuous variable and DFS (HR 0.97 per mm, 95%CI 0.87-1.4, p = 0.96) or OS (HR 0.96 per mm, 95%CI 0.83-1.11, p = 0.58). The benefit of concurrent chemotherapy on OS was not seen (HR 0.74, 95%CI 0.44-1.22, p = 0.24), though those patients on average had more advanced nodal disease (85% N3b vs 66%). Conclusions: No significant relationship was seen between extent of ENE and DFS or OS in individuals with locally advanced oral cavity cancer. This analysis was limited by the small number of patients, that most patients had ≤2 mm of ENE, and the presence of confounding risk factors such as nodal stage and receipt of chemotherapy. Overall, the effect of the degree of ENE on outcomes in advanced oral cavity cancer remains unclear.

TIRA study: A phase III, multicenter, randomized controlled study of toripalimab plus radical chemoradiotherapy with or without concurrent cisplatin in patients with high-risk locoregionally advanced nasopharyngeal carcinoma.

TPS6101 Background: Patients with locoregionally advanced nasopharyngeal carcinoma (LA-NPC) suffer a high risk of distant metastasis and require guideline-recommended multimodality therapy. However, cisplatin-based concurrent chemotherapy leads to a high incidence of severe toxicities and low patient compliance, consequently limiting survival improvement. Toripalimab, an immune checkpoint inhibitor targeting programmed cell death 1 (PD-1), has a novel anti-cancer mechanism and mild toxicity spectrum. Robust evidence showed that given toripalimab + gemcitabine-cisplatin (GP) chemotherapy regimen, the median progression-free survival could be markedly improved in patients with recurrent and metastatic NPC. Besides, PD-1 antibody + radiotherapy is also regarded as a promising therapeutic strategy due to the synergistic effect. Therefore, we hypothesized that the de-intensification strategy using toripalimab + induction chemotherapy (IC) followed by radiotherapy alone would obtain equivalent survival and low toxicity in patients with LA-NPC compared with toripalimab + IC followed by concurrent chemoradiotherapy. Methods: TheTIRA study is a multicenter, randomized, controlled, open-label, phase III study. Since August 2021, we have been recruiting high-risk LA-NPC patients (stage III-IVa, except T3-4N0M0 &amp; T3N1M0) from 12 Chinese centers. Our target sample size is temporarily set at 494 patients with 247 for each arm. Patients will be 1:1 ratio randomized to the experimental or control arm. Patients in the experimental arm will receive induction-concurrent toripalimab (240 mg, d1, Q3W × 6 cycle) with IC (gemcitabine 1000 mg/m2, d1 &amp; d8 + cisplatin 80 mg/m2, d1, Q3W × 3 cycle) + intensity-modulated radiotherapy (IMRT, 70 Gy in 33 fractions), and thereafter adjuvant toripalimab (240 mg, d1, Q3W × 11 cycle). Patients in the controlled arm will receive an additional concurrent cisplatin (100 mg/m2, d1, Q3W × 2 cycle). The primary endpoint is the 3-year failure-free survival. Secondary endpoints include 3-year overall survival, 3-year distant metastasis-free survival, 3-year locoregional recurrence-free survival, quality-of-life assessment according to the systems of the European Organization for Research and Treatment of Cancer and the Functional Assessment of Cancer Therapy, and safety profile. Exploratory analysis will be performed for potential biomarkers of survival prediction including PD-L1 expression and tumor-infiltrating lymphocytes. Clinical trial information: NCT04907370.

Loss of cell division cycle‑associated 5 promotes cell apoptosis by activating DNA damage response in clear cell renal cell carcinoma.

Cell division cycle-associated 5 (CDCA5) protein, which is involved in cohesion, contributes to cell cycle regulation and chromosome segregation by maintaining genomic stability. Accumulating evidence indicates that CDCA5 expression is upregulated in a number of types of cancer associated with a poor prognosis. However, the biological function of CDCA5 in clear cell renal cell carcinoma (ccRCC) remains largely unknown. In the present study, The Cancer Genome Atlas data mining revealed that CDCA5 was more highly expressed in ccRCC than in adjacent normal tissues. Importantly, such a high expression was associated with a higher risk of distant metastasis and poorer clinical outcomes. Moreover, the clinical and prognostic value of CDCA5 expression was further investigated using immunohistochemistry on tissue microarrays containing paired tumor tissues and adjacent normal tissues from 137 patients with ccRCC. Functional analyses revealed that CDCA5 knockdown significantly inhibited the proliferation and migration of ccRCC cells, and suppressed the growth of xenografts in nude mice. Mechanistically, CDCA5 knockdown induced severe DNA damage with the persistent accumulation of γ-H2A histone family member X foci, resulting in G2/M cell cycle arrest and finally, in chromosomal instability and apoptosis. CDCA5 knockdown significantly decreased the phosphorylation levels of Stat3 and NF-κB, suggesting that CDCA5 plays a role in regulating the inflammatory response. Collectively, the findings of the present study indicate that ccRCC cells require CDCA5 for malignant progression, and that CDCA5 inhibition may enhance the outcomes of patients with high-risk ccRCC.

CircRIP2 aggravates the deterioration of colorectal carcinoma by negatively regulating CBFB.

This study aims to detect expression pattern and clinical significance of circRIP2 in colorectal carcinoma (CRC). In the meantime, the regulatory effect of circRIP2 on CRC cell functions is clarified. Relative levels of circRIP2 in 45 cases of CRC tissues and paracancerous tissues were detected by quantitative real-time polymerase chain reaction (qRT-PCR). Its clinical significance in predicting pathological manifestations of CRC was analyzed. In vitro regulation of circRIP2 on proliferative and migratory abilities of Sw620 and HCT-116 cells was assessed by cell counting kit-8 (CCK-8), 5-Ethynyl-2'-deoxyuridine (EdU) and transwell assay, respectively. Dual-Luciferase reporter assay and rescue experiments were conducted to reveal the interaction between circRIP2 and its target gene CBFB, as well as their co-regulation on CRC cell functions. At last, in vivo regulation of circRIP2 on CRC growth in nude mice implanted with HCT-116 cells was explored. CircRIP2 was upregulated in these samples of CRC tissues and cell lines. High level of circRIP2 predicted advanced staging, and high risk of distant metastasis of CRC. In vitro knockdown of circRIP2 weakened proliferative and migratory abilities in Sw620 and HCT-116 cells. CBFB was downregulated in CRC tissues, which was negatively regulated by circRIP2 as its target gene. The attenuated proliferative and migratory abilities in Sw620 and HCT-116 cells with circRIP2 knockdown were abolished by co-silence of circRIP2 and CBFB. Moreover, in vivo knockdown of circRIP2 slowed down CRC growth in nude mice, and upregulated positive expression of CBFB in xenografted CRC tissues. CircRIP2 is a potential indicator for predicting tumor staging and distant metastasis of CRC. It aggravates the deterioration of CRC through negatively regulating CBFB.

Photon-based High-dose Single-fraction Radiosurgery, an Effective Treatment Modality for Large and Posterior Uveal Melanoma.

Uveal melanoma (UM) is the most common primary intraocular malignant tumor. This malignancy is frequently treated using brachytherapy, stereotactic radiotherapy, or proton therapy. The objective of this study was to assess the role of stereotactic radiosurgery in the treatment of large and posterior UM. From January 2014 to July 2021, we treated 65 patients (median age=71 years; range=31-89 years) affected by UM. Inclusion criteria were Eastern Cooperative Oncology Group (ECOG) performance status (PS) ≤2, life expectancy >6 months, tumor thickness >10 mm, diameter >16 mm or posterior UM. The treatment was delivered with a True Beam™ LINAC with arc modulation technique. All patients received 27 Gy in one fraction (biological effective dose ≈100 Gy, assuming an α/β of 10). The median follow-up was 36 (range=3-90) months. Acute toxicities were reported in 14 patients, whereas late toxicity occurred in 45 (69.2%). Fifteen patients (23.0%) underwent enucleation: eight (12.3%) for failure of local control and seven (10.7%) for late treatment co-morbidities. The 5-year local control, and progression-free, metastasis-free, enucleation-free, and overall survival rates were 80%, 43%, 62%, 65% and 56%, respectively. In multivariate analysis, tumor dimensions significantly influenced survival [larger basal diameter: progression-free [hazard ratio (HR)=2.42] and overall (HR=2.61) survival; greater thickness: overall survival (HR=2.36)]. In multivariate analysis, patients without local control had a higher risk of distant metastasis (HR=3.25). Stereotactic radiosurgery offers an effective and safe approach for selected cases of UM due to the satisfactory results in terms of local control, eye conservation and survival.

Induction chemotherapy followed by radical chemoradiotherapy for patients with stage IV non-metastatic nasopharyngeal carcinoma: 11-Year Experience in a tertiary centre.

T4 nasopharyngeal carcinoma (NPC) with close proximity to critical organs at risk (OARs) is usually underdosed during radiotherapy in order to respect radiation constraints. N3 disease has high risk of distant metastasis. Induction chemotherapy (IC) provides advantages of sparing of OARs during subsequent chemoradiotherapy (CCRT) and early eradication of micrometastasis. However, factors predicting successes of IC in this patient group are not well-studied. 104 T4 or N3 NPC patients were retrospectively reviewed during 2007-2018. They were planned for IC followed by CCRT using intensity-modulated radiotherapy. In the whole group, five-year failure-free survival (FFS), locoregional failure-free survival (LRFS), distant failure-free survival (DFFS) and overall survival (OS) were 40.9%, 45.7%, 46.9% and 53.6% respectively. Isolated marginal failure rate was 5% (4/80) among patients with primary tumours located close to critical OARs. Pre-IC gross tumour volume primary (GTVp) total volume > 110 cm3 correlated with worse five-year LRFS (OR 6.37, P = 0.008), DFFS (OR 8.89, P = 0.003) and OS (OR 50.12, P < 0.001). In the T4 subgroup, IC improved D100% GTVp from 61.39 Gy to 64.71 Gy (P < 0.001) and V100% GTVp from 98.78% to 99.28% (P < 0.001). Our study demonstrated improved dosimetric parameters and low isolated marginal failure rate. It supported the use of IC and CCRT for tumours located close to critical OARs. Further research is warranted to compare predictive roles of pre- and post-IC tumour volumes. For high-risk patients being defined by pre-IC volume or other prognostic models, treatment escalation should be considered.

Exosomal MMP-1 transfers metastasis potential in triple-negative breast cancer through PAR1-mediated EMT.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer with high risk of distant metastasis, in which the intercellular communication between tumor cells also plays a role. Exosomes can be released by tumor cells and promote distant metastasis through intercellular communication or changes in tumor microenvironment, it is an optimized transportation facility for biologically active payloads. This was a hypothesis-generating research on role of exosomal payload in TNBC distant metastasis. Exosomes isolated from supernatant of MDA-MB-231 and MDA-MB-231-HM (a highly pulmonary metastatic variant of parental MDA-MB-231 cells) were characterized. MMP-1 level was detected using mass spectrometry and western blot. Transwell assay, wound healing and CCK-8 assay were employed to explore the effect of exosomal MMP-1 on the metastatic capability of TNBC cells in vitro. Human breast cancer lung metastasis model in nude mice was established to observe the effect of exosomal MMP-1 in vivo. Tissue microarray and blood samples of TNBC patients were applied to analyze the relevance between MMP-1 with metastasis. MDA-MB-231-HM cells secrete exosomes enriched MMP-1, which can be taken up and enhance invasion and migration activities of TNBC cells, including MDA-MB-231, MDA-MB-468 and BT549. After ingesting exosomes enriched with MMP-1, cells secret more MMP-1, which may interact with membrane G protein receptor protease activated receptor 1 (PAR1), thereby initiating epithelial-mesenchymal transition (EMT) to enhance capability of migration and invasion. The lung colonization model shows that the expressions of MMP-1 and PAR1 in the metastases of the 231-HM-exo treated mice were both upregulated. Clinically, the enrichment of MMP-1 can be detected in exosomes extracted from serum of patients with metastasis at higher concentration than that in pre-operative patients. Moreover, in patients with multiple distant metastases, the level of MMP-1 in exosomes is also higher than that in patients with single lesion. MMP-1 from TNBC cells of high metastasis potential can promote the distant metastasis of transform those with low metastasis potential through PAR1-mediated EMT and is likely to be a potential molecular marker.

American Joint Committee on Cancer Tumor Staging System Predicts the Outcome and Metastasis Pattern in Conjunctival Melanoma

To assess the predictive value of the tumor staging system in the AJCC Cancer Staging Manual, Eighth Edition, and histologic features for outcomes and metastasis patterns in conjunctival melanoma (CM). Retrospective, single-center cohort study. Eighty-three patients with CM were treated at Shanghai Ninth People's Hospital between 2000 and2021. We reviewed the clinical and histologic parameters and used Kaplan-Meier survival curves and Cox proportional hazards regression models for risk factor analyses. Time to nodal/distant metastasis, disease-specific survival, metastatic pattern, and metastatic site. At presentation, 5 patients (6%) had clinical tumor (cT)1 disease, 34 patients (41%) had cT2 disease, and 44 patients (53%) had cT3 disease. Four patients (5%) had nodal metastasis (N1), and none had distant metastasis (M1). During follow-up, 12 patients (14%) developed nodal metastasis, 29 patients (35%) developed distant metastasis, and 26 patients (31%) died of disease. The brain, liver, and lung were common distant metastasis sites. Higher cT category was associated with increased risks of distant metastasis (P < 0.001) and disease-specific death (P= 0.002). The separate analysis of primary and recurrent tumors at presentation showed that the patients with cT3 tumors had a higher risk of distant metastasis than those with cT2 tumors. Greater tumor thickness, ulceration, and the presence of regression were correlated with distant metastasis. Previously unreported mutations were detected in the tumor suppressor genes FAT atypical cadherin 4 (FAT4) and spleen associated tyrosine kinase (SYK). Among the 29 patients who developed distant metastasis, we analyzed 2 patterns of metastasis: Eleven patients (38%) developed nodal metastasis before distant metastasis, and 18 patients (62%) developed distant metastasis without previously known nodal metastasis. The patients with cT3 tumors were more likely to follow the latter metastasis pattern (P= 0.02). Conjunctival melanoma presented with mostly advanced stages and high rates of distant metastasis in the current Chinese cohort. This study confirmed the prognostic value of the tumor staging system in the AJCC Cancer Staging Manual, Eighth Edition, for Chinese patients. Histologic features, such as tumor thickness and ulceration, should be emphasized when assessing prognosis and guiding the treatment of CM.

Abstract P4-06-03: Clinical-risk assessment of ER positive, Her2 negative breast cancer patients: Correlation between the average modified magee score and mammaprint

Abstract Background: MammaPrint (MP) is an FDA approved early breast cancer prognostic genomic assay that examines the expression levels of 70 genes and classifies clinically high-risk patients with early-stage breast cancer into low or high risk of distant metastasis. Current ASCO guidelines do not support using MP testing in clinically low-risk patients. Historically, assessing a patient’s clinical risk for breast cancer recurrence has relied on a subjective evaluation of histologic factors, immunohistochemical features, and clinical characteristics. Genomic assay testing provides more objective prognostic and predictive information than those more traditional methods; however, several studies have shown that statistical models using standard histologic variables can give valuable prognostic information, and might be used as an alternative approach to genomic assays for clinical risk-assessment and risk-stratification, particularly in lower risk breast cancer patients, potentially resulting in significant cost savings for health care systems. One of these statistical models, the average Modified Magee equation, has been shown to be prognostic for a low risk of recurrence in ER positive Her2 negative breast cancer patients who have an average Modified Magee score (aMMs) of ≤ 12. The aMMs has been shown to correlate well with the Oncotype DX recurrence score; however, there is limited data on the correlation between the aMMs and MP. In this study, we evaluated the concordance between the aMMs and the MP index (MPI). Methods: 222 consecutive patients with a new diagnosis of hormone receptor positive Her-2 negative breast cancer at the University of Rochester between April 2020 and December 2020 were sent for MP testing. The aMMs was determined for each patient based on the estrogen receptor status, progesterone receptor status, HER-2 status, Ki-67 proliferation index, Nottingham score, and tumor size. Based on the previous literature, patients were risk-stratified by the aMMs into three groups: 1) low risk (aMMs ≤ 12; n = 75); 2) low - intermediate risk (aMMs &amp;gt;12 and ≤ 18; n = 96); and, 3) high risk (aMMs &amp;gt;18, n = 51). Based on the previous literature, patients were risk-stratified by the MPI into two groups: 1) low risk (MPI 0 to +1); and, 2) high risk (MPI -1 to 0). The correlation between the aMMs and the MPI was evaluated using the Pearson correlation coefficient. Results: The aMMs showed a negative correlation (r= -0.55) with the MPI, consistent with a lower risk aMMs more likely being associated with a lower risk MPI. 92% of patients with an aMMs ≤ 12 (very low risk) were classified as low risk by MP. 72% of patients with an aMMs &amp;gt; 12 and ≤ 18 (low - intermediate risk) were classified as low risk by MP. 47% of patients with an aMMs &amp;gt; 18 (high risk) were classified as high risk by MP (Table 1). All patients with an aMMs ≥ 24.7 (n=8) were classified as high risk by MP. Conclusion: Our study suggests that hormone receptor positive, Her-2 negative breast cancer patients with a lower risk aMMs are likely to have a lower MPI, suggesting that these patients have a decreased risk for breast cancer recurrence. As the aMMs approaches higher risk, the concordance with the MPI decreases; however 100% of patients with an aMMs ≥ 24.7 were classified as high risk by MP. The aMMs can be helpful in clinical risk-assessment prior to making a decision about sending a patient specimen out for MP testing. Additional studies are warranted. Table 1.Risk of recurrence using the average Modified Magee score (aMMs) and the MammaPrint (MP) IndexaMMs Risk-stratification categoryMP Low risk n (%)MP High risk n (%)Very low (aMMs ≤ 12)69 (92%)6 (8%)Low - Intermediate (aMMs &amp;gt; 12 and ≤ 18)69 (72%)27 (28%)High (aMMs &amp;gt;18)27 (53%)24 (47%) Citation Format: Hani Katerji, Huina Zhang, David Hicks, Bradley M Turner. Clinical-risk assessment of ER positive, Her2 negative breast cancer patients: Correlation between the average modified magee score and mammaprint [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P4-06-03.

High BRCA1 gene expression increases the risk of early distant metastasis in ER+ breast cancers

Although the function of the BRCA1 gene has been extensively studied, the relationship between BRCA1 gene expression and tumor aggressiveness remains controversial in sporadic breast cancers. Because the BRCA1 protein is known to regulate estrogen signaling, we selected microarray data of ER+ breast cancers from the GEO public repository to resolve previous conflicting findings. The BRCA1 gene expression level in highly proliferative luminal B tumors was shown to be higher than that in luminal A tumors. Survival analysis using a cure model indicated that patients of early ER+ breast cancers with high BRCA1 expression developed rapid distant metastasis. In addition, the proliferation marker genes MKI67 and PCNA, which are characteristic of aggressive tumors, were also highly expressed in patients with high BRCA1 expression. The associations among high BRCA1 expression, high proliferation marker expression, and high risk of distant metastasis emerged in independent datasets, regardless of tamoxifen treatment. Tamoxifen therapy could improve the metastasis-free fraction of high BRCA1 expression patients. Our findings link BRCA1 expression with proliferation and possibly distant metastasis via the ER signaling pathway. We propose a testable hypothesis based on these consistent results and offer an interpretation for our reported associations.

Optimal surgical treatment for paratesticular leiomyosarcoma: retrospective analysis of 217 reported cases

BackgroundParatesticular leiomyosarcoma (LMS) is a rare tumor. Conventionally, tumor resection by high inguinal orchiectomy is performed as the preferred treatment approach for paratesticular sarcoma. On the other hand, testis-sparing surgery has recently attracted attention as a less-invasive treatment option for paratesticular sarcoma. However, the prognostic predictors and optimal treatment strategy for paratesticular LMS remain unclear because of its rarity. In this study, we systematically reviewed previously reported cases of paratesticular LMS to evaluate the prognostic factors and establish the optimal treatment strategy.MethodsA systematic search of Medline, Web of Science, Embase, and Google was performed to find articles describing localized paratesticular LMS published between 1971 and 2020 in English. The final cohort included 217 patients in 167 articles. The starting point of this study was the time of definitive surgical treatment, and the end point was the time of local recurrence (LR), distant metastasis (DM), and disease-specific mortality.ResultsPatients with cutaneous LMS had a slightly better LR-free survival, DM-free survival, and disease-specific survival than those with subcutaneous LMS (p = 0.745, p = 0.033, and p = 0.126, respectively). Patients with higher grade tumors had a significantly higher risk of DM and disease-specific mortality (Grade 3 vs Grade 1 p < 0.001, and Grade 3 vs Grade 1 p < 0.001, respectively). In addition, those with a microscopic positive margin had a significantly higher risk of LR and DM than those with a negative margin (p < 0.001, and p = 0.018, respectively). Patients who underwent simple tumorectomy had a slightly higher risk of LR than those who underwent high inguinal orchiectomy (p = 0.067). Subgroup analysis of cutaneous LMS demonstrated that the difference in LR between simple tumorectomy and high inguinal orchiectomy was limited (p = 0.212). On the other hand, subgroup analysis of subcutaneous LMS revealed a significant difference in LR (p = 0.039).ConclusionsOur study demonstrated that subcutaneous LMS and high-grade tumors are prognostic factors for paratesticular LMS. For subcutaneous LMS, tumorectomy with high inguinal orchiectomy should be the optimal treatment strategy to achieve a negative surgical margin.

Patient Age Is Significantly Related to Distant Metastasis of Papillary Thyroid Microcarcinoma.

ObjectiveDistant metastasis in papillary thyroid microcarcinoma (PTMC) is rare but fatal, and its relationship with patient age remains unclear. The objective of this study was to examine the association between age at diagnosis and metachronous distant metastasis in PTMC.MethodsConsecutive patients who underwent thyroidectomy for PTC measuring 10 mm or less at a tertiary hospital from January 2000 to December 2016 were enrolled. Patients who had evidence of distant metastasis at diagnosis or underwent postoperative radioiodine (RAI) ablation were excluded. A Cox proportional hazards model with restricted cubic splines (RCS) was applied to examine the association between age at diagnosis and distant metastasis.ResultsA total of 4,749 patients were evaluated. The median age was 44 years (range, 8–78 years), and 3,700 (78%) were female. After a median follow-up of 65 months, 21 distant metastases (20 lung, 1 liver) were recognized. A univariate Cox proportional model using a 5-knot RCS revealed a significant overall (p = 0.01) and a potential nonlinear association (p = 0.08) between distant metastasis and age at diagnosis. In multivariate analysis, age at diagnosis, extrathyroidal extension (ETE), and lymph node metastasis (pN+) were independent risk factors for distant metastasis. Compared with the middle-aged group (30–45 years old), younger and older patients had a higher risk of distant metastasis [HR, 95% CI, p-value, age ≤ 30, 4.54 (0.91–22.60), 0.06, age > 45, 6.36 (1.83–22.13), <0.01].ConclusionAge at diagnosis is associated with metachronous distant metastasis of PTMC, and patients with younger or older age have a higher risk of distant metastasis than middle-aged patients.