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Background A recent phase III trial (NCT01372774) comparing use of stereotactic radiosurgery [SRS] versus whole-brain radiation therapy [WBRT] after surgical resection of a single brain metastasis revealed that declines in cognitive function were more common with WBRT than with SRS. A secondary endpoint in that trial, and the primary objective in this secondary analysis, was to identify baseline biomarkers associated with cognitive impairment after either form of radiotherapy for brain metastasis. Here we report our findings on APOE genotype and serum levels of associated proteins and their association with radiation-induced neurocognitive decline. Methods In this retrospective analysis of prospectively collected samples from a completed randomized clinical trial, patients provided blood samples every 3 months that were tested by genotyping and enzyme-linked immunosorbent assay, and results were analyzed in association with cognitive impairment. Results The APOE genotype was not associated with neurocognitive impairment at 3 months. However, low serum levels of ApoJ, ApoE, or ApoA protein (all P < .01) and higher amyloid beta (Aβ 1–42) levels (P = .048) at baseline indicated a greater likelihood of neurocognitive decline at 3 months after SRS, whereas lower ApoJ levels were associated with decline after WBRT (P = .014). Conclusions Patients with these pretreatment serum markers should be counseled about radiation-related neurocognitive decline.

Background: PSMA-based targeted radionuclide therapy is now a standard of care for mCRPC since approval of 177Lu-PSMA-617. Use of antibodies (e.g., J591) to target PSMA with higher potency radionuclides (e.g., 225Ac) impacts kinetics, biodistribution, clinical efficacy, and toxicities. In our first-in-human ph I dose-escalation study of single dose 225Ac-J591 in patients with mCRPC, no MTD was reached (max dose 93.3 KBq/kg). Following this, we developed ph I/II parallel dose-escalation studies of fractionated (D1, D15) single cycle and multiple (q6w) dose regimens. Here we present safety data from the initial fractionated study in predominantly 177Lu-naive. Methods: Eligible patients had adequate organ function, ECOG performance status 0-2, and progressive mCRPC following potent AR pathway inhibitor (ARPI) and chemo (or unfit/refusing). Prior 177Lu-PSMA was allowed until an amendment developed a separate study for post-177Lu-PSMA. Baseline 68Ga-PSMA PET scans were performed, but not used to determine eligibility. A 3+3 dose-escalation design was used. Phase I primary objective: determination of dose-limiting toxicity (DLT) and recommended phase II dose (RP2D). DLT was defined as within 8 weeks of first dose: neutropenia (Gr 4 or febrile neutropenia), thrombocytopenia (TCP) (Gr 4, or Gr 3 with clinically significant bleeding), any Gr >2 non-hematologic toxicity deemed to be at least possibly related to 225Ac-J591, or any attributable toxicity precluding or delaying the second dose by >2 weeks. Secondary/exploratory objectives: efficacy measures (e.g., PSA decline, radiographic RR, biochemical/radiographic PFS, OS, CTCs, patient reported outcomes), safety (CTCAE v5), and correlatives (plasma and tissue genomics, PSMA imaging). Results: 24 patients were enrolled in phase I. Median age 73.5 (57-91), PSA 25.78 (3.39-2133.41); 53% (n=13) >1 prior ARPI, 58% (n=14) taxane chemo, 8% (n=2) anti-PSMA therapy, 12.5% (n=3) prior 223Ra. CALGB prognostic groups: Good 4 (16%), Intermediate 8 (33%), Poor 12 (50%). No DLTs were observed in Cohort 1 (n=3) or 2 (n=6). In C3, 2/6 subjects experienced DLTs (Gr 3 weakness, Gr 2 TCP with >2 week delay in second fraction). 8 patients were enrolled in an intermediate dose cohort (2.5) with 1 DLT (Gr 4 TCP). Two patients withdrew before the second dose (intercurrent illness; interruption of 225Ac supply). Most common low gr non-hematologic treatment emergent AEs: fatigue (95%), xerostomia (69%), and nausea (57%). Among evaluable patients for PSA change (n=22), 21 (95%) experienced PSA decline with 14 (67%) with decline of 50% and 6 (37%) with decline of 90%. 13/21 patients had CTCs samples collected at baseline and 12 wks; 5 were unfavorable at baseline (≥5/7.5 mL); 10/13 (77%) remained favorable or converted from unfavorable to favorable; 6/12 (50%) had 50% decline in CTC count; and 5/13 (38%) converted from detectable to undetectable. Conclusions: A single fractionated cycle of 225Ac-J591 was delivered with few high grade AEs and with evidence of preliminary efficacy by PSA and CTC changes across all dose levels. Citation Format: Jones T. Nauseef, Michael Sun, Charlene Thomas, Mahelia Bissassar, Escarleth Fernandez, Zachary Davidson, Amie Patel, Angela Tan, Tessa A. Chamberlain, Kara Earle, Rebecca Wunder, Sabrina Guervil, Sandra H. Castellanos, Judith Stangl-Kremser, Peter S. Gregos, Joseph R. Osborne, Karla V. Ballman, Ana M. Molina, Cora N. Sternberg, David M. Nanus, Neil H. Bander, Scott T. Tagawa. Phase I dose-escalation study of fractionated dose 225Ac J591 for metastatic castration resistant prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT014.

Background In preclinical Ewing sarcoma (ES) models, poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors were identified as a potential therapeutic strategy with synergy in combination with cytotoxic agents. This study evaluated the safety and dosing of the PARP1/2 inhibitor niraparib (NIR) with temozolomide (TMZ; arm 1) or irinotecan (IRN; arm 2) in patients with pretreated ES. Methods Eligible patients in arm 1 received continuous NIR daily and escalating TMZ (days 2‐6 [D2‐6]) in cohort A. Subsequent patients received intermittent NIR dosing (cohort B), with TMZ re‐escalation in cohort C. In arm 2, patients were assigned to NIR (days 1‐7 [D1‐7]) and escalating doses of IRN (D2‐6). Results From July 2014 to May 2018, 29 eligible patients (23 males and 6 females) were enrolled in arms 1 and 2, which had 7 dose levels combined. Five patients experienced at least 1 dose‐limiting toxicity (DLT) in arm 1 (grade 4 [G4] neutropenia for >7 days or G4 thrombocytopenia), and 3 patients experienced at least 1 DLT in arm 2 (grade 3 [G3] colitis, G3 anorexia, or G3 alanine aminotransferase elevation). The maximum tolerated dose was NIR at 200 mg every day on D1‐7 plus TMZ at 30 mg/m2 every day on D2‐6 (arm 1) or NIR at 100 mg every day on D1‐7 plus IRN at 20 mg/m2 every day on D2‐6 (arm 2). One confirmed partial response was observed in arm 2; the median progression‐free survival was 9.0 weeks (95% CI, 7.0‐10.1 weeks) and 16.3 weeks (95% CI, 5.1‐69.7 weeks) in arms 1 and 2, respectively. The median decrease in tumor poly(ADP‐ribose) activity was 89% (range, 83%‐98%). Conclusions The combination of NIR and TMZ or IRN was tolerable, but at lower doses in comparison with conventional cytotoxic combinations. A triple‐combination study of NIR, IRN, and TMZ has commenced., Preclinical evaluations have identified the EWS‐FLI1 translocation, pathognomonic of Ewing sarcoma, as a predictive factor of response to poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors with synergistic cell death in vivo with DNA damaging agents. This phase 1 study examines the dosing and safety of a combination of the PARP inhibitor niraparib with temozolomide or irinotecan.

The role of adjuvant therapy in renal cell carcinoma and urothelial carcinoma is rapidly evolving. To date, the U.S. Food and Drug Administration has approved sunitinib and pembrolizumab in the adjuvant setting for renal cell carcinoma and nivolumab for urothelial carcinoma based on disease-free survival benefit. The U.S. Food and Drug Administration held a joint workshop with the National Cancer Institute and the Society of Urologic Oncology in 2017 to harmonize design elements, including eligibility and radiologic assessments across adjuvant trials in renal cell carcinoma and urothelial carcinoma. Considerations from the discussion at these workshops led the U.S. Food and Drug Administration to draft guidances to help inform subsequent adjuvant trial design for renal cell carcinoma and urothelial carcinoma. Patient-centered decision-making is crucial when determining therapeutic choices in the adjuvant setting; utility functions can be used to help quantify each patient’s goals, values, and risk/benefit trade-offs to ensure that the decision regarding adjuvant therapy is informed by their preferences and the evolving outcomes data.

Statistical methods are essential in medical research. They are used for data analysis and drawing appropriate conclusions. Clarity and accuracy of statistical reporting in medical journals can enhance readers' understanding of the research conducted and the results obtained. In this manuscript, we provide guidelines for statistical reporting in medical journals for authors to consider, with a focus on the Journal of Thoracic Oncology.

Concurrent with the decrease in the number of men diagnosed with prostate cancer (PCa), the proportion of men with low-risk PCa managed conservatively (active surveillance or watchful waiting) has increased in the United States. We aimed to determine whether this increase is a result of more men being managed conservatively or rather a higher proportion of the diminishing number of low-risk PCa managed this way. The SEER “Prostate Watchful Waiting Database” identified men managed initially with conservative management between 2010 and 2016. Men > 40 years old who were diagnosed with low-risk (Gleason score 3 + 3, T1–T2a, PSA level

Epidermal Growth Factor Receptor variant III (EGFRvIII) is an active mutant form of EGFR that drives tumor growth in a subset of glioblastoma (GBM). It occurs in over 20% of GBMs, making it a promising receptor for small molecule targeted therapy. We hypothesize that poor penetration of the blood-brain barrier by previously tested EGFR-tyrosine kinase inhibitors (EGFR-TKIs) such as afateninb, erlotinib, gefitinib, and lapatinib played a role in their limited efficacy. The present study examined the effects of osimertinib (previously known as AZD9291) on EGFRvIII+ GBM models, both in vitro and in vivo. Therefore, a panel of six GBM stem cells (GSCs) expressing EGFRvIII+ was evaluated. The EGFRvIII+ GSC differed in the expression of EGFRvIII and other key genes. The GSC line D317, which expresses high levels of EGFRvIII and has robust tyrosine kinase activity, was selected for assessing osimertinib’s efficacy. Herein, we report that osimertinib inhibits the constitutive activity of EGFRvIII tyrosine kinase with high potency (

Background The optimal radiation dose for adult supratentorial low-grade glioma is unknown. The aim of this study was to provide a final update on oncologic and cognitive outcomes of high-dose versus low-dose radiation for low-grade glioma. Methods Between 1986 and 1994, 203 patients with supratentorial low-grade glioma were randomized (1:1) to 50.4 Gy in 28 fractions versus 64.8 Gy in 36 fractions after any degree of resection. Results For all patients, median overall survival (OS) was 8.4 years (95% CI: 7.2–10.8). Median progression-free survival (PFS) was 5.2 years (95% CI: 4.3–6.6). Median follow-up is 17.2 years for the 33 patients still alive. High-dose radiation did not improve 15-year OS (22.4%) versus low-dose radiation (24.9%, log-rank P = 0.978) or 15-year PFS (high dose, 15.2% vs low dose, 9.5%; P = 0.7142). OS was significantly better for patients with preoperative tumor diameter 27 and who underwent gross total resection. PFS was improved for patients with oligodendroglioma versus astrocytoma, preoperative tumor diameter 27. For patients who had normal MMSE at baseline, at 7 years only 1 patient (5%) had a clinically significant decrease in MMSE from the previous time point, with the remainder (95%) stable. None had decrease in MMSE at 10, 12, or 15 years. Conclusions Long-term follow-up indicates no benefit to high-dose over low-dose radiation for low-grade gliomas. Cognitive function appeared to be stable after radiation as measured by MMSE.

Objective To demonstrate feasibility of performing geriatric assessment (GA) in the National Clinical Trials Network (NCTN) and to explore the utility of GA to characterize treatment tolerance. Materials and methods We conducted a multisite companion study (CALGB 361006) to CALGB 11001, a phase 2 trial of adults ≥60 years old with newly diagnosed FLT3- mutated AML, testing the efficacy of adding sorafenib to intensive chemotherapy. On 361006, a GA was administered prior to induction and prior to post-remission therapy. The GA is divided into items requiring administration by a health care professional (HCP) and patient self-administered questionnaires. Feasibility outcomes were recruitment rate, time to GA completion, difficulty with GA administration, percent of patients requiring assistance, and satisfaction. Change in GA measures pre- and post-induction were compared using Wilcoxon signed rank test and McNemar's tests. Results The recruitment rate was 80% (N = 43, median age 68 years). Median completion time of the GA was 30 min; (10 and 21 min for HCP and patients, respectively). HCP reported no difficulty completing assessments (100%). Most patients completed questionnaires without assistance (77%), and were satisfied with the length (89%). Self-reported physical function, mental health, social activity and nutritional parameters worsened after induction. Conclusion GA is feasible to administer in the setting of intensive induction for older adults with AML in the NCTN and provides evidence of the impact of induction therapy on physical and emotional health.

TPS288 Background: As prostate-specific membrane antigen targeted radiotherapy (PSMA-TRT) is now an active standard-of-care treatment in mCRPC, ongoing studies with alternative approaches to targeting PSMA will increasingly need to consider the consequences of sequential PSMA-TRT exposure. Our past and ongoing investigations into antibody-based targeting (e.g., J591) and potent alpha emitting payloads (e.g., 225Ac) impact drug kinetics, biodistribution, and resultant clinical toxicities. In a first-in-human phase I dose-escalation study of 225Ac-J591, patients with mCRPC were treated with a single dose of 225Ac-J591 on seven dose levels, up to 93.3 KBq/kg without achievement of maximal tolerated dose (MTD). One patient treated at 80 KBq/kg developed dose-limiting toxicity (DLT) of Gr 4 anemia and thrombocytopenia, but 0 of 6 at 93.3 KBq/Kg had Gr > 3 heme toxicity or Gr > 2 non-heme toxicity. Although not intentionally preselected for prior exposure, 55% (12/22) of patients had 177Lu-PSMA previously. With approval of 177Lu vipivotide tetraxetan, we amended an ongoing phase I dose-escalation study to include a post-177-Lu-PSMA cohort. Methods: Entry criteria include progressive mCRPC by PCWG3 criteria, ECOG PS 0-2, intact organ function, and prior receipt of AR pathway inhibitor and chemotherapy (or refused/ineligible). There is no limit to prior lines of therapy except alpha-emitting therapies (i.e., PSMA-TRT, 223Ra) and in this amended dose-escalation cohort, all patients must have had prior treatment with 177Lu-PSMA. Treatment will be given in a single fractionated cycle of 225Ac-J591 administered on D1 and D15. The phase I component is a 3+3 dose-escalation study design with up to 18 patients, with the goal of identifying MTD. The phase II component will include up to 16-19 patients in a Simon 2-stage design with 90% power to exclude the null hypothesis (35% or fewer patients with PSA50). Eligible men with negative PSMA PET scans will be offered treatment with informed consent in an exploratory subgroup but will not be counted towards phase II efficacy. Secondary outcomes include radiographic response by PCWG3-modified RECIST 1.1 criteria and PSMA PET, biochemical and radiographic progression-free survival, circulating tumor cell counts, and overall survival. Patient reported outcomes, genomic, and immune analyses are exploratory. Enrollment to the post-177Lu-PSMA cohort began in August 2022. Clinical trial information: NCT04506567 .

LBA21 Background: Up to 1/3 of pts develop biochemical relapse following primary therapy. Many are not cured with salvage local therapy, likely because of undetectable distant disease. PSMA is expressed on most PC and can be targeted by radiolabeled J591. 177Lu is a predominantly β-emitting radionuclide and also has γ emission which allows imaging. 111In is predominantly a γ emitter, also with some auger emission for therapy. Hormonal therapy is effective and may increase PSMA expression and radiosensitize. In this DOD-funded study initiated in the pre-PSMA PET and AR signaling inhibitor era, we hypothesized that 177Lu prolongs 18-month (mo) met-free survival (MFS) more than 111In in pts with high risk, M0 CRPC when targeting PSMA via J591 in combo with keto and HC. Methods: Pts with high-risk M0 CRPC defined by PSA DT < 8 mo and/or absolute PSA > 20 ng/mL and serum testosterone < 50 ng/mL with no evidence of metastatic disease on CT/MRI and bone scan were eligible. Treatment included a minimum 4 week lead-in with keto 400 mg TID and HC 20 mg AM, 10 mg PM (both of which could be continued until unacceptable toxicity or development of mets) and a single infusion of J591 with 2:1 randomization to 177Lu (70 mCi/m2) or 111In (5 mCi) in double-blinded fashion. The final version of the protocol was designed to randomize 55 pts for 80% power to detect a difference in 18-mo MFS with one-sided alpha of 10%. Secondary endpoints include median MFS, PSA response, overall survival, and toxicity. Results: 55 pts with median age 68 (range 52 - 88), 75% prostatectomy, 23% primary radiation, 2% primary ADT; 19% local salvage therapy. Median PSA doubling time 3 mo (range 0.87 – 7.85), median baseline PSA 8.0 (range 1-78). In intent to treat analysis (5 without imaging and 4 lost to follow up by 18 mo), 50% developed mets by 18 mo with 177Lu vs 76% with 111In (p=0.066). Median MFS was 23.8 mo vs 20.8 mo, and biochemical PFS was 18.67 vs 8.87 mo, favoring 177Lu in analyses censoring start of new treatment. Confirmed >50% PSA decline occurred in 82% with 177Lu and 71% with 111In. Grade >3 heme AEs were more common with 177Lu vs 111In, including neutropenia (57% vs 11%, with 1 febrile neutropenia) and thrombocytopenia (77% vs 11%, with 25% vs 6% platelet transfusions), whereas Gr >3 non-heme AEs were less common with 177Lu vs 111In, including abdominal pain (0 vs 11%), ALT increase (3.3% vs 22%), and diarrhea (0 vs 22%). Conclusions: Anti-PSMA mAb J591 with keto/HC when radiolabeled with 177Lu leads to improved 18-month met-free survival vs 111In. Most pts had significant PSA decline with either version of radiolabeled J591 with keto/HC. Hematologic toxicity is more common with 177Lu. This supports the development of anti-PSMA radioimmunotherapy for low volume advanced PC, though the optimal radionuclide and targeting agent is unknown. Clinical trial information: NCT00859781 .

TPS589 Background: In patients (pts) with metastatic unresectable urothelial cancer, platinum-based chemotherapy remains the standard of care for first-line treatment followed by switch maintenance avelumab if disease control is achieved with chemotherapy. Outside of this setting, single agent immunotherapy is often used in pts that have recurrence after platinum-based chemotherapy or are platinum ineligible. Atezolizumab is a PD-L1 inhibitor currently approved for pts that have urothelial cancers expressing positive PD-L1 or pts ineligible for receiving platinum-based chemotherapy. Tumor-targeted radiotherapy can generate immune-stimulating effects without immune suppression as was previously thought. Moreover, it has become clear that radiotherapy can induce profound effects on tumor cells and the tumor microenvironment that can enhance or trigger an anticancer immune response. While numerous trials have investigated the abscopal effect, this trial will have specific parameters regarding drug type, radiation dose and administration. Methods: A032002 is a phase 2 trial addressing pts that are platinum ineligible or refractory to platinum-based chemotherapy. 144 pts will be randomized to receive either atezolizumab or atezolizumab and single site radiation therapy. The atezolizumab regimen is 1200 mg every 3 weeks. Administration of radiotherapy will occur to one non-target site (8 Gy x 3) for pts randomized to the atezolizumab + radiotherapy arm. All pts will undergo centralized PD-L1 testing (SP142 monoclonal primary antibody), which can be performed on archival tissue; a new biopsy is only required if no archival tissue is available. Key eligibility criteria include age ≥ 18 years, ECOG performance status 0-2, histologically confirmed metastatic urothelial cancer, having at least one measurable site per RECIST 1.1 to monitor for abscopal response, one site targetable for radiation, and tissue available for PD-L1 testing. The primary endpoint is tumor response within 6 months of randomization. Tumor response is defined as a complete response (CR) or partial response (PR) as assessed by the treating physician using RECIST 1.1 criteria. For a one-sided log rank test with a type 1 error rateof 0.10, the study has 90% power to detect a 20% increase in response rate. Key secondary endpoints include tumor response using iRECIST, progression-free survival and overall survival. Quality of life assessments include EORTC QLQ-C30, QLQ-BLM30 and PROMIS-Fatigue. Tissue, urine and blood samples will be collected and biobanked for future correlative science. Enrollment to ART began in December 2021. The study is available for participation at all US NCTN sites with a projected enrollment of 3 years. Support: U10CA180821, U10CA180882. Clinical trial information: NCT04936230 .

TPS403 Background: The objective of the RTIRE clinical trial (NCT05345444) is to demonstrate the feasibility, safety, and early oncologic efficacy of combining MRI-guided stereotactic body radiation therapy (MRgSBRT) with irreversible electroporation (IRE) for men with intermediate-risk localized prostate cancer. Methods: Inclusion criteria: 1) Men aged ≥18, 2) ECOG 0 –1, 3) Histologically confirmed intermediate risk prostate cancer per NCCN guidelines, 4) Focal grade group 2 (GG2) or 3 (GG3) cancer in multi-parametric magnetic resonance imaging (mpMRI) target, 5) Gland size < 80cc, 6) Ability to undergo IRE, 7) Ability to receive MRI-guided SBRT, 8) Ability to complete the HRQOL assessment surveys, 9) Willingness to undergo 12 month follow up biopsy. Exclusion criteria: 1) Prior TURP, 2) Prior history of focal therapy, 3) Prior history of receiving pelvic radiotherapy, 4) Patient with history of inflammatory bowel disease, 5) History of bladder neck or urethral stricture. Study Design/Endpoints: This is a feasibility and safety study assessing the ability to perform IRE followed by real-time MRgSBRT. Subjects will undergo focal IRE followed by MRgSBRT (>6 weeks after IRE) to the prostate +/- seminal vesicles prescribed to 32.5 Gy in 5 fractions. The primary endpoint of the first portion of the trial is feasibility, defined as at least 80% of subjects (8 of 10 subjects) undergoing assessment at 12-weeks post-IRE and at 6-weeks post-MRgSBRT within 1 year from enrollment of the first subject. The expansion phase will include an additional 40 subjects to assess side effect profile and early oncologic efficacy (n=50) at 12 months post RTIRE. RTIRE has enrolled 8 subjects in 3 months and will proceed to the expansion phase. Secondary endpoints include: 1) short-term safety as measured by treatment-related adverse events, 2) oncologic efficacy as measured by number of subjects with presence of ≥GG2 cancer at 12 months post-RTIRE therapy, 3) health-related quality of life (HRQOL) as measured by Expanded Prostate Cancer Index Composite for Clinical Practice (EPIC-CP), International Prostate Symptom Score (IPSS), International Index of Erectile Function (IIEF-5) 4) post-RTIRE prostate-specific antigen (PSA) kinetics including time to PSA nadir and post-nadir PSA stability, 5) assessment of pre and post-RTIRE mpMRI changes to evaluate the area of necrosis and presence of residual tissue, 6) rates of biochemical and clinical progression and the need for secondary or adjuvant treatment following RTIRE. Clinical trial information: NCT05345444 .

ImportanceLong-term outcomes of radiotherapy are important in understanding the risks and benefits of therapies for patients with brain metastases.ObjectiveTo determine how the use of postoperative whole-brain radiotherapy (WBRT) or stereotactic radiosurgery (SRS) is associated with quality of life (QOL), cognitive function, and intracranial tumor control in long-term survivors with 1 to 4 brain metastases.Design, Setting, and ParticipantsThis secondary analysis of a randomized phase 3 clinical trial included 48 institutions in the US and Canada. Adult patients with 1 resected brain metastases but limited to those with 1 to 4 brain metastasis were eligible. Unresected metastases were treated with SRS. Long-term survivors were defined as evaluable patients who lived longer than 1 year from randomization. Patients were recruited between July 2011 and December 2015, and data were first analyzed in February 2017. For the present study, intracranial tumor control, cognitive deterioration, QOL, and cognitive outcomes were measured in evaluable patients who were alive at 12 months from randomization and reanalyzed in June 2017.InterventionsStereotactic radiosurgery or WBRT.Main Outcomes and MeasuresIntracranial tumor control, toxic effects, cognitive deterioration, and QOL.ResultsFifty-four patients (27 SRS arm, 27 WBRT arm; female to male ratio, 65% vs 35%) were included for analysis with a median follow-up of 23.8 months. Cognitive deterioration was less frequent with SRS (37%-60%) compared with WBRT (75%-91%) at all time points. More patients declined by 2 or more standard deviations (SDs) in 1 or more cognitive tests for WBRT compared with SRS at 3, 6, and 9 months (70% vs 22%, 46% vs 19%, and 50% vs 20%, respectively). A 2 SD decline in at least 2 cognitive tests was associated with worse 12-month QOL in emotional well-being, functional well-being, general, additional concerns, and total scores. Overall QOL and functional independence favored SRS alone for categorical change at all time points. Total intracranial control for SRS alone vs WBRT at 12 months was 40.7% vs 81.5% (difference, −40.7; 95% CI, −68.1% to −13.4%), respectively. Data were first analyzed in February 2017.Conclusions and RelevanceThe use of SRS alone compared with WBRT resulted in less cognitive deterioration among long-term survivors. The association of late cognitive deterioration with WBRT was clinically meaningful. A significant decline in cognition (2 SD) was associated with overall QOL. However, intracranial tumor control was improved with WBRT. This study provides detailed insight into cognitive function over time in this patient population.Trial RegistrationClinicalTrials.gov Identifier: NCT01372774; ALLIANCE/CCTG: N107C/CEC.3 (Alliance for Clinical Trials in Oncology/Canadian Cancer Trials Group)

Purpose: We sought to determine whether the detection of circulating tumor DNA (ctDNA) in samples of patients undergoing chemotherapy for advanced leiomyosarcoma (LMS) is associated with objective response or survival. Experimental Design: Using ultra–low-passage whole-genome sequencing (ULP-WGS) of plasma cell-free DNA from patients treated on a prospective clinical trial, we tested whether detection of ctDNA evaluated prior to the start of therapy and after two cycles of chemotherapy was associated with treatment response and outcome. Associations between detection of ctDNA and pathologic measures of disease burden were evaluated. Results: We found that ctDNA was detectable by ULP-WGS in 49% patients prior to treatment and in 24.6% patients after two cycles of chemotherapy. Detection of pretreatment ctDNA was significantly associated with a lower overall survival [HR, 1.55; 95% confidence interval (CI), 1.03–2.31; P = 0.03] and a significantly lower likelihood of objective response [odds ratio (OR), 0.21; 95% CI, 0.06–0.59; P = 0.005]. After two cycles of chemotherapy, patients who continued to have detectable levels of ctDNA experienced a significantly worse overall survival (HR, 1.77; 95% CI, 1–3.14; P = 0.05) and were unlikely to experience an objective response (OR, 0.05; 95% CI, 0–0.39; P = 0.001). Conclusions: Our results demonstrate that detection of ctDNA is associated with outcome and objective response to chemotherapy in patients with advanced LMS. These results suggest that liquid biopsy assays could be used to inform treatment decisions by recognizing patients who are likely and unlikely to benefit from chemotherapy. See related commentary by Kasper and Wilky, p. 2480

INTRODUCTION AND OBJECTIVE:Early infant male circumcision (EIMC) is expected to help reduce HIV incidence and transmission given the compelling evidence in adults and adolescents. The ShangRing (SR...

This report describes the rationale, purpose and design of A011801 (CompassHER2 RD), an ongoing prospective, multicenter, Phase III randomized trial. Eligible patients in the United States (US) and Canada with high-risk (defined as ER-negative and/or node-positive) HER2-positive (HER2+) residual disease (RD) after a predefined course of neoadjuvant chemotherapy and HER2-directed treatment are randomized 1:1 to adjuvant T-DM1 and placebo, versus T-DM1 and tucatinib. Patients have also received adjuvant radiotherapy and/or endocrine therapy, if indicated per standard of care guidelines. The primary objective of the trial is to determine if the invasive disease-free survival (iDFS) with T-DM1 plus tucatinib is superior to iDFS with T-DM1 plus placebo; other outcomes of interest include overall survival (OS), breast cancer-free survival (BCFS), distant recurrence-free survival (DRFS), brain metastases-free survival (BMFS) and disease-free survival (DFS). Correlative biomarker, quality of life (QoL) and pharmacokinetic (PK) end points are also evaluated.Lay abstract In this research study (A011801; CompassHER2 RD), patients with early stage HER2-positive breast cancer who already received treatment with chemotherapy and anti-HER2 targeted therapies followed by surgery are mainly enrolled. If cancer is still present in the breast and/or lymph nodes at the time of surgery, there is a higher risk of a recurrence in the future, and enrollment on A011801 is an option. Usually, if there is tumor remaining after chemotherapy and anti-HER2 targeted therapies, the main treatment is the use of an FDA-approved intravenous drug called T-DM1. Additional treatment may also include radiotherapy and/or medications to block the activity of estrogen. The usual treatment approach reduces the likelihood of breast cancer recurring in the future. This study has been performed to answer the following question: Is the combination of T-DM1 and a newer drug tucatinib better than usual treatment with T-DM1 alone at preventing cancer from returning? Study participants will receive treatment with T-DM1 and placebo (a pill that looks like the study drug but contains no medication) or T-DM1 and tucatinib, for up to 14 cycles, unless their breast cancer returns or the side effects become too severe. Research bloods are taken on study along with standard blood work, and we also request a stored tumor sample from the original biopsy and from the breast cancer surgery for research purposes. Optional Quality of Life Questionnaires are also included in the trial. After the study, participants finish T-DM1 and placebo, or T-DM1 and tucatinib, and their doctor will continue to follow their condition with clinic visits every 6 months for 10 years and watch for side effects and for signs of breast cancer recurring.

INTRODUCTION AND OBJECTIVE:Early infant male circumcision (EIMC) efforts can help reduce the global burden of Human Immunodeficiency Virus (HIV). However, a shortage of highly trained providers has...

Quantitation of androgen receptor variant (AR-V) expression in circulating tumor cells (CTCs) from patients with metastatic castration-resistant prostate cancer (mCRPC) has great potential for treatment customization. However, the absence of a uniform CTC isolation platform and consensus on an analytical assay has prevented the incorporation of these measurements in routine clinical practice. Here, we present a single-CTC sensitive digital droplet PCR (ddPCR) assay for the quantitation of the two most common AR-Vs, AR-V7, and AR-v567es, using antigen agnostic CTC enrichment. In a cohort of 29 mCRPC patients, we identify AR-V7 in 66% and AR-v567es in 52% of patients. These results are corroborated using another gene expression platform (NanoStringTM) and by analysis of RNA-Seq data from patients with mCRPC (SU2C- PCF Dream Team). We next quantify AR-V expression in matching EpCAM-positive vs EpCAM-negative CTCs, as EpCAM-based CTC enrichment is commonly used. We identify lower AR-V prevalence in the EpCAM-positive fraction, suggesting that EpCAM-based CTC enrichment likely underestimates AR-V prevalence. Lastly, using single CTC analysis we identify enrichment for AR-v567es in patients with neuroendocrine prostate cancer (NEPC) indicating that AR-v567es may be involved in lineage plasticity, which warrants further mechanistic interrogation., Ada Gjyrezi et al. show that ddPCR can be used to accurately measure androgen receptor variant (AR-V) expression levels in single circulating tumor cells (CTCs) from prostate cancer patients. They show that current methods for isolating CTCs tend to underestimate the prevalence of AR-V and that a specific variant, AR-v567es, could be potentially used as a biomarker for an aggressive subtype of prostate cancer.

PURPOSE Historically, multiple ipsilateral breast cancer (MIBC) has been a contraindication to breast-conserving therapy. We report the feasibility of radiation therapy (RT) after breast-conserving therapy in MIBC from the Alliance Z11102 trial. METHODS AND MATERIALS Delineation of targets and organs at risk was performed according to the Radiation Therapy Oncology Group contouring consensus definitions. RT was delivered to the whole breast to 45 to 50 Gy in standard daily fractions of 1.8 to 2.0 Gy. A boost of 10 to 16 Gy in 2.0-Gy daily fractions to each tumor bed was mandatory. RESULTS A total of 236 eligible patients were enrolled in the study between July 23, 2012 and August 19, 2016. Of those, 195 (83%) completed RT. No patient underwent mastectomy for failure to meet the RT dose constraints. Higher absolute boost volume was associated with increased incidence of grade 2 or higher dermatitis (odds ratio, 1.21; 95% confidence interval, 1.04-1.41; P = .014). Higher relative boost volume as a percentage of the overall breast volume was not associated with increased dermatitis. Neither absolute nor relative boost volume appeared to significantly influence overall cosmesis. CONCLUSIONS Breast conservation followed by whole breast RT plus boost to each tumor bed was feasible in the majority of patients with MIBC. Increasing radiation boost volume was associated with increased incidence of acute dermatitis, but was not associated with worse overall cosmesis.

Background Parkinson's disease (PD) is associated with α-synuclein (αS) aggregation within the enteric nervous system (ENS) and constipation. Squalamine displaces proteins that are electrostatically bound to intracellular membranes and through this mechanism suppresses aggregation of αS monomers into neurotoxic oligomers. Objective We sought to evaluate the safety of ENT-01 oral tablets (a synthetic squalamine salt), its pharmacokinetics, and its effect on bowel function in PD patients with constipation. Methods In Stage 1, 10 patients received escalating single doses from 25 to 200 mg/day or maximum tolerated dose (MTD). In Stage 2, 34 patients received daily doses escalating from 75 to a maximum of 250 mg/day, a dose that induced change in bowel function or MTD, followed by a fixed dose for 7 days, and a 2-week washout. Primary efficacy endpoint was defined as an increase of 1 complete spontaneous bowel movement (CSBM)/week, or 3 CSBM/week over the baseline period, as defined by FDA guidelines for prokinetic agents. Safety was also assessed. Results Over 80% of patients achieved the primary efficacy endpoint, with the mean number of CSBM/week increasing from 1.2 at baseline to 3.6 during fixed dosing (p = 1.2 × 10−7). Common adverse events included nausea in 21/44 (47%) and diarrhea in 18/44 (40%) patients. Systemic absorption was Conclusions Orally administered ENT-01 was safe and significantly improved bowel function in PD, suggesting that the ENS is not irreversibly damaged in PD. Minimal systemic absorption suggests that improvements result from local stimulation of the ENS. A double-blind, placebo-controlled study is now ongoing.

PURPOSE/OBJECTIVE(S) Post-operative spine SBRT presents unique clinical challenges. Spinal hardware produces CT and high-field strength MRI artifacts that obscure visualization of the spinal cord and unresected disease. Existing workflows incorporate additional invasive procedures with CT myelogram and quality control for these procedures can introduce uncertainty into SBRT planning. Reducing metallic imaging artifact with a low-field strength (0.35 T) MRI integrated into a MR-Linac (MRL) may facilitate superior visualization of the spinal cord, improved target delineation and treatment localization. The primary objective is to determine the feasibility of MRL-based simulation workflow to facilitate MR-guided post-operative spine SBRT without the need for CT myelogram or CT-based target delineation. MATERIALS/METHODS A single-institution, single-arm interventional feasibility study is planned. A total of 10 patients who underwent surgical resection of solid tumor spinal metastases with an indication for post-operative SBRT will be enrolled and undergo radiation planning and treatment on a MRL platform that combines a 6MV Linac and 0.35 T on-board MRI system. Enrolled subjects will undergo CT and MR simulation followed by standard-of-care post-operative spine SBRT and follow-up spine imaging every 3 months. RESULTS The primary endpoint is feasibility of MR-guided post-operative spine SBRT without CT myelogram. Feasibility is defined as > 70% of participants with clinically acceptable visualization/delineation as determined by blinded dual neuroradiologist review for clinically acceptable visualization/delineation of organs-at-risk (OARs) and target volume(s). Exploratory endpoints involve radiation dosimetry analysis of OARs and target volumes as well as documenting the use of adaptive planning. Radiation site progression-free survival will be recorded at 6-months after SBRT. CONCLUSION If feasible, an MRL-based workflow for post-operative spine SBRT represents a patient-centric approach to improve efficiency, minimize treatment delays, and avoid invasive procedures that may improve clinical management of solid tumor spinal metastases.

Background: Previous studies have demonstrated poorer survival of Black women with breast cancer. We assessed whether race/ethnicity was associated with disease-free (DFS) and overall survival (OS) among women with breast cancer enrolled in clinical trials for early-stage breast cancer according to tumor subtype, age, and body mass index (BMI). Methods: 10,011 women enrolled in one of four adjuvant chemotherapy trials: CALGB 9741, CALGB 49907, CALGB 40101, or NCCTG N9831. 9918 participants had available DFS and/or OS data and were included in the analysis. Cox models were used to estimate multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between race/ethnicity and DFS and OS. We compared Non-Hispanic (NH) Black (n=871), Hispanic (n=436), and other race participants (n=283) to NH Whites (n=7889). We assessed associations within strata of age group ( Results: In multivariable-adjusted models, NH Black patients under 50 years of age had worse DFS compared to NH White patients (HR: 1.34, 95% CI: 1.10-1.62) and worse OS (HR: 1.64, 95% CI: 1.30-2.07). The differences in DFS and OS persisted in patients ages 50 to Conclusions: Our results identified subgroups that may contribute to the observed disparities in survival between NH Black and NH White women with early-stage breast cancer. The greatest disparities are among individuals Support: U10CA180821 and U10CA180882; ClinicalTrials.gov Identifiers: NCT00003088, NCT00005970, NCT00024102, NCT00041119; https://acknowledgments.alliancefound.org Citation Format: Marla Lipsyc-Sharf, Karla V. Ballman, Jordan D. Campbell, Hyman B. Muss, Edith A. Perez, Lawrence N. Shulman, Lisa A. Carey, Ann H. Partridge, Erica T. Warner. Role of age, BMI, and tumor subtype in racial/ethnic disparities in breast cancer survival: A pooled analysis of four Alliance adjuvant clinical trials [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 494.

Previous studies have suggested liquid biopsy may be a useful prognostic biomarker for patients with leiomyosarcoma (LMS) but this has never been tested prospectively in a patient cohort receiving uniform therapy. We sought to determine whether the detection of circulating tumor DNA (ctDNA) in samples of patients undergoing chemotherapy for advanced leiomyosarcoma (LMS) is associated with objective response or survival. Our cohort consisted of 98 patients treated on the SARC021 trial, an open-label, randomized, phase 3, multicenter trial testing the efficacy of adding evofosfamide to doxorubicin compared to treatment with doxorubicin alone for patients with advanced soft-tissue sarcomas. Using ultra-low passage whole genome sequencing of plasma cell-free DNA we tested whether detection of ctDNA evaluated prior to the start of therapy and after 2 cycles of chemotherapy were associated with treatment response and outcome. Associations between detection of ctDNA and pathological measures of disease burden were evaluated. Kaplan Meier curves were used to estimate survival in patients with or without detectable ctDNA and the log-rank test was used to estimate the significance of the difference between these two groups. We also tested for an association between disease response, stage and number of metastatic sites with the presence or absence of ctDNA with Fisher’s exact test and with ctDNA levels by Student t test. We found that ctDNA was detectable by ULP-WGS in 49% of patients prior to treatment and in 24.6% patients after two cycles of chemotherapy. Detection of pre-treatment ctDNA was associated with a lower overall survival (hazard ratio [HR] = 1.55; 95% CI: 1.03 - 2.31; p=0.03) and a lower likelihood of objective response (odds ratio [OR] = 0.21; 95% CI: 0.06 - 0.59; p=0.005). After two cycles of chemotherapy, patients who continued to have detectable levels of ctDNA experienced a significantly worse overall survival (HR=1.77; 95% CI: 1 - 3.14; p=0.05) and were unlikely to experience an objective response (OR=0.05; 95% CI: 0 - 0.39; p=0.001). We found that detectable levels of ctDNA prior to the start of treatment was significantly associated with patients who had primary tumors measuring greater than 10 cm (75% versus 28%, respectively; p < 0.001), and had more than 5 sites of metastatic disease (73.9% versus 26.1%, respectively; p < 0.001). Detection of ctDNA is associated with outcome and objective response to chemotherapy in patients with advanced LMS. These results suggest that liquid biopsy assays could be used to inform treatment decisions by recognizing patients who are likely and unlikely to benefit from chemotherapy.Ongoing work focuses on identification of ctDNA features, such as copy-number alterations or changes in ctDNA levels over time, that may also be associated with disease progression or response to therapy. Citation Format: Laura Madanat-Harjuoja, Kelly Klega, Yao Lu, David S. Shulman, Aaron R. Thorner, Anwesha Nag, William Tap, Denise K. Reinke, Lisa Diller, Karla V. Ballman, Suzanne George, Brian D. Crompton. Circulating tumor DNA is associated with response and survival in patients with advanced leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3407.

TPS4607 Background: First-line platinum-based chemotherapy followed by maintenance avelumab (Av) is the current preferred standard of care in patients (pts) with mUC who do not progress after platinum-based chemotherapy. There is an unmet need to further improve outcomes by combining Av with an effective, non-cross resistant therapy with non-overlapping toxicity. Cabozantinib (CABO) is an oral inhibitor of MET, VEGFR and TAM family receptors involved in tumor growth, angiogenesis and immune cell regulation and has shown efficacy in UC in combination with PD-1/PD-1L1 inhibitors. We hypothesize that CABO-Av combination will be synergistic in pts with mUC with an acceptable safety profile and will improve upon the benefit seen with Av maintenance in mUC. Methods: MAIN-CAV is a phase III randomized, multicenter, international trial for locally advanced/mUC pts (including N3 only disease) who do not progress after 4-6 cycles of any platinum-based chemotherapy (gem-cis, gem-carbo, MVAC or ddMVAC). 654 adult pts will be randomized 1:1 within 3-10 weeks (wk) after last dose of chemotherapy to receive Av 800 mg IV every 2 wk or combination of Av and CABO 40 mg orally daily for up to 2 yrs. Key eligibility criteria include ECOG PS 0-1, no prior use of immunotherapy (exception of BCG), no central nervous system metastases, no major surgery within 4 wk, no uncontrolled hypertension or cardiovascular disorders. Pts will be stratified based on 1) best response to 1L therapy: complete response vs partial response vs stable disease and 2) presence or absence of visceral metastases. The primary endpoint is overall survival (OS) with assumptions of one-sided alpha of 0.025, power of 80%, median OS of 21 months (mo) on Av arm and hazard ratio (HR) of 0.75, thus hypothesizing a median OS of 28 mo on CABO-Av combination arm. Key secondary endpoints include progression-free survival, safety, tolerability, and activity of CABO-Av compared to Av alone based on RECIST 1.1 and iRECIST criteria and PD-L1 status of pts’ tumors. Quality of life (QOL) will be assessed using EQ-5D-5L, PROMIS-Fatigue 4a, EORTC QLQ-C30, EORTC QLQ-BLM30 between pts on CABO-avelumab vs avelumab alone. Biomarkers of response and resistance to Av will be assessed using baseline archival tissues, baseline and serial blood, ctDNA, stool and urine. Imaging studies will test correlation of established and new radiomic signatures with OS, adverse events and QOL and incorporate both radiologic and biologic features to predict outcomes. This trial would be the first to systematically address whether adding a multitargeted TKI, CABO to Av leads to improved clinical outcomes compared to Av alone. Support: U10CA180821, U10CA180882, U24CA196171,U10CA180863 (CCTG); Clinical trial information: NCT05092958.

2001 Background: PolyADP-ribose polymerase (PARP) is an important modulator of DNA repair following temozolomide (TMZ) therapy. Pre-clinical testing demonstrated significant survival benefit for the combination of TMZ and PARP inhibitor veliparib in a subset of GBM pt-derived xenografts with MGMT promoter hypermethylation. Methods: After central pathology review and MGMT testing, patients (pts) with newly diagnosed, MGMT promoter hypermethylated GBM who had completed concurrent radiation and TMZ were randomized to adjuvant therapy with TMZ (Days 1-5 q28 days) combined with either placebo or veliparib (Days 1-7 q28 days). Veliparib/placebo+TMZ treatment was continued for up to 6 cycles. Pts accrued on the phase II and III portions of the trial were included in the primary endpoint analysis of overall survival (OS), with 90% power to detect a hazard ratio of 0.71 using a one-sided log-rank test with type I error rate of 0.05. The planned phase III sample size was 400 pts with data maturity after 302 deaths. Results: The phase II and III portions of the trial were open to accrual from 12/15/2014 to 2/6/2017 and 11/8/2017 to 10/15/2018, respectively; 447 pts were accrued to the trial and used in this intention to treat analysis. The two treatment groups were well balanced for prognostic factors, 421 pts initiated treatment, median follow-up was 57.8 months (mos), 380 pts had disease progression and 335 pts have died. There was no difference in OS (p = 0.15; HR 0.89 (0.71-1.11), median OS 28.1 vs. 24.8 mo. for TMZ+veliparib vs. TMZ+placebo, respectively) and no difference in secondary endpoint progression free survival (PFS, p = 0.31; HR 1.05 (0.86-1.30), median 13.2 vs. 12.1 mo, respectively). There was a notable trend for extended OS with TMZ+veliparib treatment at intermediate time-points between 24 and 42 mos (3-year OS 36.6% vs. 28.9% with TMZ+placebo, p = 0.09). In an unplanned exploratory analysis, treatment with TMZ at the time of first recurrence was associated with extended post-recurrence OS (p = 0.03) for pts treated on the experimental arm; median post-recurrence OS with TMZ salvage was 17.0 mo in the TMZ+veliparib arm and 12.6 mo in the TMZ+placebo arm, as compared to 9.6 mo in either arm if TMZ salvage was not used. These data are consistent with a possible effect of veliparib limiting the emergence of TMZ resistance in a subset of GBM pts. Conclusions: Veliparib combined with adjuvant TMZ therapy was not associated with significant extension in OS or PFS in newly diagnosed, MGMT hypermethylated GBM pts. However, a subset of pts treated with TMZ+veliparib may have an extended survival following re-treatment with TMZ at first recurrence. Clinical trial information: NCT02152982.

4521 Background: Platinum-based chemotherapy is the standard 1st-line therapy for metastatic urothelial cancer (mUC). C90601 was a randomized phase III trial testing gemcitabine and cisplatin (GC) with bevacizumab (B) or placebo (P) in patients (pts) with untreated mUC. Median overall survival (OS) for GCB vs GCP was 14.5 months (mo) vs 14.3 mo (p=0.14) and median progression-free survival (PFS) was 8 vs 6.7 mo, respectively. DDR mts have been implicated in response and survival in mUC and were investigated in this negative trial. Methods: C90601 enrolled 506 pts randomized 1:1 to GCB or GCP from 7/15/09-12/2/14, with stratification for prior chemotherapy and visceral metastases. Consenting pts submitted archival FFPE tumor specimens and blood for matched germline (g)DNA. Tumor and gDNA were sequenced by MSK-IMPACT, a 468-gene exon capture assay, to detect mts in select DDR genes. The proportional hazards model was used to correlate mts in the DNA helicase ERCC2 (pre-specified hypothesis) and additional DDR gene panels being explored in prospective trials in muscle-invasive disease with OS and PFS, adjusting for tumor mt burden and stratification factors. Mts were categorized as deleterious (del) or non-del using pre-defined published criteria. Results: 208 pts underwent DNA sequencing. Clinical features and PFS/OS were comparable to the 506-pt cohort. Median sequencing coverage was 497X. Median mutation count was 13.2 and 8.8 for DDR mt and wild-type tumors, respectively. A non-significant improvement in OS and PFS was seen in pts with ERCC2 mts (HR 0.70), but the 5.3% frequency of ERCC2 mts was lower than in historical series. Neither del mts (table) nor any mts in DDR genes were associated with PFS/OS. Conclusions: DDR mts were not associated with improved outcomes in C90601. The reliance on archival specimens, lower-than-expected ERCC2 mt frequency, small sample sizes, and tumor genomic heterogeneity may have influenced the predictive capacity of DDR mts in this cohort. Similar analyses are underway in pts who received neoadjuvant chemotherapy prior to cystectomy from completed prospective trials. Support: U10CA180821, U10CA180882, Genentech.[Table: see text]

TPS4615 Background: While a standard approach to muscle-invasive bladder cancer (MIBC) management involves neoadjuvant cisplatin-based chemotherapy (NAC) followed by radical cystectomy (RC), up to 50% of pts recur with metastatic disease. Moreover, removal of the bladder has a significant impact on pts’ quality of life. Pathologic downstaging to non-muscle-invasive disease (5 cm by cystoscopic assessment, and Bacillus Calmette-Guérin (BCG)-refractory disease (beyond standard induction and maintenance) are not allowed. Intravesical chemotherapy is allowed. Pts must be eligible for cisplatin chemotherapy. Eligible pts will receive either standard dose or dose dense gemcitabine and cisplatin chemotherapy (investigator’s choice) with simultaneous genetic sequencing of pre-treatment transurethral resection specimens. Pts whose tumors contain deleterious alterations in any 1 of 9 pre-selected DDR genes ( ERCC2, ERCC5, BRCA1, BRCA2, RECQL4, RAD51C, ATM, ATR, and FANCC) and who exhibit T1 disease after NAC will undergo RC or chemoradiation therapy (investigator/patient choice). The primary endpoint is 3-year event-free survival in DDR-altered pts who undergo bladder sparing, defined as the proportion of pts without BCG-unresponsive non-muscle invasive recurrences, any >T2 recurrences, or any metastatic recurrences. Secondary endpoints include clinical response rate (

505 Background: We investigated the clinical utility of SET2,3, a novel biomarker designed to measure to endocrine sensitivity. SET2,3 measures nonproliferative hormone receptor-related transcription (SETER/PR) adjusted for a baseline prognosis index derived from tumor size, nodes involved and a 4-gene molecular subtype (RNA4). CALGB 9471 is a seminal phase III study that showed improved DFS and OS from 2-weekly dose-dense (DD) vs 3-weekly chemotherapy in ER-negative cancers. Risk of recurrence (ROR-PT) score (intrinsic subtype, proliferation score and tumor size) measured by Nanostring assay was reported to be prognostic in CALGB 9741, but did not predict benefit from DD chemotherapy. Methods: SET2,3 was performed using an aliquot of 200-300 ng RNA (residual from prior ROR-PT testing) from 682 ER+ tumor samples and tested using the QuantiGene Plex bead-based hybridization assay (ThermoFisher, Luminex). We report results for the primary and two secondary objectives of the NCI/CTEP-approved correlative science proposal CSC0154) to evaluate SET2,3 in CALGB 9741 for prognosis (primary endpoint: 95%CI for 5-year (yr) DFS > 75% for High SET2,3 using the predefined prognostic cutpoint 2.10), SET2,3 prognostic independence from ROR-PT, and prediction of outcome according to chemotherapy regimen. We used Cox models to estimate hazard ratios (HR) for prognosis and comparison with ROR-PT results (using c-indices) and for prediction according to chemotherapy schedule using an interaction term (prespecified significance level for interaction: p < 0.10). Results: The study met its primary endpoint with a 5-yr DFS of 85.6% (95%CI 81.3-90.2) in the High-SET subset (244/613, 40%). High-SET vs Low-SET was significantly associated with favorable outcomes at 5 yr (DFS 85.6% vs 69%, p

4562 Background: Our previous work showed that basal tumors were associated with the best clinical outcomes in a Phase 2 clinical trial of neoadjuvant dose-dense MVAC plus B, and in other work we showed that basal tumors were enriched with hypoxia-associated gene expression signatures. Here we attempted to validate these findings in the C90601 Phase 3 clinical trial of GC plus B versus GC plus P. Methods: Whole transcriptome RNAseq was performed on all available tumors using Ion Torrent’s Ampliseq platform (n = 189). Tumors were assigned to molecular subtypes using 3 different classifiers - BASE47 (k=2), MDA oneNN (k=3), and the Consensus classifier (k=6). Tumor hypoxia signature enrichment was determined using 2 different gene expression signatures and gene set variation analysis (GSVA). The proportional hazards model was used to correlate molecular subtype calls and hypoxia signature enrichment with overall survival (OS) and progression-free survival (PFS) adjusting for stratification factors and treatment arm (for PFS). Results: The median OS & PFS by different signatures and the hazard ratios (HR) are presented in the Table. Conclusions: Predefined signatures associated with clinical benefit in the Phase-2 neoadjuvant clinical trial were not associated with benefit in C90601. Possible explanations include the lack of strong therapeutic effects of the treatments, potential heterogeneity (“subtype plasticity”) between the profiled tissue samples and the metastatic lesions under treatment pressure, and differences in biology associated with the disease states (muscle-invasive vs advanced/metastatic disease). Support: U10CA180821, U10CA180882, Department of Defense (CA160312), Genentech; ClinicalTrials.gov Identifier: NCT00942331. [Table: see text]

BACKGROUND: De-escalation of axillary surgery after neoadjuvant chemotherapy (NAC) requires careful patient selection. We sought to determine predictors of nodal pathologic complete response (ypN0) among patients treated on CALGB 40601 or 40603, which tested NAC regimens in HER2+ and triple-negative breast cancer (TNBC), respectively. METHODS: 760 patients with stage II-III HER2+ or TNBC were analyzed. Those who had axillary surgery before NAC (n=122), or who had missing pre-treatment clinical nodal status (cN) (n=58) or ypN status (n=41) were excluded. The proportion of patients with ypN0 disease was estimated for those with and without breast pathologic complete response (pCR) according to pre-treatment nodal status. RESULTS: In 539 patients, the overall ypN0 rate was 76.3% (411/539) – 93.2% (245/263) in patients with breast pCR and 60.1% (166/276) with residual breast disease (RD) (P

Aims The objective of the Randomized comparison of the Outcome of single vs. Multiple Arterial grafts: Quality of Life (ROMA:QOL) trial is to evaluate the impact of coronary artery bypass graft surgery (CABG) on quality of life (QOL). The primary hypothesis of ROMA:QOL is that participants in the multiple arterial graft (MAG) will report time-varying changes in QOL that will be lower in the post-operative recovery period and higher after 12 months compared to patients in the single arterial graft (SAG). The secondary hypotheses are that both groups will have improvements in symptoms at 12 months, and that compared to the SAG group, participants in the MAG group will experience better physical functioning and physical and mental health symptoms. Methods and Results An estimated 2111 participants will be enrolled from the parent ROMA trial from 13 countries. Outcome assessments include the Seattle Angina Questionnaire (SAQ) (primary outcome), Short Form-12v2, EuroQol-5D (EQ-5D)-5L, PROMIS-29, and PROMIS Neuropathic Pain measured at baseline, first post-operative visit, 6, 12, 24, 36, 48, and 60 months. The analysis for the primary outcome, the change in the SAQ from baseline to 12 months, will be compared across all time-points between the two treatment arms. Conclusion The ROMA:QOL trial will answer whether there are differences in QOL, physical and mental health symptoms overall for CABG, by MAG and SAG intervention arms, by sex, and between patients with and without diabetes.

We surveyed breast providers from a national oncology cooperative group to evaluate axillary management recommendations for patients with 1-2 positive sentinel lymph nodes (+SLNs) with scenarios not explicitly included in the Z0011 trial. These scenarios included patients underrepresented (premenopausal, HER2+/triple-negative tumors, and invasive lobular carcinoma) or excluded (treated with mastectomy or neo-adjuvant chemotherapy [NAC]) from the ACOSOG Z0011 trial. Survey response rate was 94/149 (64%). For patients in underrepresented groups, 45-63% of providers recommended no further axillary treatment. For mastectomy patients, 45-55% recommended multi-disciplinary discussion. 83% felt more data are needed to change practice, but 41% believed there would be significant accrual challenges to a clinical trial. For patients treated with NAC, recommendations varied widely. 85% felt more data are needed to change practice, but 26% felt there would be significant accrual challenges. For all scenarios, 86-100% of radiation oncologists recommended axillary radiation, while surgeons more often recommended no further axillary treatment. Traditional randomized trials are likely not feasible to provide answers to these critical management questions, so more pragmatic or big data studies may be needed.

Background We report the analysis involving patients treated on the initial CODEL design. Methods Adults (>18) with newly diagnosed 1p/19q World Health Organization (WHO) grade III oligodendroglioma were randomized to radiotherapy (RT; 5940 centigray ) alone (arm A); RT with concomitant and adjuvant temozolomide (TMZ) (arm B); or TMZ alone (arm C). Primary endpoint was overall survival (OS), arm A versus B. Secondary comparisons were performed for OS and progression-free survival (PFS), comparing pooled RT arms versus TMZ-alone arm. Results Thirty-six patients were randomized equally. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients progressed, versus 37.5% (9/24) on the RT arms. PFS was significantly shorter in TMZ-alone patients compared with RT patients (hazard ratio [HR] = 3.12; 95% CI: 1.26, 7.69; P = 0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) on the RT arms. OS did not statistically differ between arms (comparison underpowered). After adjustment for isocitrate dehydrogenase (IDH) status (mutated/wildtype) in a Cox regression model utilizing IDH and RT treatment status as covariables (arm C vs pooled arms A + B), PFS remained shorter for patients not receiving RT (HR = 3.33; 95% CI: 1.31, 8.45; P = 0.011), but not OS ((HR = 2.78; 95% CI: 0.58, 13.22, P = 0.20). Grade 3+ adverse events occurred in 25%, 42%, and 33% of patients (arms A, B, and C). There were no differences between arms in neurocognitive decline comparing baseline to 3 months. Conclusions TMZ-alone patients experienced significantly shorter PFS than patients treated on the RT arms. The ongoing CODEL trial has been redesigned to compare RT + PCV versus RT + TMZ.

PURPOSE: To compare efficacy and safety of capecitabine and lapatinib with or without IMC-A12 (cituxumumab) in patients with HER2-positive metastatic breast cancer (MBC) previously treated with trastuzumab. PATIENTS AND METHODS: Following an initial safety run-in cohort, patients were randomized 1:2 to Arm A (capecitabine and lapatinib) or to Arm B (capecitabine, lapatinib, and cituxumumab). Given the frequency of non-hematologic grade ≥3 adverse events in those receiving the three-drug combination in the safety cohort, lapatinib and capecitabine doses were reduced in Arm B only. The primary objective was to determine if the addition of cituxumumab to capecitabine and lapatinib improved progression-free survival (PFS) compared with capecitabine and lapatinib. Secondary objectives included a comparison between arms of other clinical endpoints, safety, change in overall quality of life (QOL) and self-assessed fatigue, rash, diarrhea, and hand-foot syndrome. RESULTS: From July 2008 to March 2012, 68 patients (out of 142 planned) were enrolled and 63 were evaluable, including 8 for the safety run-in and 55 for the randomized cohort. Study enrollment was stopped early due to slow accrual. The addition of cituxumumab to capecitabine and lapatinib did not improve PFS (HR 0.93, 95% CI: 0.52-1.64). Furthermore, no difference in objective response rate or overall survival (OS) was observed. No difference between arms was observed in grade ≥3 adverse events, overall QOL change from baseline after 4 cycles of treatment. CONCLUSION: The addition of cituxumumab to lapatinib and capecitabine did not improve PFS or OS compared with lapatinib and capecitabine in patients with HER2-positive MBC.

Background There is a lack of mechanism-driven, clinically relevant biomarkers in chronic obstructive pulmonary disease (COPD). Mitochondrial dysfunction, a proposed disease mechanism in COPD, is associated with the release of mitochondrial DNA (mtDNA), but plasma cell-free mtDNA has not been previously examined prospectively for associations with clinical COPD measures. Methods P-mtDNA, defined as copy number of mitochondrially-encoded NADH dehydrogenase-1 (MT-ND1) gene, was measured by real-time quantitative PCR in 700 plasma samples from participants enrolled in the Subpopulations and Intermediate Outcome Measures in COPD Study (SPIROMICS) cohort. Associations between p-mtDNA and clinical disease parameters were examined, adjusting for age, sex, smoking status, and for informative loss to follow-up. Results P-mtDNA levels were higher in participants with mild or moderate COPD, compared to smokers without airflow obstruction, and to participants with severe COPD. Baseline increased p-mtDNA levels were associated with better CAT scores in female smokers without airflow obstruction and female participants with mild or moderate COPD on 1-year follow-up, but worse 6MWD in females with severe COPD. Higher p-mtDNA levels were associated with better 6MWD in male participants with severe COPD. These associations were no longer significant after adjusting for informative loss to follow-up. Conclusion In this study, p-mtDNA levels associated with baseline COPD status but not future changes in clinical COPD measures after accounting for informative loss to follow-up. To better characterize mitochondrial dysfunction as a potential COPD endotype, these results should be confirmed and validated in future studies. Trial Registration: ClinicalTrials.gov NCT01969344 (SPIROMICS)

Previous phase 2 trials of neoadjuvant anti-PD-1 or anti-PD-L1 monotherapy in patients with early-stage non-small-cell lung cancer have reported major pathological response rates in the range of 15-45%. Evidence suggests that stereotactic body radiotherapy might be a potent immunomodulator in advanced non-small-cell lung cancer (NSCLC). In this trial, we aimed to evaluate the use of stereotactic body radiotherapy in patients with early-stage NSCLC as an immunomodulator to enhance the anti-tumour immune response associated with the anti-PD-L1 antibody durvalumab.We did a single-centre, open-label, randomised, controlled, phase 2 trial, comparing neoadjuvant durvalumab alone with neoadjuvant durvalumab plus stereotactic radiotherapy in patients with early-stage NSCLC, at NewYork-Presbyterian and Weill Cornell Medical Center (New York, NY, USA). We enrolled patients with potentially resectable early-stage NSCLC (clinical stages I-IIIA as per the 7th edition of the American Joint Committee on Cancer) who were aged 18 years or older with an Eastern Cooperative Oncology Group performance status of 0 or 1. Eligible patients were randomly assigned (1:1) to either neoadjuvant durvalumab monotherapy or neoadjuvant durvalumab plus stereotactic body radiotherapy (8 Gy × 3 fractions), using permuted blocks with varied sizes and no stratification for clinical or molecular variables. Patients, treating physicians, and all study personnel were unmasked to treatment assignment after all patients were randomly assigned. All patients received two cycles of durvalumab 3 weeks apart at a dose of 1·12 g by intravenous infusion over 60 min. Those in the durvalumab plus radiotherapy group also received three consecutive daily fractions of 8 Gy stereotactic body radiotherapy delivered to the primary tumour immediately before the first cycle of durvalumab. Patients without systemic disease progression proceeded to surgical resection. The primary endpoint was major pathological response in the primary tumour. All analyses were done on an intention-to-treat basis. This trial is registered with ClinicalTrial.gov, NCT02904954, and is ongoing but closed to accrual.Between Jan 25, 2017, and Sept 15, 2020, 96 patients were screened and 60 were enrolled and randomly assigned to either the durvalumab monotherapy group (n=30) or the durvalumab plus radiotherapy group (n=30). 26 (87%) of 30 patients in each group had their tumours surgically resected. Major pathological response was observed in two (6·7% [95% CI 0·8-22·1]) of 30 patients in the durvalumab monotherapy group and 16 (53·3% [34·3-71·7]) of 30 patients in the durvalumab plus radiotherapy group. The difference in the major pathological response rates between both groups was significant (crude odds ratio 16·0 [95% CI 3·2-79·6]; p0·0001). In the 16 patients in the dual therapy group with a major pathological response, eight (50%) had a complete pathological response. The second cycle of durvalumab was withheld in three (10%) of 30 patients in the dual therapy group due to immune-related adverse events (grade 3 hepatitis, grade 2 pancreatitis, and grade 3 fatigue and thrombocytopaenia). Grade 3-4 adverse events occurred in five (17%) of 30 patients in the durvalumab monotherapy group and six (20%) of 30 patients in the durvalumab plus radiotherapy group. The most frequent grade 3-4 events were hyponatraemia (three [10%] patients in the durvalumab monotherapy group) and hyperlipasaemia (three [10%] patients in the durvalumab plus radiotherapy group). Two patients in each group had serious adverse events (pulmonary embolism [n=1] and stroke [n=1] in the durvalumab monotherapy group, and pancreatitis [n=1] and fatigue [n=1] in the durvalumab plus radiotherapy group). No treatment-related deaths or deaths within 30 days of surgery were reported.Neoadjuvant durvalumab combined with stereotactic body radiotherapy is well tolerated, safe, and associated with a high major pathological response rate. This neoadjuvant strategy should be validated in a larger trial.AstraZeneca.

Introduction Periodontal disease is a chronic, inflammatory bacterial dysbiosis that is associated with both Alzheimer's disease (AD) and Down syndrome. Methods A total of 48 elderly cognitively normal subjects were evaluated for differences in subgingival periodontal bacteria (assayed by 16S rRNA sequencing) between cerebrospinal fluid (CSF) biomarker groups of amyloid and neurofibrillary pathology. A dysbiotic index (DI) was defined at the genus level as the abundance ratio of known periodontal bacteria to healthy bacteria. Analysis of variance/analysis of covariance (ANOVA/ANCOVA), linear discriminant effect‐size analyses (LEfSe) were used to determine the bacterial genera and species differences between the CSF biomarker groups. Results At genera and species levels, higher subgingival periodontal dysbiosis was associated with reduced CSF amyloid beta (Aβ)42 (P = 0.02 and 0.01) but not with P‐tau. Discussion We show a selective relationship between periodontal disease bacterial dysbiosis and CSF biomarkers of amyloidosis, but not for tau. Further modeling is needed to establish the direct link between oral bacteria and Aβ.

360922 Background: In-vitro and in-vivo evidence suggests that aspirin may have an anti-tumor effect. Multiple epidemiologic studies have reported improved breast cancer survival among regular aspirin users compared to non-users. Pooled data from randomized trials of aspirin for cardiovascular disease have also reported a decreased risk of metastatic cancer among aspirin users. Thus, we conducted a prospective randomized controlled trial to determine the true benefits and risks of adjuvant aspirin therapy for breast cancer survivors. Methods: The primary objective was to compare the effect of 300 mg aspirin daily versus placebo upon invasive disease-free survival (iDFS) in patients with high-risk, HER2-negative breast cancer. Secondary objectives included effects on overall survival, cardiovascular disease, toxicity, and adherence. Eligible participants included patients aged 18-70 diagnosed with a primary invasive HER2-negative breast cancer. If hormone receptor (HR)–positive, tumors needed to be node positive and diagnosed within the past 10 years. If HR negative, tumors could be node positive or T2-4N0 and diagnosed within the past 18 months. Participants were randomly selected (1:1) to aspirin 300 mg versus placebo daily for 5 years in a double-blinded fashion. Stratification factors include HR status (positive vs. negative), body mass index (< or ≥ 30 kg/m2), and stage (II vs. III). Based upon an accrual goal of 2,936 patients to reach 381 iDFS events, the study was estimated to have 80% power to detect HR 0.75. Results: From January 2017 to December 2020, 3,021 participants were enrolled. Treatment arms were well balanced in terms of key characteristics. In November 2021, the Data Safety and Monitoring Board recommended that the trial be unblinded because the stratified hazard ratio had crossed a pre-specified futility boundary. After 191 iDFS events (aspirin: 107, placebo: 84) and median follow-up of 20 months, the stratified hazard ratio comparing aspirin to placebo was 1.27 (z-score: -1.64), which is greater than the pre-specified hazard ratio of futility 1.03 (z-score < -0.192). There was no difference in the frequency of grade 3/4 adverse events by study arm. Compliance was high and similar across arms. Non-protocol use of aspirin/non-steroidal anti-inflammatory drugs was similar across arms and less than 14%, consistent with prior randomized aspirin trials. Updated results on iDFS events will be provided at presentation. Conclusions: In this double-blinded, placebo-controlled, randomized trial, there was no benefit in breast cancer invasive disease-free survival with the addition of 300 mg aspirin daily. Although inflammation may still play a role in cancer progression, aspirin is not recommended for prevention of breast cancer recurrence. Clinical trial information: NCT02927249.

BACKGROUND The original 3-arm CODEL design included a radiotherapy (RT)-alone control arm, an RT plus temozolomide (TMZ) arm, and an exploratory TMZ-alone arm. We report the analysis involving patients treated per the initial design. METHODS Adults (18+ years) with newly-diagnosed 1p/19q codeleted WHO grade III oligodendroglioma were randomized to RT (5940 cGy) alone (Arm A); RT with concomitant and adjuvant TMZ (Arm B); or TMZ alone (Arm C). Primary endpoint was OS, Arm A vs. B. Secondary comparisons were performed for OS and PFS, comparing pooled RT arms with the TMZ-alone arm. RESULTS 36 patients were randomized equally to the three arms. At median follow-up of 7.5 years, 83.3% (10/12) TMZ-alone patients had progressed, versus 37.5% (9/24) patients on the RT arms. PFS was shorter in TMZ-alone patients compared to RT-treated patients (HR=3.12; 95% CI: 1.26, 7.69; p=0.014). Death from disease progression occurred in 3/12 (25%) of TMZ-alone patients and 4/24 (16.7%) of RT-treated patients. OS did not statistically differ between arms, although this comparison was underpowered. After adjustment for IDH status (mutated vs. wildtype) in a Cox regression model, with IDH status and RT treatment status as co-variables (Arm C vs pooled A and B), PFS remained shorter for patients not receiving RT (HR= 3.33; 95% CI: 1.31, 8.45; p=0.011), and OS differences remained non-significant ((HR = 2.78; 95% CI 0.58, 13.22, p=0.20). Grade 3+ adverse events occurred in 25%, 42% and 33% patients (Arms A, B and C, respectively). Neurocognitive assessments, comparing baseline and 3 month timepoints, showed no significant differences between arms. CONCLUSIONS TMZ-alone treated patients experienced significantly shorter PFS than patients treated on the pooled RT arms, which remained significant when adjusting for IDH status. CODEL has been redesigned to compare the efficacy and toxicity of RT+PCV versus RT+TMZ. Clinicaltrials.gov Identifier: NCT00887146. Support: U10CA180821, U10CA180882, https://acknowledgments.alliancefound.org.

Importance. Observational studies have suggested that the use of radial artery grafts for coronary artery bypass grafting may improve clinical outcomes compared with the use of saphenous vein grafts, but this has not been confirmed in randomized trials.Objective. To compare clinical outcomes between patients receiving radial artery or saphenous vein grafts for coronary artery bypass grafting at long-term follow-up.Design, Setting, and Participants. Patient-level pooled analysis comparing radial artery and saphenous vein grafts in adult patients undergoing isolated coronary artery bypass grafting from five countries (Australia, Italy, Serbia, South Korea, and United Kingdom; enrollment years: 1997 to 2009, follow-up completed in 2019).Intervention. Patients were randomized to receive either radial artery or saphenous vein grafts for coronary artery bypass grafting.Main outcomes and measures. The primary outcome was a composite of death, myocardial infarction or repeat revascularization, and the secondary outcome was a composite of death or myocardial infarction.Results. 1036 patients (534 radial artery group) were randomized (mean age 66.6 vs 67.1 years, males 70.4% vs 69.9% in the radial artery and the saphenous vein groups, respectively); 942 (90.9%) of the originally randomized patients completed 10 years of follow-up (510 radial artery group). At a median follow-up of 10 years (interquartile range 10-11), the use of the radial artery was associated with a statistically significant reduction in the incidence of the composite outcome of death, myocardial infarction or repeat revascularization (220 vs 237 events; 41 vs 47 events per 1000 patient-years; hazard ratio[HR] 0.73, 95%confidence interval[CI] 0.61-0.88, pConclusions and relevance. In this individual participant data meta-analysis with a median follow up of 10 years, among patients undergoing coronary artery bypass grafting, the use of the radial artery compared with saphenous vein grafts was associated with a lower risk of a composite of cardiovascular outcomes.

Levels of iron and iron-related proteins including ferritin are higher in the lung tissue and lavage fluid of individuals with chronic obstructive pulmonary disease (COPD), when compared to healthy controls. Whether more iron in the extracellular milieu of the lung associates with distinct clinical phenotypes of COPD, including increased exacerbation susceptibility, is unknown. We measured iron and ferritin levels in the bronchoalveolar lavage fluid (BALF) of participants enrolled in the SubPopulations and InteRmediate Outcome Measures In COPD (SPIROMICS) bronchoscopy sub-study (n = 195). BALF Iron parameters were compared to systemic markers of iron availability and tested for association with FEV1 % predicted and exacerbation frequency. Exacerbations were modelled using a zero-inflated negative binomial model using age, sex, smoking, and FEV1 % predicted as clinical covariates. BALF iron and ferritin were higher in participants with COPD and in smokers without COPD when compared to non-smoker control participants but did not correlate with systemic iron markers. BALF ferritin and iron were elevated in participants who had COPD exacerbations, with a 2-fold increase in BALF ferritin and iron conveying a 24% and 2-fold increase in exacerbation risk, respectively. Similar associations were not observed with plasma ferritin. Increased airway iron levels may be representative of a distinct pathobiological phenomenon that results in more frequent COPD exacerbation events, contributing to disease progression in these individuals.

Purpose: We evaluated the prognostic and predictive value of circulating tumor cells (CTCs) hormone receptor–positive (HR+) metastatic breast cancer (MBC) patients randomized to letrozole alone or letrozole plus bevacizumab in the first-line setting (CALGB 40503). Experimental Design: Blood samples were collected at pretreatment and three additional time points during therapy. The presence of ≥5 CTCs per 7.5 mL of blood was considered CTC positive. Association of CTCs with progression-free survival (PFS) and overall survival (OS) was assessed using Cox regression models. Results: Of 343 patients treated, 294 had CTC data and were included in this analysis. Median follow-up was 39 months. In multivariable analysis, CTC-positive patients at baseline (31%) had significantly reduced PFS [HR, 1.49; 95% confidence interval (CI), 1.12–1.97] and OS (HR, 2.08; 95% CI, 1.49–2.93) compared with CTC negative. Failure to clear CTCs during treatment was associated with significantly increased risk of progression (HR, 2.2; 95% CI, 1.58–3.07) and death (HR, 3.4; 95% CI, 2.36–4.88). CTC-positive patients who received only letrozole had the worse PFS (HR, 2.3; 95% CI, 1.54–3.47) and OS (HR, 2.6; 95% CI, 1.59–4.40). Median PFS in CTC-positive patients was significantly longer (18.0 vs. 7.0 months) in letrozole plus bevacizumab versus letrozole arm (P = 0.0009). Restricted mean survival time analysis further revealed that addition of bevacizumab was associated with PFS benefit in both CTC-positive and CTC-negative patients, but OS benefit was only observed in CTC-positive patients. Conclusions: CTCs were highly prognostic for the addition of bevacizumab to first-line letrozole in patients with HR+ MBC in CALGB 40503. Further research to determine the potential predictive value of CTCs in this setting is warranted.

Trial Information Click here to access other published clinical trials. Lessons Learned The results from the liposarcoma cohort of SARC024 confirm previously published data and do not support the routine use of regorafenib in this patient population. Continued exploration of novel therapies, including combination approaches, is warranted for a patient population in whom limited treatment options exist. Background Regorafenib is a multitargeted kinase inhibitor with a kinase profile overlapping, but distinct from, pazopanib, an agent approved for recurrent and metastatic non-gastrointestinal stromal tumor (GIST), non-adipocytic soft tissue sarcoma. We conducted a randomized, phase II study of regorafenib versus placebo in refractory liposarcoma patients. Methods Patients with advanced or metastatic, treatment-refractory liposarcoma were randomized 1:1 to receive regorafenib 160 mg or placebo once daily (3 weeks on, 1 week off). Patients with well-differentiated liposarcoma only were excluded. Crossover for placebo was allowed upon progression. The primary endpoint was progression-free survival (PFS), according to RECIST version 1.1. Results Forty-eight subjects with liposarcoma (34 dedifferentiated, 12 myxoid/round cell, 2 pleomorphic) were enrolled. Median PFS was 1.87 (95% confidence interval [CI], 0.92–3.67) months for regorafenib versus 2.07 (95% CI, 1.64–3.44) months for placebo; stratified hazard ratio [HR], 0.85 (95% CI, 0.46, 1.58), p = .62. No responses were seen on regorafenib. One PR was observed on placebo. Median overall survival was 6.46 (95% CI, 4.16–23.48) months for regorafenib and 4.89 (95% CI, 3.02–9.77) months for placebo, stratified HR, 0.66 (95% CI, 0.31–1.40), p = .28). Treatment-related adverse events were similar to the known safety profile of regorafenib. Conclusion Regorafenib did not appear to improve PFS in treatment-refractory liposarcoma. No new significant safety signals were observed.

Introduction Surgical resection is curative for some patients with early lung squamous cell carcinoma. Staging and clinical factors do not adequately predict recurrence risk. We sought to validate the discriminative performance of proposed prognostic gene expression signatures at a level of rigor sufficient to support clinical use. Methods The two-stage validation used independent core laboratories, objective quality control standards, locked test parameters, and large multi-institutional specimen and data sets. The first stage validation confirmed a signature’s ability to stratify patient survival. The second-stage validation determined which signature(s) optimally improved risk discrimination when added to baseline clinical predictors. Participants were prospectively enrolled in institutional (cohort I) or cooperative group (cohort II) biospecimen and data collection protocols. All cases underwent a central review of clinical, pathologic, and biospecimen parameters using objective criteria to determine final inclusion (cohort I: n = 249; cohort II: n = 234). Primary selection required that a signature significantly predict a 3-year survival after surgical resection in cohort I. Signatures meeting this criterion were further tested in cohort II, comparing risk prediction using baseline risk factors alone versus in combination with the signature. Results Male sex, advanced age, and higher stage were associated with shorter survival in cohort I and established a baseline clinical model. Of the three signatures validated in cohort I, one signature was validated in cohort II and statistically significantly enhanced the prognosis relative to the baseline model (C-index difference 0.122; p Conclusions These results represent the first rigorous validation of a test appropriate to direct adjuvant treatment or clinical trials for patients with lung squamous cell carcinoma.

Background Patients who have undergone solid organ transplants (SOT) have an increased risk for sepsis compared with the general population. Paradoxically, studies suggest that SOT patients with sepsis may experience better outcomes compared with those without a SOT. However, these analyses used previous definitions of sepsis. It remains unknown whether the more recent definitions of sepsis and modern analytic approaches demonstrate a similar relationship. Methods Using the Weill Cornell-Critical Care Database for Advanced Research, we analyzed granular physiologic, microbiologic, comorbidity, and therapeutic data in patients with and without SOT admitted to intensive care units (ICUs). We used a survival analysis with a targeted minimum loss-based estimation, adjusting for within-group (SOT and non-SOT) potential confounders to ascertain whether the effect of sepsis, defined by sepsis-3, on 28-day mortality was modified by SOT status. We performed additional analyses on restricted populations. Results We analyzed 28 431 patients: 439 with SOT and sepsis, 281 with SOT without sepsis, 6793 with sepsis and without SOT, and 20 918 with neither. The most common SOT types were kidney (475) and liver (163). Despite a higher severity of illness in both sepsis groups, the adjusted sepsis-attributable effect on 28-day mortality for non-SOT patients was 4.1% (95% confidence interval [CI], 3.8–4.5) and −14.4% (95% CI, −16.8 to −12) for SOT patients. The adjusted SOT effect modification was −18.5% (95% CI, −21.2 to −15.9). The adjusted sepsis-attributable effect for immunocompromised controls was −3.5% (95% CI, −4.5 to −2.6). Conclusions Across a large database of patients admitted to ICUs, the sepsis-associated 28-day mortality effect was significantly lower in SOT patients compared with controls.

Advanced prostate cancer initially responds to hormonal treatment, but ultimately becomes resistant and requires more potent therapies. One mechanism of resistance observed in ∼10% of these patients is through lineage plasticity, which manifests in a partial or complete small cell or neuroendocrine prostate cancer (NEPC) phenotype. Here, we investigate the role of the mammalian SWI/SNF (mSWI/SNF) chromatin remodeling complex in NEPC. Using large patient datasets, patient-derived organoids and cancer cell lines, we identify mSWI/SNF subunits that are deregulated in NEPC and demonstrate that SMARCA4 (BRG1) overexpression is associated with aggressive disease. We also show that SWI/SNF complexes interact with different lineage-specific factors in NEPC compared to prostate adenocarcinoma. These data suggest a role for mSWI/SNF complexes in therapy-related lineage plasticity, which may be relevant for other solid tumors.