Search

Cutaneous metastases in pancreatic cancer (PC) are rare. Herein, we evaluate the clinical, genomic, and other descriptors of patients with PC and cutaneous metastases.Institutional databases were queried, and clinical history, demographics, PC cutaneous metastasis details, and overall survival (OS) from cutaneous metastasis diagnosis were abstracted. OS was estimated using Kaplan-Meier methods.Forty patients were identified, and median age (Q1-Q3, IQR) of PC diagnosis was 66.0 (59.3-72.3, 12.9) years. Most patients had Stage IV disease at diagnosis (n = 26, 65%). The most common location of the primary tumor was the tail of the pancreas (n = 17, 43%). The most common cutaneous metastasis site was the abdomen (n = 31, 78%), with umbilical lesions occurring in 74% (n = 23) of abdominal lesions. The median OS (95% CI) was 11.4 months (7.0, 20.4). Twenty-three patients had umbilical metastases (58%), and 17 patients had non-umbilical metastases (43%). The median OS (95% CI) was 13.7 (7.0, 28.7) months in patients with umbilical metastases and 8.9 (4.1, Not reached) months in patients with non-umbilical metastases (p = 0.1). Sixteen of 40 (40%) patients underwent somatic testing, and findings were consistent with known profiles. Germline testing in 12 (30%) patients identified pathogenic variants in patients: CHEK2, BRCA1, and ATM.Cutaneous metastases from PC most frequently arise from a pancreas tail primary site and most frequently occur in the umbilicus. Cutaneous metastases may generally be categorized as umbilical or non-umbilical metastases.

The incidence of esophagogastric cancer is rapidly rising, but only a minority of patients derive durable benefit from current therapies. Chemotherapy as well as anti-HER2 and PD-1 antibodies are standard treatments. To identify predictive biomarkers of drug sensitivity and mechanisms of resistance, we implemented prospective tumor sequencing of patients with metastatic esophagogastric cancer. There was no association between homologous recombination deficiency defects and response to platinum-based chemotherapy. Patients with microsatellite instability–high tumors were intrinsically resistant to chemotherapy but more likely to achieve durable responses to immunotherapy. The single Epstein–Barr virus–positive patient achieved a durable, complete response to immunotherapy. The level of ERBB2 amplification as determined by sequencing was predictive of trastuzumab benefit. Selection for a tumor subclone lacking ERBB2 amplification, deletion of ERBB2 exon 16, and comutations in the receptor tyrosine kinase, RAS, and PI3K pathways were associated with intrinsic and/or acquired trastuzumab resistance. Prospective genomic profiling can identify patients most likely to derive durable benefit to immunotherapy and trastuzumab and guide strategies to overcome drug resistance.Significance: Clinical application of multiplex sequencing can identify biomarkers of treatment response to contemporary systemic therapies in metastatic esophagogastric cancer. This large prospective analysis sheds light on the biological complexity and the dynamic nature of therapeutic resistance in metastatic esophagogastric cancers. Cancer Discov; 8(1); 49–58. ©2017 AACR.See related commentary by Sundar and Tan, p. 14.See related article by Pectasides et al., p. 37.This article is highlighted in the In This Issue feature, p. 1

Concordance between copy-number inferred from next generation sequencing and protein overexpression by IHC or gene amplification by FISH.

Additional results for dual probe EGFR and ERBB2 FISH from Patients 9, 30 and 32.

Text legends for Supplementary Figures S1-S4.

Supplementary Table 1: Comprehensive clinical data and sample IDs. Supplementary Table 2: Summary of baseline patient and sample characteristics. Supplementary Table 3: List of somatic mutations identified in all samples. Supplementary Table 4: Detailed data for assesment of ERBB2 amplification. Supplementary Table 5: Genes included on MSK-IMPACT platform

Supplementary Figure Legends

Supplementary Data from Clinico-genomic Characterization of ATM and HRD in Pancreas Cancer: Application for Practice

Supplementary Figure from Clinico-genomic Characterization of ATM and HRD in Pancreas Cancer: Application for Practice

Purpose:Characterizing germline and somatic ATM variants (gATMm, sATMm) zygosity and their contribution to homologous recombination deficiency (HRD) is important for therapeutic strategy in pancreatic ductal adenocarcinoma (PDAC).Experimental Design:Clinico-genomic data for patients with PDAC and other cancers with ATM variants were abstracted. Genomic instability scores (GIS) were derived from ATM-mutant cancers and overall survival (OS) was evaluated.Results:Forty-six patients had PDAC and pathogenic ATM variants including 24 (52%) stage III/IV: gATMm (N = 24), and sATMm (N = 22). Twenty-seven (59%) had biallelic, 15 (33%) monoallelic, and 4 indeterminate (8%) variants. Median OS for advanced-stage cohort at diagnosis (N = 24) was 19.7 months [95% confidence interval (CI): 12.3–not reached (NR)], 27.1 months (95% CI: 22.7–NR) for gATMm (n = 11), and 12.3 months for sATMm (n = 13; 95% CI: 11.9–NR; P = 0.025). GIS was computed for 33 patients with PDAC and compared with other ATM-mutant cancers enriched for HRD. The median was lower (median, 11; range, 2–29) relative to breast (18, 3–55) or ovarian (25, 3–56) ATM-mutant cancers (P < 0.001 and P = 0.003, respectively). Interestingly, biallelic pathogenic ATM variants were mutually exclusive with TP53. Other canonical driver gene (KRAS, CDKN2A, SMAD4) variants were less frequent in ATM-mutant PDAC.Conclusions:ATM variants in PDAC represent a distinct biologic group and appear to have favorable OS. Nonetheless, pathogenic ATM variants do not confer an HRD signature in PDAC and ATM should be considered as a non-core HR gene in this disease.

Purpose: BRAF-mutant metastatic colorectal cancer (mCRC) forms an aggressive subset of colorectal cancer with minimal response to selective RAF inhibitors. Preclinical data show that reactivation of EGFR signaling occurs in colorectal tumor cells treated with RAF inhibitors and that the addition of an EGFR inhibitor enhances antitumor activity. These data suggest that combined therapy with RAF and EGFR inhibitors could be an effective strategy for treating BRAF V600E mCRC.Experimental Design: We undertook a pilot trial to assess the response rate and safety of the BRAF inhibitor vemurafenib combined with anti-EGFR antibody panitumumab in patients with BRAF-mutant mCRC. Patients received standard approved doses of panitumumab and vemurafenib.Results: Fifteen patients were treated. Performance status was Eastern Cooperative Oncology Group (ECOG) 0 in 4 patients (27%) and ECOG 1 in 11 patients (73%). All patients had progressed through at least one standard treatment regimen, and 8 (53%) had received previous fluoropyrimidine, oxaliplatin, and irinotecan chemotherapy. Treatment was well tolerated, with less cutaneous toxicity than would be expected with either agent, and no cases of keratoacanthomas/squamous cell carcinomas. Tumor regressions were seen in 10 of 12 evaluable patients with partial responses in 2 patients (100% and 64% regression lasting 40 and 24 weeks, respectively), and stable disease lasting over 6 months in 2 patients.Conclusions: Combined RAF and EGFR inhibition is well tolerated, with less cutaneous toxicity than would be expected with either agent, and results in modest clinical activity in this highly aggressive and chemoresistant subset of CRC. Clin Cancer Res; 21(6); 1313–20. ©2015 AACR.

Flow dot plots

Supplementary Figure Legends

Supplemental table 1. Genes included in custom next-generation sequencing assay.

Purpose: NRAS mutations are now routinely included in RAS testing prior to EGFR inhibitor therapy for metastatic colorectal cancer (mCRC). The clinical implications of NRAS mutation beyond lack of response to anti-EGFR therapy, however, are not known. We undertook this study to determine the clinical features and treatment outcomes of patients with NRAS-mutant mCRC.Experimental Design: We reviewed clinical characteristics, concurrent mutations, and outcomes for all mCRC cases with NRAS mutations undergoing standard genotyping at our institution from 2008 to 2015. Comparison groups consisted of RAS wild-type and KRAS-mutant mCRC consecutive cases genotyped from 2008 to 2012.Results: Three percent (87/2764) of mCRC patients had NRAS-mutant tumors (45% exon 2 and 55% exon 3), including three cases with concurrent NRAS and KRAS mutations. Left-sided primary site and African American self-reported race were associated with NRAS mutation (P < 0.01). Resection rate at 12 months was lower for NRAS-mutant mCRC than for RAS wild-type or KRAS-mutant mCRC. Median survival from time of first known metastasis was 33 months for NRAS-mutant, 47 months for KRAS-mutant, and 78 months for RAS wild-type cases (P < 0.001). Multivariate analysis assigned an HR for overall survival of 2.0 for NRAS mutation and 1.5 for KRAS mutation (P < 0.01).Conclusions: NRAS defines a molecular subset with distinct clinical characteristics from KRAS-mutant and wild-type mCRC. NRAS mutations are enriched in left-sided primary tumors and among African Americans. Mutations in NRAS are associated with poor survival and worse outcomes than either KRAS-mutant or wild-type mCRC. Clin Cancer Res; 23(16); 4753–60. ©2017 AACR.

Molecular predictors of progression free survival in patients treated with cytotoxic chemotherapy

Overall survival from diagnosis with advanced disease by KRAS, ERBB2 and CDKN2A/B status

Supplementary Data 1-8

Purpose:Immune checkpoint inhibition (ICI) alone is not active in mismatch repair–proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy alone result in objective systemic benefit. However, combined radiotherapy plus ICI can induce systemic antitumor immunity in preclinical and clinical models.Patients and Methods:In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1,500 mg plus tremelimumab 75 mg every 4 weeks plus radiotherapy. The primary endpoint was objective response rate (ORR) in nonirradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles.Results:We enrolled 24 patients, and report outcomes after a median follow-up of 21.8 (range: 15.9–26.3) months. The ORR was 8.3% (2 patients) [95% confidence interval (CI), 1.0–27.0]. The median progression-free survival was 1.8 (95% CI, 1.7–1.9) months, median overall survival was 11.4 (95% CI, 10.1–17.4) months. Twenty five percent of patients (n = 6) had treatment-related grade 3–4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response.Conclusions:This combination of radiotherapy plus ICI study did not meet the prespecified endpoint criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in nonirradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus radiotherapy is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.

Purpose:Genomic methods can identify homologous recombination deficiency (HRD). Rigorous evaluation of their outcome association to DNA damage response–targeted therapies like platinum in pancreatic ductal adenocarcinoma (PDAC) is essential in maximizing therapeutic outcome.Experimental Design:We evaluated progression-free survival (PFS) and overall survival (OS) of patients with advanced-stage PDAC, who had both germline- and somatic-targeted gene sequencing. Homologous recombination gene mutations (HRm) were evaluated: BRCA1, BRCA2, PALB2, ATM, BAP1, BARD1, BLM, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, RAD50, RAD51, RAD51C, and RTEL1 HRm status was grouped as: (i) germline versus somatic; (ii) core (BRCAs and PALB2) versus non-core (other HRm); and (iii) monoallelic versus biallelic. Genomic instability was compared using large-scale state transition, signature 3, and tumor mutation burden.Results:Among 262 patients, 50 (19%) had HRD (15% germline and 4% somatic). Both groups were analyzed together due to lack of difference in their genomic instability and outcome. Median [95% confidence interval (CI)] follow-up was 21.9 (1.4–57.0) months. Median OS and PFS were 15.5 (14.6–19) and 7 (6.1–8.1) months, respectively. Patients with HRD had improved PFS compared with no HRD when treated with first-line (1L) platinum [HR, 0.44 (95% CI: 0.29–0.67); P < 0.01], but not with 1L-non-platinum. Multivariate analysis showed HRD patients had improved OS regardless of their first-line treatment, but most had platinum exposure during their course. Biallelic HRm (11%) and core HRm (12%) had higher genomic instability, which translated to improved PFS on first-line platinum (1L-platinum) versus 1L-non-platinum.Conclusions:Pathogenic HRm identifies HRD in patients with PDAC with the best outcome when treated with 1L-platinum. Biallelic HRm and core HRm further enriched benefit from 1L-platinum from HRD.

Supplementary Data Legends

Supplementary Table 1

Radiation treatment summary

Purpose: Various genetic driver aberrations have been identified among distinct anatomic and clinical subtypes of intrahepatic and extrahepatic cholangiocarcinoma, and these molecular alterations may be prognostic biomarkers and/or predictive of drug response.Experimental Design: Tumor samples from patients with cholangiocarcinoma who consented prospectively were analyzed using the MSK-IMPACT platform, a targeted next-generation sequencing assay that analyzes all exons and selected introns of 410 cancer-associated genes. Fisher exact tests were performed to identify associations between clinical characteristics and genetic alterations.Results: A total of 195 patients were studied: 78% intrahepatic and 22% extrahepatic cholangiocarcinoma. The most commonly altered genes in intrahepatic cholangiocarcinoma were IDH1 (30%), ARID1A (23%), BAP1 (20%), TP53 (20%), and FGFR2 gene fusions (14%). A tendency toward mutual exclusivity was seen between multiple genes in intrahepatic cholangiocarcinoma including TP53:IDH1, IDH1:KRAS, TP53:BAP1, and IDH1:FGFR2. Alterations in CDKN2A/B and ERBB2 were associated with reduced survival and time to progression on chemotherapy in patients with locally advanced or metastatic disease. Genetic alterations with potential therapeutic implications were identified in 47% of patients, leading to biomarker-directed therapy or clinical trial enrollment in 16% of patients.Conclusions: Cholangiocarcinoma is a genetically diverse cancer. Alterations in CDKN2A/B and ERBB2 are associated with negative prognostic implications in patients with advanced disease. Somatic alterations with therapeutic implications were identified in almost half of patients. These prospective data provide a contemporary benchmark for guiding the development of targeted therapies in molecularly profiled cholangiocarcinoma, and support to the use of molecular profiling to guide therapy selection in patients with advanced biliary cancers. Clin Cancer Res; 24(17); 4154–61. ©2018 AACR.

Purpose:Immune checkpoint inhibitors (ICI) are effective in only a minority of patients with esophagogastric cancer (EGC). Here, we aimed to identify predictors of durable clinical benefit to ICI in EGC.Experimental Design:Patients with advanced EGC treated with ICIs at Memorial Sloan Kettering Cancer Center (New York, NY) were identified. Clinicopathologic variables were assessed. In patients profiled by MSK-IMPACT–targeted sequencing, outcomes were correlated with tumor genomic features.Results:One-hundred sixty-one patients were treated with ICIs (110 with anti–PD-1/PD-L1 antibodies and 51 with anti–CTLA-4 and PD-1/PD-L1 antibodies). The median progression-free survival (PFS) and overall survival (OS) were 1.7 and 4.9 months, respectively. Greater number of disease sites (≥3), liver metastases, treatment with ≥3 prior therapies and ECOG performance status ≥2 were associated with poorer PFS and OS. Patients treated with combination ICI and those with PD-L1–positive tumors had improved outcomes. There was no difference in outcomes between patients treated with antibiotics during or in the 2 months preceding ICI treatment versus those who were not. Occurrence of irAEs was associated with improved OS. In genomically profiled tumors (n = 89), survival was associated with increasing tumor mutation burden (TMB). However, in multivariable analyses and when microsatellite unstable (MSI) patients were excluded, a significant association was no longer observed.Conclusions:In patients with advanced EGC, heavily pretreated patients, those with high-volume disease and/or poor PS were less likely to benefit from ICI. irAEs were associated with improved OS. TMB correlated with improved survival, but this association was not observed when MSI-high patients were excluded.

Supplementary Figure 1

Supplementary table 2. Tumor genetic mutations identified with next generation sequencing

PFS analysis by gene alteration occurring in 10% or more of MSS patients who received combination therapy

Introduction: Lutetium-177 (177Lu)-DOTATATE received FDA approval in 2018 to treat somatostatin receptor-positive gastroenteropancreatic neuroendocrine tumors (NETs). Little data are available on response and outcomes for well-differentiated (WD) high-grade (HG) NETs treated with 177Lu-DOTATATE. Materials and Methods: Patients with WD HG NETs treated with 177Lu-DOTATATE at MSK from 2018 to 2020 were identified. Demographics, response (RECIST 1.1), and progression-free survival (PFS) were determined. Next-generation sequencing (NGS) was performed in the archival tumor. Results: Nineteen patients, all with progressive, heavily treated disease, were identified. Sites of tumor origin were: pancreas (74%), small bowel (11%), rectum (11%), and lung (5%); median Ki-67 was 32% (range 22–56). Thirteen patients (68%) completed all four 177Lu-DOTATATE cycles. Best response (N = 18 evaluable) was: 5/18 (28%) partial response, 8/18 (44%) stable disease, and 5/18 (28%) disease progression. Median PFS was 13.1 months (95% CI: 8.7–20.9). Most common treatment-related toxicities were thrombocytopenia (9 patients, 47%; G3/4, 1 patient, 5%), anemia (7 patients, 37%; G3/4, 2 patients, 11%), leukopenia (6 patients, 32%; G3/4, 0 patients), and liver function test elevation (4 patients, 21%; G3/4, 0 patients). NGS results were available from 13/19 tumors (68%). The most observed alterations were in MEN1 (6/13, 46%) and DAXX (4/13, 31%). No RB1 alterations identified. Conclusion: We observed a meaningful disease control rate of 72% during treatment of WD HG NETs with 177Lu-DOTATATE. In this heavily pre-treated population, more than half of patients received all four treatment cycles with toxicities largely bone marrow-related. As would be expected in WD NETs, the vast majority had alterations in chromatin remodeling genes and no RB1 alterations.

Background Hepatocellular carcinoma (HCC) patient‐derived xenograft (PDX) models hold potential to advance knowledge in HCC biology to help improve systemic therapies. Beside hepatitis B virus‐associated tumors, HCC is poorly established in PDX. Methods PDX formation from fresh HCC biopsies were obtained and implanted intrahepatically or in subrenal capsule (SRC). Mouse liver injury was induced in immunodeficient Fah−/− mice through cycling off nitisinone after HCC biopsy implantation, versus continuous nitisinone as non‐liver injury controls. Mice with macroscopically detectable PDX showed rising human alpha1‐antitrypsin (hAAT) serum levels, and conversely, no PDX was observed in mice with undetectable hAAT. Results Using rising hAAT as a marker for PDX formation, 20 PDX were established out of 45 HCC biopsy specimens (44%) reflecting the four major HCC etiologies most commonly identified at Memorial SloanKettering similar to many other institutions in the United States. PDX was established only in severely immunodeficient mice lacking lymphocytes and NK cells. Implantation under the renal capsule improved PDX formation two‐fold compared to intrahepatic implantation. Two out of 18 biopsies required murine liver injury to establish PDX, one associated with hepatitis C virus and one with alcoholic liver disease. PDX tumors were histologically comparable to biopsy specimens and 75% of PDX lines could be passaged. Conclusions Using cycling off nitisinone‐induced liver injury, HCC biopsies implanted under the renal capsule of severely immunodeficient mice formed PDX with 57% efficiency as determined by rising hAAT levels. These findings facilitate a more efficient make‐up of PDX for research into subset‐specific HCC.

Objectives To investigate the inter- and intra-reader agreement of immune Response Evaluation Criteria in Solid Tumors (iRECIST) and Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1) in patients with lung cancer treated with immunotherapy. Materials and Methods This retrospective study included 85 patients with lung cancer treated with PD-1 blockade. Four radiologists evaluated computed topography (CT) scans before and after initiation of immunotherapy using iRECIST and RECIST 1.1. Weighted kappa (k) with equal weights was used to assess the intra-reader agreement between 2 repeated reads on overall response at all time points, best overall response, and the response at the time point of progression, as well as the intra-reader agreement between iRECIST and RECIST. The inter-reader agreement was calculated using Light’s kappa. Results Intra-reader agreement for overall response at all time points, best overall response, and time point of progression was substantial to almost perfect for both iRECIST and RECIST 1.1 (k = 0.651–0.983). Inter-reader agreement was substantial for iRECIST (κ = 0.657–0.742) while RECIST 1.1 was moderate to substantial (κ = 0.587–0.686). The level of inter-reader agreement was not higher on repeat read for iRECIST (κ = 0.677–0.709 and κ = 0.657–0.742 for first and second read, respectively) as well as for RECIST 1.1 (κ = 0.587–0.659 and κ = 0.633–0.686 for first and second read, respectively). Almost perfect agreement was observed between RECIST 1.1 and iRECIST at first (κ = 0.813–0.923) and second read (κ = 0.841–0.912). Conclusion The inter- and intra-reader agreement of iRECIST is high and similar to RECIST 1.1 in patients with lung cancer treated with immunotherapy.

Background Radiation therapy (RT) for breast cancer increases risk of coronary artery disease (CAD). Women treated for left- vs right-sided breast cancer receive greater heart radiation exposure, which may further increase this risk. The risk of radiation-associated CAD specifically among younger breast cancer survivors is not well defined. Objectives The purpose of this study was to report CAD risk among participants in the Women’s Environmental Cancer and Radiation Epidemiology Study. Methods A total of 1,583 women who were, Central Illustration

Pancreatic ductal adenocarcinoma (PDAC) is characterized by the occurrence of pathogenic variants in BRCA1/2 in 5-6% of patients. Biallelic loss of BRCA1/2 enriches for response to platinum agents and poly (ADP-ribose) polymerase 1 inhibitors. There is a dearth of evidence on the mechanism of inactivation of the wild-type BRCA1 allele in PDAC tumors with a germline BRCA1 (gBRCA1) pathogenic or likely pathogenic variant (P/LPV). Herein, we examine promotor hypermethylation as a "second hit" mechanism in patients with gBRCA1-PDAC.We evaluated patients with PDAC who underwent Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets (MSK-IMPACT) somatic and germline testing from an institutional database. DNA isolated from tumor tissue and matched normal peripheral blood were sequenced by MSK-IMPACT. In patients with gBRCA1-PDAC, we examined the somatic BRCA1 mutation status and promotor methylation status of the tumor BRCA1 allele via a methylation array analysis. In patients with sufficient remaining DNA, a second methylation analysis by pyrosequencing was performed.Of 1012 patients with PDAC, 19 (1.9%) were identified to harbor a gBRCA1 P/LPV. Fifteen patients underwent a methylation array and the mean percentage of BRCA1 promotor methylation was 3.62%. In seven patients in whom sufficient DNA was available, subsequent pyrosequencing confirmed an unmethylated BRCA1 promotor. Loss of heterozygosity was detected in 12 of 19 (63%, 95% confidence interval 38-84) patients, demonstrating loss of heterozygosity is the major molecular mechanism of BRCA1 inactivation in PDAC. Two (10.5%) cases had a somatic BRCA1 mutation.In patients with gBRCA1-P/LPV-PDAC, loss of heterozygosity is the main inactivating mechanism of the wild-type BRCA1 allele in the tumor, and methylation of the BRCA1 promoter is a distinctly uncommon occurrence.

Most pancreatic ductal adenocarcinomas (PDAC) are lethal and resistant to immunotherapy. Thus, identifying the immunogenic subgroup (iPDAC) and therapeutic targets can save lives. Herein, we present molecular features of iPDAC. 3 cohorts (A, B, C) from 288 patients whose sequenced tumors (MSK-IMPACT) were classified by homologous recombination deficiency groups. MSI-H were excluded. Survival, tumor mutation burden, genomic instability score, and enriched pathways for each cohort are included in Table 1. Patients in A (BRCA1/2/PALB2) had longer survivals vs B/C. 61 samples were selected for bulk RNAseq analysis for A vs C. Gene Ontology was enriched for upregulated humoral, T cell, and neutrophil immunity. CIBERSORT suggested higher infiltration of gamma delta T (Tgd) cells (p=0.039) and neutrophils (p=0.012), but lower Treg (p=0.001). Multidimensional insights in cellular components of cancer, immune, stroma, and neural genes were obtained by single nuclear RNA (snRNAseq) analysis from 30 biopsies for A vs C. 10x Genomics Chromium platform for library and Scanpy for computational analysis after Cell Ranger pipelines were used. 61,868 nuclei were profiled from 18 (13 baseline and 5 matched longitudinal) samples after quality evaluation. UMAP accurately clustered cells from each patient. Long-term survivors (LTS) had heterogenous baseline immune cell infiltrates of plasma cells, neutrophils, and CD8 (+) cytotoxic T cells. In matched samples of LTS, evolution of more prominent CD8 (+) T cells, macrophage, plasma cell, and neutrophil were observed. Single nucleus T-Cell Receptor sequencing for clonal trajectory inference will be done to determine the associated single cell molecular features contributing to iPDAC and identify novel targets for future intervention. Table 1. Cohort (Total: N=288) A: core HRD (BRCA1/2/PALB2) B: non-core HRD (ATM, BARD1, BLM, CHEK2, RAD50, RAD51C, RTEL1, MUTYH) C: others without HR-gene alterations Number (%) 48 (16.6) 19 (6.5) 221 (76) Median overall survival (95% confidence Interval) 33 months (3.6-64) 16 (11- not reached) 16 (14-18) Tumor Mutation Burden (TMB) 4.4 3.5 3.9 Genomic Instability Score (GIS, HRD score) 26 12 13 Gene Ongology term, enrichment score, adjusted p-value Adaptive immune response, GO:0002250, 0.49, 1.69e-10 Not included Reference to cohort A Humoral immune response, GO:0006959, 0.58, 1.67e-9 T cell activation, GO:0042110, 0.44, 2.75e-8 Neutrophil chemotaxis, GO:0030593, 0.73, 4.3e-10 Citation Format: Wungki Park, Catherine O'Connor, Shigeaki Umeda, Roshan Sharma, Yingjie Zhu, Elias-Ramzey Karnoub, Anna Varghese, Kevin C. Soares, Alejandro Jimemez, Asli Yavas, Kenneth H. Yu, Balachandran P. Vinod, Joanne F. Chou, Danny N. Khalil, Kelsen David, Hulya Sahin Ozkan, Olca Basturk, Marinela Capanu, Tal Nawy, Michael F. Berger, Ghassan K. Abou-Alfa, Jorge S. Reis-Filho, Ronan Chaligne, Nadeem Riaz, Dana Pe'er, Christine Iacobuzio-Donahue, Eileen M. O'Reilly. Molecular profiles and single cell analysis identify immunogenic pancreatic ductal adenocarcinoma (iPDAC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6421.

PURPOSE: A T1 sequence on routine baseline staging rectal magnetic resonance imaging (MRI) is thought to help detect bone lesions. Our primary aim was to evaluate the incidence of bone lesions encountered on baseline staging rectal MRI, particularly the prevalence of bone metastases. METHODS: This retrospective study included patients with rectal adenocarcinoma who underwent baseline rectal MRI at our institution between January 2010 and December 2017. The MRI report was reviewed for presence of bone lesions. When found, lesion type, presence of axial T1 non-fat-suppressed sequence, primary tumor T-stage, and presence of other organ metastases were recorded. In the absence of bone biopsy, the reference standard was follow-up imaging via computed tomography (CT), MRI, and/or positron emission tomography/CT (PET/CT) ≥ 1 year after the baseline MRI. The Wilcoxon rank-sum test and Fisher’s exact test were used to compare clinicopathologic data of patients with malignant or benign bone lesions. RESULTS: A total of 1,197 patients were included. 62/1197 patients (mean age 56.8 years (SD: 13.8), with 39 men) had bone lesions on baseline imaging, with 6 being bone metastases (0.5%, 95% CI: 0.2%–1.1%). Of the 6 patients with bone metastases, 5/6 had other metastases (i.e. liver, lung) at baseline. CONCLUSION: Bone metastases on baseline rectal MRI performed for rectal adenocarcinoma are extremely rare. Furthermore, bone metastases without other organ (i.e. liver, lung) involvement is extremely rare.

Introduction This study assessed (i) the ability to identify the solid components of part-solid nodules (PSN) during computed tomography (CT) guided lung biopsy (CTGLB), (ii) the ability of CTGLB to assess the invasive nature of a nodule on pathology. Materials and methods Sixty-nine nodules were studied in 68 patients who underwent CTGLB between 1/1/2014 and 10/31/2015. Diagnostic CT images and CTGLB images were reviewed. On diagnostic CT images, nodules were classified as ground glass nodules (GGN) or PSNs. Nodule size, location, and percentage of solid component were recorded. At the time of biopsy, the ability to visualize the solid component of a PSN, depth of lesion from skin, and ability to identify the needle within the solid component were recorded. Results There were 42 (61%) part-solid nodules and 27 (39%) GGNs. During biopsy, it was possible to differentiate the solid from the ground glass components in 35 (83%) PSNs. Fifty-nine (86%) nodules were neoplastic based on biopsy pathology (all non-small cell lung carcinoma). Thirty-nine (66%) were resected. In all cases biopsy pathology and surgical pathology agreed regarding the presence of lung carcinoma. In 6 (15%) cases biopsy pathology demonstrated purely lepidic growth but had some non-lepidic growth on surgical pathology, including 2 cases with acinar growth as a dominant pattern. Conclusion In most patients, the solid and ground glass components of a PSN were distinguishable when performing a CTGLB. In a minority of patients, discrepancy was noted between biopsy pathology and surgical pathology regarding the invasive nature of a nodule.

Purpose: Characterizing germline and somatic ATM variants (gATMm, sATMm) zygosity and their contribution to homologous recombination deficiency (HRD) is important for therapeutic strategy in pancreatic ductal adenocarcinoma (PDAC). Experimental Design: Clinico-genomic data for patients with PDAC and other cancers with ATM variants were abstracted. Genomic instability scores (GIS) were derived from ATM-mutant cancers and overall survival (OS) was evaluated. Results: Forty-six patients had PDAC and pathogenic ATM variants including 24 (52%) stage III/IV: gATMm (N = 24), and sATMm (N = 22). Twenty-seven (59%) had biallelic, 15 (33%) monoallelic, and 4 indeterminate (8%) variants. Median OS for advanced-stage cohort at diagnosis (N = 24) was 19.7 months [95% confidence interval (CI): 12.3–not reached (NR)], 27.1 months (95% CI: 22.7–NR) for gATMm (n = 11), and 12.3 months for sATMm (n = 13; 95% CI: 11.9–NR; P = 0.025). GIS was computed for 33 patients with PDAC and compared with other ATM-mutant cancers enriched for HRD. The median was lower (median, 11; range, 2–29) relative to breast (18, 3–55) or ovarian (25, 3–56) ATM-mutant cancers (P < 0.001 and P = 0.003, respectively). Interestingly, biallelic pathogenic ATM variants were mutually exclusive with TP53. Other canonical driver gene (KRAS, CDKN2A, SMAD4) variants were less frequent in ATM-mutant PDAC. Conclusions: ATM variants in PDAC represent a distinct biologic group and appear to have favorable OS. Nonetheless, pathogenic ATM variants do not confer an HRD signature in PDAC and ATM should be considered as a non-core HR gene in this disease.

Background It is unknown how body fat distribution modulates the cardiometabolic risk of testicular cancer survivors after cisplatin-based chemotherapy. Methods For 455 patients enrolled in the Platinum Study at Memorial Sloan Kettering Cancer Center, visceral (VAT) and subcutaneous (SAT) adipose tissue was quantified on prechemotherapy computed tomography. The VAT-to-SAT ratio was calculated as a quantitative measure of central adiposity. Endpoints were incidence of new posthemotherapy cardiometabolic disease (new antihypertensive, lipid-lowering, or diabetes medication), and postchemotherapy Framingham risk scores. Cox models and linear regression with interaction terms were applied. Postchemotherapy body fat distribution was analyzed in 108 patients. All statistical tests were 2-sided. Results The baseline median age was 31 years (interquartile range [IQR] = 26-39 years), body mass index (BMI) was 26 kg/m2 (IQR = 24-29 kg/m2), and the VAT-to-SAT ratio was 0.49 (IQR = 0.31-0.75). The median follow-up was 26 months (IQR = 16-59 months). Higher prechemotherapy VAT-to-SAT ratios inferred a higher likelihood of new cardiometabolic disease among patients with a BMI of 30 kg/m2 or greater (age-adjusted hazard ratio = 3.14, 95% confidence interval = 1.02 to 9.71, P = .047), but not other BMI groups. The prechemotherapy VAT-to-SAT ratio was associated with postchemotherapy Framingham risk scores in univariate regression analysis (exp(β)-estimate: 2.10, 95% confidence interval = 1.84 to 2.39, P Conclusions In testicular cancer survivors, central adiposity is associated with increased cardiometabolic risk after cisplatin-based chemotherapy, particularly in obese or young men. Weight gain after chemotherapy occurs preferentially in the visceral compartment, providing insight into the pathogenesis of cardiovascular disease in this population.