Citations

227 Background: Circulating tumor DNA (ctDNA) consists of small fragments of DNA released into the plasma from cancer cells. Tumor informed ctDNA testing by whole exome sequencing of the primary tumor coupled with multiplex polymerase chain reaction (PCR)-based next generation sequencing of cell free DNA in serum, can detect and quantify ctDNA, allowing for detection of minimal residual disease (MRD). Methods: We conducted a retrospective analysis of 120 patients with colorectal cancer who had at least one tumor-informed ctDNA MRD assay completed between May 6, 2019, and July 1, 2022, at Mayo Clinic, Rochester. Disease recurrence was defined as radiographic evidence consistent with recurrence with or without biopsy confirmation. Data are presented descriptively, including number of ctDNA assays completed, ctDNA positivity prior to disease recurrence, and ctDNA concordance with carcinoembryonic antigen (CEA). The study protocol was exempt after review by the Mayo Clinic Institutional Review Board. Results: One-hundred twenty patients were included in the study with median age at initial disease diagnosis of 67.0 years. Sixty-four percent were male and 94% were white. At time of initial diagnosis, 10 had stage I, 23 stage II, 60 stage III, and 25 stage IV disease. In 120 patients, 476 ctDNA assays were performed, and 110 recurrences were observed among 62 patients. There were 39 instances in which ctDNA was obtained prior to clinical detection of recurrence and of these, at least one ctDNA assay was positive in 28 cases (72%). CEA was obtained prior to recurrence in 88 instances and was elevated in only 39 cases (44%). Among 37 instances where both ctDNA and CEA testing were obtained prior to recurrence, ctDNA was positive in 27 cases (73%) while CEA was positive in 14 cases (38%). ctDNA was positive in 83% of recurrences involving liver and 62.5% of recurrences involving only the lungs. ctDNA and CEA positivity are shown by location of recurrence. ctDNA and CEA were discordant in 44% of instances in which the assays were completed within 2-weeks of each other. Results of a ctDNA assay impacted management decisions in 16% of cases. Conclusions: ctDNA detected 72% of recurrences with higher rates of detection in liver versus lung metastasis. ctDNA performed superiorly to serum CEA in detection of recurrence, suggesting a role in disease surveillance. However, ctDNA impacted disease management in only 16% of patients, suggesting need for better patient selection and further study for ctDNA-based disease management strategy (more details will be reported). [Table: see text]

147 Background: PolyPEPI1018 is an off-the-shelf, multi-peptide vaccine containing 12 immunogenic epitopes derived from 7 cancer testis antigens (CTAs) frequently expressed in patients with colorectal cancer (CRC). PolyPEPI1018 successfully induced anticancer immunity and triggered recruitment and infiltration of cytotoxic T cells into the tumor of MSS mCRC subjects demonstrating also early evidence of clinical activity, in first-line mCRC. Here we report the initial results of the phase Ib study of PolyPEPI1018 vaccine plus trifluridine/tipiracil (TAS-102) in late-stage mCRC patients. Methods: Patients with MSS mCRC who have progressed on ≤2 lines of prior chemotherapy regimen for mCRC received PolyPEPI1018 subcutaneously on days 1 and 15 and TAS-102 orally twice daily on days 1-5 and 8-12 of a 28-day cycle. Treatment continued for up to 7 cycles until disease progression or unacceptable toxicity. Immunomonitoring was performed at both blood and tumor levels prior to- and on study treatment. The primary endpoint of the study was safety and tolerability. Data on objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), overall survival (OS) and correlation studies will be also presented. Results: 15 patients (67% male) started treatment. At baseline, median age was 55 years (range 31–71), 73% had liver metastases and the primary tumor site was colon-sigmoid in 40% and rectum in 33%. The combination was well-tolerated; most common side effect related to PolyPEPI1018 was Grade (Gr) 1-2 local skin reactions in 93% of patients. Gr 3 events. There were no Gr 4 or 5 events. The ORR was 0% and the DCR was 50%. The mPFS was 2.5 months (95%CI 2.1-NR). At the data cut-off (September 7, 2022), the mOS has not been reached; median follow-up was 4.0 months (95% CI 2.2-4.4). Post-treatment, vaccine-specific T cell responses were detected ex vivo in the PBMC of 4/5 subjects tested. In addition, one subject who had no detectable T cell response at peripheral level, responded at the tumor level with more than 300% increase of both CD3+ and CD8+ tumor-infiltrating lymphocytes compared to baseline. Patients with increased PFS (≥ 16 weeks) had robust vaccine-specific T cell responses. Conclusions: To our knowledge, this is the first phase Ib study investigating combination of a cancer vaccine with TAS-102 chemotherapy in advanced MSS mCRC. Our results show that PolyPEPI1018 plus TAS-102 was well-tolerated with few grade 3 AEs beyond what is expected with TAS-102 monotherapy. PolyPEPI1018 induced immunological responses at both peripheral and tumor level, albeit no objective tumor responses could be detected. The study is on-going for the collection of overall survival data. Clinical trial information: NCT05130060 .

139 Background: The fibroblast growth factor receptor (FGFR) pathway plays a key role in cellular proliferation, migration, survival and angiogenesis. Aberrant signaling through FGFR in colorectal cancer and other malignancies results from gene amplification or mutation, chromosomal translocation or ligand-dependent activation of the receptors. Pemigatinib is an oral inhibitor of FGFR1-3 with proven efficacy in FGFR-altered cholangiocarcinoma and myeloid/lymphoid neoplasms, among others. We hypothesized that pemigatinib would improve response rates compared to historical controls in patients with refractory FGF/FGFR-altered mCRC. Methods: ACCRU-GI-1701 was a multicenter, single-arm, Simon’s two-stage phase II clinical trial (NCT04096417) of the FGFR inhibitor pemigatinib in patients (pts) with FGF/FGFR-altered mCRC. Eligible pts had received prior fluoropyrimidine, oxaliplatin, irinotecan, and anti-VEGF/anti-EGFR/anti-PD-1 if eligible. Pts received pemigatinib 13.5 mg once daily on d1-21 of each cycle, with option to escalate to 18 mg in c2 if well tolerated. The primary endpoint was (unconfirmed) objective response (OR). A sample size of 21 evaluable pts would provide 82% power to detect a true OR rate of 20% or greater compared to a historical control of 5 % with a one-sided type I error rate of 0.1. A prespecified interim analysis for futility was planned after 12 evaluable patients. Results: A total of 14 patients were enrolled in the first stage of the study, and all were evaluable for the primary endpoint. No OR were observed (out of 12) crossing the futility boundary and resulting in permanent closure of the study. Among all enrolled patients, median age was 60.5 years, 71.4% were male, 92.9% Caucasian, 42.9% with no prior exposure to TAS-102 or regorafenib, and 64.3% with left-sided primary tumors. Treated patients all had tumors with FGFR1-4 mutations and/or FGF/FGFR amplifications by tissue- and/or blood-based molecular testing; no FGFR translocations were present. OR rate for this study was 0% (95% CI, 0-23.2%), with one patient achieving stable disease as best response. Median progression-free survival was 9.1 weeks (95% CI, 7.9-not evaluable [NE]), and median overall survival was 7.9 months (95% CI, 3.4-NE). Grade 3+ adverse events (AE) were seen in 42.9% of treated patients (including 1 grade 5 AE). Most commonly occurring AEs of any grade were anemia, hyperphosphatemia, alkaline phosphatase increased, aspartate aminotransferase increase, and fatigue. Conclusions: Pemigatinib demonstrated evidence of safety but not clinical activity in this population of patients with FGF/FGFR-altered mCRC. It is unknown whether pemigatinib would be active in mCRC patients with FGFR translocations/fusions as these were not represented in our trial. Translational studies are planned to investigate mechanisms of resistance to this therapy. Clinical trial information: NCT04096417 .

PURPOSE The College of American Pathologists (CAP) has developed a guideline on testing for mismatch repair (MMR) and microsatellite instability (MSI) for patients considered for immune checkpoint inhibitor therapy. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS The CAP guideline was reviewed for developmental rigor by methodologists. An ASCO Endorsement Panel subsequently reviewed the content and the recommendations. RESULTS The ASCO Endorsement Panel determined that the recommendations from the CAP guideline, published on August 3, 2022, are clear, thorough, and based on the most relevant scientific evidence. ASCO endorses Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the College of American Pathologists in Collaboration With the Association for Molecular Pathology and Fight Colorectal Cancer. RECOMMENDATIONS Within the guideline, MMR immunohistochemistry (IHC), MSI polymerase chain reaction, and MSI next-generation sequencing are all recommended testing options for colorectal cancer, MMR-IHC and MSI-polymerase chain reaction for gastroesophageal and small bowel cancer, and only MMR-IHC for endometrial cancer. No recommendation in favor of any testing method over another could be made for any other cancer. Tumor mutational burden was not recommended as a surrogate for DNA MMR deficiency. If MMR deficiency consistent with Lynch syndrome is detected, it should be communicated to the treating physician. Additional information is available at www.asco.org/molecular-testing-and-biomarkers-guidelines .

Abstract We have previously shown that murine epidermal cells (EC) from 5 H-2 compatible donor strains induce cytotoxic T lymphocytes (CTL) in C3H hosts that preferentially lyse donor EC as opposed to donor lymphoid cells (LC). This preference has been shown to be dependent on a single alloantigen disparity, designated epidermal alloantigen (Epa). In this report we studied the specificity of the CTL to determine whether Epa-antigens are in fact EC specific. Two populations of CTL could be identified by cross-immunization, cold-target inhibition, antigen-driven suicide, and limiting-dilution analyses. A minor CTL population recognizes alloantigens that are expressed by both EC and LC, but this population is necessary only for lysis of LC targets. The major CTL population is specific for Epa-antigens and reacts only with EC targets. At the induction phase of CTL responses, donor LC stimulators can weakly stimulate Epa-specific CTL, indicating LC populations express Epa-antigens in immunogenic form but at very low levels compared with EC. The preferential lysis of EC targets in these strain combinations can be attributed to the major Epa-specific CTL population, whereas lysis of LC targets is due to CTL specific for other alloantigens that are shared by EC and LC. The identification of CTL-activating, EC-specific alloantigens may help to explain the extreme immunogenicity of MHC compatible skin allografts.

Abstract Epidermal cells (EC) of AKR and CBA (H-2k) mouse strains share non-H-2 alloantigens that induce potent cytotoxic T lymphocytes (CTL) in H-2 compatible C3H hosts, and these CTL lyse EC targets in preference to lymphoid cell (LC) targets in H-2-restricted fashion in short-term cell-mediated cytotoxicity (CMC) assays. In contrast, C3H EC are not immunogenic in this regard in AKR and CBA hosts. (C3H × CBA)F1 hybrid hosts are nonresponders to AKR EC, exactly like the CBA parent strain hosts, and their own EC are immunogenic in C3H hosts and susceptible to lysis by the CTL so generated. Hence, CBA mice express a non–H-2 CMC determinant on EC that is absent on C3H EC. Offspring produced by backcrossing (C3H × CBA)F1 hybrids to the antigen-negative C3H parent strain were tested individually for their responsiveness to AKR EC immunogens and for the susceptibility of their own EC to lysis by C3H anti-AKR EC effectors. There was a clear 1: 1 distribution of the backcross offspring into 2 populations in both test systems. Moreover, responsiveness and antigenicity were inversely correlated in individual mice. Thus, the expression of EC alloantigens in the segregating offspring depends on the activity of genes at a single Mendelian locus. These results are most compatible with the hypothesis that a loss mutation occurred early in the history of the C3H strain at a non-H-2 locus that specifies a system of alloantigens expressed preferentially on EC. The finding that CTL generated by AKR EC immunogens in C3H/Heston and C3H/Andervont mice exhibit the same preferential lysis of EC as opposed to LC targets is consistent with this hypothesis because these C3H strains separated over 40 yr ago. Because this locus does not appear to correspond to any known locus, we have provisionally designated it the Epa (epidermal alloantigen) locus.

Abstract Epidermal cells (EC) obtained by trypsinization of tail skin of H-2k haplotype mouse strains AKR, B10.BR, B10.K, CBA, C3H, and RF were used as stimulators and targets of cell-mediated cytotoxicity (CMC) in 3-hour chromium-release assays. Host splenic effector cells were generated by priming mice with an injection of EC and boosting in mixed culture with irradiated donor-strain EC stimulators; then assayed for CMC towards donorstrain EC and lymphoid cell (LC) targets. When C3H is the donor strain and any of the other strains the host, little CMC is registered with EC targets. However, when C3H is the host and any of the other strains the donor, the CMC registered with donor-strain EC targets invariably is greater than that registered with LC targets, even with mitogen-induced lymphoblasts, indicating that C3H mice respond to non-H-2 alloantigens preferentially expressed by EC. The CMC evoked in C3H hosts by EC from any of the other other H-2k strains cross-reacts with EC targets from all of them, indicating extensive sharing of target-cell determinants. However, the CMC is H-2 restricted, and mapping tests with recombinant lines on the C57BL/10 background proved that the restriction depends on antigens mapping in the K region of the H-2 complex. T cell elimination tests indicate that the effector cells in these reactions are cytotoxic T lymphocytes. Moreover, tests conducted with medium supplemented with adult mouse serum instead of fetal calf serum indicate that the reactions are not dependent on xenogeneic serum but represent true examples of H-2-restricted CMC directed towards non-H-2 alloantigens expressed preferentially on EC.

Background: Research regarding financial trends in craniofacial trauma surgery is limited. Understanding these trends is important to the evolvement of suitable reimbursement models in craniofacial plastic surgery. The purpose of this study was to evaluate the trends in Medicare reimbursement rates for the top 20 most utilized surgical procedures for facial trauma. Methods: The 20 most commonly utilized Current Procedural Terminology (CPT) codes for facial trauma repairs in 2018 were queried from The National Summary Data File from the Centers for Medicare & Medicaid Services (CMS). Reimbursement data for each procedure was then extracted from The Physician Fee Schedule Lookup Tool. Changes to the United States consumer price index (CPI) were used to adjust all gathered data for inflation to 2021 US dollars (USD). The average annual and the total percent change in reimbursement were calculated for the included procedures based on the adjusted trends from the years 2000 to 2021. Results: From 2000 to 2021, the average reimbursement for all procedures decreased by 16.6% after adjusting for inflation. Closed treatment of temporomandibular joint dislocation and closed treatment of nasal bone fractures without manipulation demonstrated the greatest decrease in mean adjusted reimbursement at −48.7% and −48.3%, respectively, while closed treatment of nasal bone fractures without stabilization demonstrated the smallest mean decrease at −1.4% during the study period. Open treatment of nasal septal fractures with or without stabilization demonstrated the greatest increase in mean adjusted reimbursement at 18.9%, while closed treatment of nasal septal fractures with or without stabilization demonstrated the smallest increase at 1.2%. The average reimbursement for all closed procedures in the top 20 decreased by 19.3%, while that for all open procedures decreased by 15.5%. The adjusted reimbursement rate for all top 20 procedures decreased by an average of 0.8% each year. Conclusions: To the best of our knowledge, this is the first study to comprehensively evaluate trends in Medicare reimbursement for facial trauma surgical repairs. Adjusting for inflation, Medicare reimbursement for the top 20 most commonly utilized procedures has largely decreased from 2000 to 2021. Consideration of these trends by surgeons, hospital systems, and policymakers will be important to assure continued access to meaningful surgical facial trauma care in the United States.

AbstractBackgroundIn familial frontotemporal lobar degeneration (f‐FTLD), plasma levels of neurofilament light (NfL) are elevated at least two years prior to symptom onset and predict future clinical status. The Neurofilament Surveillance Project (NSP), an actively recruiting observational study, seeks to obtain higher resolution data of temporal changes in plasma NfL to better understand its clinical utility in f‐FTLD interventional trials. The NSP is a pre‐competitive collaboration sponsored by the Bluefield Project to Cure FTD and funded by biotechnology and pharmaceutical companies and nonprofit organizations.MethodParticipants must be members of families with disease‐causing mutations in C9orf72, MAPT or GRN and enrolled in the ALLFTD natural history study. Up to 335 participants, with roughly equal representation across mutation type, provide plasma quarterly for 3 years (4355 samples total) to enable the observation of peripheral NfL levels longitudinally during disease onset and progression. Plasma is collected by certified mobile research nurses during remote visits, and NfL is measured in batch at least every 6 months. NfL measurements from one plasma aliquot per draw will be correlated with annual assessments obtained in the ALLFTD study, including measures of disease severity (CDRÒ+NACC‐FTLD, CGI, etc.), cognitive function from the UDS Neuropsychology Battery, and volumetric MRI data. Additional plasma aliquots are reserved for future analyses of other biomarkers during the course of the study; another subset of aliquots is reserved to share with interested investigators after the study ends.ResultAs of 1/19/22, the NSP had enrolled 161 participants, including 62 from C9orf72 kindreds, 60 from MAPT kindreds, and 28 from GRN kindreds. One‐hundred forty‐five participants had completed their initial visit, and 109 had completed more than 3, and up to 5, quarterly blood draws. Enrollment and study visits are ongoing despite COVID‐related limitations.ConclusionThe quarterly blood sampling from this study, combined with annual comprehensive clinical assessments through the ALLFTD natural history study, will enable a more detailed understanding of when and how NfL levels change during phenoconversion and/or disease progression in f‐FTLD mutation carriers. These data will be especially informative in the context of the targeted investigational therapeutics for f‐FTLD now entering clinical trials.

AbstractBackgroundWe developed the Institute on Methods and Protocols for Advancement of Clinical Trials in ADRD (IMPACT‐AD) to address the shortage of qualified investigators with adequate training and expertise to conduct Alzheimer’s Disease (AD) and AD Related Dementias (ADRD) clinical trials.MethodWe describe the experience of the first two years of funding of the IMPACT‐AD course, specifically the rates of applications to the course, descriptive summaries of the accepted trainees, and the measures of participant satisfaction and learning.ResultOver the first two years of the course, we received 195 eligible applications to the course. Most (n = 121, 62%) applicants were female and nearly half self‐reported as being African American/Black, Asian, or Pacific Islander race and/or Hispanic/Latino ethnicity. Forty‐one applicants (21%) indicated that they were the first in their family to attend collegeOf 69 total trainees accepted to the course (36% acceptance rate), a majority (n = 44, 64%) were female. Twenty‐eight (41%) self‐reported as being African American/Black, Asian, or Pacific Islander race and eleven (16%) were of Hispanic ethnicity. Fourteen trainees (20%) identified as being the first person in their family to attend college. Among trainees, 24 (35%) were MDs, 30 (43%) were PhDs, and 9 (13%) held master’s degrees.Course lecture topics were rated, on average, as “essential” or “valuable” by 98% of trainees. Across lecture topics, on average, 48% of trainees rated their prior knowledge of topics as “very strong” or “strong,” and 11% of trainees rated their prior knowledge as “weak.” Overall, 52% of trainees evaluated their change in knowledge based on the lectures as “very much increased,” 46% as “somewhat” or “slightly” increased, and 2% as “no change.” Results were similar for the two tracks. Based on pre‐ and post‐course assessments, trainees improved their knowledge of covered content (from 62% to 79% correct responses on knowledge assessments).ConclusionThe IMPACT‐AD course is achieving its mission of educating and diversifying the next generation of ADRD trialists.We thank Dr. Laurie Ryan and Dr. Kristina McLinden from the National Institute on Aging for their key contributions in leadership and scientific guidance of IMPACT‐AD.