Radiographic Disease Progression Research Articles

Factors associated with poor survival outcomes in patients with prostate cancer (PCa) with radiographic disease progression in the setting of low PSA.

60 Background: Recent studies, including a post-hoc analysis of the ARCHES trial, highlight radiographic disease progression (rDP) occurring without concordant rise in prostate specific antigen (PSA). In a previous study by our group, we reported that almost 40% of patients on 2nd generation hormone therapy experience rDP with non-rising PSA and have poor survival outcomes. The current analysis more specifically focuses on the subgroup of patients with rDP occurring at low PSA (<0.5 ng/dL) and describes factors associated with poorer survival outcomes in this patient population. Methods: In a single institution study, we reviewed the prospectively maintained Mayo Clinic C-11 Choline PET registry for patients treated between 2011 and 2021, who experienced rDP at low PSA (value < 0.5 ng/mL). Disease progression on C-11 choline PET was confirmed by either tissue biopsy or subsequent response to therapy. We investigated factors associated with poor cancer-specific survival outcomes in univariable and multivariable cox regression analyses. Results: In total, 220 (16%) patients experiencing rDP at low PSA were identified. Median (IQR) age at rDP was 67.91 (61.10 – 73.87) yrs., median (IQR) primary Gleason score was 9 (7-9), and median (IQR) PSA was 0.17 (0 – 0.32) ng/ml. 75% of the patients (n=166) had CRPC disease status at time of rDP. Prior systemic treatments included 2nd generation HT in 18% (n= 40) and chemotherapy in 31% (n=70). Sites of rDP were divided into 7% local (n=16), 42% lymph nodes (n=91), 43% bone (n=95), and 8% visceral metastases (n=18). Over a median follow-up duration of 55 months, 46% of patients (n=100) reported death. Factors associated with poor survival outcomes are demonstrated in the table and include age at rDP, CRPC status, and disease location (P-value <0.05). Conclusions: We found that radiographic disease progression commonly occurs at low PSA (<0.5 ng/mL). CRPC-disease status and the development of visceral metastases are associated with particularly poor survival outcomes. To identify early progression, monitoring with imaging may be warranted, even in the patients with low PSA. [Table: see text]

LITESPARK-024: A randomized phase 1/2 study of belzutifan with or without palbociclib in patients with advanced renal cell carcinoma.

TPS747 Background: The combination of immunotherapy with antiangiogenic agents is a well-established first-line treatment option for patients (pts) with advanced renal cell carcinoma (RCC), but many pts develop resistance, and effective second- or subsequent-line options are needed. The von Hippel-Lindau ( VHL) gene is inactivated in approximately 90% of RCC cases, which results in the constitutive activation of hypoxia-inducible factor 2α (HIF-2α) signaling. HIF-2α is involved in angiogenesis, tumor growth, proliferation, and metastasis, and is a key oncogenic driver in RCC. The HIF-2α inhibitor belzutifan has demonstrated promising antitumor activity with manageable safety in pts with heavily pretreated RCC. The cyclin-dependent kinase (CDK) pathway is altered in several cancer types, including RCC, and is associated with poor clinical outcomes. The CDK 4/6 inhibitor palbociclib inhibited cell growth in RCC cell lines, and the antiproliferative effects of CDK 4/6 inhibition were synergistic with HIF-2α inhibition in HIF-2α–dependent VHL -/- clear cell RCC cell lines. We hypothesized palbociclib could potentially enhance the efficacy of belzutifan as combination therapy for previously treated pts with advanced RCC. Methods: LITESPARK-024 (NCT05468697) is an open-label, multicenter, phase 1/2 randomized study of belzutifan + palbociclib versus belzutifan monotherapy in pts with advanced RCC. Pts must have histologically confirmed unresectable stage IV RCC with a clear cell component, received at least 2 prior systemic regimens (both an anti–PD-1/PD-L1 monoclonal antibody and a VEGF receptor–targeted TKI, in sequence or in combination), have measurable disease per RECIST v1.1 by BICR, have KPS score of ≥70%, and have radiographic disease progression on or after the most recent regimen per investigator. Part 1 will evaluate the safety of belzutifan + palbociclib and determine the recommended phase 2 dose (RP2D) for the combination using a modified toxicity probability interval design. Part 2 will evaluate the safety and efficacy of belzutifan + palbociclib versus belzutifan alone. In part 1, ≤30 pts will be enrolled into 3 dose groups and receive belzutifan 120 mg once daily + palbociclib (75, 100, or 125 mg) daily for 21 consecutive days followed by 7 days off. In part 2, approximately 150 pts will be randomly assigned 2:1 to receive belzutifan 120 mg once daily + palbociclib RP2D (21 consecutive days/7 days off) or belzutifan 120 mg once daily. Pts will be stratified by IMDC risk (0 vs 1-2 vs 3-6) and sarcomatoid histology (yes vs no) at randomization in part 2. The primary end point for part 1 is to assess dose-limiting toxicities and adverse events to determine the RP2D of belzutifan + palbociclib. The primary end point for part 2 is ORR per RECIST v1.1 by investigator assessment. Secondary end points for part 2 are clinical benefit rate, DOR, PFS, OS, and safety and tolerability. Clinical trial information: NCT05468697 .

Final overall survival (OS) in PROpel: Abiraterone (abi) and olaparib (ola) versus abiraterone and placebo (pbo) as first-line (1L) therapy for metastatic castration-resistant prostate cancer (mCRPC).

LBA16 Background: PROpel (NCT03732820) met its primary endpoint showing significant investigator-assessed radiographic progression-free survival (rPFS) benefit for patients with mCRPC treated with abi + ola vs abi + pbo in the 1L setting (hazard ratio [HR] 0.66, 95% confidence interval [CI] 0.54–0.81, P< 0.001, data cut-off: 7/30/2021). Sensitivity analysis by blinded independent central review was consistent. A trend toward OS benefit with abi + ola was observed at the time of the primary rPFS analysis (28.6% maturity, HR 0.86, 95% CI 0.66–1.12) and a subsequent interim analysis (40.1% maturity, HR 0.83, 95% CI 0.66–1.03). We report OS and safety from the pre-planned final analysis (data cut-off: 10/12/2022). Methods: PROpel is a randomized, double-blind phase 3 trial of 1L therapy for patients with mCRPC eligible for abiraterone. Patients were prospectively assessed for homologous recombination repair mutation (HRRm) status using tumor tissue (FoundationOne CDx) and/or circulating tumor DNA (ctDNA; FoundationOne Liquid CDx) tests after randomization 1:1 to ola (300 mg twice daily [bid]) or pbo, and abi (1000 mg once daily) plus prednisone/prednisolone (5 mg bid). Treatment continued until radiographic disease progression, unacceptable toxicity or withdrawal of consent. OS was a key secondary endpoint (2-sided boundary for significance 0.0377). Aggregate results from tumor tissue and ctDNA tests were used to assign patients to HRRm/BRCAm subgroups. Results: Patient (n = 796) characteristics (including prior docetaxel, site of metastasis, symptom score and HRRm status) were generally balanced. There was a consistent trend toward OS benefit in the intention-to-treat (ITT) population with abi + ola vs abi + pbo (maturity 47.9%, HR 0.81, 95% CI 0.67–1.00, P= 0.0544), with median OS 42.1 months (m) vs 34.7 m, respectively. OS medians and HRs for HRRm, non-HRRm, BRCAm and non-BRCAm subgroups all favored abi + ola vs abi + pbo. In the abi + ola arm the most common Grade ≥3 adverse event was anemia (16.1%). Conclusions: At the prespecified final analysis in PROpel, abi + ola prolonged OS by > 7 m vs standard-of-care abiraterone (abi + pbo) in the ITT population. The median OS of > 42 m is the longest median reported to date in a phase 3 trial in 1L mCRPC. Consistent with rPFS results, a trend toward OS benefit was observed in HRRm, non-HRRm, BRCAm and non-BRCAm subgroups with greatest benefit in the BRCAm subgroup. No new long-term safety issues were identified. These results support the use of abi + ola in 1L mCRPC. Clinical trial information: NCT03732820 . [Table: see text]

Nivolumab plus ipilimumab for the treatment of post-chemotherapy metastatic castration-resistant prostate cancer (mCRPC): Additional results from the randomized phase 2 CheckMate 650 trial.

22 Background: In preliminary analyses from the randomized phase 2, open-label CheckMate 650 trial, nivolumab (NIVO) 1 mg/kg (N1) plus ipilimumab (IPI) 3 mg/kg (I3) Q3W × 4 doses showed clinical activity in patients (pts) with post-chemotherapy (post-CT) mCRPC, particularly those with high tumor mutational burden (TMB), but early toxicity contributed to treatment discontinuations. Here, we report results from pts with post-CT mCRPC receiving alternative NIVO+IPI dosing regimens vs IPI alone vs cabazitaxel (CABA) in CheckMate 650. Methods: Newly enrolled pts previously treated with docetaxel for mCRPC were randomized 2:2:1:2 to cohorts D1 (NIVO 3 mg/kg [N3] + IPI 1 mg/kg [I1] Q3W × 4 doses then NIVO 480 mg Q4W), D2 (N1 Q3W × 8 doses + I3 Q6W × 4 doses then NIVO 480 mg Q4W), D3 (I3 Q3W × 4 doses), or D4 (CABA 20 or 25 mg/m2 Q3W + prednisone 10 mg × 10 doses). Crossover from cohorts D3 and D4 to cohort D1 was allowed after radiographic progressive disease. Outcomes included safety, objective response rate (ORR), prostate-specific antigen response rate (PSA-RR; confirmed PSA decline ≥ 50% from baseline), radiographic progression-free survival (rPFS) per blinded independent central review (BICR), and overall survival (OS). Associations between efficacy and TMB were assessed. Results: Overall, 259 pts were randomized (D1, n = 73; D2, n = 74; D3, n = 38; D4, n = 74). Median (range) follow-up for OS was 23.3 (6.0–31.5) months. In the NIVO+IPI cohorts (D1 and D2), median duration of therapy was 2.8 and 2.4 months; the median number of IPI doses received was 4 and 2, and 15% and 26% of pts discontinued due to study drug toxicity, respectively. Two pts died due to study drug toxicity (1 each in cohorts D1 and D2). Key safety and efficacy data are shown. Several pts in cohorts D1 and D2 showed notable reductions (75-100%) in tumor size and PSA. Approximately one-third of pts in cohorts D3 and D4 crossed over to D1. Based on preliminary analyses in small numbers of evaluable pts, there was no clear and consistent association between efficacy and tissue or blood TMB in the NIVO+IPI cohorts (D1 and D2). Conclusions: These results further support the clinical activity of NIVO+IPI in select pts with post-CT mCRPC. Detailed evaluations of the characteristics of responders to NIVO+IPI, including more expansive biomarker analyses, are warranted. Clinical trial information: NCT02985957 . [Table: see text]

Effect of early PSA decline after starting second-generation hormone therapy in the post-docetaxel setting on cancer-specific survival in metastatic castrate-resistant prostate cancer.

189 Background: The objective of this study is to evaluate the prognostic value of early PSA decline following initiation of second-generation hormone therapy (2nd HT), namely abiraterone acetate or enzalutamide, in the post-chemotherapy setting in patients with metastatic castrate-resistant prostate cancer (mCRPC). Methods: We retrospectively identified 75 m-CRPC patients treated with 2nd HT following docetaxel failure (defined as PSA rise and radiographic progression). Patients were categorized into two groups based on first PSA within 3 months after initiation of therapy: PSA reduction ≥ 50% (Group A) and PSA reduction < 50% (Group B). The primary endpoint was cancer-specific mortality and the secondary endpoint was radiographic progression free survival. Results: There were 75 patients (52 in group A, 23 in group B) in the analytic cohort. Baseline clinical and demographic characteristics, including median age, primary Gleason score risk group, median pre-treatment PSA, disease burden, site of metastases, and pre-treatment ECOG score were not statistically different between the two groups. PSA reduction ≥50% was significantly associated with decreased risk of radiographic disease progression (HR 0.41, 95%CI 0.21-0.80, p = 0.0113) as well as decreased risk of cancer-specific mortality (HR 0.29, 95%CI 0.09-0.87, p = 0.0325). Conclusions: PSA reduction ≥50% within 3 months of starting 2nd HT for patients with mCRPC who have failed first-line docetaxel is associated with significantly improved 3-year cancer-specific mortality and progression free survival. Our data supports the use of PSA as an early prognosticating marker for patient outcomes on this second line therapy. [Table: see text]

A phase II single-arm trial of niraparib in platinum-sensitive metastatic castration-resistant prostate cancer with DNA repair defects (PLATPARP).

TPS291 Background: Platinum-based chemotherapy, either as monotherapy or in combination with taxanes, is increasingly used for patients with metastatic castration-resistant prostate cancer (mCRPC) harboring germline and/or somatic homologous recombination repair gene mutations (HRRm). However, clinical responses with platinum-based therapy are often of limited duration and limited by cumulative toxicities. The PARP inhibitor (PARPi) olaparib is approved for the treatment of mCRPC patients with pathogenic HRRm after progression on enzalutamide or abiraterone. Importantly, sensitivity to platinum-based chemotherapy may predict improved clinical outcomes with PARPi, and ‘maintenance’ PARPi strategies are routinely used in patients with advanced ovarian and pancreatic malignancies with HRRm with initial clinical response to platinum chemotherapy. We hypothesize that maintenance niraparib, a PARPi with demonstrated activity in mCRPC with HRRm, will prolong clinical responses to platinum-based chemotherapy with acceptable toxicity in mCRPC patients harboring germline and/or somatic HRRm. Methods: We are conducting an open-label, single-arm, phase II study to evaluate the clinical benefit of maintenance niraparib in biomarker-defined, platinum-sensitive mCRPC patients. Eligible subjects harbor a pathogenic germline and/or somatic mutation in BRCA1/2, ATM, FANCA, CDK12, RAD51B, RAD54L, PALB2, CHEK2, HDAC2, or BRIP1 and have received at least 3 cycles (or minimum 9 weeks) of platinum-based chemotherapy for the treatment of mCRPC per investigator discretion. Following ³4 weeks since completion of chemotherapy, subjects without evidence of clinical or radiographic disease progression receive investigational treatment with maintenance niraparib (starting dose 200 mg daily). The primary objective is an improvement in 6 month PFS rate (PFS6) (H0: PFS6 rate 25%; H1: PFS6 rate 50%; power 0.77 with one-sided α = 0.05). Serial plasma samples are obtained for correlative analyses of markers of response and/or resistance to maintenance niraparib. Eight of a planned total of 18 subjects have enrolled (N=3 germline BRCA2; N=2 somatic BRCA2; N=1 germline PALB2; N=1 germline ATM; N=1 germline CHEK2). This study incorporates a novel, combined genetic and clinical patient-selection approach for PARPi therapy to optimize clinical outcomes. Clinical trial information: NCT04288687 .

High-volume mCRPC is associated with decreased cancer specific survival in patients on second-generation hormone therapy in the post docetaxel setting.

192 Background: In the setting of disease progression of metastatic castrate resistant prostate cancer (mCRPC) on docetaxel, abiraterone acetate (AA) and enzalutamide are two commonly used second line therapies with data demonstrating survival benefits. Less is known about patient specific factors that contribute to success with these therapies. The objective of this study is to improve patient selection for post-docetaxel second generation hormone therapy (AA or enzalutamide) by evaluating whether overall metastatic burden is associated with treatment response in this setting. Methods: By retrospective chart review, patients with mCRPC treated with AA or enzalutamide following docetaxel failure (defined as PSA rise and radiographic progression) were identified. Patients were categorized into low volume and high volume metastatic disease based on the number of pre-treatment metastatic lesions; where low volume disease describes patients with ≤ 5 metastatic lesions (e.g. oligometastatic disease), and high volume disease represents patients with > 5 individual lesions. The primary endpoint was cancer-specific mortality and the secondary endpoint was radiographic progression free survival. Median follow-up time was 29.5 months. Results: 75 patients were identified and included in our analysis: 39 with high volume metastatic disease, and 36 with low volume metastatic disease. Baseline characteristics of age and pre-treatment ECOG were not statistically different between these groups. Pre-treatment high-volume disease burden was significantly associated with increased risk of radiographic disease progression (HR 4.21, 95%CI 1.97-8.99, p < 0.0001) and cancer specific mortality (HR 5.84, 95% CI 1.58-21.53, p = 0.0026) during treatment with second generation androgen deprivation therapy. Conclusions: High volume metastatic disease burden is associated with significantly increased cancer specific mortality and decreased progression free survival for patients on second line therapy with AA or enzalutamide following docetaxel treatment failure.

A multi-center, open-label, randomized dose expansion study of PF-06821497, a potent and selective inhibitor of enhancer of zeste homolog 2 (EZH2), in patients with metastatic castration-resistant prostate cancer (mCRPC).

TPS282 Background: Enhancer of zeste homolog 2 (EZH2) encodes the histone methyltransferase component of the polycomb repressive complex-2, inducing transcriptional silencing of target genes, and is altered in cancers such as follicular lymphoma (FL), small cell lung cancer (SCLC), and metastatic castration-resistant prostate cancer (mCRPC). We evaluated the pharmacokinetics (PK), safety, and antitumor activity of PF-06821497, a potent and selective inhibitor of EZH2, in an ongoing phase I trial (NCT03460977 ) in patients (pts) with SCLC, CRPC, and FL as monotherapy and in combination with standard of care therapies. For pts with CRPC, the PF-06821497 recommended dose for expansion (RDE) is 1250 mg BID, in combination with enzalutamide plus androgen deprivation therapy (E). Part 2B of this trial further explores outcomes for pts dosed with PF-06821497 and E compared with E monotherapy. Methods: Part 2B compares the safety and efficacy of twice-daily PF-06821497 in combination with E (160 mg daily) (treatment arm) versus E monotherapy (control arm) administered continuously in patients with mCRPC previously treated with abiraterone. At trial entry, all pts will have evidence of prostate cancer progression per the modified Prostate Cancer Working Group 3 Criteria. Prior treatment with E is not allowed. Approximately 80 participants will be randomized in a 1:1 fashion into two arms, in US, Spain, and other countries. Approximately 40 participants are required in each arm to have 80% power in the study in order to detect a hazard ratio of 0.5 (E plus PF-06821497: E alone). Patients randomized to E alone have the option to add PF-06821497 to their regimen upon confirmed radiographic disease progression. The primary objectives are to confirm the safety and tolerability of PF-06821497 in combination with E in pts with mCRPC, and to assess the effect of PF-06821497 in combination with E versus E monotherapy on radiographic progression free survival. Secondary objectives include further evaluation of anti-tumor activity of PF-06821497, and assessment of single and multiple dose PK when given in combination with E. The impact of PF-06821497 in combination with E and of E alone in men with mCRPC on patient reported outcomes will also be assessed. Clinical trial information: NCT03460977 .

Association of Symptoms of Gastroesophageal Reflux, Esophageal Dilation, and Progression of Systemic Sclerosis-Related Interstitial Lung Disease.

To investigate whether symptoms of gastroesophageal reflux disease and radiographic measures of esophageal dilation are associated with radiographic progression of systemic sclerosis-related interstitial lung disease (SSc-ILD). Participants of the Scleroderma Lung Study II, which compared mycophenolate versus cyclophosphamide for SSc-ILD, completed the reflux domain of the University of California Los Angeles Scleroderma Clinical Trials Consortium Gastrointestinal Tract 2.0 at baseline. The diameter and area of the esophagus in the region of maximum dilation was measured by quantitative image analysis. Univariate and multivariable linear regression analyses were created to evaluate the relationship between these measures of esophageal involvement and progression of SSc-ILD over 2 years, based on the radiologic quantitative interstitial lung disease (QILD) and quantitative lung fibrosis (QLF) in the lobe of maximum involvement (LM). All multivariable models controlled for the treatment arm, baseline ILD severity, and proton-pump inhibitor use. The baseline mean patient-reported reflux score was 0.57, indicating moderate reflux (n=141). Baseline mean maximal esophageal diameter and area were 22 mm and 242 mm2 , respectively. Baseline reflux scores were significantly associated with the change in QLF-LM and QILD-LM in the univariate and multivariable models. Neither radiographic measure of esophageal dilation was associated with the change in radiographic measures of lung involvement. Severity of reflux symptoms as measured by an SSc-specific questionnaire was independently associated with the change in the radiographic extent of ILD and fibrosis over 2 years in patients with SSc-ILD. Two objective measures of esophageal dilation were not associated with radiographic progression of ILD, highlighting the need for improved objective measures of esophageal dysfunction in SSc.

Next-generation sequencing (NGS) of circulating cell-free DNA (cfDNA) in advanced pancreatic neuroendocrine neoplasms (PanNENs).

653 Background: PanNENs represent 1-2% of all pancreatic neoplasms. The genomic landscape derived from PanNEN tumor tissue has been described previously. There are little data detailing the frequency of genetic alterations identified in cfDNA in an advanced PanNEN population, the plasma-tissue concordance of detected alterations, and the clinical utility of cfDNA. Methods: Patients (pts) with metastatic PanNENs underwent collection of cfDNA for NGS using the MSK-IMPACT 505 gene assay between March 2017 and April 2020. Matched tissue based NGS with the FDA authorized MSK-IMPACT gene assay was completed when tumor tissue was available. For some pts, plasma and tumor tissue were sequenced at multiple time points. Clinical actionability of sequence variants was annotated by OncoKB. Clinicopathologic characteristics were extracted, and data are herein reported. Results: 25 unique pts with metastatic PanNENs had 32 plasma samples analyzed. The majority had well differentiated (22/25; 88%), intermediate grade disease (13/25; 52%). 6 (24%) pts had well differentiated high grade disease and 3 (12%) had poorly differentiated neuroendocrine carcinomas. After extraction, median cfDNA yield per sample was 23.98ng (range: 3.2 to 500.1). Mutations were detected in 21(66%) of 32 samples (10 pre systemic therapy, 10 at progression, 12 post response to therapy or while stable on therapy). The most frequently mutated genes occurring in >10% of patients were DAXX (28%), TSC2 (24%), MEN1 (24%), ARID1B (20%), ARID1A (12%) and ATRX (12%). 23 (92%) pts underwent tumor tissue sequencing with MSK-IMPACT with a median time of 6.9 (range: 0.5-33.4) months between tissue collection and time of plasma analysis. NGS of cfDNA identified the most common mutations observed in tumor tissue for: DAXX (5/6; 83%), TSC2 (3/6; 50%), MEN1 (5/12; 42%), ARID1A (3/5; 60%) and ATRX (3/6; 50%). In 21/23 (91%) paired samples, additional mutations not seen in tissue were detected in plasma and included TSC2, TP53, EGFR, VHL, and BRCA2. Potentially actionable mutations were identified in sequenced cfDNA in 8/25 (32%) patients including 4 TSC2 mutations (level 3b), 1 ATM mutation (level 3b), 2 ARID1A mutations (level 4) and 1 KRAS mutation (level 4). One patient who was treated with larotrectinib for an ETV6:NTRK3 fusion detected on tumor sequencing ultimately developed resistance with a NRTK3 G623R alteration identified through sequencing of cfDNA at radiographic disease progression. Conclusions: NGS of cfDNA in metastatic PanNENs, across the spectrum of WHO-defined tumor grade/differentiation, revealed tumor-associated genetic alterations in 66% of plasma samples. Clonal evolution, actionable alterations, and resistance mechanisms can be detected through circulating cfDNA genotyping and may serve as a powerful tool to better understand disease biology of a disease that often changes over time and through therapy.

Relationship between RANO-PRO Working Group standardised priority constructs and disease progression among malignant glioma patients: A retrospective cohort study.

Recognising the importance of clinical outcomes assessments (COAs), the Response Assessment in Neuro-Oncology-Patient Reported Outcome (RANO-PRO) Working Group recommended inclusion of core symptoms and functions in clinical care or research for malignant glioma patients. This study evaluated the association of the recommended symptoms (pain, perceived cognition, seizures, aphasia, symptomatic adverse events) and functions (weakness, walking, work, usual activities) with disease progression in these patients. In this retrospective cohort study, patients with malignant glioma were included from the US National Cancer Institute Neuro-Oncology Branch Natural History Study (NOB-NHS) which follows primary central nervous system tumour patients aged 18 years and older throughout their disease trajectory. The M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT), EQ-5D-3L, Karnofsky Performance Status (KPS), and Neurologic Function scores (NFS) were evaluated in relation to disease progression by chi-square tests, independent- and paired-samples t-tests, adjusted for multiple comparisons at first assessment and over time to a second assessment. Radiographic disease progression was determined on the interpretation of the imaging study by a radiologist and neuro-oncologist using standard criteria as part of clinical trial participation or routine standard of care. The priority constructs were evaluated to provide initial evidence of their relevance, relationship to disease status over time, and sensitivity to change in a diverse group of patients with malignant glioma. Seven hundred and sixty-five patients had enrolled into the NOB-NHS between September 1, 2016 and January 31, 2020. Three hundred and thirty-six patients had a diagnosis of a malignant glioma (anaplastic astrocytoma, anaplastic oligodendroglioma, glioblastoma, and gliosarcoma) and were included in the current study. The sample was 64% male (n=215), 36% female (n=121), median age of 52 years (IQR=18.75), 82% White (n=276), and 65% had tumour recurrence (n=219). One hundred and fifty-four (46%) had radiographic disease progression. Difficulty remembering, fatigue, and weakness were worse in the group whose imaging was interpreted as radiographic disease progression versus stable disease, as well as the functions of walking, work, activity, and self-care (1.1 < difference < 1.8). Patients with disease progression were four times more likely to have a poor KPS (≤80) and worse NFS. Among patients with disease progression at a second assessment (n=112), all symptoms, except seizures, worsened between first assessment and disease progression and up to 22% of patients (n=25) reported worsening mobility, self-care, and usual activity; 46% (n=51) and 35% (n=30) had worsened KPS and NFS, respectively. On average, 4 symptoms or functions (SD=3) were reported as moderate-to-severe and 30% (n=33) and 23% (n=26) had a change to moderate-to-severe fatigue and walking, respectively, at time of disease progression. Over 7% of patients with worsening (n=7 of 100) reported every symptom and function as having changed the most severely including seizures with fatigue and activity reported as the top symptom and function, respectively. The identified core symptoms and functions worsened at the time of progression, supporting the relevance and sensitivity of the priority constructs identified by the RANO-PRO Working Group for clinical care and clinical trials for malignant glioma patients. The Natural History Study is supported by Intramural Project 1ZIABC011786-03.

Retrospective Analysis of Imaging Characteristics of Tectal Gliomas.

Tectal gliomas (TGs) are rare tumors that involve critical locations in the brainstem, including the superior and inferior colliculi and the Sylvian aqueduct. The rarity of these tumors and the lack of large clinical studies have hindered adequate understanding of this disease. We sought to determine the association between imaging characteristics of TG and progression-free survival (PFS). In this retrospective cohort study, impact of imaging characteristics (contrast enhancement, calcifications, cystic changes, presence of hydrocephalus) on survival was analyzed for 39 patients with TG. We used the Kaplan-Meier survival analysis method for determining the association between imaging characteristics and PFS. Progression-free survival was measured from time of diagnosis to radiographic or pathological disease progression during observation period. Progression was defined as more than 25% increase of the lesion in size, per response assessment in neuro-oncology, together with clinical deterioration and/or a need for intervention. Progression-free survival differences by various imaging characteristics were assessed using the log-rank test and univariable Cox proportional hazard regression. Because most of the studies in the current literature tend to overrepresent pediatric patients, we aimed to determine the association between TG tumors' imaging characteristics and PFS in both adult and pediatric patients. All statistical analyses were performed using STATA version 16.1 (Stata Corp, College Station, Tex). Of the 39 patients, radiographic tumor progression was observed in 15 cases (38.5%). Median PFS for 39 patients during observation was 21.8 years. Tectal gliomas that showed contrast enhancement initially or developed contrast enhancement during surveillance on magnetic resonance imaging had significantly lower PFS than those without (hazard ratio, 3.55; 95% confidence interval, 1.09-11.58; log-rank P value, 0.02). Analysis of this patient population showed that contrast-enhancing TGs should not be categorically defined as benign lesions. This subgroup of patients should be followed closely for signs of progression.

Glenohumeral osteoarthritis: what the surgeon needs from the radiologist.

Glenohumeral osteoarthritis (GHOA) is a widely prevalent disease with increasing frequency due to population aging. Both clinical manifestations and radiography play key roles in the initial diagnosis, staging, and management decisions. Radiographic disease progression evaluation is performed using validated staging systems, such as Kellgren and Lawrence, Samilson, and Hamada. For young patients with mild to moderate GHOA and failed conservative treatment, arthroscopic preservation surgery (APS) is usually considered. Older patients and those with severe GHOA benefit from different types of arthroplasties. Preoperative magnetic resonance imaging (MRI) is essential for APS surgical planning, as it maps repairable labral, cartilage, and rotator cuff lesions. For arthroplasty planning, the status of glenoid cartilage and intactness of rotator cuff as well as glenoid morphology represent key factors guiding the decision regarding the most suitable hardware design, whether resurfacing, partial, total, or reverse joint replacement. Pre-surgical MRI or alternatively computed tomography arthrogram is employed to evaluate the cartilage and rotator cuff. Finally, three-dimensional computed tomography (3D CT) is indicated to optimally assess the glenoid morphology (to determine Walch classification, version, inclination, and bone loss) and analyze the necessity for glenoid osteotomy or graft augmentation to correct the glenoid structural abnormalities for future success and longevity of the shoulder implants or chosen constructs. Understanding the purpose of each imaging and treatment modality allows more efficient image interpretation. This article reviews the above concepts and details what a surgeon needs from a radiologist and could benefit from accurate reporting of preoperative imaging studies.

Serum Tumor Marker Response Predicts Survival and Intracranial Control after Radiation Therapy for Germ Cell Tumor Brain Metastases

<h3>Purpose/Objective(s)</h3> Patients with brain metastases (BM) from germ cell tumors (GCT) demonstrate poor overall survival (OS). However, multimodality treatment enables durable disease control in some patients. Serum tumor markers including beta-human chorionic gonadotropin (β-HCG) and alpha-fetoprotein (AFP) are used to evaluate response to systemic therapy. However, their utility in assessing the efficacy of intracranial radiation therapy (RT) is unclear. We evaluated whether changes in β-HCG and AFP after RT for GCT BM predict OS and freedom from intracranial progression (iPFS). <h3>Materials/Methods</h3> Patients with GCT BM who received intracranial RT at our institution were identified retrospectively. At least one β-HCG or AFP value before and after RT was required for inclusion. Serum tumor marker values were obtained prior to RT and 1 month after RT. Univariate and multivariate Cox regression analyses evaluated changes in β-HCG and AFP as predictors of OS and iPFS. Patients with normal tumor markers prior to RT were excluded from analyses. <h3>Results</h3> Sixty-two male patients who received RT between 2002 and 2021 were included. Median age was 30 years (range, 2 to 61). The primary tumor was testicular in 81% and mediastinal in 15%. Histology was seminoma in 10%. At diagnosis, the median number of BM was 2, and the median largest diameter was 1.8 cm. Initial RT included whole brain radiation therapy in 55%, stereotactic radiosurgery in 34%, and both in 10%. 31% had resection preceding RT. Most patients had extracranial disease (79%) and received chemotherapy within a month of RT (66%). During RT, radiographic progression of extracranial disease occurred in 34% of patients. Median OS and iPFS were 20.6 and 27.7 months, respectively. Among 41 patients with baseline β-HCG above the normal range, β-HCG decreased at 1 month after RT in 51%. Patients with decreased β-HCG, versus those with increased β-HCG, had significantly better OS (median not reached versus 5.4 months) and iPFS (median not reached versus 4.7 months). These correlations remained significant on multivariate analysis, controlling for largest BM diameter and RT modality (OS: HR = 13, 95% CI = [4.6, 37], p = 1 × 10⁻⁶; iPFS: HR = 6.4, 95% CI = [2.2, 19], p = 6 × 10⁻⁴). These correlations also remained significant whether or not patients had extracranial disease progression during RT (p < 0.05). Among 20 patients with baseline AFP above the normal range, AFP decreased at 1 month after RT in 75%. Likewise, decreased AFP was correlated with better OS on univariate regression (p = 0.04). <h3>Conclusion</h3> To our knowledge, this is the first study to evaluate changes in serum tumor markers as predictors of outcomes after RT for GCT BM. Decrease in β-HCG one month after RT was associated with better OS and iPFS on multivariate analysis, and likewise, decrease in AFP was associated with better OS on univariate analysis. These data indicate that post-RT β-HCG and AFP levels are useful predictors of outcomes in patients with GCT BM.

1st Line Pembrolizumab in Treatment of Stage IV NSCLC Patients – A Pattern of Failure Analysis with Associated Survival Outcomes

<h3>Purpose/Objective(s)</h3> To investigate patterns of failure in metastatic NSCLC patients treated with pembrolizumab and analyze factors associated with oncologic outcomes. By discerning these patterns, a subset of patients could be identified that may benefit from local consolidative therapy. <h3>Materials/Methods</h3> This retrospective analysis included 118 patients diagnosed with metastatic NSCLC from January 2015 to May 2020 at a single institution. Each patient received at least one cycle of pembrolizumab and had radiographic follow up of at least 3 months. Patterns of failure were identified by first radiographic disease progression event after initiation of pembrolizumab. Initial failures were grouped by site of first progression (local (L), regional (R), distant (D), or any synchronous combination of the three (L+/-R+/-D)) as well as pattern of progression (existing lesions only (E), new lesions only (N), or both (B)). Descriptive statistics were used to report patterns of failure. Kaplan-Meier method, log-rank test, and Cox proportional hazard model were used to calculate OS/PFS outcomes, compare subgroups, and analyze patient characteristics for significance. <h3>Results</h3> Median follow up was 8.6 months. The majority of patients presented with synchronous and poly-metastatic (>5 metastases) disease (86% and 70%, respectively). Overall, 71 patients (60%) demonstrated progression. The most common site of first failure was a combination of local, regional, and/or distant progression (51%) and the most common pattern was progression at an existing lesion alone (42%) or at both a new and existing lesion (42%). By anatomical location of first progression, the majority of progression events occurred in existing locoregional lesions: 26 lung events and 24 regional LN (mediastinal/hilar) events. Median time to treatment failure was 4.6 months. Median OS and PFS for the entire cohort were 15.8 and 7.3 months, respectively. Median OS was 41.7 (no progression) vs 12.6 (progression) months (p<0.0001). Stratified by site/pattern of failure, only OS (L: 15.8 mo, R: 21.6 mo, D: 14.3 mo, combination 8.2 mo (p=0.001) and E: 12.6 mo, N: 22.2 mo, B: 8.5 mo (p=0.004)) was statistically significant. Median OS was significantly improved in patients who experienced oligoprogression vs systemic progression (19.4 vs 8.5 mo, p<0.0001). On UVA, only history of prior systemic therapy (OS and PFS) and intracranial disease at initial time of diagnosis (PFS only) were significant. On MVA, age < 65 (OS only), history of prior systemic therapy (OS and PFS), lower N stage (PFS only), and intracranial disease (PFS only) were found to be significant. <h3>Conclusion</h3> As the paradigm for treating metastatic NSCLC patients continues to evolve, elucidating patterns of failure and the factors associated with it can aid in identifying those who would benefit from additional (and potentially aggressive) local therapy. Further investigation is warranted.

Clinical utility of interim CT scans in patients receiving chemoimmuntherapy for first line treatment of follicular lymphoma

Interim imaging with computed tomography (iCT) to assess response is common during frontline chemoimmunotherapy for follicular lymphoma (FL), but there is little evidence of its utility. We retrospectively reviewed outcomes of iCT in 190 patients with biopsy-proven FL who received first-line chemoimmunotherapy from 2003–2018. Most iCTs showed partial response (PR, 83%), with a minority showing complete response (CR, 8%) or stable disease (5%). Seven patients (4%) had radiographic disease progression (PD) on iCT; on repeat biopsy, four had another malignancy identified and three had transformation to DLBCL. Only one had asymptomatic PD. The 3-year PFS of all patients was 74% (median follow up 75 months). Patients with PR on iCT had similar 3-year PFS and OS as those with CR. In conclusion, iCT has limited utility in identifying patients with asymptomatic early progression during first-line treatment. Patients with PD mid-treatment warrant biopsy to identify histologic transformation or other malignancies.

Postexposure progression of pneumoconiosis among former Appalachian coal miners.

The prevalence of pneumoconiosis among working United States underground coal miners has been increasing for the past two decades, with the highest rates of disease observed among miners in the central Appalachian states of Kentucky, Virginia, and West Virginia. Surveillance for this disease in the United States focuses on working coal miners, who continue to be occupationally exposed to dust. This study examines the radiographic evidence for postexposure progression of pneumoconiosis in a population of former coal miners no longer occupationally exposed to coal mine dust who were seen at a community radiology clinic in eastern Kentucky. Data were obtained and analyzed from clinical records of former coal miners who had a clinic encounter during January 1, 2017-August 1, 2019, a recorded final year of employment, and ≥2 postemployment digital chest radiographs. Radiographs were classified according to the International Labour Office guidelines by at least two B Readers. A final summary pneumoconiosis severity score (range, 0-13), accounting for both small and large opacities, was assigned to each chest radiograph. Progression was defined as an increase in severity score between a miner's radiographs over time. Data for 130 former coal miners were analyzed. All miners were male and most (n = 114, 88%) had worked primarily in Kentucky. Information on race/ethnicity was not available. The most common job types were roof bolters (n = 51, 39%) and continuous miner operators (n = 46, 35%). Forty-one (31.5%) miners had evidence of radiographic disease progression after leaving the workforce, with a median of 3.6 years between first and latest postretirement radiograph. A total of 80 (62%) miners had evidence of pneumoconiosis on their latest radiograph, and two-thirds (n = 53) of these were classified as progressive massive fibrosis (PMF), the most severe form of the disease. Postexposure progression can occur in former coal miners, emphasizing the potential benefits of continued radiographic follow-up postemployment. In addition to participating in disease screening throughout their careers to detect pneumoconiosis early and facilitate intervention, radiographic follow-up of former coal miners can identify new or progressive radiographic findings even after workplace exposure to respirable coal mine dust ends. Identification of progressive pneumoconiosis in former miners has potential implications for clinical management and eligibility for disability compensation.

Incidence, molecular characteristics, and imaging features of "clinically-defined pseudoprogression" in newly diagnosed glioblastoma treated with chemoradiation.

Pseudoprogression (PsP) remains an elusive and clinically important, yet ill-defined, phenomena that, generally, involves a period of early radiographic progression (enhancement) followed by a period of radiographic stability or regression. In the current study, we utilized data from the control arm of a phase III clinical trial in newly-diagnosed glioblastoma to explore imaging characteristics of "clinically-defined PsP", or early radiographic progression (PFS < 6months from chemoradiation) followed by a long post-progression residual overall survival (ROS > 12months). One hundred sixty-nine patients with newly-diagnosed GBM from the control arm of the AVAglio trial (NCT00943826) who presented with early radiographic progressive disease (PD) (< 6months) were included. Clinical characteristics, topographical patterns, and radiomic features were compared between newly-diagnosed GBM exhibiting early PD and early death (< 12-month ROS, "true PD") with those exhibiting early PD and a long residual survival (> 12-month ROS, "clinically-defined PsP"). "Clinically-defined PsP" occurred to 38.5% of patients with early PD, and was more associated with MGMT methylation (P = 0.02), younger age (P = 0.003), better neurological performance (P = 0.01), and lower contrast-enhancing tumor volume (P = 0.002) at baseline. GBM showing "true PD" occurred more frequently in the right internal capsule, thalamus, lentiform nucleus, and temporal lobe than those with "clinical PsP". Radiomic analysis predicted "clinical PsP" with > 70% accuracy on the validation dataset. Patients with early PD that eventually exhibit "clinically-defined PsP" have distinct clinical, molecular, and MRI characteristics. This information may be useful for treating clinicians to better understand the potential risks and outcome in patients exhibiting early radiographic changes following chemoradiation.

Outcomes and Principles of Patient Selection for Laser Interstitial Thermal Therapy for Metastatic Brain Tumor Management: A Multisite Institutional Case Series

Laser interstitial thermal therapy (LITT) is an emerging treatment modality for both primary brain tumors and metastases. We report initial outcomes after LITT for metastatic brain tumors across 3 sites at our institution and discuss potential strategies for optimal patient selection and outcomes. International Classification of Diseases, Ninth Revision and Tenth Revision codes were used to identify patients with malignant brain tumors treated via LITT across all 3 Mayo Clinic sites with at least 6 months follow-up. Local control was based on radiologic and clinical evidence. Overall survival was measured from time of receiving LITT until death or end of the study period. Twenty-three patients were treated for progression of a single (n= 21) or multiple (n= 2) previously radiated metastatic lesions and/or radiation necrosis. Median age was 56 years (interquartile range, 47-66.5 years). LITT achieved local control of the lesion in most patients with metastatic tumors or radiation necrosis (n= 18; 81.8%) for the duration of follow-up. One patient did not have local control data available. Thirteen (56.5%) patients remained alive at the end of the study period. No other patients died of their treated disease during the study period; 5 of 10 deaths were attributable to central nervous system progression outside the treated lesion. Although median survival for this cohort has not yet been reached, the current median survival is 16 months (interquartile range, 12-48.5 months) after LITT for metastatic/radiation necrosis lesions. LITT was associated with sustained local control in 81.8% of patients treated for radiographic progression of metastatic central nervous system disease.

Abstract 1239: Prognostic and predictive value of PIK3CA mutations in metastatic CRC (mCRC)

Abstract Background: Molecular aberrations including MSI, RAS, RAF, and HER2 have been used to guide the management of mCRC. However, the role of PIK3CA mutations is unclear in mCRC. In this study, we aimed to determine the prognostic value of PIK3CA mutations and their predictive value of response to anti-EGFR therapy in mCRC patients (pts). Methods: Pts with mCRC and clinical next generation sequencing were identified from the Clinical Genomics Action Committee database at Moffitt Cancer Center. Clinical and molecular aberration data were retrospectively collected. Progression-free survival (PFS) was the time from treatment initiation to clinical or radiographic disease progression. Overall survival (OS) was the time from diagnosis of metastatic disease to death. Kaplan Meier method and log-rank test were used for survival analysis. A parametric exponential model was implemented for PIK3CA exon analysis to account for small sample size. Pearson correlation coefficient was determined for correlation between PIK3CA and co-mutations. An additional meta-analysis was performed including prior studies of pts with KRAS wild-type (wt) PIK3CA mutant (mut) mCRC receiving anti-EGFR therapy using random effects model. Results: Among 639 pts with mCRC, PIK3CA mutation was positively correlated with KRAS mutation (r=0.11, p=0.006) and negatively correlated with TP53 mutation (r=-0.18, p=&amp;lt;0.001). It was not correlated with BRAF or APC mutations. Among 335 pts with KRAS wt mCRC, 174 were PIK3CA wt without anti-EGFR therapy; 111 were PIK3CA wt with anti-EGFR therapy; 33 were PIK3CA mut without anti-EGFR therapy; and 16 were PIK3CA mut with anti-EGFR therapy. Median OS of PIK3CA mut pts was 35.5 months, significantly shorter (HR 2.0, 95%CI 1.2-3.1) that median OS of 55.3 months in PIK3CA wt mCRC pts. The same was observed in pts (n=10) with PIK3CA exon 20 mutation (mOS: 18.5 months, HR 2.6, 95%CI 1.1-6.0) and pts (n=18) with PIK3CA exon 9 mutation (mOS: 38 months, HR 2.15, 95%CI 1.1-4.3). Among 166 pts evaluable for response rate, 44% PIK3CA wt pts responded to anti-EGFR therapy compared to 56% PIK3CA mut pts (p=0.51). Median PFS between PIK3CA mut and PIK3CA wt pts receiving anti-EGFR therapy was 10.3 versus 7.2 months (p=0.6), respectively. Our study and previously published 12 studies from 2005 to 2015 were examined in a meta-analysis where the included studies lacked significant heterogeneity (I2=0%, p=0.6). Among 1047 pts with KRAS wt mCRC who received anti-EGFR therapy, 104 of them were PIK3CA mut. The estimated risk ratio for response to anti-EGFR therapy was 0.77 (95%CI 0.5-1.1) with prediction interval between 0.4 and 1.6. Conclusion: PIK3CA mutation has positive correlation with KRAS mutation and negative correlation with TP53 mutation in mCRC. PIK3CA mutation confers a worse prognosis but is not predictive for response to anti-EGFR therapy in pts with KRAS wt mCRC. The latter finding was confirmed in an updated meta-analysis of 13 studies including ours. Citation Format: Elaine Tan, Wenyi Fan, Michael Schell, Ibrahim Sahin, Jason Fleming, Todd Knepper, Hao Xie. Prognostic and predictive value of PIK3CA mutations in metastatic CRC (mCRC) [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 1239.