Metastasis-free Survival In Patients Research Articles

P4.07F.01 Real World Characteristics and Distant Metastasis Free Survival of Patients with Early NSCLC Treated with Chemoimmunotherapy

P4.07F.01 Real World Characteristics and Distant Metastasis Free Survival of Patients with Early NSCLC Treated with Chemoimmunotherapy

Abstract PO5-18-12: Can we cure de novo oligometastatic stage IV HER2+ breast cancer with multimodality therapy? (CHLOE)

Abstract Background: The current standard of care is to treat all patients with metastatic breast cancer with palliative intent, regardless of extent of disease. However, in real world practice patients with oligometastatic disease are sometimes treated with surgery and/or radiation/ablation in combination with systemic therapy to render them as having no evidence of disease. Previous randomized clinical trials have not shown a benefit to adding surgery or radiation in metastatic breast cancer, however, these trials had a small number of HER2+ patients. HER2+ patients are uniquely responsive to combination of chemotherapy and targeted HER2 therapy and therefore may have different outcomes with a multimodality approach. The goal of this project is to use a novel, user friendly, on-line clinical study platform that registers patients and enables follow-up data collection to test the hypothesis that de novo stage IV oligometastatic HER2+ patients treated with multimodality therapy may result in improved long-term distant metastasis free survival and overall survival. Trial design: This is a prospective, nationwide registry study that will enroll newly diagnosed (de novo) oligometastatic (operationally defined by local tumor boards as disease where all metastatic lesions can be ablated) HER2+ breast cancer. A secure online portal has been created by the Yale IT team in accordance with HIPPA and cybersecurity guidelines. Data will be directly entered into the online portal by participating investigators and information regarding what treatment the patient received, if they completed treatment, and survival data will be collected. All treatment decisions will be at the discretion of the treating provider. Eligibility criteria: Patients with de novo oligometastatic HER2+ breast cancer in whom local treatment of all metastatic sites by either surgery, radiation, or ablative techniques is feasible as determined by multidisciplinary discussion or local tumor board. Specific aims: Primary: To estimate the 3 year distant metastasis free survival in patients with de novo oligometastatic HER2+ breast cancer treated with a multi-modality treatment plan. Secondary: To estimate 3 year overall survival and to monitor QOL. Statistical methods: The major analysis will occur after at least 3 years following the last subject’s enrollment in a cohort, to ensure that the objective of distant metastasis free survival at 3 years will be analyzed. It will include: tabulation of all cases entered, number and location of metastases, if treatment plan was implemented, compliance rate of treatment delivery, observed results with respect to the primary endpoint. Kaplan-Meier estimates will be presented for the analysis of survival endpoints together with a summary of associated statistics (median survival time if reached, landmark survival rate estimates and estimates for every 6 months thereafter if applicable), including the corresponding two-sided 95% confidence intervals. The 95% exact Clopper Pearson confidence intervals will be presented for binary endpoints. Paired t-test or Wilcoxon signed rank test will be used to assess the difference of continuous variables measured at different time points. The secondary clinical outcome is overall survival at 3 years, defined as the percentage of patients without an event at the 3-year follow-up time point measured from the study registration date. An event is considered death from any cause. OS time will be measured from the date of randomization to the date of first OS failure or last follow-up. OS will be estimated by the Kaplan-Meier method with OS failure defined as: death from any cause. Present accrual and target accrual: 4/42 patients Contact information for people with a specific interest in the trial: Mariya.Rozenblit@yale.edu https://chloe.yalepathaws.org Citation Format: Mariya Rozenblit, Nathalie Wiesendanger, Kelly Shanahan, Christine Hodgdon, Peter Gershkovich, Mehra Golshan, Meena Moran, Maryam Lustberg, Lajos Pusztai. Can we cure de novo oligometastatic stage IV HER2+ breast cancer with multimodality therapy? (CHLOE) [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 PO5-18-12.

Frequent Amplification and Overexpression of PSMA in Basallike Breast Cancer from Analysis of The Cancer Genome Atlas.

Prostate-specific membrane antigen (PSMA) is frequently overexpressed in nonprostate malignancies. This preclinical study investigated the molecular basis of the application of PMSA-targeting radiopharmaceuticals in breast cancer subtypes. Methods: The somatic copy number status and the transcriptomic and protein expressions of FOLH1 (gene name of PSMA) were analyzed across breast cancer subtypes in 998 patients from The Cancer Genome Atlas dataset. Results: FOLH1 was frequently amplified in basallike breast cancer (BLBC) (32%) compared with luminal and human epidermal growth factor receptor 2-positive subtypes (16% and 17%, respectively; P < 0.01). FOLH1 expression was higher in BLBC (P < 0.001) and was negatively correlated with estrogen-receptor and progesterone-receptor expressions. Consistently, the PSMA protein level was higher in BLBC (P < 0.05). Interestingly, FOLH1 expression was associated with relapse-free and distant metastasis-free survival in patients with BLBC. Conclusion: The BLBC subtype exhibited frequent amplification and overexpression of PSMA, supporting the exploration of PSMA-targeting radiopharmaceuticals in this aggressive breast cancer subtype.

A multidisciplinary approach to address unmet needs in the management of patients with non-metastatic castration-resistant prostate cancer.

With the availability of second-generation androgen receptor inhibitors (SGARIs), the treatment landscape has changed dramatically for patients with nonmetastatic castration-resistant prostate cancer (nmCRPC). In clinical trials, the SGARIs (apalutamide, enzalutamide, darolutamide) increased metastasis-free survival (MFS), overall survival (OS), and patient quality of life compared to placebo. These drugs were subsequently integrated into nmCRPC clinical practice guidelines. With advances in radiographic imaging, disease assessment, and patient monitoring, nmCRPC strategies are evolving to address limitations related to tracking disease progression using prostate-specific antigen (PSA) kinetics. A panel of 10 multidisciplinary experts in prostate cancer conducted reviews and discussions of unmet needs in the management and monitoring of patients with nmCRPC in order to develop consensus recommendations. Across the SGARI literature, patient MFS and OS are generally comparable for all treatments, but important distinctions exist regarding short- and long-term drug safety profiles and drug-drug interactions. With respect to disease monitoring, a substantial proportion of patients using SGARIs may experience disease progression without rising PSA levels, suggesting a need for enhanced radiographic imaging in addition to PSA monitoring. Recent data also indicate that novel prostate-specific membrane antigen positron emission tomography radiotracers provide enhanced accuracy for disease detection, as compared to conventional imaging. Clinical decision-making in nmCRPC has become more complex, with new opportunities to apply precision medicine to patient care. Multidisciplinary teams can ensure that patients with nmCRPC receive optimal and individualized disease management.

Association of multiparametric magnetic resonance imaging findings with oncologic outcomes in non-palpable localized prostate cancer.

281 Background: Multiparametric magnetic resonance imaging (mpMRI) is becoming increasingly integrated into the evaluation and medical decision making for localized prostate cancer. However, mpMRI findings have not been correlated with prostate cancer outcomes and therefore are not currently included in staging. The purpose of this study was to test the association between mpMRI detected extraprostatic extension with oncologic outcomes in patients with non-palpable prostate cancer. Methods: We used the Veterans Affairs Prostate Data Core to identify patients diagnosed with cT1N0M0 prostate cancer between 2000-2021 with an mpMRI prior to definitive treatment. We reviewed MRI reports to identify presence of extracapsular extension (MRI-T3a), seminal vesicle invasion (MRI-T3b), and adjacent organ invasion (MRI-T4). We assessed the impact of mpMRI findings on metastasis free survival with multivariable Fine-Gray competing-risks regression. Results: Overall, 3,142 veterans with cT1N0M0 prostate cancer were included. There were 1,411 (45%) Black patients. By clinical staging, 904 (29%) had low risk, 1,626 (52%) had intermediate risk, and 612 (19%) had high risk disease. The majority of patients were treated with radiation (N=2,267; 72%). There were 217 (7%) patients with MRI-T3a disease, 87 (3%) patients with MRI-T3b disease, and 26 (1%) patients with MRI-T4 disease. The median follow-up time was 5.4 years (90% CI, 1-13 years). The 5-year cumulative incidence of metastases for patients with low, intermediate, and high risk prostate cancer were 3% (95% CI, 2-4%), 7% (95% CI, 6-8%), and 15% (95% CI, 12-18%). The 5-year cumulative incidence of metastases for patients with MRI-T3a, MRI-T3b, and MRI-T4 disease were 15% (95% CI, 10-20%), 29% (95% CI, 29-39%), and 40% (95% CI, 13-66%). After controlling for age, race, risk stratification (which includes prostate specific antigen (PSA) and grade group), local therapy, and co-morbidities, the presence of MRI-T3a (HR 1.58, 95% CI 1.09-2.29, p=0.02), MRI-T3b (HR 3.38, 95% CI 2.31-4.95, p&lt;0.0001), and MRI-T4 disease (HR 4.47, 95% CI 2.32-8.62, p&lt;0.0001) were independently associated with worse metastasis free survival. Similar results were obtained with PSA and grade group as individual variables. Conclusions: Extraprostatic extension observed on mpMRI is independently prognostic of metastasis free survival in patients with non-palpable prostate cancer. mpMRI is a critical imaging modality that should be widely available for patients with prostate cancer, and studies are ongoing to define its role as a standard staging modality.

Patients with high nuclear grade pT1-ccRCC are more suitable for radical nephrectomy than partial nephrectomy: a multicenter retrospective study using propensity score

BackgroundPartial nephrectomy (PN) is usually recommended for T1 stage clear cell renal cell carcinoma (ccRCC) regardless of the nuclear grades. However, the question remains unresolved as to whether PN is non-inferior to RN in patients with T1-ccRCC at higher risk of recurrence. In fact, we found that patients with high nuclear grades treated with PN had poorer prognosis compared with those treated with radical nephrectomy (RN). Therefore, this study was designed to evaluate the associations of PN and RN in the four nuclear grade subsets with oncologic outcomes.MethodsA retrospective study was conducted in three Chinese urological centers that included 1,714 patients who underwent PN or RN for sporadic, unilateral, pT1, N0, and M0 ccRCC without positive surgical margins and neoadjuvant therapy between 2010 and 2019. Associations of nephrectomy type with local ipsilateral recurrence, distant metastases, and all-cause mortality (ACM) were evaluated using the Kaplan–Meier method and multivariable Cox proportional hazards regression models after overlap weighting (OW).ResultsA total of 1675 patients entered the OW cohort. After OW, in comparison to PN, RN associated with a reduced risk of local ipsilateral recurrence in the G2 subset (HR = 0.148, 95% CI 0.046–0.474; p < 0.05), G3 subset (HR = 0.097, 95% CI 0.021–0.455; p < 0.05), and G4 subset (HR = 0.091, 95% CI 0.011–0.736; p < 0.05), and resulting in increased five-year local recurrence-free survival rates of 7.0%, 17.9%, and 36.2%, respectively. An association between RN and a reduced risk of distant metastases in the G4 subset (HR = 0.071, 95% CI 0.016–0.325; p < 0.05), with the five-year distant metastases-free survival rate increasing by 33.1% was also observed. No significant difference in ACM between PN and RN was identified.ConclusionsOur findings substantiate that opting for RN, as opposed to PN, is more advantageous for local recurrence-free survival and distant metastases-free survival in patients with high nuclear grade (especially G4) pT1-ccRCC. We recommend placing a heightened emphasis on enhancing preoperative nuclear grade assessment, as it can significantly influence the choice of surgical plan.Trial registrationThis study was registered at Chinese Clinical Trial Registry (ID: ChiCTR2200063333).

KNSTRN Is a Prognostic Biomarker That Is Correlated with Immune Infiltration in Breast Cancer and Promotes Cell Cycle and Proliferation

Kinetochore-localized astrin/SPAG5-binding protein (KNSTRN) promotes the progression of bladder cancer and lung adenocarcinoma. However, its expression and biological function in breast cancer remain largely unknown. Therefore, this study aimed to analyze KNSTRN expression, prognoses, correlation with immune infiltration, expression-associated genes, and regulated signaling pathways to characterize its role in regulating the cell cycle using both bioinformatics and in vitro functional experiments. Analyses of The Cancer Genome Atlas, Gene Expression Omnibus, TIMER, and The Human Protein Atlas databases revealed a significant upregulation of KNSTRN transcript and protein levels in breast cancer. Kaplan–Meier survival analyses demonstrated a significant association between high expression of KNSTRN and poor overall survival, relapse-free survival, post-progression survival, and distant metastases-free survival in patients with breast cancer. Furthermore, multivariate Cox regression analyses confirmed that KNSTRN is an independent prognostic factor for breast cancer. Immune infiltration analysis indicated a positive correlation between KNSTRN expression and T regulatory cell infiltration while showing a negative correlation with Tgd and natural killer cell infiltration. Gene set enrichment analysis along with single-cell transcriptome data analysis suggested that KNSTRN promoted cell cycle progression by regulating the expression of key cell cycle proteins. The overexpression and silencing of KNSTRN in vitro, respectively, promoted and inhibited the proliferation of breast cancer cells. The overexpression of KNSTRN enhanced the expression of key cell cycle regulators, including CDK4, CDK6, and cyclin D3, thereby accelerating the G1/S phase transition and leading to aberrant proliferation of breast cancer cells. In conclusion, our study demonstrates that KNSTRN functions as an oncogene in breast cancer by regulating immune response, promoting G1/S transition, and facilitating breast cancer cell proliferation. Moreover, KNSTRN has potential as a molecular biomarker for diagnostic and prognostic prediction in breast cancer.

ATRX and Its Prognostic Significance in Soft Tissue Sarcoma.

Recently, the association between ATRX and a more aggressive sarcoma phenotype has been shown. We performed a retrospective study of sarcomas from an individual institution to evaluate ATRX as a prognosticator in soft tissue sarcoma. Experimental Design. 128 sarcomas were collected from a single institution and stained for ATRX. The prognostic significance of these markers was evaluated in a smaller cohort of primary soft tissue sarcomas (n = 68). Kaplan-Meier curves were created for univariate analysis, and Cox regression was utilized for multivariate analysis. High expression of ATRX was found to be a positive prognostic indicator for overall survival and metastasis-free survival in our group of soft tissue sarcomas both in univariate analysis and multivariate analysis (HR: 0.38 (0.17-0.85), P=0.02 and HR: 0.49 (0.24-0.99), P=0.05, respectively). High expression of ATRX is a positive prognostic indicator of overall survival and metastasis-free survival in patients with STS. This is consistent with studies in osteosarcoma, which indicate possible mechanisms through which loss of ATRX leads to more aggressive phenotypes. Future prospective clinical studies are required to validate the prognostic significance of these findings.

Ubiquitin-conjugating enzyme E2C (UBE2C) is a prognostic indicator for cholangiocarcinoma

Cholangiocarcinoma is the most common malignant bile duct tumor in Southeast Asia. The special location of cholangiocarcinoma leads to it being difficult to diagnose. Currently, the progress in clinical prognosis outcomes remains abysmal owing to the lack of definitive diagnostic criteria. Therefore, uncovering the potential markers for cholangiocarcinoma is a pressing issue. Ubiquitin-conjugating enzyme E2 C (UBE2C) is a critical ubiquitination enzyme; it is involved in the tumorigenesis of various malignancies and affects the patient’s prognosis. However, there is currently no relevant literature to indicate whether UBE2C is related to the clinical survival outcome of cholangiocarcinoma patients. In this report, we mined the published cholangiocarcinoma transcriptome data set (GSE26566), compared it with the ubiquitination-associated gene (GO:0016567), and identified that UBE2C was highly expressed in cholangiocarcinoma tumor tissue. Moreover, high expression of UBE2C was markedly correlated with surgical margin, primary tumor, histological variants, and histological grade. More specifically, high expression of UBE2C was negatively associated with overall survival, disease-specific survival, local recurrence-free survival, and metastasis-free survival in patients with cholangiocarcinoma. Our findings demonstrate that UBE2C may provide a potential therapeutic marker and prognostic factor for cholangiocarcinoma patients.

Use of focal radiotherapy boost for prostate cancer: radiation oncologists’ perspectives and perceived barriers to implementation

BackgroundIn a recent phase III randomized control trial, delivering a focal radiotherapy (RT) boost to tumors visible on MRI was shown to improve disease-free survival and regional/distant metastasis-free survival for patients with prostate cancer—without increasing toxicity. The aim of this study was to assess how widely this technique is being applied in current practice, as well as physicians’ perceived barriers toward its implementation.MethodsWe invited radiation oncologists to complete an online questionnaire assessing their use of intraprostatic focal boost in December 2022 and February 2023. To include perspectives from a broad range of practice settings, the invitation was distributed to radiation oncologists worldwide via email list, group text platform, and social media.Results263 radiation oncologist participants responded. The highest-represented countries were the United States (42%), Mexico (13%), and the United Kingdom (8%). The majority of participants worked at an academic medical center (52%) and considered their practice to be at least partially genitourinary (GU)-subspecialized (74%). Overall, 43% of participants reported routinely using intraprostatic focal boost. Complete GU-subspecialists were more likely to implement focal boost, with 61% reporting routine use. In both high-income and low-to-middle-income countries, less than half of participants routinely use focal boost. The most cited barriers were concerns about registration accuracy between MRI and CT (37%), concerns about risk of additional toxicity (35%), and challenges to accessing high-quality MRI (29%).ConclusionsTwo years following publication of a randomized trial of patient benefit without increased toxicity, almost half of the radiation oncologists surveyed are now routinely offering focal RT boost. Further adoption of this technique might be aided by increased access to high-quality MRI, better registration algorithms of MRI to CT simulation images, physician education on benefit-to-harm ratio, and training on contouring prostate lesions on MRI.

LAMC2 is a potential prognostic biomarker for cholangiocarcinoma.

Cholangiocarcinoma is a common malignancy with increasing incidence worldwide. Most patients are diagnosed at the advanced stage with poor survival rate. Laminin subunit γ2 (LAMC2) is a heparin binding-associated gene involved in tumorigenesis and has been implicated in the prognosis of various types of cancers. However, it is unclear whether expression of LAMC2 is associated with the clinical outcome of patients with cholangiocarcinoma. In the present study, the role and prognostic value of LAMC2 expression in patients with cholangiocarcinoma was investigated. Clinical information and pathological characteristics were analyzed and the association between LAMC2 expression and clinical characteristics, pathological findings and patient outcomes, including metastasis-free and disease-specific survival, were investigated. Data from 182 patients with cholangiocarcinoma were evaluated. High LAMC2 expression was associated with higher tumor stage (P<0.001), large duct type (P=0.024) and poor histological grade (P=0.002). Kaplan-Meier analysis showed high LAMC2 expression was associated with lower overall (P=0.003), disease-specific (P=0.0025), local recurrence-free (P<0.0001) and metastasis-free survival (P<0.0001). Moreover, multivariate analysis demonstrated that increased LAMC2 expression was a significant predictive risk factor for overall [hazard ratio (HR) 1.713; P=0.034], disease-specific (HR 2.011; P=0.039), local recurrence-free (HR 2.721; P<0.001) and metastasis-free survival (HR 3.117; P<0.001). Gene enrichment analysis using Gene Ontology showed that terms associated with LAMC2 upregulation were 'regulation of platelet-derived growth factor receptor-βsignaling pathway' and 'platelet-derived growth factor receptor-β signaling pathway'. The present study indicated that LAMC2 was upregulated in cholangiocarcinoma tumor tissue and had an inverse association with overall, disease-specific, local recurrence-free and metastasis-free survival in patients with cholangiocarcinoma. These results suggested that LAMC2 may serve as a potential biomarker for cholangiocarcinoma.

SMAD4 loss predicts worse overall and distant metastasis-free survival in patients with resected pancreatic adenocarcinoma.

In select patients, pancreatic adenocarcinoma remains a local disease, yet there are no validated biomarkers to predict this behavior and who may benefit from aggressive local treatments. This study sought to determine if SMAD4 (mothers against decapentaplegic homolog 4) messenger RNA-sequencing (RNA-seq) expression is a robust method for predicting overall survival (OS) and distant metastasis-free survival (DMFS) in patients with resected pancreatic adenocarcinoma. Utilizing The Cancer Genome Atlas (TCGA) and the International Cancer Genome Consortium (ICGC), 322 patients with resected stage I-III pancreatic adenocarcinoma were identified. In TCGA, multivariable proportional hazards models were used to determine the association of SMAD4 genomic aberrations and RNA-seq expression with OS and DMFS. In the ICGC, analysis sought to confirm the predictive performance of RNA-seq via multivariable models and receiver operator characteristic curves. In TCGA, the presence of SMAD4 genomic aberrations was associated with worse OS (hazard ratio [HR], 1.55; 95% CI, 1.00-2.40; p=.048) but not DMFS (HR, 1.33; 95% CI, .87-2.03; p=.19). Low SMAD4 RNA-seq expression was associated with worse OS (HR, 1.83; 95% CI, 1.17-2.86; p=.008) and DMFS (HR, 1.70; 95% CI, 1.14-2.54; p=.009). In the ICGC, increased SMAD4 RNA-seq expression correlated with improved OS (area under the curve [AUC], .92; 95% CI, .86-.94) and DMFS (AUC, .84; 95% CI, .82-.87). In patients with resected pancreatic adenocarcinoma, SMAD4 genomic aberrations are associated with worse OS but do not predict for DMFS. Increased SMAD4 RNA-seq expression is associated with improved OS and DMFS in patients with resected pancreatic adenocarcinoma. This reproducible finding suggests SMAD4 RNA-seq expression may be a useful marker to predict metastatic spread.

Gemcitabine and cisplatin plus nivolumab as organ-sparing treatment for muscle-invasive bladder cancer: a phase 2 trial

Cystectomy is a standard treatment for muscle-invasive bladder cancer (MIBC), but it is life-altering. We initiated a phase 2 study in which patients with MIBC received four cycles of gemcitabine, cisplatin, plus nivolumab followed by clinical restaging. Patients achieving a clinical complete response (cCR) could proceed without cystectomy. The co-primary objectives were to assess the cCR rate and the positive predictive value of cCR for a composite outcome: 2-year metastasis-free survival in patients forgoing immediate cystectomy or <ypT1N0 in patients electing immediate cystectomy. Seventy-six patients were enrolled; of these, 33 achieved a cCR (43%, 95% confidence interval (CI): 32%, 55%), and 32 of 33 who achieved a cCR opted to forgo immediate cystectomy. The positive predictive value of cCR was 0.97 (95% CI: 0.91, 1), meeting the co-primary objective. The most common adverse events were fatigue, anemia, neutropenia and nausea. Somatic alterations in pre-specified genes (ATM, RB1, FANCC and ERCC2) or increased tumor mutational burden did not improve the positive predictive value of cCR. Exploratory analyses of peripheral blood mass cytometry and soluble protein analytes demonstrated an association between the baseline and on-treatment immune contexture with clinical outcomes. Stringently defined cCR after gemcitabine, cisplatin, plus nivolumab facilitated bladder sparing and warrants further study. ClinicalTrials.gov identifier: NCT03451331.

Effect of Adjuvant Chemotherapy in Highly Malignant Non-Metastatic Prostate Cancer: An Interim Analysis of Non-Randomized Comparative Trials.

Gleason grade group 5 (GG5) prostate cancers is aggressive with high metastatic rates and is not sensitive to androgen deprivation therapy (ADT). Even the presence of a limited (tertiary) Gleason pattern 5 component may have high aggressive biological behavior. This study aims to prospectively evaluate whether a non-androgen receptor pathway therapy - adjuvant chemotherapy could improve clinical outcomes among non-metastatic prostate cancer with the above highly malignant characters. This prospective non-randomized clinical trial included non-metastatic prostate cancer patients with pathologically proven Gleason score of 9-10 or tertiary Gleason pattern 5. Each subject was allowed to decide whether to receive four to six cycles chemotherapy of docetaxel after receiving a standard treatment (i.e., radical surgery ± radiotherapy or radical radiotherapy combined with long-term ADT). The primary endpoint was event-free survival (EFS). Event was defined as any of biochemical failure or imaging failure, or change of systemic therapy due to PSA arises, or death. The secondary end points were distant metastasis-free survival (MFS), overall survival (OS), and treatment-related adverse events. A total of 188 consecutive patients were enrolled from November 2019 to November 2022. Median prostate-specific antigen was 26.6 ng/ml. 52% had T3b to T4 disease, 27% had N1 disease. 140 patients received standard therapy only, and 48 patients received adjuvant chemotherapy after radical therapy. The median follow-up time was 18.4 (3.0-36.7) months. The estimated 36-month EFS of the chemotherapy group and the control group were 94.7% vs. 72.8% (p = 0.044). There were 1 event who added novel endocrine therapy in the chemotherapy group, and 21 events in the control group, including 6 cases of biochemical recurrence and 9 cases of lymph node and distant metastasis, 4 cases that changed systemic therapy and 2 cases died. The MFS of the two groups at 36 months were 100% and 90.7%, respectively (P = 0.143). After the 1:1 propensity score match, the EFS and MFS of the two groups were 94.7% and 80.8% (P = 0.069), and 100% and 93.1% (P = 0.132), respectively. The urinary toxicity of grade 2 and 3 in the chemotherapy group and the control group were 4.2% and 7.1% (P = 0.134) while the grade 2 rectal toxicity were 5.0% and 10.4% (P = 0.317), respectively. No grade 4 toxicity occurred. Considering the chemotherapy-related side effects, grade 3 or above toxicity were leukopenia (41.7%), alopecia (27.1%), thrombocytopenia (2.1%) and edema (2.1%). Results of this interim analysis shows that the addition of adjuvant chemotherapy after standard radical therapy tends to improve the overall recurrence and metastasis free survival of patients with highly malignant prostate cancer, and the adverse effects are tolerable, which should be confirmed by long-term follow-up results.

Effect of Interval between Neoadjuvant Chemotherapy and Radiation Therapy on Metastasis Risk for Inoperable Non-Metastatic Pancreatic Adenocarcinoma

In inoperable pancreatic cancer patients requiring radiotherapy (RT) after neoadjuvant chemotherapy (CT), there can be delays in starting radiation due to multiple complications. However, pancreatic cancer can progress rapidly during short intervals without treatment. We hypothesize that longer intervals between neoadjuvant chemotherapy and radiation could expediate the development of metastatic disease. We identified patients with inoperable non-metastatic borderline resectable or locally advanced pancreatic cancer treated with neoadjuvant CT followed by RT from 2011 to 2021 at a single institution. Patients who completed palliative RT as defined by a biologic effective dose (BED) of less than 50 Gy, or those who were lost to follow-up within 3 months after completing RT without documented disease progression were excluded. The interval between RT and CT was defined as the time between last date of CT administration and initiation of RT. The primary endpoint was metastasis-free survival (MFS) after RT completion. Differences in MFS between patients who started RT within or after 4, 6, and 8 weeks of completing CT were examined utilizing log rank analysis of MFS generated via the Kaplan-Meier method. At a median follow-up of 5.45 months, twenty-three patients were included. Most patients were male (61%) with cT4 (61%), cN0 (83%) pancreatic adenocarcinoma. Almost all patients completed combination neoadjuvant CT (91%) followed by either intensity modulated RT to 50.4 Gy in 28 fractions with capecitabine (n = 9) or stereotactic body RT to 33-40 Gy in 5 fractions (n = 14). Eleven (48%) patients received adjuvant CT after radiation therapy. The median time between last CT and RT initiation was 34 days (range 13-142). The MFS of patients who initiated RT within 4 weeks of CT compared to after was higher but not significant (16.8 vs 9.9 months, p = 0.144). Those who received RT within 6 or 8 weeks of completing CT exhibited significantly longer MFS compared to later than 6 (16.0 vs 6.9 mo, p = 0.016) or 8 weeks (15.1 vs 2.1 mo, p = 0.004). There was no statistical correlation between MFS and other variables (CA 19-9 before radiation, T-stage, receipt of adjuvant CT, BED). These results suggest that a longer interval between CT and RT is associated with the risk of developing metastatic disease sooner but requires validation in a prospective cohort. Root causes of delays in starting radiation (e.g., insurance authorization) should be investigated as well.

Effect of crossover from placebo to darolutamide on overall survival in men with non-metastatic prostate cancer: sensitivity analyses from the randomised phase 3 ARAMIS study

BackgroundIn the phase 3 ARAMIS study (NCT02200614), darolutamide significantly improved metastasis-free survival in patients with non-metastatic castration-resistant prostate cancer (nmCRPC). Following the primary analysis, the study was unblinded, and placebo recipients were permitted to cross over to open-label darolutamide. Despite crossover, darolutamide significantly improved overall survival (OS). We conducted sensitivity analyses to estimate the effect of placebo–darolutamide crossover on OS. MethodsPatients with nmCRPC were randomised to oral darolutamide 600 mg twice daily (n = 955) or placebo (n = 554). Prespecified (rank-preserving structural failure time [RPSFT] and iterative parameter estimation [IPE]) and post hoc (OS-adjusted censoring and inverse probability of censoring weighting [IPCW], with weightings for baseline testosterone and prostate-specific antigen) sensitivity analyses were conducted. ResultsAfter unblinding, 170 of 554 placebo recipients (30.7%) crossed over to darolutamide. At the final OS intention-to-treat analysis (median 11.2 months after unblinding), darolutamide significantly improved OS by 31% versus placebo (hazard ratio [HR] 0.69, 95% confidence interval [CI] 0.53–0.88; P = 0.003). The benefit increased in the analyses adjusting for crossover is as follows: RPSFT HR 0.68, 95% CI 0.51–0.90; P = 0.007; IPE HR 0.66, 95% CI 0.51–0.84; P < 0.001; OS-adjusted censoring HR 0.59, 95% CI 0.45–0.76; IPCW HR 0.63, 95% CI 0.48–0.81. The favourable safety profile of darolutamide was maintained, including in crossover patients. ConclusionsAfter adjusting for crossover, darolutamide reduced the risk of death by up to 41% in patients with nmCRPC. The effect of darolutamide on OS may have been underestimated in the original intention-to-treat analysis.

Bone-matrix mineralization dampens integrin-mediated mechanosignalling and metastatic progression in breast cancer.

In patients with breast cancer, lower bone mineral density increases the risk of bone metastasis. Although the relationship between bone-matrix mineralization and tumour-cell phenotype in breast cancer is not well understood, mineralization-induced rigidity is thought to drive metastatic progression via increased cell-adhesion forces. Here, by using collagen-based matrices with adjustable intrafibrillar mineralization, we show that, unexpectedly, matrix mineralization dampens integrin-mediated mechanosignalling and induces a less proliferative stem-cell-like phenotype in breast cancer cells. In mice with xenografted decellularized physiological bone matrices seeded with human breast tumour cells, the presence of bone mineral reduced tumour growth and upregulated a gene-expression signature that is associated with longer metastasis-free survival in patients with breast cancer. Our findings suggest that bone-matrix changes in osteogenic niches regulate metastatic progression in breast cancer and that in vitro models of bone metastasis should integrate organic and inorganic matrix components to mimic physiological and pathologic mineralization.

Prognostic significance of the preoperative platelet-lymphocyte ratio in nonmetastatic renal cell carcinoma: cross-sectional study.

The objective of our study was to evaluate the prognostic significance of the PLR in patients with nonmetastatic RCC. The authors performed a retrospective analysis of patients with nonmetastatic RCC who were operated between 2004 and 2020. Five years recurrence-free survival and metastasis-free survival were calculated. The prognostic significance of the preoperative PLR was assessed. The Kaplan-Meier method was utilized to graphically display survivor functions. Univariate and multivariate Cox's proportional hazards regression models were utilized to analyze the association between PLR and oncological outcomes. Differences were considered significant if P<0.05. Two hundred and two patients were included. The mean follow-up was 56.8±3 months. Patients with a higher PLR had larger tumors (P=0.02), higher ASA score (P=0.001), symptomatic forms (P=0.01), and more frequent tumor necrosis (P=0.02). Recurrence-free survival and metastasis-free survival rates were significantly lower in patients with high PLR than in those with low ratios (each P<0.005). Multivariate analysis identified PLR as an independent predictor of recurrence-free survival (P=0.002) and metastasis-free survival (P<0.001). A higher PLR was associated with aggressive renal cancer. In addition, the PLR was a significant prognostic factor for both recurrence-free survival and metastasis-free survival in patients with nonmetastatic RCC.

Artificial Intelligence-Based PTEN Loss Assessment as an Early Predictor of Prostate Cancer Metastasis After Surgery: A Multicenter Retrospective Study

Phosphatase and tensin homolog (PTEN) loss is associated with adverse outcomes in prostate cancer and can be measured via immunohistochemistry. The purpose of the study was to establish the clinical application of an in-house developed artificial intelligence (AI) image analysis workflow for automated detection of PTEN loss on digital images for identifying patients at risk of early recurrence and metastasis. Postsurgical tissue microarray sections from the Canary Foundation (n = 1264) stained with anti-PTEN antibody were evaluated independently by pathologist conventional visual scoring (cPTEN) and an automated AI-based image analysis pipeline (AI-PTEN). The relationship of PTEN evaluation methods with cancer recurrence and metastasis was analyzed using multivariable Cox proportional hazard and decision curve models. Both cPTEN scoring by the pathologist and quantification of PTEN loss by AI (high-risk AI-qPTEN) were significantly associated with shorter metastasis-free survival (MFS) in univariable analysis (cPTEN hazard ratio [HR], 1.54; CI, 1.07-2.21; P = .019; AI-qPTEN HR, 2.55; CI, 1.83-3.56; P < .001). In multivariable analyses, AI-qPTEN showed a statistically significant association with shorter MFS (HR, 2.17; CI, 1.49-3.17; P < .001) and recurrence-free survival (HR, 1.36; CI, 1.06-1.75; P = .016) when adjusting for relevant postsurgical clinical nomogram (Cancer of the Prostate Risk Assessment [CAPRA] postsurgical score [CAPRA-S]), whereas cPTEN does not show a statistically significant association (HR, 1.33; CI, 0.89-2; P = .2 and HR, 1.26; CI, 0.99-1.62; P = .063, respectively) when adjusting for CAPRA-S risk stratification. More importantly, AI-qPTEN was associated with shorter MFS in patients with favorable pathological stage and negative surgical margins (HR, 2.72; CI, 1.46-5.06; P = .002). Workflow also demonstrated enhanced clinical utility in decision curve analysis, more accurately identifying men who might benefit from adjuvant therapy postsurgery. This study demonstrates the clinical value of an affordable and fully automated AI-powered PTEN assessment for evaluating the risk of developing metastasis or disease recurrence after radical prostatectomy. Adding the AI-qPTEN assessment workflow to clinical variables may affect postoperative surveillance or management options, particularly in low-risk patients.

Abstract B036: Immune cell profiling of human prostate tumors identifies a protective and pathological role for intratumoral mast cells in the development of biochemical recurrence and metastasis

Abstract Background: Immunobiological factors may, in part, contribute to racial disparities in prostate cancer (PCa), the second leading cause of cancer-related death for US men. African American (AA) men face a greater risk of developing PCa and having a poorer outcome of this disease, compared to Caucasian American (CA) men. The goal of this study is to identify immune-specific differences influencing PCa health disparity as well as PCa progression. Methods: Ex vivo tumor biopsies were obtained following radical prostatectomy (RP) from 51 treatment-naïve patients (26 AA, 25 CA) under approved IRB protocols. Total RNA from fresh frozen tissue was isolated and amplified by PCR using NanoString multiplexed target enrichment protocols. We evaluated differences in resulting transcripts by self-reported race, pathology, and other clinical and pathologic features. Relative abundances of immune cell subsets were determined using computational methods, including previously published deconvolution algorithms, to estimate cellular content. Results: We identified differentially expressed genes between AA and CA tumors that are characterized by genes regulating Natural Killer (NK) cell function and Wnt signaling cancer pathways. Among the entire cohort, high expression of two of these differentially expressed genes, DVL2 and MAP3K5, were associated with worse biochemical recurrence (BCR)-free and metastasis-free survival. No difference in immune cell abundance was observed by self-reported race. Strikingly, among the entire cohort, low abundance of intratumoral mast cells was also associated with worse PCa pathology and poorer BCR-free and metastasis-free survival. Conclusions: Using a race-matched military cohort, we found that AA and CA tumors differ in the expression levels of Wnt and NK signaling-related pathways, yet cellular estimations of immune abundance did not significantly differ. Remarkably, the level of mast cell abundance within tumors at time of RP may be protective and prolong BCR-free and metastasis-free survival of patients. These types of in-depth immune profiling assessments have the potential to guide precision medicine and treatment decisions in the clinic. Disclaimer: The contents of this publication are the sole responsibility of the author(s) and do not necessarily reflect the views, opinions or policies of Uniformed Services University of the Health Sciences (USUHS), The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc., the Department of Defense (DoD), the Departments of the Army, Navy, or Air Force. Mention of trade names, commercial products, or organizations does not imply endorsement by the U.S. Government. Citation Format: Cara Schafer, Jiji Jiang, Sally Elsamanoudi, Darryl Nousome, Denise Young, Yingjie Song, Isabell Sesterhenn, Gregory Chesnut, Shyh-Han Tan. Immune cell profiling of human prostate tumors identifies a protective and pathological role for intratumoral mast cells in the development of biochemical recurrence and metastasis [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B036.