Citations

Abstract Interpretation of the clinical significance of somatic gene variants in cancer remains a major challenge in cancer diagnosis, prognosis and treatment response prediction. We will report on progress and plans of the Clinical Genome Resource (ClinGen) Somatic Cancer Clinical Domain Working Group (CDWG). The CDWG membership consists of over 150 multi-disciplinary experts in cancer biology, oncology, pathology, genetics, genomics and informatics. The mission of the ClinGen Somatic Cancer CDWG is to facilitate the development of data curation guidelines and standards to determine the clinical significance of somatic alterations in cancer, thereby enhancing the usability, dissemination and implementation of cancer somatic changes in the ClinGen resource and other knowledgebases including CIViC, ClinVar, and the Variant Interpretation for Cancer Consortium (VICC) MetaKB. Our goal is to create high-quality assertions of the clinical significance of specific somatic variants in cancer by leveraging the CIViC curation interface, adapting the germline procedures of ClinGen to somatic variant interpretation, and implementing the interoperability standards of the Global Alliance for Genomics and Health (GA4GH). The ClinGen Somatic effort is overseen by the Somatic CDWG and reports progress to the overall ClinGen consortium. There are Somatic Cancer subdomains focused on particular clinically important domains of cancer variant interpretation including three Task Forces (covering Pediatric Cancer, Hematologic Cancer, and Solid Tumors) and a growing number of Somatic Cancer Variant Curation Expert Panels (SC-VCEPs). To improve quality and consistency of clinical interpretations, each candidate somatic cancer VCEP must complete a four step approval process adapted from ClinGen’s work in Germline disease domains. The Somatic CDWG works to ensure that each group is aware of available training materials and detailed standard operating procedures. Each SC-VCEP also coordinates with the ClinGen Cancer Variant Interpretation Committee (CVI) whose goal is to support development of granular specifications for the AMP/ASCO/CAP guidelines for somatic variant interpretation. New SC-VCEPs are anticipated to focus on specific clinically relevant genes, pathways, disease entities, variant classes or treatment modalities. Currently, three SC-VCEPs have begun to work through the four step process (focused on FGFR mutations, NTRK fusions, and FLT3 mutations respectively), and two more SC-VCEPs are in the planning stage (Histone H3 and Ph-like ALL). To date, ClinGen Somatic groups have contributed 619 evidence lines into CIViC from 353 published papers and 21 assertions of clinical significance. Input from the AACR community is critical for the establishment of new SC-VCEPs that address areas of variant interpretation with the greatest need. Citation Format: Jason Saliba, Gordana Raca, Angshumoy Roy, Ian King, Shamini Selvarajah, Xinjie Xu, Rashmi Kanagal-Shamanna, Laveniya Satgunaseelan, David Meredith, Mark Evans, Alanna Church, Panieh Terraf, Yassmine Akkari, Heather E. Williams, Wan-Hsin Lin, Chimene Kesserwan, Deborah I. Ritter, Kilannin Krysiak, Arpad Danos, Alex Wagner, Marilyn M. Li, Dmitriy Sonkin, Jonathan S. Berg, Sharon E. Plon, Heidi L. Rehm, Shashikant Kulkarni, Ramaswamy Govindan, Obi L. Griffith, Malachi Griffith, on behalf of the ClinGen Somatic CDWG. The Clinical Genome Resource (ClinGen) somatic cancer clinical domain working group [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 1192.

Abstract Background The pathogenesis of pityriasis rubra pilaris (PRP) is not completely understood, but interleukin (IL)-17 has been shown to play a critical role. There are no reliable immunomodulatory agents to treat PRP. We conducted an open-label, single-arm clinical trial of secukinumab, a monoclonal antibody that inhibits IL-17A, for the treatment of PRP. Objectives To evaluate the clinical efficacy of secukinumab and define the transcriptomic landscape of PRP and its response to IL-17A blockade. Methods Twelve patients with PRP were recruited for an open-label trial of secukinumab. Patients received a 24-week course of secukinumab. The primary endpoint was a ≥ 75% reduction in Psoriasis Area and Severity Index (PASI 75) from baseline to week 28. Secondary endpoints included PASI 90, change in Physician’s Global Assessment (PGA), and change in Dermatology Life Quality Index (DLQI). RNA sequencing was performed on lesional and nonlesional skin biopsies obtained at baseline and week 2. Sample groups were compared to identify differential gene expression and pathway enrichment. This trial was registered with ClinicalTrials.gov: ‘Cosentyx (secukinumab) for the treatment of adult onset pityriasis rubra pilaris’ – NCT03342573. Results At week 28, six of 11 patients (55%) achieved PASI 75, and three patients (27%) achieved PASI 90. PGA (P = 0.008) and DLQI scores (P = 0.010) showed significant improvement with treatment. No serious treatment-related adverse events were encountered. Treatment with secukinumab normalized transcriptional differences between lesional and nonlesional skin. Transcriptomic data from nonresponsive patients suggest that overactivity of innate immune pathways may be driving resistance to secukinumab. Conclusions Secukinumab appears to be an effective treatment for PRP and warrants further investigation. PRP is a transcriptionally heterogeneous disease, reflecting its variable response to therapy. Agents targeting other IL-17 isoforms and innate immune mediators should be considered for future clinical trials. What is already known about this topic? The pathogenesis of pityriasis rubra pilaris is incompletely understood. Successful treatment has been reported with a variety of immunomodulatory agents, but disease is often refractory to therapy.Interleukin (IL)-17 is thought to drive keratinocyte proliferation and vascular dysfunction in this disease.A previous trial demonstrated efficacy of the anti-IL-17A drug ixekizumab for pityriasis rubra pilaris. What does this study add? Herein we describe the findings of a clinical trial of secukinumab, an anti-IL-17A monoclonal antibody, for the treatment of pityriasis rubra pilaris.Secukinumab was effective in treating pityriasis rubra pilaris.Our transcriptomic data give new insight into the expressional changes that occur in response to secukinumab and suggest mechanisms of treatment resistance.

Abstract Background: Genome-wide association studies (GWAS) of multiple myeloma in populations of European ancestry (EA) identified and confirmed 24 susceptibility loci. For other cancers (e.g., colorectum and melanoma), risk loci have also been associated with patient survival. Methods: We explored the possible association of all the known risk variants and their polygenic risk score (PRS) with multiple myeloma overall survival (OS) in multiple populations of EA [the International Multiple Myeloma rESEarch (IMMEnSE) consortium, the International Lymphoma Epidemiology consortium, CoMMpass, and the German GWAS] for a total of 3,748 multiple myeloma cases. Cox proportional hazards regression was used to assess the association between each risk SNP with OS under the allelic and codominant models of inheritance. All analyses were adjusted for age, sex, country of origin (for IMMEnSE) or principal components (for the others) and disease stage (ISS). SNP associations were meta-analyzed. Results: SNP associations were meta-analyzed. From the meta-analysis, two multiple myeloma risk SNPs were associated with OS (P < 0.05), specifically POT1-AS1-rs2170352 [HR = 1.37; 95% confidence interval (CI) = 1.09–1.73; P = 0.007] and TNFRSF13B-rs4273077 (HR = 1.19; 95% CI = 1.01–1.41; P = 0.04). The association between the combined 24 SNP MM-PRS and OS, however, was not significant. Conclusions: Overall, our results did not support an association between the majority of multiple myeloma risk SNPs and OS. Impact: This is the first study to investigate the association between multiple myeloma PRS and OS in multiple myeloma.

Context.— Clinical testing for tumor cell-free DNA (cfDNA) has evolved rapidly, but no practice guidelines exist. Objective.— To summarize cfDNA laboratory practices based on self-reporting and assess preanalytical, analytical, and postanalytical trends that may influence the quality, accuracy, and consistency of cfDNA testing. Design.— Data were derived from the College of American Pathologists cfDNA proficiency testing program submitted by 101 participating laboratories from 2018 to 2019. Results.— Most laboratories performing clinical circulating tumor DNA testing are commercial/nonhospital (71.2%; 72 of 101) and international (77.2%; 78 of 101) laboratories. Commercial laboratories had higher monthly test volumes than hospital-based laboratories (median, 36 versus 7–8) and tended to have larger gene panels (median, 50 versus 11 genes) when panel-based testing was offered. The main clinical indications include therapy selection and treatment/disease monitoring. Plasma is the most commonly accepted specimen, which is predominantly collected in cell-stabilizing tubes. Equal proportions of laboratories use next-generation sequencing (NGS) and non-NGS methods to assess key genes, including EGFR, BRAF, KRAS, NRAS, and IDH1. Most laboratories reported a lower limit of detection (LLOD) of 0.5%, variant allele frequency or less, which did not differ by method, NGS or non-NGS, except for EGFR. Sixty-five percent (17 of 26) of laboratories using the US Food and Drug Administration (FDA)-approved non-NGS EGFR assay report analytical sensitivities higher than 0.5%, as compared to 15% (16 of 104) of laboratories using an alternative NGS or non-NGS method. There is also a wider range in LLODs obtained for the FDA-approved EGFR assay than nonapproved assays. Conclusions.— These results highlight emerging practice trends and serve as a foundation to initiate future practice recommendations.

Background: Specialty exposure is most influential in a medical student’s decision to pursue plastic surgery training. We aimed to understand what opportunities exist for students through national plastic surgery organizations. Methods: The American Board of Plastic Surgery, American Society of Plastic Surgeons, and The Aesthetic Society provide online lists of related organizations. Cross-referencing lists yielded 47 unique organizations. Screening for presence of annual meeting and relevance to student and resident education yielded 14 organizations. Bylaws/web-domains were reviewed for information related to the annual meeting, leadership opportunities, membership, grants, and travel scholarships. If available, previrtual/in-person and virtual meeting prices were collected. Lastly, discrepancies between webpage information and phone/email correspondence were noted. Results: All (100%) organizations welcomed students at annual meetings. Eleven promoted student presentation/submission. Average student registration fee was $109.3 ± SD$136.5 compared with $181.20 ± SD$157.20 for residents. Of organizations providing previrtual and virtual pricing (n = 10, 71.4%), there was an average price reduction in student registration of $92 (range: $0–375). Average student membership was $31.70/year ± SD $45.50 compared with $38.80 per year ± SD $65.90 for residents. The percentages of organizations offering student research grants, travel scholarships, and national student leadership were 21.4% (n = 3), 35.8% (n = 5), and 28.6% (n = 4) respectively. No organizations had student chapters/committees. All organizations (100%) contained at least one discrepancy between webpage/bylaw and email/phone. Conclusions: Our results suggest that although national opportunities seem to be limited, a role exists for further engagement, with interested students eager to take the initiative. Virtual conferences present a lower-cost alternative for students and residents.

9135 Background: Bronchial carcinoid (BC) is often categorized into multifocal (MBC) or solitary (SBC). MBC, excluding tumorlet and diffuse idiopathic pulmonary neuroendocrine cell hyperplasia, is considered a relatively uncommon subgroup of BC, with much of the MBC literature stemming from case reports/small series. Our study analyzes MBC among a large cohort of 569 patients with BC and argues for change to the current clinical understanding of MBC. We suggest using the term bronchial neuroendocrine tumor (bNET) to more accurately represent its cells of origin and move away from “carcinoid” (historically meaning “carcinoma-like”) and the outdated associated connotation that carcinoids all have a similar, benign clinical and biological behavior. Methods: Using the Mayo Clinic Epidemiology and Genetics of Lung Cancer Database with Institutional Review Board approval, we retrospectively reviewed 569 patients with bNET (204 males, 365 females) presenting to Mayo Clinic Rochester between 1/1997-12/2012. We used univariate and multivariate Cox regression analyses to evaluate factors affecting overall survival. Results: 80 patients (of 569, 14.1%) were diagnosed with multifocal (MbNET) and 489 with solitary (SbNET). Two-sided Fisher’s exact tests found that older age, female gender, never having smoked cigarettes, and tumorlets were associated with MbNET diagnosis. Family lung cancer history, histopathologic grading (pathology: typical vs. atypical), Ki67, and presence of syndromes (carcinoid, Cushing, and MEN1 syndromes) were similar between MbNET and SbNET groups. Most MbNET cases were stage III-IV at the time of diagnosis, while the majority of SbNET cases were stage I. 5-year OS (83%) and 5-year PFS (75%) of MbNET patients were higher than those of their SbNET counterparts (74% and 68%, respectively). Metastasis status was an independent prognostic factor of poor OS in SbNET (P<0.001) but not in MbNET (P=0.71)(Table). Conclusions: Clinical, radiologic, and histopathologic characteristics and prognostic factors differed between SbNET and MbNET. MbNET arose as a new entity often with advanced stage disease, but good prognosis, which does not follow the NSCLC TNM staging system as in the 2009 NCCN guidelines (used during this study) or the updated 2021 NCCN guidelines which continue to stage lung carcinoid similarly to NSCLC. It may be beneficial to consider multifocal lung carcinoid instead as multifocal bNET, a new clinical entity, warranting a novel staging approach that more accurately reflects prognosis.[Table: see text]

8054 Background: The introduction of immunomodulatory agents, proteasome inhibitors, and autologous stem cell transplantation (ASCT) has improved outcomes for patients with multiple myeloma (MM), but those with high risk MM (HRMM) have a poor long-term prognosis. Herein we provide survival outcomes on the first randomized trial in newly diagnosed HRMM, S1211, to follow-up on the previously reported progression-free survival (PFS) (NCT01668719, Usmani SZ et al, Lancet Haem 2021). Methods: S1211 is a randomized phase II trial comparing 8 cycles of lenalidomide, bortezomib and dexamethasone (RVd) induction followed by dose-attenuated RVd maintenance until disease progression with or without elotuzumab (RVd-Elo). Stem cell collection was allowed, but ASCT was deferred until progression. HRMM was defined by one of the following: gene expression profiling high-risk (GEPhi), t(14;16), t(14;20), del(17p), amplification 1q21, primary plasma cell leukemia (pPCL), or elevated serum LDH (> 2X ULN). Median PFS was the primary endpoint, using a one-sided stratified log-rank test at a one-sided significance level of 0.1. Secondary endpoints included overall response rate (ORR), adverse events (AE), serious adverse events (SAE) and OS. Response was assessed using the IMWG 2009 criteria. Results: S1211 enrolled 103 evaluable patients, RVd n=54, RVd-Elo n=49. 74% had ISS II/III, 48% amp1q21, 38% del(17p), 11% t(14;16), 9% GEPhi, 7% pPCL, 5% t(14;20) and 4% elevated LDH (17% >1 feature). With median follow-up of 72 months (mos.), no difference in median PFS was observed [RVd-Elo=29 mos., RVd= 34 mos., HR = 1.11 (80% CI=0.82, 1.49, p=0.66]. No difference in OS was observed [RVd-Elo = median not reached (NR), RVd= 68 mos., HR = 0.85 (80% CI: 0.59, 1.23), p-value = 0.58]. 76% pts had >Grade 3 AEs, no differences in the safety profile were observed. Amongst patients with gain/amp 1q21, median PFS was [RVd-Elo=31 mos., RVd= 37 mos., HR = 1.48 (80% CI= 0.95, 2.31), p=0.25], median OS was [RVd-Elo = 61 mos., RVd= 68 mos., HR = 1.23 (80% CI: 0.72, 2.10), p-value = 0.63]. In patients with del(17p), median PFS was RVd-Elo=41 mos., RVd= 30 mos.[HR = 0.98 (80% CI= 0.60, 1.58), p=0.95], median OS RVd-Elo = NR, RVd= 72 mos., [HR = 0.77 (80% CI: 0.40, 1.48), p-value = 0.61]. Conclusions: In the first randomized HRMM study reported to date, the addition of Elo to RVd induction and maintenance did not improve PFS and OS with a median follow-up of 6 years. Although the median PFS for Del17p subgroup on RVd-Elo arm is higher than RVd, it did not achieve statistical significance. The PFS and OS observed for gain/amp 1q21 and del17p in the RVd control arm may serve as important benchmarks for future enrichment design HRMM clinical trials. The PFS and OS in both arms of the study exceeded the original statistical assumptions and support the role for PI/IMiD combination induction/maintenance therapy for this population. Clinical trial information: NCT01668719.

e19533 Background: Pneumocystis pneumonia (PJP) is a catastrophic infection seen in the context of low CD4 counts. Brentuximab vedotin (BV) is a drug antibody conjugate targeting CD30 and is used to treat patients with Hodgkin’s lymphoma (HL) and T-cell lymphoma (TCL). PJP prophylaxis is not currently recommended for patients receiving BV-based treatment despite co-expression of CD30 on CD4 cells. The frequency of PJP following BV remains poorly defined. Methods: We evaluated patients who received BV between January 1, 2011 and October 31, 2021 at Mayo Clinic for the development of PJP. Patient demographics and clinical characteristics including underlying disease, chemotherapy regimen, absolute lymphocyte count (ALC), and steroid exposure were collected. Patients who developed PJP more than 3 months after their last BV exposure were excluded. Results: Of 402 BV recipients identified, 63 received PJP prophylaxis and were omitted. Fourteen of the 339 (4.1%) not on prophylaxis developed PJP following BV. Those infected had a median age of 61 (22-87), 71% were male. The most common diagnoses were HL, TCL, and primary mediastinal B-cell lymphoma at rates of 57%, 21%, and 14% respectively. Therapy regimens included BV monotherapy, BV-CHP, and BV-AVD at rates of 43%, 21%, and 14% respectively. BV represented median 2nd line of therapy (1-10) and patients received median of 3 doses (1-10) prior to PJP diagnosis. Patients with PJP had median ALC of 620 (370-3500). 71.4% (10/14) had an ALC less than 750 and among those with ALC greater than 1000, 75% (3/4) had underlying diagnosis of HL. Three patients had CD4 count measured at time of PJP diagnosis with median value of 157 (5-175). 57.1% (8/14) had no steroid exposure beyond the treatment regimen. 14.3% (2/14) were on chronic doses of 5mg prednisone for autoimmune conditions. Short bursts of steroids (prednisone 40 mg) prior to PJP were seen in 21.4% (3/14) with median exposure of 8 days (7-10). One patient had prolonged steroid exposure but was weaned off 17 days prior to PJP diagnosis. 71.4% were older than 50 years at time of PJP. Conclusions: We observed rates of PJP above the commonly accepted threshold of 3.5% for recommending prophylaxis. Among patients with an ALC greater than 1000, 75% had HL raising the question of a qualitative defect in immunity. Close ALC monitoring is recommended for patients receiving BV with a low threshold to institute PJP prophylaxis, especially amongst those older than 50 or with a diagnosis of HL.[Table: see text]

e19532 Background: The traditional approach to the treatment of early-stage classical Hodgkin lymphoma (cHL) has been combined modality therapy (CMT) with both chemotherapy and radiotherapy (RT). CMT has shown improved disease control, but RT can lead to long-term adverse effects, including secondary malignancies and cardiac toxicity. Multiple clinical trials have assessed treatment de-escalation strategies to chemotherapy-alone regimens, but results are conflicting. We aimed to assess the real-world implications of these trials by comparing patient outcomes based upon treatment with CMT or chemotherapy-alone. Furthermore, we proposed to assess differences in treatment outcomes stratified by disease bulk, favorable/unfavorable disease, and PET2 response. Methods: We conducted a retrospective, multi-center cohort study of consecutive adult patients with early-stage (stage IA-IIB) cHL treated between January 2010-December 2020. Baseline characteristics, treatment modality, and outcomes were abstracted by chart review. Available PET2 scans (n=110) were independently reviewed by a blinded nuclear radiologist. Deauville score (DS) ≥4 was characterized as positive (+), and DS≤3 negative (-). All analysis was conducted using intention-to-treat principles based upon the initial treatment plan (CMT or chemotherapy-alone). Results: In 125 patients [58% male, median age 34 (range, 18-78)] with early-stage cHL, CMT was intended in 63 (50%) patients, with chemotherapy-alone in 62 (50%). Bulky disease was observed in 43 (34%), unfavorable disease in 81 (65%), and 15 (14%) were found to be PET2+. With median follow-up of 59.8 months (95%CI, 48.6 to 71.0), 5 (4%) deaths occurred, and 17 (14%) patients had relapsed/refractory disease. No significant differences in overall survival (OS) were seen based upon treatment intention. However, there was substantially reduced progression-free survival (PFS) (Table) with chemotherapy-alone in the whole cohort, and also in those with bulky, unfavorable, and PET2+ disease. No significant PFS differences were seen based upon treatment intention for patients with non-bulky, favorable, or PET2- disease. Conclusions: Based on our real-world experience, CMT appears particularly beneficial for patients with bulky disease, unfavorable prognostic factors, and PET2+ disease. However, while recent trials showed a benefit of CMT in non-bulky, favorable and PET2- patients, chemotherapy-alone may be comparable for these patients in actual clinical practice.[Table: see text]