Kenneth M. Boucher

Purpose: Advanced molecular imaging has enabled detection of oligorecurrent prostate cancer (PCa) at low PSA levels, but optimal management of positron emission tomography (PET)–defined recurrence remains uncertain. We conducted a phase II trial to evaluate biochemical response, oncologic outcomes, and safety of salvage metastasis-directed therapy (MDT) delivered without concurrent androgen deprivation therapy (ADT). Materials and Methods: Twenty men with PET-defined oligometastatic recurrence (≤ 10 nodal or osseous lesions) after radical prostatectomy were prospectively enrolled (2019-2023). Treatment was assigned based on disease distribution: bone-directed radiotherapy (arm A), salvage lymph node dissection (sLND; arm B), or combined therapy (arm C). The primary endpoint was a ≥ 50% PSA decline at 6 months; secondary endpoints included PSA progression, ADT-free survival, and treatment-related morbidity. Results: The median age was 65 years (IQR 61.5-70.0); 18 patients had nodal-only recurrence, and 2 had bone-only disease. At 6 months, 8 of 20 patients (40%) achieved ≥ 50% PSA reduction. Over a median follow-up of 11.4 months, 12-month PSA-PFS was 74.1% (95% confidence interval [CI] 54.8%-100%) and ADT-free survival was 71.4% (95% CI 52.7%-96.6%), with a median of 13.3 months. Among sLND patients, pathologic carcinoma was confirmed in 15 of 18 (83%) and pathologic assessment frequently revealed more extensive nodal disease than predicted by PET. No Clavien-Dindo grade III-V complications occurred. Conclusions: Salvage MDT without ADT is feasible, safe, and associated with meaningful biochemical responses in selected patients with PET-defined oligorecurrent PCa. Pathologic findings demonstrate that PET imaging may underestimate true nodal disease burden, supporting comprehensive treatment strategies and further prospective investigation.

Use of recommended sun protection strategies among minor children of melanoma survivors is suboptimal and as a result, these children receive excess ultraviolet radiation exposure that further increases their melanoma risk. Among a sample of 368 melanoma survivor-child dyads, the relationship between family-focused factors and child sun protection and related outcomes was examined, as well as the relations of family factors with individual sun-protective behaviors. The findings indicated that sun protection, tanning, and sunburn were positively associated between survivors and their children. Certain family-focused factors including parental perceived risk for the child to develop melanoma later in life and problem-solving skills were associated with child melanoma risk and protection outcomes. These factors could be important intervention targets to improve sun protection behavior use and skin cancer risk behavior avoidance among children with a familial risk for melanoma. This trial is registered at ClinicalTrials.gov (NCT04201223).

PURPOSE: Vaginal cuff brachytherapy (VCB) is widely used for adjuvant treatment of endometrial cancer, yet limited randomized data examine the optimal dose/fractionation. We aimed to study short-course VCB using patient-reported outcomes. METHODS: We conducted a prospective, randomized, multicenter trial examining short-course adjuvant VCB (11 Gy × two fractions at the surface) compared with standard regimens (7 Gy × three fractions at 0.5 cm depth, 6 Gy × five fractions at the vaginal surface, or 5-5.5 Gy × four fractions at 0.5 cm depth). Eligible patients underwent hysterectomy and had pathologically confirmed endometrioid adenocarcinoma, serous sarcoma, clear cell sarcoma, or carcinosarcoma. Patients with stage I and II cancers were included, with lymphovascular invasion required for stage IAG1. The primary outcome was Global Health Status measured by European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core Module (QLQ-C30) with a prespecified noninferiority margin of 15 points. Secondary outcomes included patient-reported outcomes, toxicities, and recurrences. RESULTS: Fifty-four patients enrolled in each arm. The QLQ-C30 for the experimental arm was within the predefined boundary, and thus two fractions were noninferior to standard of care at 1 month ( P = .000005) and 12 months ( P = .0005). Using EORTC Quality of Life Questionnaire - Endometrial Cancer Module for patient-reported vaginal/sexual, urologic, and GI symptoms, the change in mean patient-reported symptom score from baseline to 1 and 12 months was not significantly different between arms. Using Common Terminology Criteria for Adverse Events v5 20 patients (37%) in the experimental arm and 31 patients (57%) in the control arm experienced short-term adverse events related to study treatment ( P = .053). At 28-month median follow-up, the vaginal control rate was 96% in both arms. The isolated vaginal control rate in the experimental arm was 100%. CONCLUSION: Short-course VCB has noninferior short-term quality of life compared with standard regimens with acceptable short-term acute toxicity and cancer control outcomes.

Tumour-host immune interactions lead to complex changes in the tumour microenvironment (TME), impacting progression, metastasis and response to therapy. While it is clear that cancer cells can have the capacity to alter immune landscapes, our understanding of this process is incomplete. Herein we show that endocytic trafficking at the plasma membrane, mediated by the small GTPase ARF6, enables melanoma cells to impose an immunosuppressive TME that accelerates tumour development. This ARF6-dependent TME is vulnerable to immune checkpoint blockade therapy (ICB) but in murine melanoma, loss of Arf6 causes resistance to ICB. Likewise, downregulation of ARF6 in patient tumours correlates with inferior overall survival after ICB. Mechanistically, these phenotypes are at least partially explained by ARF6-dependent recycling, which controls plasma membrane density of the interferon-gamma receptor. Collectively, our findings reveal the importance of endomembrane trafficking in outfitting tumour cells with the ability to shape their immune microenvironment and respond to immunotherapy.

PURPOSE: Assessing risk of recurrence for nonmetastatic triple-negative breast cancer (TNBC) is a key determinant of therapeutic strategy. The best predictor of recurrence risk is failure to achieve a pathologic complete response after preoperative chemotherapy, but it imperfectly correlates with the definitive end points of relapse-free and overall survival (OS). The inability to accurately predict recurrence has led to increasingly toxic treatment regimens for patients with early-stage TNBC. Better assays for recurrence risk are needed to tailor aggressive therapy for patients who need it and avoid overtreatment and unnecessary toxicity for those at low risk. The purpose of this study was to determine if patient-derived xenograft (PDX) engraftment of newly diagnosed breast tumors can serve as an accurate predictor of recurrence and death from breast cancer. METHODS: This study was a blinded noninterventional trial comprising 80 patients with newly diagnosed, nonmetastatic, estrogen receptor (ER)-negative or ER-low breast cancer. RESULTS: PDX engraftment was strongly associated with relapse in 1 year: 8 of 18 (44.4%) patients whose tumors engrafted relapsed versus 1 of 62 (1.6%) patients whose tumors did not engraft ( P < .0001). Patients whose tumors engrafted had a hazard ratio (HR) for relapse of 17.5. HRs for OS and breast cancer-specific survival in PDX+ patients were 21.1 and 39.5, respectively. CONCLUSION: We report that the ability of a tumor to engraft as a PDX predicts early recurrence by serving as a functional readout of aggressiveness and prospectively identifies the most devastating tumors. This provides new opportunity to develop surrogate assays, such as biomarkers of engraftment, which will extend the clinical feasibility of this finding.

PURPOSE: This study investigates a real-world multicenter cohort of patients with urinary tract cancer (UTC), with primary disease sites including the bladder, urethra, and upper tract, who enrolled for research molecular testing of their germline and tumor. The purpose of this study was to evaluate factors that could affect the likelihood of identifying a clinically actionable germline pathogenic variant (PV). METHODS: Patients with UTC were identified from 10 cancer institutes of the Oncology Research Information Exchange Network consortium. The data set comprised abstracted clinical data with germline and tumor genomic data, and comparative analyses were conducted. RESULTS: Clinically actionable germline PVs in cancer predisposition genes were identified in 16 (4.5%) of 354 patients. A higher proportion of patients with the urethra and the upper tract as the primary sites of disease had PVs with a prevalence of 11% (5/45), compared with only 3.6% (11/308) in those with the bladder as the primary site of disease ( P = .04). There were no significant differences in markers of genomic instability (such as tumor mutational burden, microsatellite instability [MSI], and loss of heterozygosity, copy number, and chromosomal instability) between those with PVs and those without ( P > .05). Of the PVs identified, 10 (62%) were in homologous recombination repair (HRR) genes, three (19%) in mismatch repair (MMR) genes, and three (19%) in genes associated with other pathways. CONCLUSION: Tissue-based assessment of genomic instability, such as MSI, does not reliably indicate germline PV. A comprehensive clinical germline testing approach that includes HRR genes in addition to MMR genes is likely to yield PVs in approximately one of 10 patients with nonbladder primary disease sites such as the upper tract and the urethra.

Alterations in the PI3K/AKT pathway occur in up to 70% of melanomas and are associated with disease progression. The three AKT paralogs are highly conserved but data suggest they have distinct functions. Activating mutations of AKT1 and AKT3 occur in human melanoma but their role in melanoma formation and metastasis remains unclear. Using an established melanoma mouse model, we evaluated E17K, E40K, and Q79K mutations in AKT1, AKT2, and AKT3 and show that mice harboring tumors expressing AKT1E17K had the highest incidence of brain metastasis and lowest mean survival. Tumors expressing AKT1E17K displayed elevated levels of focal adhesion factors and enhanced phosphorylation of focal adhesion kinase (FAK). AKT1E17K expression in melanoma cells increased invasion and this was reduced by pharmacologic inhibition of either AKT or FAK. These data suggest that the different AKT paralogs have distinct roles in melanoma brain metastasis and that AKT and FAK may be promising therapeutic targets.Implications:This study suggests that AKT1E17K promotes melanoma brain metastasis through activation of FAK and provides a rationale for the therapeutic targeting of AKT and/or FAK to reduce melanoma metastasis.