OBJECTIVES:To report long-term oncological outcomes for men with clinically localised prostate cancer (PCa) treated with contemporary modalities in a population-based United States cohort. PATIENTS AND METHODS:The Comparative Effectiveness Analysis of Surgery and Radiation (CEASAR) study prospectively enrolled men with clinically localised PCa from 2011 to 2012. Patients were stratified into two groups: favourable prognosis (clinical T stage [cT]1-T2a/bN0M0, prostate-specific antigen [PSA] level ≤ 20 ng/mL, Grade Group 1-2) and unfavourable prognosis (cT2cN0M0, PSA level 20-50 ng/mL, or Grade Group 3-5). Main outcomes were PCa-specific mortality (PCSM), composite progression to advanced disease (metastasis, PCSM event, or systemic therapy), and overall survival (OS). Cox regression models adjusted for demographic and clinical covariates. RESULTS:Of the 2604 men included, 73% were White, 15% Black, and 7% Hispanic. All hazard ratios (HRs) were adjusted for demographic and clinical covariates using multivariable Cox and Fine-Gray models. In the favourable group, compared with surgery, external beam radiotherapy (EBRT; HR 1.5, 95% confidence interval [CI] 1.1-2.1, P < 0.01), brachytherapy (HR 2.1, 95% CI 1.3-3.3, P < 0.01), and active surveillance (HR 1.5, 95% CI 1.1-2.1, P = 0.02) were associated with higher all-cause mortality; the 10-year cumulative incidence of PCSM was ≤1.5% for all five strategies, and progression did not differ. In the unfavourable group, EBRT was associated with worse OS (HR 2.8, 95% CI 1.9-4.3, P < 0.01), with no adjusted differences in PCSM (10-year cumulative incidence 3.5% after surgery vs 8.8% after EBRT) or progression across treatments. CONCLUSION:In this population-based cohort treated with contemporary modalities, the 10-year risk of PCa death was low across all treatment strategies, including active surveillance. OS differences favouring surgery likely reflect residual confounding from baseline health and treatment selection. These findings underscore the importance of patient values and comorbidities in shared decision-making for localised PCa.

5111 Background: The NRG/RTOG 0521 trial evaluated adding adjuvant docetaxel (DTX) to standard radiotherapy plus androgen deprivation therapy (ADT) in high-risk localized prostate cancer. Adjuvant DTX modestly improved overall survival (OS) in the trial, but the benefit was limited and not all patients benefited. Thus, biomarkers are needed to identify patients most likely to benefit from chemotherapy intensification. ST-DoxPCa (Spatial Transcriptomics–Guided Docetaxel Therapy Stratification in Prostate Cancer) is a novel artificial intelligence (AI) driven histology biomarker that predicts gene expression from H&E slides (virtual spatial transcriptomics). We assessed whether ST-DoxPCa can stratify patients in RTOG 0521 for differential benefit from adjuvant DTX. Methods: A Vision Transformer trained on paired histology–spatial transcriptomics (HEST1K) predicts a 208-gene prostate panel at spot level; predictions are distilled into a biologically informed 26-gene signature and aggregated into patient-level features. A prognostic Cox model and fixed median threshold were developed independently in a Cleveland Clinic radical prostatectomy cohort (CCF, n=352; endpoint: biochemical recurrence-free survival). This locked model and threshold were applied unchanged (no refitting or recalibration) to digitized pretreatment diagnostic biopsies from NRG/RTOG 0521 (n=350; RT+ADT n=169, RT+ADT+DTX n=181) to stratify patients into ST-DoxPCa-positive (high-risk) and ST-DoxPCa-negative (low-risk) groups. Overall survival (OS) was compared between treatment arms within each stratum. Results: ST-DoxPCa stratified patients into biomarker-defined risk groups using aggregated spatial-expression features from a biologically informed gene panel; key genes included PTEN, NKX3-1, ACPP, FASN and TMPRSS2. ST-DoxPCa-positive (high-risk) patients experienced a significant OS benefit from adding DTX to RT+ADT versus RT+ADT alone (HR=0.38, 95% CI 0.18–0.83; p=0.012), whereas ST-DoxPCa-negative (low-risk) patients derived no OS benefit (HR=1.05, 95% CI 0.67–1.63; p=0.84). Conclusions: The ST-DoxPCa model identified a subgroup with substantial OS benefit from adjuvant DTX and a subgroup with no benefit within RTOG 0521, supporting risk-aligned chemotherapy intensification using routine histology. Clinical trial information: NRG/RTOG 0521 ( NCT00288080 ) .

BACKGROUND:Early-stage, hormone receptor positive (HR+) breast cancer has excellent outcomes with lumpectomy, radiotherapy, and endocrine therapy (ET), prompting interest in treatment de-escalation. Advances in stereotactic ablative radiotherapy (SABR) raise the possibility of definitive local therapy without surgery in select patients. We conducted a prospective, phase II trial (NCT02945579) evaluating SABR with ET as a non-operative strategy. MATERIALS AND METHODS:Patients aged ≥ 40 years with cT1N0M0, unicentric, HR+, HER2-negative breast cancer received 3 months of ET followed by SABR in 5 fractions. Vacuum-assisted image-guided core biopsy of the tumor bed was performed 6-12 months after SABR. Patients with pathologic complete response (pCR) omitted surgery. Co-primary endpoints were pCR and 3-year progression-free survival (PFS) rates. Patient-reported outcomes were collected as a secondary endpoint. A Bayesian framework evaluated futility using posterior probabilities to assess a clinically meaningful pCR rate. RESULTS:Twenty patients were enrolled (median age 70.5 years). Nineteen underwent biopsy after SABR. pCR was observed in 10/19 patients (53%, 95% CI 30-73%), and 7 (37%) had near complete response. Among the 12 patients managed without surgery, median follow-up was 44.9 months. Three-year PFS was 92% (95% CI 54-99%), with one non-breast cancer-related death and no breast cancer recurrences. Longitudinal patient-reported outcomes of decisional regret and breast-specific outcomes remained stable. CONCLUSION:Definitive SABR combined with ET achieved substantial pCR rates and encouraging tumor control. These findings support further evaluation of radiotherapy-based definitive treatment and potential surgery omission in carefully selected patients with favorable, HR + breast cancer.

BACKGROUND:To determine outcomes of MRI-assisted radiosurgery (MARS) for salvage brachytherapy using the radioisotope 103Pd after various upfront treatments including surgery, external beam radiotherapy, and brachytherapy. METHODS:We retrospectively reviewed data for patients who underwent salvage MARS for intraprostatic lesions or prostate bed recurrences from 2016 to 2022. Biochemical recurrence, prostate cancer-specific, and overall survival, and the cumulative incidences of toxicities, were determined by Kaplan-Meier estimates. Cox proportional hazards models were used to determine associations between clinical and treatment variables and risk of toxicity. RESULTS:Study included 31 patients with local recurrence after initial definitive treatment. Four (13%) were initially treated with prostatectomy and salvage radiation, twenty-four (77%) with external beam radiation, and three with brachytherapy. Most had intermediate- or high-risk prostate cancer at the time of diagnosis. Twenty-two patients (71%) had focal-gland and nine (29%) had whole-gland MARS LDR salvage brachytherapy. Median follow-up was 35-28 months. By last follow-up, 5 patients (16%) experienced recurrence and started ADT, 3 patients started ADT before experiencing recurrence due to physician discretion, and 23 patients (74%) remained without recurrence. No patients died of prostate cancer. Median PSA nadir for recurrence-free patients was 0.2 ng/mL (range, 0-0.9 ng/mL). Grade 3 toxicities occurred in 4 patients (13%) including 3 patients (13%) with genitourinary events only and 1 patient (3%) with both a grade 3 genitourinary and a grade 3 gastrointestinal event. CONCLUSIONS:In this modern series of patients undergoing salvage MARS with 103Pd, we observed acceptable toxicity and early, promising biochemical disease control. These findings highlight the broader applicability of salvage MARS regardless of upfront treatment modality.

Objective(s): To define pathologic response rates to endocrine therapy and ablative radiotherapy, with omission of breast surgery, for early-stage, hormone receptor (HR)+ breast cancer in a prospective, phase II trial (NCT02945579). Methods: Twenty eligible patients with HR+, HER2-, clinical stage I, unicentric, non-lobular breast cancers with no lymphovascular space invasion, Oncotype ≤25 and age ≥50 were accrued to an IRB approved-protocol. Enrolled patients received three months of endocrine therapy followed by restaging ultrasound and ablative radiotherapy, 37.5Gy/5 fractions every other day. MR LINAC was used when feasible. After radiotherapy, patients continued on endocrine therapy and underwent percutaneous vacuum-assisted, image-guided core biopsy (VAIGCB) of the tumor 6-12 months following radiation, with a minimum of 12 9G cores. Near complete response (nCR) was defined as Miller-Payne 4 and pCR as 5. Patients with a pathologic complete response (pCR) were followed every 6 months with imaging; those without a pCR were recommended for standard-of-care surgery. Miller-Payne score was evaluated on core biopsy and surgical specimens. Co-primary endpoints are pCR on VAIGCB and tumor control at 3 years. We report here the former co-primary endpoint of pCR along with the 95% credible interval (CI). Results: 19 of 20 (95%) of patients underwent VAIGCB; 1 declined and elected continued observation. Of the 19 biopsies, 10 (52.6%) demonstrated pCR (Miller-Payne 5), 7 (36.8%) nCR (Miller-Payne 4) and 2 (10.5%) Miller-Payne 3. Of patients who had a VAIGCB 6 months after radiotherapy, 5/11 (45.4%, 95% CI 18.9%-71.5%) had pCR; of those with VAIGCB 12 months after RT, 5/8 (62.5%, 95% CI 27.4%-86.6%) had pCR. 7/9 patients with residual disease (Miller-Payne <5) underwent surgery, one of whom had pCR in the surgical specimen, consistent with complete removal at VAIGCB. There were no postoperative complications. Two patients with nCR declined surgery: one underwent cryoablation and one continued endocrine therapy and underwent repeat biopsy 4 months later with pCR. In total, 17/19 pts who underwent VAIGCB (89.5%) had pCR or nCR. The 1 patient who declined VAIGCB has no residual disease on imaging 2 years after RT. Median follow-up time for all patients who did not have surgery is 26 (range 18 to 38 mo months), with none (0/12) experiencing progression or recurrence. Conclusion: This is the first study to demonstrate a high rate of VAIGCB pCR and nCR following endocrine therapy and ablative radiotherapy for early stage, HR+, HER2- breast cancers. This may be an appealing approach for patients with breast cancer interested in non-surgical approaches to definitively treat their tumors and highlights the efficacy for non-surgical candidates. Citation Format: Simona Shaitelman, Savitri Krishnamurthy, Gaiane M. Rauch, Yu Shen, PhD, Yan H. Lin, Benjamin D. Smith, Melissa P. Mitchell, Karen E. Hoffman, Chelain R. Goodman, Vicente Valero, Helen M. Johnson, Wendy A. Woodward, Henry Kuerer. Eliminating breast surgery for invasive, hormone-positive breast cancers with an exceptional response to endocrine therapy and ablative radiotherapy: a single-arm, phase 2 trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS6-04.

Background: Regional nodal irradiation (RNI) improves breast cancer survival but is associated with treatment-related toxicity. Volumetric Modulated Arc Therapy (VMAT)/Intensity Modulated Radiation Therapy (IMRT) treatment technique has been shown in other disease sites to improve dose homogeneity while reducing side effects compared to 3-Dimensional Conformal Radiation Therapy (3D-CRT). To evaluate the association of radiotherapy (RT) treatment technique with acute toxicity for patients receiving RNI, we performed a secondary analysis of the Shortening Adjuvant Photon Irradiation to Reduce Edema (SAPHIRe) trial, a Phase III trial evaluating conventional (CFx) vs. hypofractionation (HFx). We hypothesized that VMAT technique would be associated with reduced acute toxicity compared to 3D-CRT. Methods: Patients with clinical or pathologic T0-3 N0-2a/3a invasive breast cancer dispositioned to receive comprehensive RNI were randomized to CFx vs. HFx (50Gy/25Fx or 40.05Gy/15Fx). Nodal target volumes included the axilla, infraclavicular and supraclavicular nodal basins, and internal mammary chain. Acute RT-related toxicity was graded utilizing the NCI CTCAE v4.0 scale at the end of RT. Associations between treatment technique with clinicopathologic and treatment variables, dosimetric data, and toxicity endpoints were determined using the Fisher’s Exact, Mann-Whitney U, and Kruskal-Wallis tests. Univariate analysis and multivariable binomial logistic regression were performed to calculate adjusted odds ratios (OR) for factors associated with Grade 2+ toxicity at the end of RT. Results: A total of 645 patients with available RT variables and end of RT toxicity assessments were enrolled from 2017-2024 (median follow-up, 20 months [IQR, 7-35]). Patients treated with VMAT technique were balanced across randomization arm (CFx vs HFx) as well as clinicopathologic and treatment variables but had significantly higher body mass index (BMI) (30 [25-34] vs. 28 [24-33], p=0.004) and were more likely to undergo plastic surgery reconstruction (40% vs. 21%, p<0.001). Patients treated with VMAT technique experienced significantly reduced Grade 2+ toxicity at the end of RT treatment compared to 3D-CRT (38% vs. 51%, p=0.002), including Grade 2+ dermatitis (32% vs. 47%, p<0.001), Grade 1+ fatigue (50% vs. 60%, P=0.03), Grade 1+ pruritus (40% vs. 49%, p=0.02), and Grade 1+ breast edema (0.4% vs. 3.9%, p=0.02). VMAT technique was associated with significantly reduced volume of the body receiving ≥105% (V105%) of the prescription dose (72cc vs. 351cc), V107% (2cc vs. 186cc), and V110% (0cc vs. 77cc; all p<0.001), as well as the maximum percentage dose (Dmax) to the nodes (106% vs 120%, p<0.001). 3D-CRT technique was associated with significantly increased dose to the ipsilateral lung (V20Gy [CFx]/V16Gy [HFx]>35% = 12% vs. 1%, p<0.001) as well as mean heart dose (MHD>4Gy [CFx]/3.2Gy [HFx] = 6% vs. 1%, p=0.007). V105% to the body and Dmax to the nodes were significantly associated with increased rates of acute dermatitis (p=0.004 and p=0.01, respectively) and breast edema (p=0.02 and p=0.005, respectively) while V107% was associated with significantly increased fatigue (p=0.02). On multivariable analysis, increased BMI (OR [95% CI]=1.04 [1.00-1.07], p=0.03) was significantly associated with increased rates of Grade 2+ toxicity at the end of RT while hypofractionation (OR=0.28 [0.19-0.42], p<0.001), VMAT treatment technique (OR=0.38 [0.21-0.68], p=0.001), and absence of boost (OR=0.38 [0.15-0.87], p=0.03) were associated with significantly decreased rates of Grade 2+ toxicity at the End of RT. Conclusion: In this secondary analysis of a prospective randomized clinical trial, patients treated with RNI utilizing VMAT technique compared with 3D-CRT experienced significantly decreased rates of acute treatment-related toxicity, including any Grade 2+ toxicity, in the setting of improved dose homogeneity. Citation Format: Chelain Goodman, Melissa P. Mitchell, Saleh Ramezani, Simona F. Shaitelman, Rensi F. Zacharia, Isidora Y. Arzu, Elizabeth Bloom, Clifton D. Fuller, Melissa M. Joyner, Lauren L. Mayo, George H. Perkins, Jay Reddy, Puneet Singh, Michael C. Stauder, Eric A. Strom, Valerie K. Reed, Pamela J. Schlembach, Wendy A. Woodward, Benjamin D. Smith, Karen E. Hoffman. Association of VMAT versus 3D-CRT Radiotherapy Treatment Technique with Acute Toxicity of Regional Nodal Irradiation: A Secondary Analysis of the SAPHIRe Phase III Randomized Clinical Trial [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr PS6-02.

BACKGROUND:This study compared complication rates and outcomes between patients who underwent premastectomy radiation therapy (Pre-MRT) followed by mastectomy with microsurgical immediate breast reconstruction (IMBR) and patients who underwent mastectomy followed by postmastectomy RT (PMRT) then microsurgical delayed breast reconstruction (DBR). STUDY DESIGN:This is a secondary analysis of a randomized clinical trial (NCT02912312) that randomized patients with breast cancer to receive hypofractionated (40.05 Gy in 15 fractions) or conventionally fractionated (50 Gy in 25 fractions) regional nodal irradiation between August 2018 and August 2022. Demographic, treatment, and outcomes data were collected. The primary outcome was the rate of autologous flap loss. Secondary outcomes included rates of other recipient-site complications. RESULTS:A total of 144 patients were included: 41 underwent Pre-MRT with IMBR and 103 underwent PMRT with DBR, including 66 patients who had tissue expander (TE) placement at the time of mastectomy and 37 who underwent total mastectomy. The median time from mastectomy to DBR was 12.8 months (interquartile range 9.7 to 16.3 months). There were no complete autologous flap losses in either group, and rates of other recipient-site complications were similar between the groups. Infection at the recipient site occurred in 20% (13 of 66) of patients in the PMRT group who underwent TE placement, and 9 (14%) required TE explantation because of complications. CONCLUSIONS:Pre-MRT with microvascular IMBR is associated with a similar complication rate to PMRT with microvascular DBR while avoiding complications relating to TE placement and a reduced time to achieve definitive breast reconstruction. A larger randomized clinical trial of Pre-MRT followed by mastectomy and IMBR is currently underway (NCT05774678).

BACKGROUND AND OBJECTIVE:Biochemical recurrence (BCR) after radical prostatectomy (RP) is a heterogeneous disease state in prostate cancer with multiple treatment options. Improved risk stratification could enable more personalized decision-making. We developed and validated a digital pathology-based multimodal artificial intelligence (MMAI) model to predict outcomes in post-RP BCR patients undergoing salvage therapy. METHODS:An MMAI model was trained to predict distant metastasis (DM) using prostate histopathology image features and clinical variables (pathologic grade group, pathologic T stage, prostate-specific antigen level before salvage radiotherapy [SRT], age, and surgical margin). The locked model was validated in 533 patients from NRG/RTOG 9601 and 0534 treated with SRT ± hormone therapy (HT), using Cox regression and time-dependent area under the receiver operating characteristic curve. KEY FINDINGS AND LIMITATIONS:With a median follow-up of 9.3 yrs, MMAI score was significantly associated with DM (subdistribution hazard ratio = 2.17 per standard deviation [95% confidence interval 1.65-2.85]; p < 0.001) and remained independently prognostic after adjusting for clinical variables and treatment. The 10-yr time-dependent area under the receiver operating characteristic curve for MMAI was 0.74 compared with 0.68 for a clinical nomogram. Binary risk categorization demonstrated higher 10-yr DM incidence in the MMAI high-risk (25%) than in the low-risk (8.8%) group. The absolute reduction in 10-yr DM incidence with HT plus SRT versus SRT alone was 21% in the high-risk group versus 2.5% in the low-risk group. Limitations include the use of archived trial cohorts. CONCLUSIONS AND CLINICAL IMPLICATIONS:The post-RP MMAI model provides individualized risk estimates after SRT ± HT and may support shared decision-making about salvage treatment. External and prospective validation are ongoing.

This cross-sectional study analyzes social media posts to explore patient concerns and the extent of patient–clinician communication regarding cancer risks associated with glucagon-like peptide-1 (GLP-1) medications.

799 Background: Metastasis-directed therapy (MDT) for oligometastatic cancer is a concept utilized for prostate and kidney cancer. Clinical research in MDT for oligometastatic urothelial carcinoma (UC) remains sparse especially in the modern era where systemic therapy advancements have substantially improved patient’s outcomes overall. We explored our institutional experience of patients with oligometastatic carcinoma of the bladder and upper tract undergoing MDT utilizing radiotherapy (RT). Methods: Patients were retrospectively identified with oligometastatic bladder or upper tract cancer from January 2016 to July 2024 with five or less sites of metastases. Those with equivalent dose of RT (EQD2 10 ) ≥ 45Gy to metastases were included. Progression free survival (PFS) and overall survival (OS) were evaluated using Kaplan Meier from time of diagnosis to metastatic disease. Cox proportional hazards analysis was conducted to determine covariates associated with survival endpoints. Results: 60 patients with oligometastasis were included with 8 patients excluded due to a RT dose EQD2 10 < 45Gy. 52 patients were in final analysis. Most were men (67%) with a median age 68 years (range, 35-91). Most had bladder primary (79%) with the remaining including upper tract. Majority had pure UC (85%) and the remainder were UC subtypes with variant histology including small cell (8%), squamous (6%), sarcomatoid (2%). Median number of metastases was 1 site, while 23% had 3+ sites. Bony metastases (27%) were most common site, then retroperitoneal nodes (18%) and lung (17%). Most received ≥2 systemic therapy cycles before MDT (62%) with 8% without any therapy prior to MDT. Most commonly used therapy included ddMVAC (21%), Gem/Cis (20%), pembrolizumab (15%), and EV (12%). MDT was delivered to all metastases in 71%, while the remaining had MDT to select sites. Most common MDT dose was 30Gy in 3 fractions (21%) followed by 50Gy in 4 fractions (17%). Median follow up from metastatic diagnosis was 19 months (range, 3-106 months). Median PFS and OS was 21 months (95% CI 8-33 months), and 39 months (95% CI, 14-64 months), respectively. At last follow up, 31 patients were alive (60%). Most common first recurrence was distant from site of MDT (96%) while 2 patients had in-field recurrence in pelvic bones. On univariate analysis, those with 1 vs 2+ sites had improved PFS with MDT (p=0.03, 95% CI 1.1-6.0). Univariate showed no association with MDT to all sites vs select, age, or # lines of systemic therapy. Conclusions: As systemic therapy has improved for patients with bladder and upper tract cancers, MDT may serve as an effective adjunct to improve cancer control. Baseline characteristics. Characteristic (n=52) No % Median Age (yrs) 68 Histology UC 44 85% UC subtype with variant histology 7 15% Site of Primary Bladder 41 79% Upper Tract 11 21% Lines of therapy before MDT 0 4 8% 1 17 33% 2+ 31 60%

1557 Background: The benefit of adding docetaxel (DTX) to standard of care (SOC) for high-risk localized prostate cancer remains debated. The NRG/RTOG 0521 randomized phase III trial demonstrated that docetaxel, when added to SOC—comprising radiotherapy (RT) and long-term androgen deprivation therapy (ADT)—improved overall survival (OS). However, while RTOG 0521 demonstrated improved OS with DTX, the observed improvement did not meet the predetermined threshold for clinical significance, leaving the role of DTX intensification uncertain. Enhanced stratification methods are needed to identify aggressive disease phenotypes and guide patient selection for adjuvant chemotherapy. This study aims to develop and validate a computational AI derived pathology image classifier (APIC) to quantify the tumor-immune microenvironment from diagnostic biopsy specimens and predict DTX benefit in patients from the NRG/RTOG 0521 trial. Methods: The study included patients with available high-quality biopsy images from the NRG/RTOG 0521 trial. Primary outcome was OS, median follow-up was 5.7 years. After segmenting nuclei and identifying lymphocytes, we derived features that captured immune-tumor spatial patterns and nuclear diversity in the tumor microenvironment to construct APIC. DTX benefit was evaluated using Cox proportional hazards models with interaction terms, log-rank tests and Kaplan-Meier analyses by comparing OS between treatment arms within APIC-stratified groups. Results: Among NRG/RTOG 0521 trial participants, 350 patients had evaluable quality biopsy slide images. Half of the SOC (RT+ADT) arm was used for training (84 patients), and 266 patients were used for validation (SOC: 85 patients, and SOC+DTX arm: 181 patients). DTX significantly improved OS in APIC-positive (n = 119, 45%) patients (HR = 0.49, 95% CI: 0.26-0.92, p = 0.023) but not in APIC-negative (n = 147, 55%) patients (HR = 1.17, 95% CI: 0.59-2.3, p = 0.66). APIC-positive patients derived 22% 10-year OS benefit (95% CI: 1.7%-41.6%) from DTX. The 10-year OS was 74% in the DTX arm compared to 52% with RT and ADT alone in the APIC-positive group. A significant interaction (p = 0.024) was observed between APIC status and treatment. Conclusions: We validated APIC as a predictive biomarker for DTX benefit in high-risk localized prostate cancer patients from NRG/RTOG 0521, identifying a subset who achieved significant survival improvement from treatment intensification – a benefit not reached in the unselected trial population. Further investigation is warranted to evaluate APIC's predictive potential of DTX intensification in metastatic disease settings.

BACKGROUND:Trials comparing moderately hypofractionated radiotherapy (MHFRT) to conventionally-fractionated radiotherapy (CFRT) for prostate cancer have varied considerably in intent (non-inferiority vs superiority) and MHFRT dose. We compare the efficacy and toxicity profiles of isodose MHFRT and dose-escalated MHFRT. METHODS:This was an individual patient data meta-analysis that identified randomised phase 3 trials of CFRT versus MHFRT that had published individual patient-level data on efficacy and late toxicity. A systematic literature search using MEDLINE, Embase, trial registries, the Web of Science, Scopus, and relevant conference proceedings was initially conducted on Dec 15, 2023, and was re-conducted on Jan 8, 2025. Trials that did not publish efficacy data, did not publish late toxicity data, or did not use modern dose radiotherapy (≥70 Gy in 2 Gy equivalents) in the CFRT group were excluded. Individual patient data were provided to MARCAP by study investigators. Three separate meta-analyses were designed to compare efficacy (primary endpoint was progression-free survival), physician-scored late toxicity (co-primary endpoints were late grade 2 or higher genitourinary and late grade 2 or higher gastrointestinal toxic effects), and patient-reported outcomes (co-primary endpoints were clinically-significant decrements in patient-reported urinary or bowel quality of life) between patients receiving CFRT versus MHFRT. FINDINGS:We identified 1696 records for review. Seven phase 3 trials comparing MHFRT with CFRT were eligible for inclusion in our analysis. Individual patient data were obtained from these seven studies (3454 patients from three trials comparing CFRT with isodose MHFRT and 2426 patients from four trials comparing CFRT with dose-escalated MHFRT). At a median follow-up of 5·4 years (IQR 4·6-7·2) for isodose MHFRT and 7·1 years (5·7-8·4) for dose-escalated MHFRT, no differences in progression-free survival were detected (hazard ratio 0·92, 95% CI 0·81-1·05; p=0·21 and 0·94, 0·82-1·09; p=0·43 respectively). No increased odds of grade 2 or higher genitourinary toxic effects were identified for either isodose (odds ratio [OR] 1·16, 95 CI% 0·86-1·57; p=0·32) or dose-escalated MHFRT (1·20, 0·95-1·51; p=0·13). The odds of grade 2 or higher gastrointestinal toxic effects were significantly higher with dose-escalated (OR 1·48, 95% CI 1·14-1·92; p=0·0035) but not isodose MHFRT (1·30, 0·59-2·87; p=0·51). Isodose MHFRT was not found to show different odds of urinary quality-of-life decrement (OR 1·03, 95% CI 0·51-2·09; p=0·93) or bowel quality-of-life decrement (0·76, 0·40-1·43; p=0·39). Dose-escalated MHFRT was associated with greater odds of bowel quality-of-life decrement (OR 1·68, 95% CI 1·07-2·61; p=0·023), but no evidence of greater urinary quality-of-life decrement was found (1·57, 0·87-2·85; p=0·13). INTERPRETATION:Isodose MHFRT and dose-escalated MHFRT both have similar efficacy compared with CFRT, but dose-escalated MHFRT is associated with higher physician-scored and patient-reported bowel toxicity. Isodose regimens, eg, 60 Gy in 20 fractions, should be the standard MHFRT regimen for localised prostate cancer. FUNDING:None.

Objectives: Compare functional outcomes and treatment-related regret over 10 years in Spanish- and English-speaking Hispanic men compared to non-Hispanic men following treatment of localized prostate cancer. Methods and Materials: Data from a prospective cohort study of men with localized prostate cancer treated with active surveillance, radical prostatectomy or radiotherapy were used to examine the effect of survey language (Spanish speaking vs. English speaking) and ethnicity (Hispanic vs. non-Hispanic) on functional outcomes and treatment-related regret over 10 years. Outcomes were measured using validated questionaries adjusting for baseline patient and disease characteristics. Results: A total of 770 men were included, 12% were Spanish-speaking and 12% were English-speaking Hispanic men. Compared to non-Hispanic men, Spanish-speaking Hispanic men had clinically meaningfully better urinary incontinence scores at years 3, 5 and 10 (adjusted mean difference [aMD], 12.4, 95% CI, 4.8 to 20.0; at year 10), as well as better bowel function scores at 10 years (aMD, 5.1, 95% CI 2.3 to 8.0). Englishspeaking Hispanic men had clinically worse urinary incontinence at 3 and 5 years (aMD,-10.7 [95% CI,-17.6 to-3.9]; at year 5) and bowel function at 10 years (aMD,-4.3 [95% CI,-8.2 to-0.4]) compared to Spanish-speaking Hispanic men. English-speaking Hispanic men were more likely to report regret than Spanish-speaking Hispanic men at 10 years (adjusted odds ratio, 7.9, 95% CI, 1.3-46.2). Conclusions: These findings underscore the importance of considering language and ethnicity when providing counseling and support for prostate cancer survivors, emphasizing the need for personalized patient-centered care. (c) 2024 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/)

Radiotherapy is a pillar of breast cancer treatment; however, it remains unclear how radiotherapy modulates the tumor microenvironment. We investigated this question in a cohort of 20 patients with estrogen-receptor positive (ER+) breast tumors who received neoadjuvant radiotherapy. Tumor biopsies were collected before and 7 days postradiation. Single-cell DNA sequencing (scDNA-seq) and scRNA-seq were conducted on 8 and 11 patients, respectively, at these two time points. The scRNA data showed increased infiltration of naive-like CD4 T cells and an early, activated CD8 T cell population following radiotherapy. Radiotherapy also eliminated existing cytotoxic T cells and resulted in myeloid cell increases. In tumor cells, the scDNA-seq data showed a high genomic selection of subclones in half of the patients with high ER expression, while the remaining number had low genomic selection and an interferon response. Collectively, these data provide insight into the impact of radiotherapy in ER+ breast cancer patients.

BACKGROUND AND OBJECTIVE:NRG/RTOG 0521 randomized men with high-risk localized prostate cancer (PC) to androgen suppression (AS) and definitive radiotherapy (RT) ± docetaxel-based chemotherapy (CT). The overall survival (OS) benefit with CT initially reported was lost on longer follow-up. The Decipher genomic classifier (GC) measures multiple transcripts relevant to docetaxel action. Basal/luminal differentiation portends differential response to AS and CT for high-risk localized and metastatic hormone-sensitive PC. We validated the Decipher GC in pretreatment biopsy samples for risk stratification and examined basal-luminal subtyping to predict docetaxel response. METHODS:Decipher GC scores and basal-luminal cellular subtypes were generated for specimens from NRG/RTOG 0521. The primary objective was to validate the independent prognostic ability of GC for metastasis-free survival (MFS). Treatment effects in luminal proliferating (LP) and non-LP cell subtypes were examined in relation to MFS, OS, and distant metastasis (DM). KEY FINDINGS AND LIMITATIONS:Samples were obtained from 283 patients and yielded 183 GC scores. Over median follow-up of 9.9 yr, 67 metastasis events were observed, including 34 DM events. Multivariable analysis revealed that GC was independently associated with DM (subdistribution hazard ratio 1.45) and MFS (hazard ratio 1.20). No biomarker-by-treatment interaction with GC and docetaxel was detected. The 10-yr restricted mean survival time difference in OS with CT was 13.7 mo for LP (p = 0.053) and 2.5 mo for non-LP (p = 0.63) tumors. CONCLUSIONS AND CLINICAL IMPLICATIONS:The Decipher GC score was independently associated with DM and MFS, and LP tumors may benefit from addition of CT. Validation of these findings may allow more effective use of CT in men with localized PC. The original NRG/RTOG 0521 trial is registered on ClinicalTrials.gov as NCT00288080.

Prostate cancer is the most commonly diagnosed malignancy among men in the United States, with high-risk localized disease accounting for approximately 15% of new cases. High-risk cancer portends increased risk of locoregional recurrence and distant metastases. Despite the longstanding use of radical prostatectomy (RP) and definitive radiotherapy (RT) with androgen deprivation therapy (ADT) as primary treatment options, there remains a lack of randomized data directly comparing these modalities. The ongoing SPCG-15 trial may eventually provide such evidence but its results are not expected until 2030. In the interim, clinicians must rely on existing observational studies to guide treatment selection. This review synthesizes current evidence comparing RP and RT+ADT for high-risk localized prostate cancer, highlighting oncologic outcomes, treatment-related toxicities, and patient-reported quality of life in survivorship. RT+ADT may offer biological advantages in addressing occult micrometastases with radiobiological foundations for synergy between modalities. Further, although observational data comparing RP and RT+ADT are heterogeneous and often methodologically limited, recent analyses using modern causal inference frameworks suggest improved distant metastatic control with RT+ADT. Toxicity profiles also differ significantly between modalities, with RT+ADT associated with fewer early and long-term urinary side effects, and less treatment regret but transient hormone-related and bowel symptoms during treatment. Here, we propose that under the shared-decision-making model RT+ADT will be the preferred first-line treatment for most men with high-risk localized prostate cancer, offering favorable oncologic control while preserving quality of life, particularly with modern advances in radiotherapy techniques.