High Risk Of Distant Metastasis Research Articles

Abstract PO5-09-01: Relative low body mass index (BMI) and fat quantity predicts prognosis better than absolute BMI in hormone receptor-positive, HER2-negative breast cancer

Abstract Purpose: Most existing research about obesity and prognosis in breast cancer patients primarily compares obese and non-obese individuals according to standard body mass index (BMI) categories. With a notably high percentage of Asian patients presenting with young age onset and normal weight, the prevalence of overweight and obesity based on absolute BMI values is lower in Asia (according to WHO guideline, BMI under 18.5 means underweight, and BMI over 25 means overweight). Understanding the impact of relatively low and high weight on prognosis can provide more insightful data than assessments based on absolute BMI thresholds. This study aimed to investigate the impact of relative low/high BMI on the prognosis of breast cancer and to explore the influence of body fat quantity (FQ), which is closely related to BMI. Methods: The study population consisted of 3,663 patients who received surgery for primary breast cancer at Seoul National University Hospital from 2006 to 2015. Pre-treatment BMI was divided into quartiles, defining low-BMI (Q1) as ≤ 21.33, high-BMI (Q4) as > 25.53, and mid-BMI as values between the two. Fat quantity (FQ) was derived from chest CT using the deep learning-based FDA-approved DeepCatch software. It measures the fat volume at the L1 level then divides this value by the square of the patient's height. It was then also divided into quartiles, establishing the definitions of low-, mid-, and high-FQ. The associations of BMI and FQ with distant metastasis-free survival (DMFS) and overall survival (OS) were examined. Results: The high-BMI group demonstrated older median age and higher T and N stages (p< 0.001). The high- and low-BMI groups also showed a higher prevalence of estrogen receptor positive cancer compared to the mid-BMI group. A strong correlation (Pearson correlation coefficient 0.83) was observed between BMI and FQ. In HR-positive, HER2-negative breast cancer, high-BMI patients had a 1.55 times higher risk of distant metastasis (95% CI: 1.15-2.11, p = 0.005), and a 1.78 times higher risk of mortality (95% CI: 1.22-2.58, p = 0.003) compared to mid-BMI patients, while low-BMI patients demonstrated better outcomes regarding DMFS (HR 0.67, p=0.035) and OS (HR 0.59, p=0.04). Comparison of FQ with prognosis revealed that the low-FQ patients exhibited better DMFS (HR 0.59, p=0.005) and OS (HR = 0.44, p=0.002) compared to mid-FQ patients in HR-positive, HER2-negative breast cancer. However, when adjusted for T and N stages, low-BMI patients in the HR-positive, HER2-negative group showed no difference in prognosis from mid-BMI patients but better prognosis compared to high-BMI patients. In contrast, when defined using absolute BMI, underweight patients did not show a difference in DMFS (HR 0.72 vs. normal BMI, p = 0.515) and OS (HR 0.91 vs. normal BMI, p = 0.87) compared to those with normal weight and overweight. The low-FQ group had the best prognosis regarding DMFS (HR 0.66 vs. mid-FQ, p=0.032) and OS (HR 0.50 vs. mid-FQ, p=0.008). Conclusions: Low-BMI is a favorable prognostic factor compared to high-BMI for DMFS and OS in HR-positive, HER2-negative breast cancer. The relative BMI defined according to BMI quartiles was a better prognostic factor than to absolute BMI standards. Investigations with FQ showed similar tendencies, suggesting that low BMI's favorable prognostic influence may be associated with fat. Future investigations should aim to validate these results and delve deeper into the underlying mechanisms. Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Soon Ho Yoon work as chief medical officer in MEDICALIP. This author did not involve data/statistical analysis. Other authors have no competing interest to declare. Citation Format: Eunhye Kang, Ji-Jung Jung, Ik Beom Shin, Hawjeong Lee, Jin Young Byeon, Changjin Lim, Hong-Kyu Kim, Hyeong-Gon Moon, Wonshik Han, Jong-Ho Cheun, Soon Ho Yoon, Han-Byoel Lee. Relative low body mass index (BMI) and fat quantity predicts prognosis better than absolute BMI in hormone receptor-positive, HER2-negative breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-09-01.

Abstract PO5-01-14: Genomic risk analyses in patients with clinical low risk ER-positive HER2-negative early breast cancer developing an early metastatic event

Abstract Background: Over the past decade, there have been notable changes in the definition of risk estimation in patients with early-stage breast cancer (EBC). Specifically, within the timeframe of 2000 to 2017, following Estrogen Receptor (ER) positive and HER2-negative EBC cases were classified as low risk according to the University Hospitals of Leuven (UHL) criteria of that time: if ER H-score was >200: all patients with tumors N0 and Grade (G) 1, ≤pT2; or G2-3 pT1a-b; in patients ≥40 years with tumors N0 and G2 pT1c-2 or G3 pT1c; in patients ≥ 55 years with tumors N0 G3 pT2 or N1 any Grade, pT≤2. For lower H-scores, other criteria applied. However, despite undergoing endocrine therapy, a subset of these patients with clinically low-risk tumors unexpectedly experienced metastasis within five years of initial diagnosis. This unforeseen outcome may indicate potential undertreatment, as these patients did not receive adjuvant chemotherapy. We have conducted a case-cohort study of those patients with early relapse and performed the current clinical risk assessment methods and genomic risk analyses. Methods: In this study, we included patients with ER-pos, HER2-neg early-stage breast cancer diagnosed between 1-1-2000 and 31-12-2017, who were classified as low-risk tumors by UHL guidelines at that time, who were older than 35 but younger than 71 years, had an unilateral, unifocal breast tumor with tumor size up to 5 cm. These patients did not receive adjuvant chemotherapy. We selected the patients that experienced early distant recurrence, defined as distant recurrence (DR) within 5 years after the initial diagnosis. To ensure comparability for the analyses they were matched to controls for grade, menopausal status, tumor size, lymphovascular invasion, progesterone receptor status, and the year of diagnosis. For each patient, we have calculated the clinical risk score according to the criteria outlined by Mymammaprint.com, based on the modified Adjuvant Online tool used in the MINDACT trial. For the analysis, formalin-fixed paraffin-embedded (FFPE) breast tumor tissue samples were subjected to in-house validated targeted RNA-based Mammaprint(MP) analysis by NGS (MP Agendia). Results: Of the 3190 patients with EBC at UHL during the study period, 2476 patients were considered for this analysis and fitted the clinical low-risk criteria defined low-risk at UHL. Among those, only 42 or 1.7% of the eligible cohort had developed metastasis within 5 years. Tissue for MP analysis was available for 35 of these cases and for their matched control. Due to technical failure, the 1:1 matching was lost and MP results were known for 28 cases and 27 controls. The patient and tumor characteristics of both groups were comparable. In this UHL clinical low-risk group, 21/28 (75%) cases would be identified as clinical high-risk by MyMammaprint.com and 18/27 (67%) controls. We identified 13 patients (46.43%) with high genomic risk within the group with DR and 9 (33.33%) within the control group. There was no statistically significant difference (p=0.412) in the proportion of genomically high-risk patients within the group with DR compared to the control group. Conclusions: In a database of patients with EBC of whom 98% did not develop metastasis within 5 years, we observed in a small series of chemotherapy naïve patients with early DR and UHL-defined clinical low-risk tumors, that nearly half had a genomically high risk of distant metastasis. Albeit numerically higher than the matched-control group, this observation was not significant and would warrant a larger sample size and power to confirm these results. Table. Genomic versus Clinical Risk by MyMammaprint.com Citation Format: Josephine Van Cauwenberge, Hava Izci, Hans Wildiers, Sileny Han, Christine Desmedt, Giuseppe Floris, Sara Vander Borght, Ann Smeets, Ines Nevelsteen, Isabelle Vanden Bempt, Patrick Neven. Genomic risk analyses in patients with clinical low risk ER-positive HER2-negative early breast cancer developing an early metastatic event [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-01-14.

YTHDC1-dependent m6A modification modulated FOXM1 promotes glycolysis and tumor progression through CENPA in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) exhibits heightened aggressiveness compared with other breast cancer (BC) subtypes, with earlier relapse, a higher risk of distant metastasis, and a worse prognosis. Transcription factors play a pivotal role in various cancers. Here, we found that factor forkhead box M1 (FOXM1) expression was significantly higher in TNBC than in other BC subtypes and normal tissues. Combining the findings of Gene Ontology (GO) enrichment analysis and a series of experiments, we found that knockdown of the FOXM1 gene attenuated the ability of TNBC cells to proliferate and metastasize both invivo and invitro. In addition, Spearman's test showed that FOXM1 significantly correlated with glycolysis-related genes, especially centromere protein A (CENPA) in datasets (GSE76250, GSE76124, GSE206912, and GSE103091). The effect of silencing FOXM1 on the inhibition of CENPA expression, TNBC proliferation, migration, and glycolysis could be recovered by overexpression of CENPA. According to MeRIP, the level of m6A modification on FOMX1 decreased in cells treated with cycloleucine (a m6A inhibitor) compared with that in the control group. The increase in FOXM1 expression caused by YTHDC1 overexpression could be reversed by the m6A inhibitor, which indicated that YTHDC1 enhanced FOXM1 expression depending on m6A modification. Therefore, we concluded that the YTHDC1-m6A modification/FOXM1/CENPA axis plays an important role in TNBC progression and glycolysis.

Need for Staging Investigations in Newly Diagnosed Breast Cancer: Establishing Local Guidelines for Radiological Staging in Bahrain

Need for Staging Investigations in Newly Diagnosed Breast Cancer: Establishing Local Guidelines for Radiological Staging in Bahrain

Camrelizumab and apatinib plus induction chemotherapy and concurrent chemoradiotherapy in stage N3 nasopharyngeal carcinoma: a phase 2 clinical trial

The antiangiogenic agent apatinib has been shown to clinically improve responses to immune checkpoint inhibitors in several cancer types. Patients with N3 nasopharyngeal carcinoma have a high risk of distant metastasis, however, if the addition of immunotherapy to standard treatment could improve efficacy is unclear. In this phase II clinical trial (ChiCTR2000032317), 49 patients with stage TanyN3M0 nasopharyngeal carcinoma were enrolled and received the combination of three cycles of induction chemotherapy, camrelizumab and apatinib followed by chemoradiotherapy. Here we report on the primary outcome of distant metastasis-free survival and secondary end points of objective response rate, failure-free survival, locoregional recurrence-free survival, overall survival and toxicity profile. After induction therapy, all patients had objective response, including 13 patients (26.5%) with complete response. After a median follow-up of 28.7 months, the primary endpoint of 1-year distant metastasis-free survival was met for the cohort (1-year DMFS rate: 98%). Grade≥3 toxicity appeared in 32 (65.3%) patients, with the most common being mucositis (14[28.6%]) and nausea/vomiting (9[18.4%]). In this work, camrelizumab and apatinib in combination with induction chemotherapy show promising distant metastasis control with acceptable safety profile in patients with stage TanyN3M0 nasopharyngeal carcinoma.

An Immune Gene Expression Risk Score for Distant Metastases after Radiotherapy for Cervical Cancer.

To develop an immune-based gene expression risk score to identify patients with cervical cancer at increased risk of distant metastases (DM). Tumor biopsies were obtained from 81 patients prior to chemoradiotherapy. Whole-transcriptome RNA sequencing was performed (Illumina NextSeq500). Beginning with 4,723 immune-related genes, a 55-gene risk score for DM was derived using Cox modeling and principal component analysis. It was validated in independent cohorts of 274 patients treated at the Norwegian Radium Hospital (NRH) and 206 patients from The Cancer Genome Atlas (TCGA). The risk score was predictive of DM (HR, 2.7; P < 0.0001) and lower cause-specific survival (CSS) by univariate analysis (HR, 2.0; P = 0.0003) and multivariate analysis adjusted for clinical factors (DM HR, 3.0; P < 0.0001; CSS HR, 2.2; P = 0.0004). The risk score predicted DM (HR, 1.4; P = 0.05) and CSS (HR, 1.48; P = 0.013) in the NRH cohort and CSS (HR, 1.4; P = 0.03) in TCGA cohort. Higher risk scores were associated with lower CIBERSORT estimates of tumor-infiltrating immune cells, including CD8 T cells and M1 and M2 macrophages (all P < 0.001). Higher risk scores were associated with lower expression (all P < 0.001) of important chemokines (CXCL12, CXCR4), IFN-regulated genes (IRF1, STAT1, IDO1), and immune checkpoint regulators (PD-1, PD-L1, CTLA-4). The immune metastatic risk score addresses important challenges in the treatment of cervical cancer-identifying patients at high risk of DM after radiotherapy. The findings of this study indicate that high tumor mutational burden and a "cold," immune-excluded tumor microenvironment influence distant metastatic recurrence. Further validation of the risk score is needed.

Long-term assessment of clinical parameters and positron emission tomography parameters in predicting recurrence in uterine cervical cancer patients receiving definitive chemoradiotherapy.

The objective of this study was to assess the prognostic value of clinical factors and metabolic parameters measured using fluorodeoxyglucose PET (FDG-PET/CT) in predicting disease recurrence, as well as distant metastasis-free survival (DMFS), local recurrence-free survival (LRFS), and overall survival (OS) in patients with uterine cervical cancer who received definitive chemoradiotherapy. The clinical data and FDG-PET parameters, including standardized uptake value (SUV), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) of 194 patients with biopsy-confirmed squamous cell carcinoma of cervical cancer were retrospectively analyzed. Univariate and multivariate analyses were used to ascertain prognostic factors associated with DMFS, LRFS, and OS. With a median follow-up of 12.5 years, 96 patients (49.5%) presented with disease recurrence, at a median of 9.9 months after chemoradiotherapy. Patients who experienced recurrence had significantly higher values for all FDG-PET parameters compared to patients who did not. In multivariate regression analysis, lymph node metastasis, MTV, and SUV mean were significantly correlated with distant metastasis, while local recurrence was only predicted by SUV max . Lymph node metastasis, high MTV, SUV mean , and TLG predicted shorter DMFS, while only the primary tumor SUV max predicted LRFS. Age, regional nodal metastasis, and higher MTV independently predicted shorter OS in multivariate analysis. We found that metabolic parameters derived from FDG-PET/CT could serve as surrogates for disease recurrence in patients with cervical cancer who were treated with definitive chemoradiotherapy. Patients at high risk of distant metastasis could be defined using SUV mean and MTV, and for local recurrence, by using SUV max .

Risk factor analysis of distant metastases in patients with primary medullary thyroid cancer: a population-based study.

Medullary thyroid carcinoma has a high rate of recurrence and distant metastasis. The aim of this study was to investigate the risk factors for distant metastasis in patients with primary medullary thyroid carcinoma. Patients diagnosed with primary medullary thyroid cancer between 2010 and 2015 were enrolled using the Surveillance, Epidemiology, and End Results (SEER) database. Patient demographics and tumor clinicopathological features were evaluated to identify potential risk factors for distant metastasis in patients with primary medullary thyroid cancer. Univariate and multivariate logistic regression analyses were used to determine independent risk factors for distant metastasis in patients with primary medullary thyroid carcinoma. All statistical analyses were performed using SPSS statistical software (version 27.0). A two-tailed P < 0.05 was considered statistically significant. We collected 685 patients with primary medullary thyroid carcinoma, 40 of whom (5.84%) developed distant metastases. Univariate logistic regression analysis showed that except marital status, age, sex, race, pT stage, N stage, multifocal and capsular infiltration were significantly correlated with distant metastasis of medullary thyroid carcinoma. Multivariate logistic regression analysis showed that patients aged ≤ 18years or > 55years, Black race, higher pT stage and N stage were independent risk factors for distant metastasis of medullary thyroid carcinoma. This study found that ≤ 18years or > 55years, black race, higher pT stage and N stage were significantly associated with distant metastasis of medullary thyroid cancer. This is important for clinicians to identify patients at high risk of distant metastasis in a timely manner.

Prognostic value of hypoxia-responsive gene expression profile in patients diagnosed with head and neck squamous cell carcinoma

Head and neck squamous cell carcinoma (HNSCC) is a disease associated with a severe mortality and high risk of distant metastasis and local recurrence. Currently, surgery and radiotherapy are the main treatment modes, however, therapeutic efficacy of radiotherapy is linked to tumor resistance. Hypoxia has been shown to affect outcome of radiotherapy in HNSCC patients. The aim of this study was to verify the expression of the previously identified hypoxia-responsive genes (CA9, CASP14, LOX, GLUT3, SERPINE1, AREG, EREG, CCNB1 and KIF14) in HNSCC patient material as well as assess their prognostic potential. Tumor biopsies obtained before start of radiotherapy from 32 HNSCC patients classified as responders or non-responders were investigated in this study. The mRNA expression was quantified using RT-qPCR. The mRNA expression of CA9, SERPINE1 and KIF14 was significantly higher in the analyzed patient material compared with the non-cancerous oral tissue. Moreover, the KIF14 mRNA expression was significantly higher in the responder group compared to non-responders. Further studies demonstrated that knockdown of KIF14 reverses its radiosensitizing capability. Additionally, low expression of KIF14 mRNA correlated with significantly shorter OS (overall survival). In conclusion, our results suggest that KIF14 might be a useful prognostic and predictive marker in HNSCC.

Treatment and outcomes in breast cancer patients: A cross section study from the EUSOMA breast centre network

IntroductionThe present study was designed to describe tumour features and treatments for patients with breast cancer. It also aimed at assessing the risk of distant metastases in relation to biological profiles, disease stages and treatment. MethodsData were analysed from 81,882 patients in the EUSOMA database (disease stages at diagnosis 0-IV; median age 61 years; range 20–100 years). All patients were treated between January 2016 and December 2021 in 53 Breast Centres within the EUSOMA certification process in 13 European countries. Cases were classified as HR+ /HER2-, HR+ /HER2 + , HR-/HER2 + or HR-/HER2- and data were analysed accordingly. ResultsUnivariable and multivariable analyses for distant metastases were conducted on a subset of 38,119 cases with information on whether or not they had developed them. Potential determinants included sub-group type, Ki67 value, disease stage, adjuvant systemic therapies and post-operative radiation therapy. In multivariable analysis, the HR-/HER2 + and HR-/HER2- sub-groups were associated with a higher risk of distant metastases than HR+ /HER2–. Ki67 > 20 % and advanced stage disease also carried a high risk. Radiation therapy emerged as a protective factor against distant metastases. ConclusionsPresent results show a large patient database offers an information stream that can be applied to reduce uncertainties in clinical practice. Database parameters need to be updated dynamically for outcome monitoring. Molecular prognostic factors, gene-expression signatures, tumour-infiltrating lymphocytes and circulating tumoral DNA should be added.

Dysfunctional TLR1 reduces the therapeutic efficacy of chemotherapy by attenuating HMGB1-mediated antitumor immunity in locally advanced colorectal cancer

Regional lymph node metastasis is an important predictor for survival outcome and an indicator for postoperative adjuvant chemotherapy in patients with colorectal cancer. Even with advances in adjuvant chemotherapeutic regimens, 5-year distant metastasis and survival rates are still unsatisfactory. Here, we evaluate the clinical significance of polymorphisms in receptors for HMGB1, which is the hallmark of chemotherapy-induced immunogenic cell death, in patients with stage II–III colon carcinoma (COAD). We found that high cytosolic HMGB1 is elicited in stage III COAD patients who received adjuvant chemotherapy. Patients with the TLR1-N248S polymorphism (rs4833095), which causes loss-of-function in HMGB1-mediated TLR1–TLR2 signaling, may influence the therapeutic efficacy of adjuvant chemotherapy, leading to a high risk of distant metastasis within 5 years [HR = 1.694, 95% CI = 1.063–2.698, p = 0.027], suggesting that TLR1-N248S is an independent prognostic factor for locally advanced colon carcinoma patients. We found that defective TLR1 impaired TLR1/2 signaling during dendritic cell (DC) maturation for the antitumor immune response under immunogenic chemotherapy oxaliplatin (OXP) treatment. Defective TLR1 on DCs impaired their maturation ability by HMGB1 and reduced the secretion of IFNγ from T cells to eradicate tumor cells in vitro. Moreover, systemic inhibition of TLR1/2 dramatically reduced the tumor-infiltrating immune cells by OXP treatment, leading to poor therapeutic response to OXP. In contrast, administration of a TLR1/2 agonist synergistically increased the benefit of OXP treatment and triggered a high density of tumor-infiltrating immune cells. We also observed that fewer tumor-infiltrating cytotoxic T lymphocytes were located within the tumor microenvironment in patients bearing the TLR1-N248S polymorphism. Overall, our results suggest that dysfunctional TLR1 may reduce the therapeutic response to adjuvant chemotherapy by impairing HMGB1-mediated DC maturation and attenuating the antitumor immune response in locally advanced colon carcinoma patients.

Vascular endothelial growth factor (VEGF) -A, -C and VE-cadherin as potential biomarkers in early breast cancer patients

BackgroundVascular endothelial growth factor (VEGF) -A and -C act as multifunctional molecules and growth factors, while VE-cadherin (cadherin 5, CDH5) is the endothelial junction protein. AimTo assess the relationship between intratumoral VEGF -A, -C and CDH5 levels and clinical outcome, in primary, early-stage, breast cancer patients. Patients and methodsThe study included 69 node-negative (N0) breast cancer patients, all of whom had not received any prior hormonal or chemotherapeutic systemic therapy that would affect the course of disease. The median follow-up period was 144 months. Intratumoral mRNA levels of VEGF -A, -C and CDH5 were determined by RT-qPCR. Prognostic performance was evaluated by Cox proportional hazards regression, Kaplan-Meier analysis, as well as by the multivariable approach based on the least absolute shrinkage and selection operator (LASSO) logit regression. Classification of patients into the low and high subgroups was performed using the outcome-oriented cut-off point categorization approach. ResultsOf the measured mRNAs, only CDH5 mRNA (t = −2.17; p = 0.04) and VEGF-C mRNA (t = −2.41; p = 0.03) showed significant differences between values in patient subgroups with distant metastasis and those without recurrences, respectively. These t-test results were in agreement with the Cox regression by which CDH5 mRNA reached the most pronounced hazard ratio (HR=2.07; p = 0.05), followed by VEGF-C mRNA (HR=1.59; p = 0.005). HR values above 1.0 indicate that high levels of either CDH5 or VEGF-C mRNAs associated with a higher risk of poor clinical outcome. Distant recurrence incidence was 26% for the CDH5high and 3% for the CDH5low subgroup (Kaplan–Meier analysis). Distant recurrence incidence was 23% for the VEGF-Chigh and 0% for VEGF-Clow subgroup. The independent prognostic value of VEGF-C mRNA was confirmed by LASSO regression. ConclusionIntratumoral VEGF-A levels did not associate with disease outcome in primary, early-stage, breast cancer patients, whilst raised levels of either CDH5 or VEGF-C prognosticated a high risk of distant metastasis.

Genomic Characterization of Locally Recurrent Prostate Cancer after Radiation Therapy.

Radiation therapy (RT) is a backbone of treatment for patients with prostate cancer (PCa). However, locally recurrent disease after definitive RT (i.e., radiorecurrent PCa) is not uncommon and is associated with a higher risk of distant metastases and death from PCa. While the genomic landscape of primary PCa is well-characterized, little is known regarding the genomic landscape of radiorecurrent PCa or how this compares to that of primary PCa. We hypothesized that the genomic landscape of radiorecurrent PCa differs significantly from primary PCa and that these differences have clinical relevance. We examined this hypothesis by performing whole exome sequencing (WES) of radiorecurrent PCa. We identified 25 patients with radiorecurrent PCa with available post-RT tissue obtained from biopsy or radical prostatectomy, as well as germline tissue. The tumor and germline tissue for 19 patients successfully underwent WES. We identified genomic variants including single nucleotide variants (SNVs), insertions/deletions, and copy number alterations. Furthermore, we estimated the tumor mutational burden (TMB; number of nonsynonymous mutations per megabase [Mb]) and contribution of individual mutational signatures. We compared our samples to a publicly available large cohort of primary PCa (n = 680) to define genomic alterations unique to radiorecurrent PCa. In the overall cohort of 25 patients, the RT modality included external beam RT (56%), brachytherapy (36%), and combination of both (8%). 40% of patients received upfront androgen deprivation therapy with RT. The median time to local recurrence was 6.5 years. For the 19 radiorecurrent patients with WES data, the median TMB was 2.7 mutations/Mb, which was significantly higher than the median TMB of 0.7 mutation/Mb for primary PCa (P = 0.002 after multivariable adjustment). Radiorecurrent PCa demonstrated an enrichment of short deletions, with a significantly higher deletion/SNV ratio compared to primary PCa (P = 0.006). TP53 was the most frequently mutated gene in radiorecurrent PCa (n = 6), and the TP53 mutation prevalence was significantly higher compared to primary PCa (32% vs 10%, P = 0.016 by Fisher's exact test). TP53 was also determined to be recurrently mutated using MutSigCV (Q = 0.0003). Additionally, 3 samples demonstrated evidence of whole genome doubling. Radiorecurrent PCa has a distinct genomic profile compared to primary PCa, characterized by a higher TMB with an enrichment of short deletions as part of the mutational composition, which may be a scar of nonhomologous end joining subsequent to RT-induced DNA double-stranded breaks. In addition, TP53 mutations may be of functional consequence in radiorecurrent PCa. Further efforts are underway to examine other genomic features apparent in WES data, as well as perform whole transcriptome sequencing to provide complementary insights into radiorecurrent PCa.

Machine Learning Based Prediction of Distant Metastasis in Rectal Cancer Patients with Complete Response following Neoadjuvant Chemoradiotherapy

Distant metastasis (DM) is the leading cause of disease recurrence in rectal cancer patients with clinical or pathological complete response (CR) following neoadjuvant chemoradiotherapy (nCRT). Identifying these patients may help to tailor the treatment approach. The aim of this study was to predict the rectal cancer patients with high risk of DM following CR with nCRT, using machine learning (ML), based on patient, disease and treatment related clinical factors. Data of the rectal cancer patients treated with nCRT at three academic centers between 2010-2022 were collected. Patients with secondary malignancies were excluded. 157 patients with CR were included in the analysis. Median age was 63 (31-85). Female/male ratio was 59/98. Tumor location was proximal-, mid- and distal-rectum in 9, 65 and 83 patients, respectively. cT stage was T2, T3 and T4 in 14, 120 and 23 patients, respectively. 122 patients had cN (+). Median tumor and regional lymph nodes doses were 50.4 (45-56) Gy and 45 (45-50.4) Gy, respectively, in 25-28 fractions, concurrently with capecitabine. 63 patients had clinical CR and were followed up without surgery, and 94 had pathological CR. Median RT-surgery interval was 11 (3.4-59) weeks. 41 patients were managed with total neoadjuvant treatment and 52 received adjuvant systemic treatment. Median follow up time was 37 (3-143) months. DM was detected in 18 patients at median 14 (2-87) months and local tumor recurrence/progression was seen in 9. A ML model was used to predict DM based on patient, disease and treatment related 37 clinical factors. Statistical analysis was conducted using Python (v.3.7). P<0.05 was accepted as statistically significant. Multiple Linear Regression was used to analyze the relationship between DM and independent continuous variables. Chi-square test was used to analyze the difference between the observed frequency distribution of a categorical variable and the expected frequency distribution. Confusion matrix algorithm was used to evaluate the performance of the model. Logistic regression algorithm (LRA) was selected as the best performing algorithm for the ML model that used 37 variables from 157 patients. The model was trained using 75% of the data and the remaining 25% was used for testing. CEA, ratio of post- to pre-RT tumor SUVmax, tumor dose, RT-surgery interval, pre-RT weight loss, smoking history, cN status, and gender were significant parameters to predict DM, based on the LRA of the ML model. Accuracy score of the model was 92% and AUC of the ROC was 74%. Precision (positive predictive value) and recall (sensitivity) of the model were 67% and 50%, respectively. Machine learning has a high rate of correctly classifying patients and good performance in predicting those with DM. Further studies with larger patient numbers are needed.

Regulatory T cells are associated with the tumor immune microenvironment and immunotherapy response in triple-negative breast cancer.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer with a high risk of distant metastasis, an extremely poor prognosis, and a high risk of death. Regulatory T cells (Tregs) contribute to the formation of a tumor immunosuppressive microenvironment, which plays an important role in the progression and treatment resistance of TNBC. A public single-cell sequencing dataset demonstrated increased infiltration of Tregs in TNBC tissues relative to normal breast tissue. Weighted gene co-expression network analysis was used to identify Treg infiltration-related modules for METABRIC TNBC samples. Subsequently, we obtained two Treg infiltration-associated clusters of TNBC by applying consensus clustering and further constructed a prognostic model based on this Treg infiltration-associated gene module. The ability of the selected gene in the prognostic model, thymidine kinase-1 (TK1), to promote the progression of TNBC was evaluated in vitro. We concluded that two Treg infiltration-associated clusters had different prognoses and sensitivities to drugs commonly used in breast cancer treatment, and multi-omics analysis revealed that the two clusters had different copy number variations of key tumor progression genes. The 7-gene risk score based on TNBC Treg infiltration was a reliable prognostic indicator both in the training and validation cohorts. Moreover, patients with TNBC with high Treg infiltration-related scores lacked the activation of immune activation pathways and exhibited resistance to anti-PD1 immunotherapy. Knocking down TK1 led to impaired proliferation, migration, and invasion of TNBC cells in vitro. In addition, specimens from patients with TNBC with high TK1 expression showed significantly higher Treg infiltration in tumors. Results of spatial transcriptome analysis showed that TK1 positive cells mainly localize in tumor area, and Treg cell infiltration in TNBC tissues was associated with high expression of TK1. Pan-cancer analysis also demonstrated that TK1 is associated with poor prognosis and activation of proliferation pathways in multiple cancers. We established a prognostic model related to Treg infiltration and this model can be used to establish a clinically relevant classification of TNBC progression. Additionally, our work revealed the underestimable potential of TK1 as a tumor biomarker and immunotherapeutic target.

The Predictive Utility of MammaPrint and BluePrint in Identifying Patients with Locally Advanced Breast Cancer Who are Most Likely to Have Nodal Downstaging and a Pathologic Complete Response After Neoadjuvant Chemotherapy

BackgroundNeoadjuvant chemotherapy (NCT) increases the feasibility of surgical resection by downstaging large primary breast tumors and nodal involvement, which may result in surgical de-escalation and improved outcomes. This subanalysis from the Multi-Institutional Neo-adjuvant Therapy MammaPrint Project I (MINT) trial evaluated the association between MammaPrint and BluePrint with nodal downstaging.Patients and MethodsThe prospective MINT trial (NCT01501487) enrolled 387 patients between 2011 and 2016 aged ≥ 18 years with invasive breast cancer (T2–T4). This subanalysis includes 146 patients with stage II–III, lymph node positive, who received NCT. MammaPrint stratifies tumors as having a Low Risk or High Risk of distant metastasis. Together with MammaPrint, BluePrint genomically (g) categorizes tumors as gLuminal A, gLuminal B, gHER2, or gBasal.ResultsOverall, 45.2% (n = 66/146) of patients had complete nodal downstaging, of whom 60.6% (n = 40/66) achieved a pathologic complete response. MammaPrint and combined MammaPrint and BluePrint were significantly associated with nodal downstaging (p = 0.007 and p < 0.001, respectively). A greater proportion of patients with MammaPrint High Risk tumors had nodal downstaging compared with Low Risk (p = 0.007). When classified with MammaPrint and BluePrint, more patients with gLuminal B, gHER2, and gBasal tumors had nodal downstaging compared with HR+HER2−, gLuminal A tumors (p = 0.538, p < 0.001, and p = 0.013, respectively).ConclusionsPatients with genomically High Risk tumors, defined by MammaPrint with or without BluePrint, respond better to NCT and have a higher likelihood of nodal downstaging compared with patients with gLuminal A tumors. These genomic signatures can be used to select node-positive patients who are more likely to have nodal downstaging and avoid invasive surgical procedures.

A machine learning-based model for predicting distant metastasis in patients with rectal cancer.

Distant metastasis from rectal cancer usually results in poorer survival and quality of life, so early identification of patients at high risk of distant metastasis from rectal cancer is essential. The study used eight machine-learning algorithms to construct a machine-learning model for the risk of distant metastasis from rectal cancer. We developed the models using 23867 patients with rectal cancer from the Surveillance, Epidemiology, and End Results (SEER) database between 2010 and 2017. Meanwhile, 1178 rectal cancer patients from Chinese hospitals were selected to validate the model performance and extrapolation. We tuned the hyperparameters by random search and tenfold cross-validation to construct the machine-learning models. We evaluated the models using the area under the receiver operating characteristic curves (AUC), the area under the precision-recall curve (AUPRC), decision curve analysis, calibration curves, and the precision and accuracy of the internal test set and external validation cohorts. In addition, Shapley's Additive explanations (SHAP) were used to interpret the machine-learning models. Finally, the best model was applied to develop a web calculator for predicting the risk of distant metastasis in rectal cancer. The study included 23,867 rectal cancer patients and 2,840 patients with distant metastasis. Multiple logistic regression analysis showed that age, differentiation grade, T-stage, N-stage, preoperative carcinoembryonic antigen (CEA), tumor deposits, perineural invasion, tumor size, radiation, and chemotherapy were-independent risk factors for distant metastasis in rectal cancer. The mean AUC value of the extreme gradient boosting (XGB) model in ten-fold cross-validation in the training set was 0.859. The XGB model performed best in the internal test set and external validation set. The XGB model in the internal test set had an AUC was 0.855, AUPRC was 0.510, accuracy was 0.900, and precision was 0.880. The metric AUC for the external validation set of the XGB model was 0.814, AUPRC was 0.609, accuracy was 0.800, and precision was 0.810. Finally, we constructed a web calculator using the XGB model for distant metastasis of rectal cancer. The study developed and validated an XGB model based on clinicopathological information for predicting the risk of distant metastasis in patients with rectal cancer, which may help physicians make clinical decisions. rectal cancer, distant metastasis, web calculator, machine learning algorithm, external validation.

Correlation between connexin 43 expression in circulating tumor cells and biological characteristics of breast cancer

BackgroundConnexin 43 (Cx43) has been closely linked to the occurrence and progression of breast cancer. Distant metastasis of breast cancer is aided by the epithelial-mesenchymal transition of circulating tumor cells (CTCs). However, the impact of Cx43 expression on CTCs and the extent of its role in the disease remain unclear. MethodsWe determined CTCs in 156 patients, who had breast cancer with a disease course of two or more years. We also measured the expression of Cx43 in the CTCs. The CTCs were detected in the blood of 139 of these patients. These 139 patients were divided into two groups: the Cx43 group and the non-Cx43 group based on their Cx43 expression. ResultsOverall, Cx43 expression was found in 83 of the 139 patients (59.7%, 83/139 cases). The two groups significantly differed in terms of the number of mixed biphenotypic type CTCs and the total number of CTCs (P < 0.05). There were significant correlations between Cx43 expression and Ki67 expression, tumor size, lymph node metastasis, and TNM stage (P < 0.05 for all). The data suggested that patients with Cx43 expression had a higher risk of distant metastasis and had later-stage disease. The difference in Cx43 expression between patients with and without epidermal growth factor receptor 2 (Her2) overexpression was statistically significant (P < 0.05). The difference in disease-free survival (DFS) between the two groups was statistically significant (P = 0.03), and the Cx43 group had a shorter duration of DFS. Univariate Cox regression analysis revealed that Cx43 expression, Her2 expression, and tumor size were significantly correlated with DFS (P = 0.03, 0.0023, and 0.01, respectively). ConclusionCx43 expression in the CTCs of patients with breast cancer is a cancer-promoting factor.

Progesterone Receptor Expression Level Predicts Prognosis of Estrogen Receptor-Positive/HER2-Negative Young Breast Cancer: A Single-Center Prospective Cohort Study

Background: Although estrogen receptor (ER) expression levels affect the prognosis of breast cancer, studies about progesterone receptor (PR) expression levels are insufficient, especially in young breast cancer (YBC). The purpose of this study was to compare clinical characteristics and prognosis according to PR expression levels in invasive breast cancer patients. Methods: A prospective cohort study was conducted to identify YBC patients with invasive carcinoma diagnosed at an age of less than 40 years old between 2013 and 2018. Clinicopathologic features and prognosis of ER-positive and human epidermal growth factor receptor 2 (HER2)-negative patients were investigated. Patients were stratified into strong PR (PR-positive cell proportion &gt; 10%), low PR (PR-positive cell proportion = 1~10%), and PR-negative (PR-positive cell proportion &lt; 1%). Results: Among 458 patients enrolled, 386 (84.3%), 26 (5.7%), and 46 (10.0%) were categorized into strong PR, low PR, and PR-negative groups, respectively. The median follow-up duration was 58.6 months. Compared with the strong PR group, low PR and PR-negative groups were more likely to have high Ki-67 and a high nuclear grade. Low R and PR-negative groups had significantly worse disease-free survival (DFS) and distant metastasis-free survival (DMFS) than the strong PR group (p = 0.0033, p = 0007). Low PR group had an even higher risk of distant metastasis than PR-negative patients. Low PR patients and PR-negative had significantly lower overall survival (OS) rates than strong PR. Conclusion: Low PR might be a prognostic factor of ER-positive/HER2-negative in YBC.

Regional transarterial chemoembolization combined with chemoradiotherapy for locally advanced rectal cancer: a retrospective study of a new combination.

Locally advanced rectal cancer (LARC) has a high risk of distant metastasis (DM). Currently, many treatment courses of LARC have arisen, but patients' DM status has not significantly improved. This study was designed to compare the effect between preoperative regional transarterial chemoembolization combined with neoadjuvant chemoradiotherapy and standard neoadjuvant therapy on preventing DM in patients with LARC. A total of 81 LARC patients between July 2013 and May 2018 were enrolled in this retrospective study. Among them, 44 patients received preoperative regional transarterial chemoembolization combined with concurrent chemoradiotherapy (the interventional group), and 37 patients received only neoadjuvant chemoradiotherapy (the control group). The baseline data; preoperative toxicities; postoperative DM rate within 1, 2, and 3 years; and postoperative complications were compared between the two groups. All patients successfully completed their treatments. There were no significant differences between the two groups in age, gender, tumor size, distance between the tumor and anal verge, CEA level, lymphovascular invasion, or tumor stage before treatment. The pathological T staging post-treatment in the interventional group was significantly reduced compared to that of the control group (p = 0.025). There were no significant differences between groups in DM rates within 1 and 2 years after surgery. In terms of DM rate within 3 years after surgery, the interventional group was significantly lower than that of the control group (9.1% vs. 29.7%, p = 0.036). Preoperative regional transarterial chemoembolization combined with concurrent chemoradiotherapy may play an important role in reducing postoperative DM in LARC.