Incidence Of Distant Metastases Research Articles

Distinct characteristics of distant metastasis in early-onset gastric cancer patients compared to late-onset patients: An observational study.

Presently, there is limited understanding of the features of distant metastasis in early-onset gastric cancer (GC). To explore these disparities, a retrospective study utilizing the Surveillance, Epidemiology, and End Results (SEER) database was undertaken. The SEER database was utilized to extract patient data, and multivariate logistic regression analysis was employed to identify the risk factors associated with distant metastasis and liver metastasis. Propensity score matching (PSM) was used to compare the occurrence of liver metastasis among patients based on their age at diagnosis. The study included 2684 early-onset GC patients and 33,289 late-onset GC patients. Preliminary data analysis indicated that early-onset GC patients exhibited more aggressive characteristics such as poor cell differentiation, advanced T stage, and a higher incidence of distant metastasis, excluding liver metastasis. Multivariate logistic regression analysis identified younger age as an independent risk factor for distant metastasis, along with T stage, lymph node metastasis (LNM), and tumor size (>3 cm). Another regression analysis revealed that younger age, diffuse type, and female gender were protective factors against liver metastasis. Through PSM, 3276 early-onset GC patients were matched with an equal number of late-onset GC patients, revealing that patients with early-onset GC had fewer instances of liver metastasis but a higher prevalence of distant metastasis. Our findings suggest that early-onset serves as a protective factor against liver metastasis in GC, while it poses a risk for distant metastasis, likely influenced by the increased prevalence of diffuse-type GC in early-onset patients.

Arenobufagin induces cell apoptosis by modulating the cell cycle regulator claspin and the JNK pathway in nasopharyngeal carcinoma cells

ABSTRACT Background The high recurrence rate and incidence of distant metastasis of nasopharyngeal carcinoma (NPC) result in poor prognosis. It is necessary to identify natural compounds that can complement combination radiation therapy. Arenobufagin is commonly used for heart diseases and liver cancer, but its effectiveness in NPC is unclear. Study Design and Methods The effect of arenobufagin-induced apoptosis was measured by a cell viability assay, tumorigenic assay, fluorescence assay, and Western blot assay through NPC-039 and NPC-BM cell lines. The protease array, Western blot assay, and transient transfection were used to investigate the underlying mechanism of arenobufagin-induced apoptosis. An NPC xenograft model was established to explore the antitumor activity of arenobufagin in vivo. Results Our findings indicated that arenobufagin exerted cytotoxic effects on NPC cells, inhibiting proliferation through apoptosis activation. Downregulation of claspin was confirmed in arenobufagin-induced apoptosis. Combined treatment with arenobufagin and mitogen-activated protein kinase inhibitors demonstrated that arenobufagin induced NPC apoptosis through the c-Jun N-terminal kinases (JNK) pathway inhibition. Furthermore, arenobufagin suppressed NPC tumor proliferation in vivo. Conclusion Our results revealed the antitumor effect of arenobufagin in vitro and in vivo. Arenobufagin may have clinical utility in treating NPC due to its suppression of claspin and inhibition of the JNK pathway.

Participation of suicide gene extracellular vesicles in metastasis prevention.

The incidence of distant metastases is associated with most cancer-related mortalities. Extracellular vesicles (EVs), secreted from tumors and cancer-associated fibroblasts, are involved in the metastatic process mediating their organotropism through their involvement in the pre-metastatic niche formation. We have been developing suicide gene therapy mediated by EVs secreted from mesenchymal stem/ stromal cells, tumor cells, and cancer-associated fibroblasts. Suicide gene EVs conjugated with prodrug are tumor tropic, penetrate tumor cells, and kill them by intracellular conversion of nontoxic prodrug to an efficient anti-cancer drug. Here, we discuss findings regarding the possibility of using suicide gene EVs as a novel therapeutic approach for metastases, via pre-metastatic niche modification. The suicide gene EVs provide a future perspective for metastasis prevention.

Abstract 3782: IASLC grading system predict distant metastases for resected lung adenocarcinoma

Abstract The International Association for the Study of Lung Cancer (IASLC) proposed a new histological grading system for invasive lung adenocarcinoma (LUAD). However, whether this new grading system is able to predict distant metastases in LUAD patients has not been evaluated. This study investigated the feasibility of using this grading system to predict the occurrence of brain and bone metastases in patients with resectable LUAD which identifies patients who have a high probability of developing distant metastases after surgery. We collected clinical information and pathological reports of 179 early stage LUAD patients who underwent resection during 2008 to 2015 from Wake Forest Comprehensive Cancer Center. All patients were followed up for 5 years and both bone and brain metastasis-free survival were calculated. Tumor grading of all samples was evaluated by both IASLC grading and predominant pattern-based grading systems. The ability of predicting distant metastases using IASLC grading and tumor stage were examined by receiver operating characteristic curves (ROC). 28 out of 179 patients developed distant metastases in five years with a median overall survival of 60 months for metastasis-free patients and 38.9 for patients with distant metastasis. Compared to predominant pattern-based grading system, IASLC grading system showed a stronger correlation with distant metastasis incidence. Complex gland pattern is enriched in patients who developed bone and brain metastases compared to metastasis-free patients. IASLC grading system also showed a superior prediction power of distant metastasis compared to tumor stage with area under curve (AUC) of 0.69 for brain metastasis and 0.71 for bone metastasis. IASLC grading system is capable of predicting the incidence of distant metastasis among early-stage invasive LUAD patients. Citation Format: Yuezhu Wang, Margaret R. Smith, Yin Liu, Mary E. Green, Omer A. Hassan, Alexandra M. Balmaceda, Tammy Sexton, Wencheng Li, Fei Xing. IASLC grading system predict distant metastases for resected lung adenocarcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3782.

Abstract 4139: Prolyl 4-hydroxylase subunit alpha 1 acts as a novel target for lung adenocarcinoma brain metastasis

Abstract Lung cancer is the most lethal cancer worldwide, with a high incidence of distant metastasis. Many lung adenocarcinoma (LUAD) patients experience brain metastasis during the disease process with unfavorable prognosis. Our previous study has discovered that P4HA1 was exclusively upregulated in brain metastatic cells. Through the analysis of single-cell RNA sequencing of LUAD samples, we found that the expression of P4HA1 in brain metastatic tumor cells is higher than that in primary tumor cells. This finding was further confirmed by immunohistochemical staining. Significantly, a strong presence of P4HA1 in primary tumors is associated with a reduced duration of disease-free survival in individuals with LUAD. Overexpression of P4HA1 in A549 and PC9 cell lines significantly increased the incidence of brain metastasis in BALB/c nude mice, whereas knockdown of P4HA1 in high brain metastatic cells significantly decreased the incidence of brain metastasis and reduced the tumor foci in brain with improved survival. Utilization of DHB, a P4HA1 inhibitor, exerts both therapeutic and preventive effects in relieving brain metastases in nude mice. Furthermore, remarkable inhibition of tumor growth by DHB was observed in patient derived xenograft (PDX) models. RNA sequencing analysis demonstrated that the reduction of P4HA1 expression had a substantial impact on cell adhesion and extracellular matrix (ECM)-receptors interactions. Western blotting analysis verified that the decrease in P4HA1 expression led to a drop in the expression of adhesion molecules ICAM1, VCAM1, NCAM1, as well as integrin molecules ITGA2 and ITGA3. Furthermore, when endothelial cells were co-cultured with conditioned medium from tumor cells, it was observed that the expression of the tight junction molecule ZO1 was reduced after co-culturing with conditioned medium from P4HA1 knockdown A549 cells. The results from the in vitro blood-brain barrier (BBB) model and in vivo biofluorescence imaging indicate that P4HA1 promoted brain metastasis of LUAD via modulating the ability of tumor cells to cross the blood-brain barrier. In conclusion, our study reveals that overexpression of P4HA1 promotes metastatic spread to the brain, and targeting P4HA1 could be a promising therapeutic strategy for the treatment of lung adenocarcinoma brain metastasis. Citation Format: Yan He, Zhenyu Luo, Yucheng Dong, Rui Wan, Xue Zhang, Hua Bai, Jie Wang. Prolyl 4-hydroxylase subunit alpha 1 acts as a novel target for lung adenocarcinoma brain metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4139.

Construction and validation of machine learning models for predicting distant metastases in newly diagnosed colorectal cancer patients: A large-scale and real-world cohort study.

More accurate prediction of distant metastases (DM) in patients with colorectal cancer (CRC) would optimize individualized treatment and follow-up strategies. Multiple prediction models based on machine learning have been developed to assess the likelihood of developing DM. Clinicopathological features of patients with CRC were obtained from the National Cancer Center (NCC, China) and the Surveillance, Epidemiology, and End Results (SEER) database. The algorithms used to create the prediction models included random forest (RF), logistic regression, extreme gradient boosting, deep neural networks, and the K-Nearest Neighbor machine. The prediction models' performances were evaluated using receiver operating characteristic (ROC) curves. In total, 200,958 patients, 3241 from NCC and 197,717 CRC from SEER were identified, of whom 21,736 (10.8%) developed DM. The machine-learning-based prediction models for DM were constructed with 12 features remaining after iterative filtering. The RF model performed the best, with areas under the ROC curve of 0.843, 0.793, and 0.806, respectively, on the training, test, and external validation sets. For the risk stratification analysis, the patients were separated into high-, middle-, and low-risk groups according to their risk scores. Patients in the high-risk group had the highest incidence of DM and the worst prognosis. Surgery, chemotherapy, and radiotherapy could significantly improve the prognosis of the high-risk and middle-risk groups, whereas the low-risk group only benefited from surgery and chemotherapy. The RF-based model accurately predicted the likelihood of DM and identified patients with CRC in the high-risk group, providing guidance for personalized clinical decision-making.

Clinicopathological features of colon cancer depending on the dMMR status of the tumor

Aim. To conduct a clinical and morphological assessment of the characteristics of colon cancer depending on the dMMR / pMMR status of the tumor.Materials and methods. A retrospective study included 66 patients with operable colorectal cancer (CRC) (T1-4bN0-2bM1), who were treated at Cancer Research Institute of Tomsk National Research Medical Center (NRMC). The average age of the patients was 64.4 ± 12.8 years. All patients underwent hemicolectomy or colon resection, as well as intraoperative resection of distant metastases, if present.Results. We determined that in CRC patients with pMMR tumors, hematogenous metastases were detected in 27.3% of cases, while in patients with dMMR tumors, hematogenous metastases were detected only in 6.1% of cases (p = 0.021). A comparative analysis of dMMR and pMMR tumors also allowed to establish higher frequency of perineural invasion among the pMMR subgroup of carcinomas (p = 0.039). The sign of tumor budding was found both in dMMR carcinomas (36%) and in pMMR tumors (45%). This sign was associated with damage to regional lymph nodes (p = 0.0017). A more detailed analysis of the tumor budding phenomenon showed that in dMMR tumors, Bd1 low-grade budding (83%) predominated. In pMMR tumors, Bd2 intermediate-grade budding (33%) and Bd3 high-grade budding (26.7%) prevailed. Bd2 and Bd3 tumor budding types were associated with hematogenous metastasis (p < 0.001).Conclusion. The obtained data demonstrate the differences in such pathomorphological parameters as perineural invasion and the degree of tumor budding depending on the dMMR / pMMR status of the tumor. These histologic parameters in tumor tissue are also associated with higher incidence of distant metastasis in patients with pMMR carcinomas as opposed to patients with dMMR tumors.

The U-Shaped association between age and distant metastasis in patients with papillary thyroid carcinoma.

To investigate the association between age distribution and synchronous distant metastasis of papillary thyroid carcinoma. Patients with PTC who were treated from January 2013 to December 2018 at a single institute in a cancer referral center in China were retrospectively reviewed. A logistic regression model with restricted cubic splines (RCS) was used to examine the association between age at diagnosis and synchronous distant metastasis. A total of 111 patients (0.7%) were diagnosed with distant metastasis. The logistic regression model with RCS revealed a "U-shape" association between age and distant metastasis. The RCS curve suggested a U-shaped pattern. The multivariable regression analysis showed that patients in the age groups ≤21 years (OR 2.33, 95% CI 1.09-4.68, P = 0.022) and >55 years (OR 3.32, 95% CI 1.99-5.46, P < 0.001) had a significantly higher incidence of distant metastasis than patients in the age group of 22 to 55 years. A U-shaped association was observed between age at diagnosis and synchronous distant metastasis in papillary thyroid carcinoma patients.

The poor prognosis of lacrimal gland adenocarcinoma: a clinical study and literature review

PurposeThe incidence of lacrimal gland adenocarcinoma is low. This study was designed to analyze the clinical and prognostic characteristics of lacrimal gland adenocarcinoma.MethodsThis was a clinical study and literature review; 25 patients diagnosed with lacrimal gland adenocarcinoma by histopathology were enrolled and their medical history data were collected.ResultsThe incidence of bone destruction and surrounding tissue invasion was 52% and 44%, respectively. The incidence of distant metastasis of lacrimal gland adenocarcinoma was about 50%. The 5-year overall survival rate of death or metastasis was 33.5%. Age, sex, laterality, tumor size, pathology type, bone destruction, nerve or perineural invasion, invasion of peripheral tissue, T stage, AR, Her-2 and treatment had no significant correlation with lacrimal adenocarcinoma’s prognosis (P > 0.05), while the higher expression of Ki-67 may have higher risk of death or metastasis (P = 0.020).ConclusionThe incidence of bone destruction and distant metastasis of lacrimal adenocarcinoma is high and the imaging examination is necessary to assess the risk of distant metastasis. The 5-year survival rate of death or metastasis is 33.5% and the high expression of Ki-67 predicts poor prognosis of lacrimal adenocarcinoma.

Oncological features and outcomes of laryngeal cancer surgery: a multicentric study.

Laryngeal cancer (LC) is among of the most frequent head and neck cancers, associated to a high social impact and mortality. Unfortunately, the current treatment outcomes of LC are often scant, with different factors affecting patient's prognosis (i.e., advanced age, advanced disease stage, lymph node involvement, tumor pathological features, type of intervention). The aims of the present study were: 1) to evaluate the epidemiological and clinical features of patients affected by LC; and 2) to focus on tumor risk factors affecting patient's overall survival (OS) and recurrences. A retrospective analysis of all patients affected by LC and surgically treated at two different hospital settings has been performed. Two hundred twenty-five patients were enrolled in the present study; of these 189 were males (84%) and 36 (16%) were females. The most frequently performed surgery was total laryngectomy. Thirty-two (14.2%) patients experienced local recurrence, while 15 patients (6.6%) had regional recurrence and 15 distant metastases. Multivariate analysis showed that locoregional recurrence was associated to the occurrence of distant metastases (P=0.002, HR=25,35). Analyzing OS, the only statistically significant factor that correlated with an increased risk of mortality (P<0.015, HR=2,45) was locoregional recurrence. The present study confirms the literature data about age and sex distribution of LC, about tumors localization, lymph nodes metastasis and distant metastasis incidence and OS rate, based on T and N stage. Interestingly, within this series, the presence of locoregional recurrence or distant metastasis is related to a worst prognosis and a lower overall survival rate.

Total neoadjuvant therapy: A new standard of care for locally advanced rectal cancer?

Delivering chemotherapy before surgery is a newer treatment approach called total neoadjuvant therapy (TNT), and the National Comprehensive Cancer Network guidelines recommend it for locally advanced rectal cancer (LARC) with cT3 / cN+ / cT4, in contrast with the European Society for Medical Oncology guidelines, in which most rectal cancers can be treated with surgery alone if good quality mesorectal resection is assured. Neoadjuvant or adjuvant treatments are reserved for patients with high-risk tumours, including cT3c/d or cT4, or that threaten the mesorectal fascia. The favourable outcomes in the RAPIDO trial for high-risk rectal cancers with a lower incidence of distant metastasis in the TNT group were observed but with an unexpected increase in the local recurrence with more extended follow-up. This suggests early surgery for nonresponding tumours. The TNT approach was also evaluated in the OPRA trial with long-course chemoradiotherapy and induction versus consolidation chemotherapy. Half the patients presented complete clinical responses and were enrolled in the watch-and-wait (WW) approach. Given the high number of trials and guidelines in this subject, the multidisciplinary team's decision-making process in rectal cancer management is complex. Looking at the actual data, it was concluded that TNT is not for all patients with LARC and is an option if organ preservation is a priority, although with a high regrowth rate in a WW strategy and increasing risk of distant metastasis, questioning the deleterious effect of deferral of surgery.

Is perioperative chemotherapy effective in patients with localized myxoid liposarcoma?

This study aimed to compare the local recurrence, distant metastasis and disease-specific survival rates of patients with localized myxoid liposarcoma in the surgery and adjuvant chemotherapy group versus the surgery alone group. A total of 456 patients in the Japanese National Bone and Soft Tissue Tumour Registry database who had localized myxoid liposarcoma and underwent surgery and adjuvant chemotherapy or surgery alone between 2001 and 2019 were included in this retrospective study. The study adjusted for background differences between patients who underwent surgery and adjuvant chemotherapy (n=228) or surgery alone (n=228) using propensity score matching. Univariate analysis showed no significant difference in local recurrence rate between the two groups (5-year local recurrence-free survival: 98.6% [95% confidence interval: 95.9-99.6] vs. 94.0% [95% confidence interval: 89.7-96.6], P=0.052). Univariate analysis showed no difference in the incidence of distant metastases between the two groups (5-year distant metastasis-free survival: 80.5% [95% confidence interval: 73.9-85.8] vs. 75.1% [95% confidence interval: 67.7-81.2], P=0.508). Univariate analysis showed no difference in disease-specific survival between the two groups (5-year disease-specific survival: 92.6% [95% confidence interval: 86.1-96.2] vs. 93.2% [95% confidence interval: 87.6-96.4], P=0.804). In the high-risk group (n=203) with high-grade tumours and tumour size ≥10cm, there were no significant differences in the local recurrence, distant metastasis and disease-specific survival rates between the surgery and adjuvant chemotherapy group and the surgery alone group. The effect of adjuvant chemotherapy on localized myxoid liposarcoma appears to be limited.

Molecular subtypes of breast cancer predicting clinical benefits of radiotherapy after breast-conserving surgery: a propensity-score-matched cohort study

BackgroundBased on the molecular expression of cancer cells, molecular subtypes of breast cancer have been applied to classify patients for predicting clinical outcomes and prognosis. However, further evidence is needed regarding the influence of molecular subtypes on the efficacy of radiotherapy (RT) after breast-conserving surgery (BCS), particularly in a population-based context. Hence, the present study employed a propensity-score-matched cohort design to investigate the potential role of molecular subtypes in stratifying patient outcomes for post-BCS RT and to identify the specific clinical benefits that may emerge.MethodsFrom 2006 to 2019, the present study included 59,502 breast cancer patients who underwent BCS from the Taiwan National Health Insurance Research Database. Propensity scores were utilized to match confounding variables between patients with and without RT within each subtype of breast cancer, namely luminal A, luminal B/HER2-negative, luminal B/HER2-positive, basal-like, and HER2-enriched ones. Several clinical outcomes were assessed, in terms of local recurrence (LR), regional recurrence (RR), distant metastasis (DM), disease-free survival (DFS), and overall survival (OS).ResultsAfter post-BCS RT, patients with luminal A and luminal B/HER2-positive breast cancers exhibited a decrease in LR (adjusted hazard ratio [aHR] = 0.18, p < 0.0001; and, 0.24, p = 0.0049, respectively). Furthermore, reduced RR and improved DFS were observed in patients with luminal A (aHR = 0.15, p = 0.0004; and 0.29, p < 0.0001), luminal B/HER2-negative (aHR = 0.06, p = 0.0093; and, 0.46, p = 0.028), and luminal B/HER2-positive (aHR = 0.14, p = 0.01; and, 0.38, p < 0.0001) breast cancers. Notably, OS benefits were found in patients with luminal A (aHR = 0.62, p = 0.002), luminal B/HER2-negative (aHR = 0.30, p < 0.0001), basal-like (aHR = 0.40, p < 0.0001), and HER2-enriched (aHR = 0.50, p = 0.03), but not luminal B/HER2-positive diseases. Remarkably, when considering DM, luminal A patients who received RT demonstrated a lower cumulative incidence of DM than those without RT (p = 0.02).ConclusionIn patients with luminal A breast cancer who undergo BCS, RT could decrease the likelihood of tumor metastasis. After RT, the tumor’s hormone receptor status may predict tumor control regarding LR, RR, and DFS. Besides, the HER2 status of luminal breast cancer patients may serve as an additional predictor of OS after post-BCS RT. However, further prospective studies are required to validate these findings.

Pathologic Exploration of the Axillary Soft Tissue Microenvironment and Its Impact on Axillary Management and Breast Cancer Outcomes.

Axillary soft tissue (AXT) involvement with tumor cells extending beyond the positive lymph node (LN+) and extracapsular extension (ECE) has been overlooked in breast pathology specimen analysis. We analyzed 2,162 LN+ patients, dividing them into four groups on the basis of axillary pathology: (1) LN+ only, (2) LN+ and ECE only, (3) LN+ and AXT without ECE, and (4) LN+ with both AXT and ECE. The primary end points were 10-year locoregional failure (LRF), the 10-year axillary failure, and 10-year distant metastasis rates. Multivariable Cox models, accounting for clinical factors, were fitted using the entire cohort, and subgroups analyses were conducted. The median follow-up was 9.4 years. The 10-year distant metastasis incidence was 42% for LN + AXT + ECE, 23% for both LN + AXT and LN + ECE only, and 13% for LN+ only. The 10-year axillary failure rates were 4.5% for LN + AXT + ECE, 4.6% for LN + AXT, 0.8% for LN + ECE only, and 1.6% for LN+ only. The 10-year LRF rates were 14% for LN + AXT + ECE, 10% for LN + AXT, 5.7% for LN + ECE only, and 6.2% for LN+ only. Multivariable analysis revealed that AXT was significantly associated with distant metastasis (hazard ratio [HR], 1.6; P < .001), locoregional failure (HR, 2.3; P < .001), and axillary failure (HR, 3.3; P = .003). Subgroup analyses showed that regional LN radiation (RLNR) improved locoregional tumor outcomes with AXT, ECE, or both (HR, 0.5; P = .03). Delivering ≤50 Gy to the axilla in the presence of AXT/ECE increased axillary failure (HR, 3.0; P = .04). Moreover, when delivering RLNR, axillary LN dissection could be de-escalated to sentinel node biopsy even in the presence of features such as AXT or ECE without significantly increasing any failure outcome: (HR, 1.0; P = .92) for LRF, (HR, 1.1; P = .94) axillary failure, and (HR, 0.4; P = .01) distant metastasis. Routine reporting of axillary tissue involvement, beyond LNs and ECE, is crucial in predicting breast cancer outcomes. Ruling out the presence of AXT is imperative before any form of axillary de-escalation, especially RLNR omission.

Prediction of liver and lung metastases in patients with early-onset colorectal cancer by nomograms based on heterogeneous and homogenous risk factors.

Identifying the risk factors for distant metastasis in early-onset colorectal cancer (EOCRC) is crucial for elucidating its etiology and facilitating preventive treatment. This study aims to characterize the variability in EOCRC incidence and discern both heterogeneous and homogeneous risk factors associated with synchronous liver, lung, and hepato-lung metastases. This study included patients with EOCRC enrolled in the SEER database between 2010 and 2015 and divided patients into three groups by synchronous liver, lung, and hepato-lung metastases. Each group of patients with different metastasis types was randomly assigned to the development and validation cohort in a ratio of 7:3. Logistic regression was used to analyze the heterogeneous and homogenous risk factors for synchronous liver, lung, and hepato-lung metastases in the development cohort of patients. Nomograms were built to calculate the risk of metastasis, and the receiver operating characteristic (ROC) curve and calibration curve were used to quantitatively evaluate their performance. A total of 16,336 eligible patients with EOCRC were included in this study, of which 17.90% (2924/16,336) had distant metastases. The overall incidences of synchronous liver, lung, and hepato-lung metastases were 11.90% (1921/16,146), 2.42% (390/16,126), and 1.50% (241/16,108), respectively. Positive CEA values before treatment, increased lymphatic metastases, and deeper invasion of intestinal wall were positively correlated with three distant types of metastases. On the contrary, the correlation of age, ethnicity, location of primary tumor, and histologic grade among the three types was inconsistent. The ROC curve and calibration curve proved to have fine performance in predicting distant metastases of EOCRC. There are significant differences in the incidence of distant metastases in EOCRC, and related risk factors are heterogeneous and homogenous. Although limited risk factors were incorporated in this study, the established nomograms indicated good predictive performance.

Patterns of Local Recurrence and Risk of Skin Recurrence in Soft Tissue Sarcomas After Surgical Resection

Although there is a theoretical risk of skin seeding during surgical resection of soft tissue sarcomas (STSs), current consensus guidelines recommend against routine use of bolus during radiation therapy (RT). However, the risk of skin recurrence has not been systematically assessed. We aimed to assess the patterns of local recurrence (LR) in patients with STS treated with surgery with or without RT. We performed a retrospective analysis of adults with STSs evaluated at our institution between 2007 and 2021. For patients who developed LR, the depth was evaluated. Progression-free survival and overall survival were analyzed from time of first LR using the Kaplan-Meier method. Cumulative incidence of distant metastasis was calculated with competing risk analysis from date of LR. Of the 206 patients evaluated, 20 had LR (9.7%). Among patients with LR, 5 patients (25.0%) were treated with surgery alone and 15 patients (75.0%) with surgery and RT. In patients treated with RT, 46.7% had preoperative RT, 53.3% had postoperative RT, and bolus was used in 46.7%. Surgical margins were close (<1 mm) in 4 patients (20.0%) and positive in 10 patients (50.0%). LR occurred in the deep subfascial tissue in 9 patients (45%), subcutaneous tissue in 10 patients (50.0%), and skin in 1 patient (5.0%). The patient with a skin recurrence was treated with surgery alone, and the tumor involved the skin at presentation. In patients treated with RT, LR occurred within the RT field in 13 patients (86.7%). At 1 year after LR, progression-free survival was 70.3%, overall survival was 81.7%, and cumulative incidence of distant metastasis was 5.9%. Skin recurrences were rare after surgical resection of STSs and only occurred in a tumor that involved the skin at initial presentation. These findings support current recommendations against routine use of bolus in STSs not involving the skin at presentation.

Patterns of Failure for Poor Response to Neoadjuvant Chemotherapy in Gastric Cancer

Peri-operative chemotherapy has emerged as the standard of care in the treatment of locally advanced gastric cancer. Improved treatment strategies are needed for patients with a poor response to neoadjuvant chemotherapy and postoperative chemoradiation has been proposed as a potential method of treatment intensification. We aimed to describe the patterns of failure for patients with no or partial response (NR, PR) to pre-operative chemotherapy. We retrospectively reviewed charts of patients with locally advanced gastric cancer treated at our institution from 2008 to 2022 with pre-operative chemotherapy followed by surgery with a D2 resection. We excluded patients who received pre-operative or post-operative radiation therapy, or patients who had a complete response (CR) following neoadjuvant chemotherapy. Cumulative incidence of locoregional failure (LRF) and distant metastases (DM) were calculated from the time of diagnosis with competing risk analysis with death as a competing risk and censored at the last follow up. Overall survival (OS) was analyzed using Kaplan-Meier. A total of 57 patients were identified and 60% are male. Median follow-up time was 31.3 months (range 6.9-181.5 months), and the median age at diagnosis was 68 years old (range 30-86). The most used pre-operative chemotherapy regimen was FLOT (38.6%), followed by FOLFOX (29.8%), and ECF/ECX/EOX (19.3%), and a majority of patients (57.9%) received adjuvant chemotherapy. The most common histology was adenocarcinoma (85.9%), and 61.4% of patients had poorly differentiated disease. Thirty-three (57.9%), and 9 patients (15.8%) were characterized as PR and NR to neoadjuvant therapy by pathology, respectively. The distribution of pathologic stages following neoadjuvant chemotherapy were as follows: 17 patients (29.8%) with Stage IA-B, 12 patients (21.1%) with Stage IIA-B, 15 patients (26.3%) with Stage IIIA, 9 patients (15.8%) with Stage IIIB, and 3 patients (5.3%) with Stage IIIC disease. Two patients had positive lymph nodes with a T0 primary tumor. Median OS was 51.4 months (95% confidence interval [CI] 39.8-68.4) for the entire cohort, and 92.1 months (95% CI 34.6-73.0) versus 42.8 months (95% CI 23.1-88.0) for patients with a PR, and NR, respectively (p = 0.14). The 2-year cumulative incidence of LRF and DM was 7.4% (95% CI 0.4-14.3) and 36.3% (95% CI 23.6-49.1), respectively. Of the five patients who experienced LRF, three of the patients also eventually or concurrently developed DM. 60% of these patients would have had their first site of recurrence covered by standard post-operative radiation treatment volumes. Patients with locally advanced gastric cancer who do have less than a CR to chemotherapy have poor outcomes due to high rates of DM. Adjuvant locoregional therapy such as radiation is unlikely to affect survival while DM is the predominant pattern of progression. Further studies are needed to identify adjuvant therapies to improve distant control.

Evaluation of Radiotherapy Dose and Survival Outcomes for Teenagers, and Young Adults with Nasopharyngeal Carcinoma in UK and Ireland

Nasopharyngeal carcinoma (NPC) follows a bimodal distribution with a smaller incidence peak in teenagers and young adults (TYAs). In TYAs, an over-whelming proportion are associated with Epstein-Barr virus (EBV). We have evaluated the variation in TYA NPC practice patterns across the UK and Ireland, along with survival outcomes. We performed a multicenter, observational cohort study, of patients aged 13-25 years, with histologically confirmed NPC, treated between the years 2002-2022. An initial expression of interest was sent to selected centers treating H&N patients in the UK and Ireland. For analysis, patients were assessed based on total prescribed dose, with a cut off for low dose (LD) (≤61.2Gy) versus a high dose (HD)(>61.2Gy). Ninety-five patients, from 9 centers, were eligible for inclusion. Patient demographics are shown in table1. At a median follow up of 45 months (IQR 23-111), 3-year overall survival (OS) was 98% (95% CI 93%-100%) with LD versus 91% (95% CI 83%-99%) with HD (Hazard ratio (HR) = 3.0; 95% CI 0.3-27, p = 0.3). 3-year progression free survival (PFS) was 84% (95% CI 71%-97%) with LD versus 83% (95% CI 72%-94%) with HD (HR 1.3; 95% CI 0.4-4.0, p = 0.6), and 5-year PFS was 84% (95% CI 71%-97%) with LD versus 83% (95% CI 72%-94%) with HD (HR 1.3; 95% CI 0.4-4.0, p = 0.6). Incidence of distant metastasis (DM) was 9.9%. 2 patients (6%) with T3-T4 tumors, treated with LD, had locoregional failure (LRF) compared to 1 patient (3%) treated with HD. We have demonstrated excellent survival outcomes for the UK & Ireland TYA NPC patients. As the majority of cases in this age group have EBV+ NPC, with survival similar between LD and HD protocols, we propose that pediatric protocols, with lower radiotherapy doses should be considered for all TYA NPC, with the aim of reducing late effects. Additional analysis to better understand the impact of heterogeneity between both groups, including choice of protocol, induction and adjuvant treatment will follow this study. Prospective evaluation, as part of an international collaboration, is required to optimize the management strategy for this rare cohort of patients.

Long-Term Outcomes of NRG/RTOG 0126, a Randomized Trial of High Dose (79.2 Gy) vs. Standard Dose (70.2 Gy) Radiation Therapy (RT) for Men with Localized Prostate Cancer

NRG/RTOG 0126, a phase III trial for men with localized prostate cancer testing whether dose escalation to 79.2 Gy with 3DCRT/IMRT improved overall survival (OS). Long-term results of this trial are presented. Patients with clinical stage T1b-T2b and either Gleason Score (GS) 2-6 and 10 ≤ PSA < 20 or GS 7 and PSA < 15 were eligible and randomized to receive 79.2 Gy or 70.2 Gy. No previous or concurrent androgen withdrawal therapy was administered. Treatment was delivered with 3DCRT/IMRT to a dose of 79.2 Gy in 44 fractions or 70.2 Gy in 39 fractions to the PTV encompassing the prostate and seminal vesicles. Image guidance was not required. ASTRO and Phoenix definitions were used for biochemical failure (ABF and PBF, respectively). OS was estimated by the Kaplan-Meier method and arms compared with the log-rank test. ABF, PBF, local progression (LP), distant metastases (DM) and time to late GI/GU toxicities were estimated by the cumulative incidence method and arms compared with Gray's test. One thousand five hundred thirty-two men were randomized, 763 to 79.2 Gy and 769 to 70.2 Gy. 1499 were eligible, 748 and 751 in the 79.2 Gy and 70.2 Gy arms respectively. Median age was 71, 70% had PSA < 10 ng/ml, 84% with GS 7, 57% had T1 disease, and 66% treated with 3D-CRT. Outcomes are shown in the TABLE: . With a median follow up of 12 years, there was no significant difference in OS. There was a statistically significant decrease in the cumulative incidence of ABF, PBF, DM, LP, and salvage therapies in the 79.2 Gy arm. There were significantly higher rates of grade 2+ GI and GU toxicity in the 79.2 Gy arm. There were no statistically significant differences in the rates of grade 3+ GU or GI toxicity between either arm. Long term follow up confirms no improvement in OS with dose escalation in this study population. However, there are significant improvements in ABF, PBF, DM, LP, and need for salvage therapy. Despite the use of more salvage therapy in the low dose arm, dose escalated RT resulted in lower rates of DM, a clinically relevant endpoint. Patients receiving dose escalation do experience a higher rate of grade 2+ GU and GI toxicity but no worse grade 3+ toxicities.

Validation of a Genomic Classifier in the NRG Oncology/RTOG 0521 Phase III Trial of Docetaxel with Androgen Suppression and Radiotherapy for Localized High-Risk Prostate Cancer

Decipher is a prognostic genomic classifier (GC) validated in several prospective NRG Oncology Phase III trials. Herein, we validate the GC in pre-treatment biopsy samples for risk stratification in a cohort of high-risk men treated with definitive radiotherapy and androgen suppression with or without docetaxel chemotherapy. As per a pre-specified and approved NCI analysis plan (Navigator #1061), we obtained available formalin-fixed paraffin-embedded tissue from biopsy specimens from the NRG biobank from patients enrolled on the NRG/RTOG 0521 randomized phase III trial. After central review, the highest-grade tumors were profiled on clinical-grade whole-transcriptome arrays (Veracyte, San Diego, CA) and GC scores were obtained. Pre-specified categorical GC scores, adjusted for archival tissue analysis, were used to define higher (>0.46) and lower (≤0.46) risk groups. The primary objective was to validate the independent prognostic ability of GC for metastasis-free survival (MFS) with Cox multivariable analyses (MVA). Samples were obtained from 283 consented, evaluable patients with tissue (50% of trial) yielding 183 (65%) GC scores that passed quality metrics, 91 from control and 92 from the interventional arm. Median age was 66 years, median PSA was 19.3 ng/uL (IQR: 8.1-41.4), 81% had clinical stage ≥T2 and 80% had Gleason score ≥8 (47% ≥9). Median GC score was 0.55 (IQR: 0.38-0.78) and overall the arms were balanced for key covariates. With a median follow-up of 9.9 years (IQR: 9.3, 10.7), 67 MFS events including 34 distant metastases (DM) were observed. On MVA, only the GC (per 0.1 unit) was independently associated with MFS (HR 1.12, 95% CI 1.01-1.25) as well as DM (sHR 1.22, 95% CI 1.06-1.41), whereas the 4 pre-defined trial risk groups used for stratification (based on Gleason score, T-stage and PSA), randomization and patient age were not. For categorical GC, on MVA, higher-risk GC patients (65%) had worse DM (sHR 2.82, 95% CI 1.1-7.3) compared to those with lower GC. Cumulative incidence of DM at 10-years was 27% for higher GC vs 9% (95% CI 7-18%) for lower GC. No biomarker-by-treatment interaction with GC and the addition of docetaxel was detected. In pre-treatment biopsy samples from a randomized Phase 3 trial cohort, GC demonstrated its ability to further risk stratify clinically high-risk men demonstrating an independent association of GC score with DM and MFS. High-risk prostate cancer is a heterogeneous disease state and GC can improve risk stratification to help personalize shared decision-making. NRG-GU009/PREDICT-RT (NCT04513717) aims to determine the optimal therapy based on GC score for high-risk prostate cancer.