PURPOSE:The association between late toxicity and biochemical recurrence (BCR) after prostate radiation therapy is unclear. We set out to characterize the relationship between late gastrointestinal (GI) and genitourinary (GU) toxicity and BCR among patients receiving conventionally fractionated (CF) or moderately hypofractionated (MHF) prostate radiation therapy. METHODS AND MATERIALS:This was an individual patient data meta-analysis that identified randomized phase 3 trials of CF or MHF prostate radiation therapy in the MARCAP (Meta-Analysis of Randomized trials in Cancer of the Prostate) Consortium that had individual-level late toxicity and BCR data available. Data were provided to MARCAP by study investigators. The associations between BCR and late (>3 months after radiation therapy) grade ≥2 GI and GU toxicities were assessed using Fine-Gray subdistribution hazard models with an 18-month landmark to address immortal time bias. RESULTS:Seven of 26 available trials met all eligibility criteria. A total of 6761 patients were included (CF: n = 4333; MHF: n = 2428). Median follow-up was 72 months (IQR, 61-94 months). BCR occurred in 17.0% of patients (1142/6732). The rate of late grade ≥2 GI toxicity was 14.3% (965/6761), although the rate of grade ≥2 GU toxicity was 15.5% (1045/6761). BCR was inversely associated with late grade ≥2 GI toxicity (subdistribution hazard ratio, 0.64; 95% CI, 0.43-0.96; P = .03). BCR was not significantly associated with late grade ≥2 GU toxicity (subdistribution hazard ratio, 1.06; 95% CI, 0.70-1.60; P = .78). CONCLUSIONS:Late grade ≥2 GI toxicity was significantly associated with lower rates of BCR. We hypothesize that this may be related to the impact of prostatic motion during treatment, specifically anterosuperior motion of the prostate that would increase the dose to the rectum and to posterior dominant intraprostatic lesions. Late grade ≥2 GU toxicity did not appear to be associated with BCR.

LRF by KRAS and assigned treatment. Rates of local failure based on treatment and KRAS-variant status, with KRAS-variant patients being depicted by blue lines and nonvariant patients by red lines and dashed lines representing cetuximab-treated patients.

Grade 3 to 4 treatment-related AEs over time by KRAS and assigned treatment. Rates of treatment-related AEs with 95% CI by treatment and KRAS-variant status, with KRAS-variant patients being depicted by blue (cisplatin-treated) and red (cetuximab-treated) and nonvariant patients depicted by green (cisplatin-treated) and brown (cetuximab-treated).

Multivariable Cox Models for KRAS as a Predictive Biomarker for Local-Regional Failure

Purpose: NRG/RTOG 1016 was a phase III noninferiority trial comparing IMRT + cisplatin versus IMRT + cetuximab for human papillomavirus-positive oropharyngeal squamous cell cancer (HPV+ OPSCC). A germline mutation (the KRAS-variant) previously identified patients with improved outcomes to radiation + cetuximab + cisplatin; thus, we investigated whether there may be similar benefits for IMRT + cetuximab.Patients and Methods: 562 patients were tested, with 16% positive for the KRAS-variant. Clinical endpoints were per NRG/RTOG 1016, and hazard ratios (HR) were estimated by Cox models. Negative binomial regression modeled treatment-related acute and late grade 3 to 5 adverse events (AE). All models included KRAS, assigned treatment, their interaction, and other prognostic variables tested at two-sided 0.05.Results: There was no association between the KRAS-variant and clinical outcomes. There were higher local-regional failure rates (LRF) in nonvariant patients treated with cetuximab [HR = 1.83 (1.19-2.82)] versus KRAS-variant patients [HR (95% CI), 0.90 (0.34-2.41)]. Grade 3 to 4 acute mucositis was higher in nonvariant patients treated with cetuximab [OR = 1.41 (95% CI, 0.98-2.03)] and lower in KRAS-variant patients [OR = 0.60 (95% CI, 0.25-1.41)]. However, the mean late toxicity ratio was lower in nonvariant patients [0.55 (95% CI, 0.35-0.87)] versus KRAS-variant patients [1.62 (95% CI, 0.57-4.62)]. KRAS by treatment interaction for acute and late AEs was not significant (P = 0.0717 and 0.0659, respectively).Conclusions: Possible lower LRF and less acute toxicity with cetuximab versus cisplatin for KRAS-variant patients seem to be offset by potentially increased late toxicity. Further evaluation of this class of biomarkers is warranted.Significance: Germline microRNA-disrupting biomarkers are functional biomarkers being studied to help guide treatment personalization in cancer. The work in this study is a hypothesis-generating evaluation of the KRAS-variant as a potential biomarker to help predict outcomes and toxicity in patients with head and neck cancer treated with radiation and cetuximab. Findings from this work suggest that these biomarkers may have the potential to differentiate patients at risk of acute versus late toxicity, supporting further study of these biomarkers in radiation studies.

Representativeness of Study Participants

e12727 Background: Invasive apocrine carcinoma (IAC) is a rare subtype of breast cancer that is classically triple negative (TN) and associated with lower grade and proliferation rates compared to ductal triple negative breast cancer. Despite these pathologic features that suggest a lack of response to cytotoxic chemotherapy, apocrine and non-apocrine breast cancers are commonly managed with similar systemic treatment approaches. We investigated the treatment courses and outcomes of patients with TN-IAC. Methods: We conducted a retrospective cohort study using electronic medical record review of patients diagnosed with early-stage IAC treated at a single academic institution to determine treatment courses and outcomes. We identified patients in which “apocrine” was used as a descriptor of pathology. Given inconsistent pathologic definitions, patients were classified into two groups. Classical apocrine (c-IAC) tumors were defined as TN disease with pathology specifically designated as “IAC” or invasive ductal carcinoma with apocrine features with low grade (grade 1–2) and Ki-67 ≤ 20%. The “Other Apocrine” group consisted of those patients with high grade disease with apocrine features, Ki-67 > 20%, and/or HER2 or hormone receptor positivity. Patients with de novo metastatic disease and those without invasive disease were excluded. Data collected included clinicopathologic characteristics and type of local/regional and systemic therapies received. Our primary outcome was recurrence free interval (RFI) defined as the absence of recurrence from the time of diagnosis to the last documented follow up date. Results: We identified 69 cases with apocrine used as a descriptor of pathology. Of those 69, we identified 18 c-IAC cases and 41 Other Apocrine cases. c-IAC patients were more likely to have chemotherapy omitted (39% vs 5%, p value of .024). In the c-IAC group there were 0 recurrences over the median follow up of 52.7 months. Among the Other Apocrine patients there were 13 recurrences over the median follow up of 104.5 months. Conclusions: Patients with TN c-IAC had no documented recurrences and were less likely to receive chemotherapy than patients with other types of apocrine-related carcinoma of the breast. Classical apocrine carcinoma of the breast represents an identifiable subtype of breast cancer which may allow for chemotherapy de-escalation. Cohort characteristics. Category c-IAC (n=18) Other Apocrine (n=41) Age (median, range) 67.5 (44-89) 62 (30-87) ER+ (>10%) (%) 0 (0) 16 (39) HER2+ (%) 0 (0) 15 (37) Elevated Ki67 ≥ 20% (%) 3 (17) 22 (54) Tumor Size in cm (median, range) 1.7 (0.8-4.1) 2.0 (0.3-11.0) Node positive (%) 3 (17) 16 (39) Receipt of chemotherapy (%) 11 (61) 39 (95) Median Follow Up (months) 52.7 (3.7-171.8) 104.5 (<0.1-292.6) Recurrence, n (%) 0 (0) 13 (32%)

TPS3175 Background: The recent LUNAR study (NCT05496959) found that adding beta-emitting 177 Lutetium-PNT2002 ( 177 Lu-PSMA) to stereotactic body radiation therapy (SBRT) more than doubled median progression-free survival (PFS) compared to SBRT alone in oligorecurrent hormone-sensitive prostate cancer (orHSPC), hazard ratio (HR)=0.37. However, the relative efficacy compared to novel alpha-emitting 225 Actinium-PSMA-617 ( 225 Ac-PSMA) is unknown. The hypothesis is that 225 Ac-PSMA will improve PFS by treating more micrometastases, given its higher radiobiologic effectiveness. We aim to compare the relative benefit of 2 cycles of 177 Lu-PSMA versus 1 cycle of 225 Ac-PSMA followed by SBRT metastasis-directed therapy (MDT). Methods: ANDROMEDA (NCT07150715) is a phase II, non-blinded, single-center randomized trial for individuals with orHSPC and 1-5 PSMA-avid metastases outside the prostate/prostate bed (N1 and/or M1). Eligibility criteria include testosterone >150 ng/dL, ≥18 years, and ECOG performance status ≤2. Exclusion criteria include de novo metastatic disease, castrate-resistance (testosterone <50 ng/mL with rising PSA), ADT/chemotherapy within 6 months of enrollment, and neuroendocrine histology. Participants are randomized 1:1 to 2 cycles 177 Lu-PSMA (7.4 GBq/cycle, 6 weeks apart) or 1 cycle of 225 Ac-PSMA (8 MBq, once), followed by SBRT to all lesions 1-2 weeks after radioligand therapy infusion. The primary endpoint of PFS is defined as the time from randomization to either 1) a new PSMA-avid lesion or 2) PSMA-PET local progression (>30% SUV increase or >20% increase in the sum of the longest lesion diameters) with a PSA rise. For those alive without progression, PFS will be censored at the time of the last scan. All randomized subjects will be analyzed based on intent-to-treat. Secondary endpoints include 24-month disease burden by PSMA-PET, physician-scored toxicity, patient-reported quality of life, ADT-free survival, local control of SBRT lesions at 24 months after last radionuclide infusion, and time-to-progression (locoregional, distant, new metastasis). We hypothesize that the 24-month post-SBRT PSA-based recurrence rate of 177 Lu-PSMA will be ~50%, which will be reduced with 225 Ac-PSMA to ~30% (PFS HR~0.51). We anticipate an accrual time of 1.5 years and a median follow-up time of 24-months. A sample size of 96 patients (48 per arm) would provide 80% power to detect the expected difference in PFS at a 0.1 alpha level. Assuming a 10% drop-out/screen failure rate, the target trial accrual is 107 patients. Early stopping guidelines include monitoring site-specific grade 4-5 toxicity with a safety threshold of 20% from the time of the first enrolled patient, which would trigger halting the trial and safety consultation. ANDROMEDA is currently open for enrollment. Clinical trial information: NCT07150715 .

Univariate and Multivariable Cause-Specific Cox Models for KRAS as a Prognostic Biomarker for Distant Metastasis

Background/Objectives: Canonical microRNAs possess a 5' phosphate required for Argonaute binding and activity. However, prior work identified an unphosphorylated, inactive nuclear pool of the important radiation-responsive microRNA, miR-34, that is rapidly phosphorylated and activated in response to ionizing radiation (IR). Here, we extend this work and investigate the role of paraspeckles, a phase-separated nuclear sub-compartment, and their association with the localization of unphosphorylated miR-34a. Methods: Mass spectrometry was performed to identify interacting partners of unphosphorylated mir-34. CRISPR-mediated deletion of the paraspeckle NEAT1_2 triple helix motif was performed to create an A549 cell line lacking paraspeckles (dTH). Activity and expression of mir-34a post-irradiation were evaluated by qRT-PCR and luciferase assays comparing dTH and wild-type (WT) A549 cell lines. In situ hybridization (ISH) was performed to evaluate mir-34a localization before and after IR, comparing dTH and WT cell lines. Results: Mass spectrometry identified paraspeckle proteins as significantly enriched interacting partners of unphosphorylated mir-34 mimics. By qRT-PCR and luciferase assays, we found that paraspeckle loss prevented radiation-induced early activation of unphosphorylated mir-34a. We found no difference in radiation-induced transcription of pri-miR-34a, but early processing to pre-miR-34a appeared delayed. ISH confirmed that loss of paraspeckles altered the nuclear localization of miR-34a before and after IR. Conclusions: These data suggest that paraspeckles are associated with nuclear localization and early radiation-responsive activation of unphosphorylated miR-34a. This suggests a coordinated nuclear sequestration of this important miR in its unphosphorylated state to enable an enhanced radiation response.

Grade 3–4 treatment-relateda acuteb mucositisc by KRAS and assigned treatment.

PURPOSE:Progression after metastasis-directed therapy via stereotactic body radiotherapy (SBRT) for oligorecurrent hormone-sensitive prostate cancer (orHSPC) is common. We aimed to assess whether the addition of neoadjuvant prostate-specific membrane antigen (PSMA)-targeting radioligand therapy to SBRT would improve outcomes. METHODS:The LUNAR trial was a single-center, randomized, open-label, controlled phase II trial conducted at the University of California, Los Angeles. Eligible participants had orHSPC as determined by the presence of one to five lesions identified on PSMA positron emission tomography/computed tomography (PET/CT). After stratifying by stage (N1/M1a v M1b) and lesion count (1 v 2-3 v 4-5), we randomly assigned patients 1:1 to receive SBRT to all lesions or two cycles of 177Lu-PNT2002 (6.8 GBq/cycle, 2 weeks apart) followed by SBRT to all lesions. The primary end point was progression-free survival (PFS), defined by PSMA PET/CT, salvage hormonal therapy, or death. PSMA PET/CT was acquired systematically at prostate-specific antigen progression and/or 12 months after SBRT. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov (identifier: NCT05496959). RESULTS:From September 2, 2022, to November 9, 2023, 92 patients were randomly assigned (SBRT n = 47 and 177Lu + SBRT n = 45), with 87 evaluable patients (SBRT n = 42 and 177Lu + SBRT n = 45). At a median follow-up of 22 months, the addition of 177Lu to SBRT significantly improved PFS (17.6 months [95% CI 15 months to not reached] v 7.4 months [95% CI, 6.0 to 13.5 months]; hazard ratio, 0.37 [95% CI, 0.22 to 0.61], P < .0001). The only grade 3 adverse events were lymphopenia (two patients [4.8%] in the SBRT group and three patients [6.7%] in the 177Lu + SBRT group). Prognostic biomarkers for PFS were identified. CONCLUSION:Compared with SBRT alone, the addition of 177Lu-PNT2002 to SBRT significantly improved PFS in patients with orHSPC without an attendant increase in toxicity.

This nonrandomized clinical trial evaluates the long-term toxic effects and clinical outcomes associated with a shorter 5-day, dose-equivalent preoperative radiation therapy (RT) regimen among patients with soft tissue sarcoma. QuestionWhat safety and clinical outcomes are associated with a shorter 5-day preoperative radiotherapy regimen for extremity and truncal soft tissue sarcoma?FindingsIn this nonrandomized phase 2 trial of 110 patients, median follow-up for the initial and expansion cohorts was 64.2 and 30.0 months, respectively. Major wound complications occurred in 33 of 110 patients (30.0%); at 2 years, 14 of 74 evaluable patients (18.9%) developed grade 2 or higher toxic effects. Two-year local control was 92.4% (95% CI, 86.3%-96.5%), and time to wound closure exceeded 6 months for 15 of 110 patients (13.6%).MeaningThese findings suggest 5-day preoperative radiotherapy was associated with favorable long-term clinical outcomes, but its potential impact on time-to-wound closure should be assessed in a randomized study. ImportanceStandard preoperative radiotherapy (RT) for high-risk soft tissue sarcoma (STS) is delivered over 5 weeks, which can be a logistical challenge for patients.ObjectiveTo evaluate the long-term toxic effects and clinical outcomes associated with a shorter 5-day, dose-equivalent preoperative RT regimen.Design, Setting, and ParticipantsPhase 2, single-group nonrandomized trial with an initial cohort (April 2016 to May 2018) and expansion cohort (October 2018 to May 2023) at a single academic center in the US. Participants were patients with histologically confirmed extremity or trunk STS recommended to undergo standard preoperative RT and surgery. Patients with planned neoadjuvant systemic therapy who were enrolled in the expansion group were excluded from this analysis. Analysis was conducted September 2024 to August 2025.InterventionA total of 30 Gy in 5 fractions were delivered preoperatively.Main Outcomes and MeasuresThe primary end point was 2-year grade 2 or higher radiation toxic effects. Secondary end points included major wound complications (MWC), local failure, distant progression, and overall survival.ResultsA total of 110 patients were treated with preoperative RT and surgery (42 patients [38%] were aged 65-79 years; 64 [58%] were male; 75 had tumors of the lower extremity [68%], and 64 patients [58%] had high-grade disease). The initial cohort accrued 50 patients who underwent surgery. The expansion cohort accrued 83 patients; 60 of 83 were treated without neoadjuvant chemotherapy and were included. Median (IQR) follow-up was 37.3 (20.1-60.6) months, including 64.2 (36.3-74.1) months for the initial cohort and 30.0 (13.5-40.2) months for the expansion cohort. At 2 years, 14 of 74 evaluable patients (18.9%) developed grade 2 or higher toxic effects (10 patients [25.0%] for the initial cohort and 4 patients [11.8%] for the expansion cohort). MWCs occurred in 33 of 110 patients (30.0%); (17 [34.0%] for the initial cohort and 16 [26.7%] for the expansion cohort). Time to wound closure exceeded 6 months for 15 patients (13.6%), including 12 of 29 patients (41.4%) who underwent local tissue advancement flaps. Two-year local control adjusting for competing risk of death was 92.4% (95% CI, 86.3%-96.5%). There were 3 (2.7%) bone fractures and 5 (4.5%) amputations.Conclusions and RelevanceThis nonrandomized clinical trial of ultrahypofractionated preoperative RT identified durable local control with MWC and favorable late grade 2 or higher toxic effects rates. Randomized data are necessary to differentiate the safety profiles of various fractionation regimens, especially duration of wound healing.Trial RegistrationClinicalTrials.gov Identifier: NCT02701153

Purpose The biology of locally radiorecurrent prostate cancer (LRR-PCa) is poorly understood. Methods and Materials We sought to explore the genomic and transcriptomic landscape of LRR-PCa with targeted DNA sequencing and RNA expression analysis from 41 biopsy-proven LRR-PCa tumors from 36 unique patients who had a recurrence at a median interval of 84 months (IQR, 70-124 months). Genomic alteration frequencies and transcriptomic data were compared between the LRR-PCa cohort and treatment-naïve patients from the Cancer Genome Atlas (genomic; n = 496) and Gleason grade-at-recurrence-matched patients from the Decipher Genomics Resource for Intelligent Discovery (transcriptomic; n = 22,320). Results Twenty-five patients (69%) had pathologic upgrading at recurrence (17% vs 64% with Gleason grade 4-5 disease; P < .001). The LRR-PCa cohort demonstrated significantly greater single-nucleotide variations in 29 genes known to be associated with prostate cancer, including several associated with increased aggressiveness and DNA repair: FAT1 (58.5% vs 1.0%), RAD51B (36.6% vs 0.4%), POLQ (34.1% vs 1.4%), KMT2C (34.1% vs 4.9%), BRCA2 (29.3% vs 1.8%), ATRX (26.8% vs 0.8%), and BRCA1 (24.4% vs 0.4%) (Pvalues < .001 for all). The LRR-PCa cohort had a significantly higher Decipher score (median, 0.80 vs 0.66; P = .05) and demonstrated significantly greater basal subtype based on PAM50 (56% vs 20%; P < .001) and lower androgen receptor activity (61% for LRR vs 9%; P < .001). Conclusions Overall, these results suggest that LRR-PCa has a distinct genomic and transcriptomic landscape from de novo prostate cancer. Specifically, LRR-PCa has an enrichment in SNVs in genes associated with tumor aggressiveness and/or DNA repair, has higher Decipher scores, a more basal subtype, and has transcriptomic evidence of lower androgen receptor activity and loss of tumor suppressor genes.

11538 Background: Soft tissue sarcomas (STS) are rare, aggressive malignancies with high variability in response to radiation therapy (RT). Our previous research in a small cohort who received preoperative hypofractionated RT (SBRT) on a phase II trial suggested that germline microRNA-based single nucleotide polymorphisms (mirSNPs) could identify patients at increased risk of major wound toxicity (MWT). This study explores the potential of this class of biomarker to predict MWT and additional outcomes to preoperative SBRT in STS. These findings could guide personalized treatment strategies and possibly the choice of RT regimen in the future. Methods: We analyzed 110 patients with high-risk extremity or trunk STS treated with five-day preoperative SBRT (30 Gy in five fractions). Over 100 mirSNPs were evaluated for their ability to predict RT outcomes, including late toxicity, MWT, distant metastases, and pathological response. Pathological response was defined as a necrosis score >= 70, late toxicity as grade >=2 at 2 years, and MWT as grade >= 3. Preliminary genetic models were developed using elastic net, random forest, and boosted tree algorithms and evaluated using leave-one-out cross-validation (LOOCV) performance metrics. mirSNPs were pre-filtered using Fisher or Jonckheere-Terpstra p-values (<0.2) for relevance to outcomes. Results: We developed preliminary genetic signatures to accurately predict 4 different outcomes in sarcoma patients undergoing preoperative SBRT: late toxicity (AUC=0.830), distant failure (AUC=0.775), pathological response (AUC=0.765), and major wound toxicity (AUC=0.736). Our pathological response genetic model has balanced sensitivity (0.750) and specificity (0.781), suggesting it could reliably predict which patients respond well to SBRT. Conclusions: Our study highlights the promise of mirSNP-based models in predicting STS outcomes to preoperative SBRT. By identifying patients with favorable versus unfavorable responses, these models could help identify patients who could be considered for preoperative SBRT versus standard fractionated radiation, as there may be fractionation-dependent radiation toxicity in sarcoma, as has been identified in other malignancies. Future directions include investigating associations among identified outcomes, inclusion of additional clinical variables, and comparison to toxicity with preoperative standard fractionated radiation. These efforts are significant steps towards paving the way for more personalized sarcoma care. Clinical trial information: NCT02701153 . LOOCV performance metrics in sarcoma data (n=110). Outcome Sensitivity Specificity PPV NPV F1 Score AUC Any Late Toxicity (Grade 2 at 2 Years) 0.786 0.875 0.478 0.966 0.595 0.830 Distant Failure 0.680 0.871 0.607 0.902 0.642 0.775 Path Response (Necrosis Score >= 70) 0.750 0.781 0.600 0.877 0.667 0.765 Major Wound Toxicity 0.667 0.805 0.595 0.849 0.629 0.736