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The genomic features of pancreatic ductal adenocarcinoma (PDAC) have been well described, yet the evolutionary contexts within which those features occur remains unexplored. We studied the genome landscapes, phylogenies and clonal compositions of 91 PDACs in relation to clinicopathologic features. There was no difference in the number of driver mutations or the evolutionary timing that each mutation occurred. High truncal density, a metric of the accumulation of somatic mutations in the lineage that gave rise to each PDAC, was significantly associated with worse overall survival. Polyclonal, monoclonal or mixed polyclonal/monoclonal metastases were identified across the cohort highlighting multiple forms of inter-tumoral heterogeneity. Advanced stage and treated PDACs had higher odds of being polyclonal, whereas oligometastatic PDACs had fewer driver alterations, a lower fractional allelic loss and increased likelihood of being monoclonal. In sum, our findings reveal novel insights into the dynamic nature of the PDAC genome beyond established genetic paradigms.
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BACKGROUND: Adjuvant mFOLFIRINOX (mFFX) is standard of care for fit individuals with resected pancreatic ductal adenocarcinoma (PDAC). There are limited data on adjuvant mFFX outcomes outside clinical trials. METHODS: Institutional databases queried to identify patients with resected PDAC who received ≥1 dose adjuvant mFFX. Primary endpoints: recurrence free survival (RFS), overall survival (OS). Secondary endpoints: clinical factors, genomic features associated with outcomes. RFS and OS were estimated with Kaplan-Meier. Cox proportional hazards regression model was used to associate clinico-genomic features correlated with survival outcomes. RESULTS: N = 147 identified between 01/2015-01/2023. Median age: 67 years; N = 57 (39%) >70 years. Unfavorable prognostic features: N = 52 (36%) N2 nodal status, N = 115 (78%) lymphovascular invasion), and N = 133 (90%) perineural invasion. Median time from surgery to start mFFX: 1.78 months (m) (IQR 1.45, 2.12). N = 124 (84%) completed 12 doses; N = 98 (67%) stopped oxaliplatin early for neuropathy (median 10 doses; range 4-12). Further dosing characteristics are summarized in Supplementary Table 3. With median follow up of 35.1 m, median RFS (mRFS) 26 m (95% CI 19, 39) and median OS (mOS) not reached. For >70 cohort, mRFS 23 m (95% CI 14, NR) and mOS 51 m (95% CI 37, NR). mFFX started <8 weeks from resection associated with improved RFS (HR 0.62; 95% CI 0.41, 0.96; p = .033) and OS (HR 0.53; 95% CI 0.3, 0.94; p = .030). KRAS mutation and whole genome doubling trended to shorter RFS and OS. Homologous recombination deficiency status did not confer improved survival outcomes. CONCLUSIONS: Adjuvant mFFX is effective and tolerable in resected PDAC in a non-trial setting, including for patients >70 years.
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INTRODUCTION: Immune checkpoint inhibitor (ICI) combinations extend overall survival (OS) while anti-PD-1/L1 monotherapy is non-inferior to sorafenib in treatment-naïve, patients with advanced hepatocellular carcinoma (HCC). Clinicogenomic features are posited to influence patient outcomes. METHODS: The primary objective of this retrospective study was to define the clinical, pathologic, and genomic factors associated with outcomes to ICI therapy in patients with HCC. Patients with histologically confirmed advanced HCC treated with ICI at Memorial Sloan Kettering Cancer Center from 2012 to 2022 were included. Association between clinical, pathological, and genomic characteristics were assessed with univariable and multivariable Cox regression model for progression-free survival (PFS) and OS. RESULTS: Two-hundred and forty-two patients were treated with ICI-based therapy. Patients were predominantly male (82%) with virally mediated HCC (53%) and Child Pugh A score (70%). Median follow-up was 28 months (0.5-78.4). Median PFS for those treated in 1st line, 2nd line andâ ≥â 3rd line was 4.9 (range: 2.9-6.2), 3.1 (2.3-4.0), and 2.5 (2.1-4.0) months, respectively. Median OS for those treated in 1st line, 2nd line, andâ ≥â 3rd line was 16 (11-22), 7.5 (6.4-11), and 6.4 (4.6-26) months, respectively. Poor liver function and performance status associated with worse PFS and OS, while viral hepatitis C was associated with favorable outcome. Genetic alterations were not associated with outcomes. CONCLUSION: Clinicopathologic factors were the major determinates of outcomes for patients with advanced HCC treated with ICI. Molecular profiling did not aid in stratification of ICI outcomes. Future studies should explore alternative biomarkers such as the level of immune activation or the pretreatment composition of the immune tumor microenvironment.
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Carcinoma Hepatocelular , Inhibidores de Puntos de Control Inmunológico , Inmunoterapia , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/patología , Carcinoma Hepatocelular/tratamiento farmacológico , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/mortalidad , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/tratamiento farmacológico , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/terapia , Masculino , Femenino , Persona de Mediana Edad , Anciano , Estudios Retrospectivos , Adulto , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inmunoterapia/métodos , Anciano de 80 o más AñosRESUMEN
BACKGROUND: Acute cholangitis (AC) is a common complication of pancreatic ductal adenocarcinoma (PDAC). Herein, we evaluated outcomes after the first AC episode and predictors of mortality and AC recurrence in patients with stage IV PDAC. METHODS: We conducted a single-center, retrospective observational study using institutional databases. Clinical data and outcomes for patients with stage IV PDAC and at least one documented episode of AC, were assessed. Overall survival (OS) was estimated using the Kaplan-Meier method, and Cox regression model was employed to identify predictors of AC recurrence and mortality. RESULTS: One hundred and twenty-four patients with stage IV PDAC and AC identified between January 01, 2014 and October 31, 2020 were included. Median OS after first episode of AC was 4.1 months (95 % CI, 4.0-5.5), and 30-day, 6, and 12-month survival was 86.2 % (95 % CI, 80.3-92.5), 37 % (95 % CI, 29.3-46.6 %) and 18.9 % (95 % CI, 13.1-27.3 %), respectively. Primary tumor in pancreatic body/tail (HR 2.29, 95 % CI: 1.26 to 4.18, p = 0.011), concomitant metastases to liver and other sites (HR 1.96, 95 % CI: 1.16 to 3.31, p = 0.003) and grade 3 AC (HR 2.26, 95 % CI: 1.45 to 3.52, p < 0.001), predicted worse outcomes. Intensive care unit admission, sepsis, systemic therapy, treatment regimen, and time to intervention did not predict survival or risk of recurrence of AC. CONCLUSIONS: AC confers significant morbidity and mortality in advanced PDAC. Worse outcomes are associated with higher grade AC, primary tumor location in pancreatic body/tail, and metastases to liver and other sites.
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Colangitis , Neoplasias Pancreáticas , Humanos , Colangitis/complicaciones , Colangitis/mortalidad , Masculino , Femenino , Neoplasias Pancreáticas/mortalidad , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/patología , Anciano , Estudios Retrospectivos , Persona de Mediana Edad , Pronóstico , Estadificación de Neoplasias , Carcinoma Ductal Pancreático/mortalidad , Carcinoma Ductal Pancreático/complicaciones , Carcinoma Ductal Pancreático/patología , Anciano de 80 o más Años , Adenocarcinoma/mortalidad , Adenocarcinoma/complicaciones , Adenocarcinoma/patología , Enfermedad Aguda , Factores de RiesgoRESUMEN
BACKGROUND: Mutated Kirsten rat sarcoma viral oncogene homolog (KRAS) is the most common oncogene alteration in pancreatic ductal adenocarcinoma, and KRAS glycine to cystine substitution at codon 12 (G12C) mutations (KRAS G12Cmut) are observed in 1%-2%. Several inhibitors of KRAS G12C have recently demonstrated promise in solid tumors, including pancreatic cancer. Little is known regarding clinical, genomics, and outcome data of this population. METHODS: Patients with pancreatic cancer and KRAS G12Cmut were identified at Memorial Sloan Kettering Cancer Center and via the American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database. Clinical, treatment, genomic, and outcomes data were analyzed. A cohort of patients at Memorial Sloan Kettering Cancer Center with non-G12C KRAS pancreatic cancer was included for comparison. RESULTS: Among 3571 patients with pancreatic ductal adenocarcinoma, 39 (1.1%) with KRAS G12Cmut were identified. Median age was 67 years, and 56% were female. Median body mass index was 29.2 kg/m2, and 67% had a smoking history. Median overall survival was 13 months (95% CI: 9.4 months, not reached) for stage IV and 26 months (95% CI: 23 months, not reached) for stage I-III. Complete genomic data (via American Association of Cancer Research Project Genomics, Evidence, Neoplasia, Information, Exchange database) was available for 74 patients. Most common co-alterations included TP53 (73%), CDKN2A (33%), SMAD4 (28%), and ARID1A (21%). Compared with a large cohort (n = 2931) of non-G12C KRAS-mutated pancreatic ductal adenocarcinoma, ARID1A co-mutations were more frequent in KRAS G12Cmut (P < .05). Overall survival did not differ between KRAS G12Cmut and non-G12C KRAS pancreatic ductal adenocarcinoma. Germline pathogenic variants were identified in 17% of patients; 2 patients received KRAS G12C-directed therapy. CONCLUSION: Pancreatic cancer and KRAS G12Cmut may be associated with a distinct clinical phenotype. Genomic features are similar to non-G12C KRAS-mutated pancreatic cancer, although enrichment of ARID1A co-mutations was observed. Targeting of KRAS G12C in pancreatic cancer provides a precedent for broader KRAS targeting in pancreatic cancer.
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Carcinoma Ductal Pancreático , Mutación , Neoplasias Pancreáticas , Medicina de Precisión , Proteínas Proto-Oncogénicas p21(ras) , Factores de Transcripción , Humanos , Femenino , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/tratamiento farmacológico , Neoplasias Pancreáticas/mortalidad , Masculino , Proteínas Proto-Oncogénicas p21(ras)/genética , Anciano , Persona de Mediana Edad , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/tratamiento farmacológico , Carcinoma Ductal Pancreático/mortalidad , Factores de Transcripción/genética , Proteínas de Unión al ADN/genética , Proteína Smad4/genética , Proteínas Nucleares/genética , Anciano de 80 o más Años , Inhibidor p16 de la Quinasa Dependiente de Ciclina/genética , Proteína p53 Supresora de Tumor/genética , Genómica , Adulto , Biomarcadores de Tumor/genéticaRESUMEN
PURPOSE: To investigate the differences in baseline staging of anal squamous cell carcinoma based on CT, MRI, and PET/CT, and the resultant impact on the radiation plan. METHODS: This retrospective study included consecutive patients with anal squamous cell carcinoma who underwent baseline pelvic MRI, CT, and PET/CT (all examinations within 3 weeks of each other) from January 2010 to April 2020. CTs, MRIs, and PET/CTs were re-interpreted by three separate radiologists. Several imaging features were assessed; tumor stage was determined based on the eight edition of the American Joint Committee on Cancer (AJCC) staging manual; and T (tumor), N (node), and M (metastasis) categories were determined based on National Comprehensive Cancer Network (NCCN) guidelines. Radiologist assessments were then randomly presented to a radiation oncologist who formulated the radiation plan in a blinded fashion. RESULTS: Across 28 patients (median age, 62 years [range, 31-78], T-category classification was significantly different on PET/CT compared to MRI and CT (p = 0.037 and 0.031, respectively). PET/CT staged a higher proportion of patients with T1/T2 disease (16/28, 57%) compared to MRI (11/28, 39%) and CT (10/28, 36%). MRI staged a higher proportion of patients with T3/T4 disease (14/28, 50%) compared to CT (12/28, 43%) and PET/CT (11/28, 39%). However, there was no significant difference between the three imaging modalities in terms of either N-category, AJCC staging, or NCCN TNM group classification, or in treatment planning. CONCLUSION: Our exploratory study showed that MRI demonstrated a higher proportion of T3/T4 tumors, while PET/CT demonstrated more T1/T2 tumors; however, MRI, CT, and PET/CT did not show any significant differences in AJCC and TNM group categories, nor was there any significant difference in treatment doses between them when assessed independently by an experienced radiation oncologist.
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Neoplasias del Ano , Carcinoma de Células Escamosas , Imagen por Resonancia Magnética , Estadificación de Neoplasias , Tomografía Computarizada por Tomografía de Emisión de Positrones , Tomografía Computarizada por Rayos X , Humanos , Tomografía Computarizada por Tomografía de Emisión de Positrones/métodos , Neoplasias del Ano/diagnóstico por imagen , Neoplasias del Ano/radioterapia , Neoplasias del Ano/patología , Femenino , Masculino , Persona de Mediana Edad , Imagen por Resonancia Magnética/métodos , Estudios Retrospectivos , Anciano , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/radioterapia , Carcinoma de Células Escamosas/patología , Adulto , Tomografía Computarizada por Rayos X/métodos , Planificación de la Radioterapia Asistida por Computador/métodosRESUMEN
PURPOSE: Targeted therapies have improved outcomes for patients with metastatic colorectal cancer, but their impact is limited by rapid emergence of resistance. We hypothesized that an understanding of the underlying genetic mechanisms and intrinsic tumor features that mediate resistance to therapy will guide new therapeutic strategies and ultimately allow the prevention of resistance. EXPERIMENTAL DESIGN: We assembled a series of 52 patients with paired pretreatment and progression samples who received therapy targeting EGFR (n = 17), BRAF V600E (n = 17), KRAS G12C (n = 15), or amplified HER2 (n = 3) to identify molecular and clinical factors associated with time on treatment (TOT). RESULTS: All patients stopped treatment for progression and TOT did not vary by oncogenic driver (P = 0.5). Baseline disease burden (≥3 vs. <3 sites, P = 0.02), the presence of hepatic metastases (P = 0.02), and gene amplification on baseline tissue (P = 0.03) were each associated with shorter TOT. We found evidence of chromosomal instability (CIN) at progression in patients with baseline MAPK pathway amplifications and those with acquired gene amplifications. At resistance, copy-number changes (P = 0.008) and high number (≥5) of acquired alterations (P = 0.04) were associated with shorter TOT. Patients with hepatic metastases demonstrated both higher number of emergent alterations at resistance and enrichment of mutations involving receptor tyrosine kinases. CONCLUSIONS: Our genomic analysis suggests that high baseline CIN or effective induction of enhanced mutagenesis on targeted therapy underlies rapid progression. Longer response appears to result from a progressive acquisition of genomic or chromosomal instability in the underlying cancer or from the chance event of a new resistance alteration.
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Neoplasias Colorrectales , Resistencia a Antineoplásicos , Terapia Molecular Dirigida , Proteínas Proto-Oncogénicas B-raf , Humanos , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/patología , Neoplasias Colorrectales/tratamiento farmacológico , Resistencia a Antineoplásicos/genética , Femenino , Masculino , Proteínas Proto-Oncogénicas B-raf/genética , Persona de Mediana Edad , Anciano , Proteínas Proto-Oncogénicas p21(ras)/genética , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Mutación , Progresión de la Enfermedad , Receptores ErbB/genética , Receptores ErbB/antagonistas & inhibidores , Adulto , Inestabilidad Cromosómica , Anciano de 80 o más Años , Amplificación de GenesRESUMEN
Anti-programmed death 1 (PD-1) inhibitors are the standard of care for advanced gastroesophageal cancer. Although recommendations and approval by regulatory agencies are often based on programmed death ligand 1 (PD-L1) expression, pathologic assessments of PD-L1 status have several limitations. Single-site biopsies do not adequately capture disease heterogeneity within individual tumor lesions or among several lesions within the same patient, the PD-L1 combined positive score is a dynamic biomarker subject to evolution throughout a patient's disease course, and repeated biopsies are invasive and not always feasible. Methods: This was a prospective pilot study of the PD-L1-targeting radiotracer, 18F-BMS-986229, with PET imaging (PD-L1 PET) in patients with gastroesophageal cancer. Patients were administered the 18F-BMS-986229 radiotracer intravenously at a dose of 370 MBq over 1-2 min and underwent whole-body PET/CT imaging 60 min later. The primary objective of this study was to evaluate the safety and feasibility of 18F-BMS-986229. The trial is registered with ClinicalTrials.gov (NCT04161781). Results: Between February 3, 2020, and February 2, 2022, 10 patients with gastroesophageal adenocarcinoma underwent PD-L1 PET. There were no adverse events associated with the 18F-BMS-986229 tracer, and imaging did not result in treatment delays; the primary endpoint was achieved. Radiographic evaluation of PD-L1 expression was concordant with pathologic assessment in 88% of biopsied lesions, and 18F-BMS-986229 uptake on PET imaging correlated with pathologic evaluation by the combined positive score (Spearman rank correlation coefficient, 0.64). Seventy-one percent of patients with 18F-BMS-986229 accumulation on PET imaging also had lesions without 18F-BMS-986229 uptake, highlighting the intrapatient heterogeneity of PD-L1 expression. Patients treated with frontline programmed death 1 inhibitors who had 18F-BMS-986229 accumulation in any lesions on PET imaging had longer progression-free survival than patients without tracer accumulation in any lesions (median progression-free survival, 28.4 vs. 9.9 mo), though the small sample size prevents any definitive conclusions. Conclusion: PD-L1 PET imaging was safe, feasible, and concordant with pathologic evaluation and offers a potential noninvasive tool to assess PD-L1 expression.
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Antígeno B7-H1 , Neoplasias Esofágicas , Tomografía Computarizada por Tomografía de Emisión de Positrones , Neoplasias Gástricas , Humanos , Antígeno B7-H1/metabolismo , Neoplasias Gástricas/diagnóstico por imagen , Neoplasias Gástricas/metabolismo , Masculino , Neoplasias Esofágicas/diagnóstico por imagen , Neoplasias Esofágicas/metabolismo , Femenino , Persona de Mediana Edad , Anciano , Proyectos Piloto , Radioisótopos de Flúor , Estudios Prospectivos , AdultoRESUMEN
PURPOSE: To evaluate the diagnostic performance of diffusion-weighted imaging (DWI) in the 6-month interval post chemoradiation therapy (CRT) in determining persistent disease and whether persistent diffusion restriction on DWI at 6 months is associated with overall survival; and secondarily, to investigate the accuracy of pelvic lymph node assessment on T2-weighted imaging and DWI in the 6-month interval post CRT, in patients with squamous cell carcinoma of the anus. METHODS AND MATERIALS: This retrospective study included patients with squamous cell carcinoma of the anus who underwent CRT followed by restaging rectal MRI from January 2010 to April 2020, with ≥1 year of follow-up after CRT. DW images were qualitatively evaluated by 2 junior and 2 senior abdominal radiologists to determine anal persistent disease. The reference standard for anal persistent disease was digital rectal examination/endoscopy and histopathology. Diagnostic performance was estimated using sensitivity, specificity, negative predictive value, and positive predictive value. Survival outcomes were evaluated via Kaplan-Meier analysis, and associations between survival outcomes and DWI status were tested for significance using the log-rank test. Additionally, DW and T2-weighted images were evaluated to determine lymph node status. RESULTS: Among 84 patients (mean age, 63 ± 10.2 years; 64/84 [76%] female), 14 of 84 (17%) had confirmed persistent disease. Interreader agreement on DWI between all 4 radiologists was moderate (Light's κ = 0.553). Overall, DWI had a sensitivity of 71.4%, specificity of 72.1%, positive predictive value of 34.5%, and negative predictive value of 92.5%. Patients with a negative DWI showed better survival than patients with a positive DWI (3-year overall survival of 92% vs 79% and 5-year overall survival of 87% vs 74%), although the difference did not reach statistical significance (P = .063). All patients with suspicious lymph nodes (14/14, 100%) showed negative pathology or decreased size during follow-up. CONCLUSIONS: At 6 months post CRT, DWI showed value in excluding anal persistent disease. Persistent diffusion restriction on DWI was not significantly associated with overall survival. Pelvic nodal assessment on DWI and T2-weighted imaging was limited in predicting persistent nodal metastases.
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Neoplasias del Ano , Carcinoma de Células Escamosas , Quimioradioterapia , Imagen de Difusión por Resonancia Magnética , Pelvis , Humanos , Masculino , Imagen de Difusión por Resonancia Magnética/métodos , Femenino , Persona de Mediana Edad , Neoplasias del Ano/diagnóstico por imagen , Neoplasias del Ano/terapia , Neoplasias del Ano/patología , Neoplasias del Ano/mortalidad , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/diagnóstico por imagen , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/mortalidad , Estudios Retrospectivos , Anciano , Pelvis/diagnóstico por imagen , Ganglios Linfáticos/diagnóstico por imagen , Ganglios Linfáticos/patología , Factores de Tiempo , Imagen por Resonancia Magnética/métodos , Metástasis Linfática/diagnóstico por imagen , AdultoRESUMEN
Purpose To investigate the prevalence of FLCN, BAP1, SDH, and MET mutations in an oncologic cohort and determine the prevalence, clinical features, and imaging features of renal cell carcinoma (RCC) associated with these mutations. Secondarily, to determine the prevalence of encountered benign renal lesions. Materials and Methods From 25 220 patients with cancer who prospectively underwent germline analysis with a panel of more than 70 cancer-predisposing genes from 2015 to 2021, patients with FLCN, BAP1, SDH, or MET mutations were retrospectively identified. Clinical records were reviewed for patient age, sex, race/ethnicity, and renal cancer diagnosis. If RCC was present, baseline CT and MRI examinations were independently assessed by two radiologists. Summary statistics were used to summarize continuous and categorical variables by mutation. Results A total of 79 of 25 220 (0.31%) patients had a germline mutation: FLCN, 17 of 25 220 (0.07%); BAP1, 22 of 25 220 (0.09%); SDH, 39 of 25 220 (0.15%); and MET, one of 25 220 (0.004%). Of these 79 patients, 18 (23%) were diagnosed with RCC (FLCN, four of 17 [24%]; BAP1, four of 22 [18%]; SDH, nine of 39 [23%]; MET, one of one [100%]). Most hereditary RCCs demonstrated ill-defined margins, central nonenhancing area (cystic or necrotic), heterogeneous enhancement, and various other CT and MR radiologic features, overlapping with the radiologic appearance of nonhereditary RCCs. The prevalence of other benign solid renal lesions (other than complex cysts) in patients was up to 11%. Conclusion FLCN, BAP1, SDH, and MET mutations were present in less than 1% of this oncologic cohort. Within the study sample size limits, imaging findings for hereditary RCC overlapped with those of nonhereditary RCC, and the prevalence of other associated benign solid renal lesions (other than complex cysts) was up to 11%. Keywords: Familial Renal Cell Carcinoma, Birt-Hogg-Dubé Syndrome, Carcinoma, Renal Cell, Paragangliomas, Urinary, Kidney © RSNA, 2024.
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Carcinoma de Células Renales , Quistes , Neoplasias Renales , Humanos , Carcinoma de Células Renales/diagnóstico por imagen , Carcinoma de Células Renales/epidemiología , Carcinoma de Células Renales/genética , Mutación de Línea Germinal/genética , Prevalencia , Estudios Retrospectivos , Proteínas Supresoras de Tumor/genética , Neoplasias Renales/diagnóstico por imagen , Neoplasias Renales/epidemiología , Neoplasias Renales/genética , Quistes/complicaciones , Proteínas Proto-Oncogénicas/genética , Ubiquitina Tiolesterasa/genéticaRESUMEN
In advanced pancreatic neuroendocrine neoplasms (PanNEN), there are little data detailing the frequency of genetic alterations identified in cell free DNA (cfDNA), plasma-tissue concordance of detected alterations, and clinical utility of cfDNA. Patients with metastatic PanNENs underwent cfDNA collection in routine practice. Next-generation sequencing (NGS) of cfDNA and matched tissue when available was performed. Clinical actionability of variants was annotated by OncoKB. Thirty-two cfDNA samples were analyzed from 25 patients, the majority who had well-differentiated intermediate grade disease (13/25; 52%). Genomic alterations were detected in 68% of patients and in 66% of all cfDNA samples. The most frequently altered genes were DAXX (28%), TSC2 (24%), MEN1 (24%), ARID1B (20%), ARID1A (12%), and ATRX (12%). Twenty-three out of 25 (92%) patients underwent tumor tissue NGS. Tissue-plasma concordance for select genes was as follows:DAXX (95.7%), ARID1A (91.1%), ATRX (87%), TSC2 (82.6%), MEN1 (69.6%). Potentially actionable alterations were identified in cfDNA of 8 patients, including TSC2 (4; level 3b), ATM (1; level 3b), ARID1A (2; level 4), and KRAS (1; level 4). An ETV6:NTRK fusion detected in tumor tissue was treated with larotrectinib; at progression, sequencing of cfDNA identified an NTRK3 G623R alteration as the acquired mechanism of resistance; the patient enrolled in a clinical trial of a second-generation TRK inhibitor with clinical benefit. In metastatic PanNENs, cfDNA-based NGS identified tumor-associated mutations in 66% of plasma samples with a high level of plasma-tissue agreement in PanNEN-associated genes. Clonal evolution, actionable alterations, and resistance mechanisms were detected through circulating cfDNA genotyping.
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Ácidos Nucleicos Libres de Células , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Humanos , Ácidos Nucleicos Libres de Células/genética , Genómica , Genoma , Tumores Neuroendocrinos/genética , Neoplasias Pancreáticas/genética , Secuenciación de Nucleótidos de Alto Rendimiento , MutaciónRESUMEN
BACKGROUND: Cancers with non-V600 BRAF-activating alterations have no matched therapy. Preclinical data suggest that these tumors depend on ERK signaling; however, clinical response to MEK/ERK inhibitors has overall been low. We hypothesized that a narrow therapeutic index, driven by ERK inhibition in healthy (wild-type) tissues, limits the efficacy of these inhibitors. As these mutants signal as activated dimers, we further hypothesized that RAF inhibitors given concurrently would improve the therapeutic index by opposing ERK inhibition in normal tissues and not activate ERK in the already activated tumor. MATERIALS AND METHODS: Using cell lines and patient-derived xenografts, we evaluated the effect of RAF inhibition, alone and in combination with MEK/ERK inhibitors. We then undertook a phase I/II clinical trial of a higher dose of the MEK inhibitor binimetinib combined with the RAF inhibitor encorafenib in patients with advanced cancer with activating non-V600 BRAF alterations. RESULTS: RAF inhibition led to modest inhibition of signaling and growth in activated non-V600 BRAF preclinical models and allowed higher dose of MEK/ERK inhibitors in vivo for more profound tumor regression. Fifteen patients received binimetinib 60 mg twice daily plus encorafenib 450 mg daily (6 gastrointestinal primaries, 6 genitourinary primaries, 3 melanoma, and 2 lung cancer; 7 BRAF mutations and 8 BRAF fusions). Treatment was well tolerated without dose-limiting toxicities. One patient had a confirmed partial response, 8 had stable disease, and 6 had radiographic or clinical progression as best response. On-treatment biopsies revealed incomplete ERK pathway inhibition. CONCLUSION: Combined RAF and MEK inhibition does not sufficiently inhibit activated non-V600 BRAF-mutant tumors in patients.
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Melanoma , Proteínas Proto-Oncogénicas B-raf , Humanos , Proteínas Proto-Oncogénicas B-raf/genética , Sulfonamidas/farmacología , Sulfonamidas/uso terapéutico , Melanoma/tratamiento farmacológico , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinasas de Proteína Quinasa Activadas por Mitógenos , MutaciónRESUMEN
BACKGROUND: The benefit of primary tumor resection in distant metastatic small bowel neuroendocrine tumors (SBNETs) is controversial, with treatment-based morbidity not well-defined. We aimed to determine the impact of primary tumor resection on development of disease-specific complications in patients with metastatic well-differentiated SBNETs. PATIENTS AND METHODS: A retrospective analysis was performed of patients diagnosed with metastatic well-differentiated jejunal/ileal SBNETs at a single tertiary care cancer center from 1980 to 2016. Outcomes were compared on the basis of treatment selected at diagnosis between patients who underwent initial medical treatment or primary tumor resection. RESULTS: Among 180 patients, 71 underwent medical management and 109 primary tumor resection. Median follow-up was 116 months. Median event-free survival did not differ between treatment approaches (log-rank p = 0.2). In patients medically managed first, 16/71 (23%) required surgery due to obstruction, perforation, or bleeding. These same complications led to resection at presentation in 31/109 (28%) surgically treated patients. Development of an obstruction from the primary tumor was not associated with disease progression/recurrence (HR 1.14, 95% CI 0.75-1.75) with all patients recovering postoperatively. Ongoing tumor progression requiring secondary laparotomy was associated with worse mortality (HR 7.51, 95% CI 3.3-16.9; p < 0.001) and occurred in 20/109 (18%) primary tumor resection and 7/16 (44%) initially medically treated patients. CONCLUSIONS: Rates of event-free survival among patients with metastatic SBNETs do not differ on the basis of primary tumor management. The development of an obstruction from the primary tumor was not associated with worse outcomes with all patients salvaged. Regardless of initial treatment selected, patients with metastatic SBNET should be closely followed for early signs of primary tumor complications.
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Neoplasias Intestinales , Tumores Neuroendocrinos , Neoplasias Pancreáticas , Neoplasias Gástricas , Humanos , Estudios Retrospectivos , Tumores Neuroendocrinos/cirugía , Neoplasias Intestinales/cirugíaRESUMEN
PURPOSE: Hepatocellular carcinoma (HCC), the fourth most common cancer in Africa, has a dismal overall survival of only 3 months like in sub-Saharan Africa. This is affected by the low gross domestic product and human development index, absence of coherent guidelines, and other factors. METHODS: An open forum for HCC-experienced health care workers from Africa and the rest of the world was held in October 2021. Participants completed a survey to help assess the real-life access to screening, diagnoses, and treatment in the North and Southern Africa (NS), East and West Africa (EW), Central Africa (C), and the rest of the world. RESULTS: Of 461 participants from all relevant subspecialties, 372 were from Africa. Most African participants provided hepatitis B vaccination and treatment for hepatitis B and C. More than half of the participants use serum alpha-fetoprotein and ultrasound for surveillance. Only 20% reported using image-guided diagnostic liver biopsy. The Barcelona Clinic Liver Cancer is the most used staging system (52%). Liver transplant is available for only 28% of NS and 3% EW. C reported a significantly lower availability of resection. Availability of local therapy ranged from 94% in NS to 62% in C. Sorafenib is the most commonly used systemic therapy (66%). Only 12.9% reported access to other medications including immune checkpoint inhibitors. Besides 42% access to regorafenib in NS, second-line treatments were not provided. CONCLUSION: Similarities and differences in the care for patients with HCC in Africa are reported. This reconfirms the major gaps in access and availability especially in C and marginally less so in EW. This is a call for concerted multidisciplinary efforts to achieve and sustain a reduction in incidence and mortality from HCC in Africa.
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Carcinoma Hepatocelular , Hepatitis B , Neoplasias Hepáticas , Humanos , Carcinoma Hepatocelular/terapia , Carcinoma Hepatocelular/tratamiento farmacológico , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/tratamiento farmacológico , Sorafenib/uso terapéutico , África/epidemiologíaRESUMEN
PURPOSE: Next-generation sequencing (NGS) of tumor-derived, circulating cell-free DNA (cfDNA) may aid in diagnosis, prognostication, and treatment of patients with hepatocellular carcinoma (HCC). The operating characteristics of cfDNA mutational profiling must be determined before routine clinical implementation. METHODS: This was a single-center, retrospective study with the primary objective of defining genomic alterations in circulating cfDNA along with plasma-tissue genotype agreement between NGS of matched tumor samples in patients with advanced HCC. cfDNA was analyzed using a clinically validated 129-gene NGS assay; matched tissue-based NGS was analyzed with a US Food and Drug Administration-authorized NGS tumor assay. RESULTS: Fifty-three plasma samples from 51 patients with histologically confirmed HCC underwent NGS-based cfDNA analysis. Genomic alterations were detected in 92.2% of patients, with the most commonly mutated genes including TERT promoter (57%), TP53 (47%), CTNNB1 (37%), ARID1A (18%), and TSC2 (14%). In total, 37 (73%) patients underwent paired tumor NGS, and concordance was high for mutations observed in patient-matched plasma samples: TERT (83%), TP53 (94%), CTNNB1 (92%), ARID1A (100%), and TSC2 (71%). In 10 (27%) of 37 tumor-plasma samples, alterations were detected by cfDNA analysis that were not detected in the patient-matched tumors. Potentially actionable mutations were identified in 37% of all cases including oncogenic/likely oncogenic alterations in TSC1/2 (18%), BRCA1/2 (8%), and PIK3CA (8%). Higher average variant allele fraction was associated with elevated alpha-fetoprotein, increased tumor volume, and no previous systemic therapy, but did not correlate with overall survival in treatment-naïve patients. CONCLUSION: Tumor mutation profiling of cfDNA in HCC represents an alternative to tissue-based genomic profiling, given the high degree of tumor-plasma NGS concordance; however, genotyping of both blood and tumor may be required to detect all clinically actionable genomic alterations.
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Carcinoma Hepatocelular , Ácidos Nucleicos Libres de Células , ADN Tumoral Circulante , Neoplasias Hepáticas , Estados Unidos , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Proteína BRCA1 , Estudios Retrospectivos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , ADN Tumoral Circulante/genética , Proteína BRCA2 , Ácidos Nucleicos Libres de Células/genéticaRESUMEN
BACKGROUND: The addition of nivolumab to chemotherapy improves survival in patients with advanced oesophagogastric (oesophageal, gastric, or gastro-oesophageal junction) adenocarcinoma; however, outcomes remain poor. We assessed the safety and activity of regorafenib in combination with nivolumab and chemotherapy in the first-line treatment of advanced oesophagogastric adenocarcinoma. METHODS: This investigator-initiated, single-arm, phase 2 trial in adult patients (aged ≥18 years) with previously untreated, HER2-negative, metastatic oesophagogastric adenocarcinoma was done at the Memorial Sloan Kettering Cancer Center (New York, NY, USA). Eligible patients had measurable disease or non-measurable disease that was evaluable (defined by Response Evaluation Criteria in Solid Tumours [RECIST] version 1.1) and Eastern Cooperative Oncology Group performance status of 0 or 1. Patients received FOLFOX chemotherapy (fluorouracil [400 mg/m2 bolus followed by 2400 mg/m2 over 48 h], leucovorin [400 mg/m2], and oxaliplatin [85 mg/m2]) and nivolumab (240 mg) intravenously on days 1 and 15, and oral regorafenib (80 mg) on days 1-21 of a 28-day cycle. Treatment was continued until disease progression (defined by RECIST version 1.1), unacceptable toxicity, or withdrawal of consent. The primary endpoint was 6-month progression-free survival in the per-protocol population (ie, all participants who received a dose of all study treatments). The regimen would be considered worthy of further investigation if at least 24 of 35 patients were progression free at 6 months. Safety was assessed in all participants who received at least one dose of any study treatment. This trial is registered with ClinicalTrials.gov, NCT04757363, and is now complete. FINDINGS: Between Feb 11, 2021, and May 4, 2022, 39 patients were enrolled, received at least one dose of study drug, and were included in safety analyses. 35 patients were evaluable for 6-month progression-free survival. Median age was 57 years (IQR 52-66), nine (26%) patients were women, 26 (74%) were men, 28 (80%) were White, and seven (20%) were Asian. At data cutoff (March 3, 2023), median follow-up was 18·1 months (IQR 12·7-20·4). The primary endpoint was reached, with 25 (71%; 95% CI 54-85) of 35 patients progression free at 6 months. Nine (26%) of 35 patients had disease progression and one (3%) patient died; the death was unrelated to treatment. The most common adverse event of any grade was fatigue (36 [92%] of 39). The most common grade 3 or 4 adverse events were decreased neutrophil count (18 [46%]), hypertension (six [15%]), dry skin, pruritus, or rash (five [13%]), and anaemia (four [10%]). Serious treatment-related adverse events occurred in ten (26%) patients, which were acute kidney injury (three [8%]), hepatotoxicity (two [5%]), sepsis (two [5%]), dry skin, pruritus, or rash (one [3%]), nausea (one [3%]), and gastric perforation (one [3%]). There were no treatment-related deaths. INTERPRETATION: Regorafenib can be safely combined with nivolumab and chemotherapy and showed promising activity in HER2-negative metastatic oesophagogastric cancer. A randomised, phase 3 clinical trial is planned. FUNDING: Bristol Myers Squibb, Bayer and National Institutes of Health/National Cancer Institute.
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Adenocarcinoma , Neoplasias Esofágicas , Exantema , Neoplasias Gástricas , Adolescente , Adulto , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adenocarcinoma/patología , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Progresión de la Enfermedad , Nivolumab/efectos adversos , Prurito/etiología , Neoplasias Gástricas/patologíaRESUMEN
Background Diffusion-weighted (DW) imaging is useful in detecting tumor in the primary tumor bed in locally advanced rectal cancer (LARC) after neoadjuvant therapy, but its value in detecting extramural venous invasion (EMVI) and tumor deposit is not well validated. Purpose To evaluate diagnostic accuracy and association with patient prognosis of viable EMVI and tumor deposit on DW images in patients with LARC after neoadjuvant therapy using whole-mount pathology specimens. Materials and Methods This retrospective study included patients who underwent neoadjuvant therapy and surgery from 2018 to 2021. Innovative five-point Likert scale was used by two radiologists to independently evaluate the likelihood of viable EMVI and tumor deposit on restaging DW MRI scans in four axial quadrants (12 to 3 o'clock, 3 to 6 o'clock, 6 to 9 o'clock, and 9 to 12 o'clock). Diagnostic accuracy was assessed at both the per-quadrant and per-patient level, with whole-mount pathology as the reference standard. Weighted κ values for interreader agreement and Cox regression models for disease-free survival and overall survival analyses were used. Results A total of 117 patients (mean age, 56 years ± 12 [SD]; 70 male, 47 female) were included. Pathologically proven viable EMVI and tumor deposit was detected in 29 of 117 patients (25%) and in 44 of 468 quadrants (9.4%). Per-quadrant analyses showed an area under the receiver operating characteristics curve of 0.75 (95% CI: 0.68, 0.83), with sensitivity and specificity of 55% and 96%, respectively. Good interreader agreement was observed between the radiologists (κ = 0.62). Per-patient analysis showed sensitivity and specificity of 62% and 93%, respectively. The presence of EMVI and tumor deposit on restaging DW MRI scans was associated with worse disease-free survival (hazard ratio [HR], 5.6; 95% CI: 2.4, 13.3) and overall survival (HR, 8.9; 95% CI: 1.6, 48.5). Conclusion DW imaging using the five-point Likert scale showed high specificity and moderate sensitivity in the detection of viable extramural venous invasion and tumor deposits in LARC after neoadjuvant therapy, and its presence on restaging DW MRI scans is associated with worse prognosis. Published under a CC BY 4.0 license. Supplemental material is available for this article. See also the editorial by Méndez and Ayuso in this issue.
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Terapia Neoadyuvante , Neoplasias del Recto , Humanos , Masculino , Femenino , Persona de Mediana Edad , Extensión Extranodal , Estudios Retrospectivos , Invasividad Neoplásica/diagnóstico por imagen , Invasividad Neoplásica/patología , Imagen de Difusión por Resonancia Magnética/métodos , Neoplasias del Recto/diagnóstico por imagen , Neoplasias del Recto/terapia , Neoplasias del Recto/patología , Imagen por Resonancia Magnética/métodosRESUMEN
PURPOSE: To determine the genetic predisposition underlying pancreatic acinar cell carcinoma (PACC) and characterize its genomic features. METHODS: Both somatic and germline analyses were performed using an Food and Drug Administration-authorized matched tumor/normal sequencing assay on a clinical cohort of 28,780 patients with cancer, 49 of whom were diagnosed with PACC. For a subset of PACCs, whole-genome sequencing (WGS; n = 12) and RNA sequencing (n = 6) were performed. RESULTS: Eighteen of 49 (36.7%) PACCs harbored germline pathogenic variants in homologous recombination (HR) and DNA damage response (DDR) genes, including BRCA1 (n = 1), BRCA2 (n = 12), PALB2 (n = 2), ATM (n = 2), and CHEK2 (n = 1). Thirty-one PACCs displayed pure, and 18 PACCs harbored mixed acinar cell histology. Fifteen of 31 (48%) pure PACCs harbored a germline pathogenic variant affecting HR-/DDR-related genes. BRCA2 germline pathogenic variants (11 of 31, 35%) were significantly more frequent in pure PACCs than in pancreatic adenocarcinoma (86 of 2,739, 3.1%; P < .001), high-grade serous ovarian carcinoma (67 of 1,318, 5.1%; P < .001), prostate cancer (116 of 3,401, 3.4%; P < .001), and breast cancer (79 of 3,196, 2.5%; P < .001). Genomic features of HR deficiency (HRD) were detected in 7 of 12 PACCs undergoing WGS, including 100% (n = 6) of PACCs with germline HR-related pathogenic mutations and 1 of 6 PACCs lacking known pathogenic alterations in HR-related genes. Exploratory analyses revealed that in PACCs, the repertoire of somatic driver genetic alterations and the load of neoantigens with high binding affinity varied according to the presence of germline pathogenic alterations affecting HR-/DDR-related genes and/or HRD. CONCLUSION: In a large pan-cancer cohort, PACC was identified as the cancer type with the highest prevalence of both BRCA2 germline pathogenic variants and genomic features of HRD, suggesting that PACC should be considered as part of the spectrum of BRCA-related malignancies.
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Carcinoma de Células Acinares , Neoplasias Pancreáticas , Masculino , Humanos , Carcinoma de Células Acinares/genética , Neoplasias Pancreáticas/genética , Proteína BRCA2/genética , Proteína BRCA1/genética , Mutación de Línea Germinal , Predisposición Genética a la Enfermedad , Recombinación Homóloga , Genómica , Neoplasias PancreáticasRESUMEN
Background: Perioperative chemotherapy is standard of care management for locally advanced gastric cancer (GC), but a substantial proportion of patients do not complete adjuvant therapy due to postoperative complications and prolonged recovery. Administration of all chemotherapy prior to surgery in the form of total neoadjuvant therapy (TNT) may optimize complete delivery of systemic therapy. Methods: We performed a retrospective review of GC patients who had surgery at Memorial Sloan Kettering Cancer Center (MSKCC) from May 2014 to June 2020. Results: One hundred and forty-nine patients were identified; 121 patients received perioperative chemotherapy and 28 patients received TNT. TNT was chosen if patients had interim radiographic and/or clinical response to treatment. Baseline characteristics were well-balanced between the two group except for chemotherapy regimen; more TNT patients received FLOT compared to the perioperative group (79% vs. 31%). There was no difference in the proportion of patients who completed all planned cycles, but TNT patients received a higher proportion of cycles containing all chemotherapy drugs (93% vs. 74%, P<0.001). Twenty-nine patients (24%) in the perioperative group did not receive intended adjuvant therapy. There was no significant difference in hospital length of stay or surgical morbidity. The overall distribution of pathologic stage was similar between the two groups. Fourteen percent of TNT patients and 5.8% of perioperative patients achieved a pathologic complete response (P=0.6). There was no significant difference in recurrence free survival (RFS) or overall survival (OS) between the TNT and perioperative groups [24-month OS rate 77% vs. 85%, HR 1.69 (95% CI: 0.80-3.56)]. Conclusions: Our study was limited by a small TNT sample size and biases inherent to a retrospective analysis. TNT appears to be feasible in a select population, without any increase in surgical morbidity.
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BACKGROUND. Imaging reports that consistently document all disease sites with a potential to increase surgical complexity or morbidity can facilitate ovarian cancer treatment planning. OBJECTIVE. The aims of this study were to compare simple structured reports and synoptic reports from pretreatment CT examinations in patients with advanced ovarian cancer in terms of completeness of documenting involvement of clinically relevant anatomic sites as well as to evaluate physician satisfaction with synoptic reports. METHODS. This retrospective study included 205 patients (median age, 65 years) who underwent contrast-enhanced abdominopelvic CT before primary treatment of advanced ovarian cancer from June 1, 2018, to January 31, 2022. A total of 128 reports generated on or before March 31, 2020, used a simple structured report (free text organized into sections); 77 reports generated on or after April 1, 2020, used a synoptic report (a list of 45 anatomic sites relevant to ovarian cancer management, each of which was classified in terms of disease absence versus presence). Reports were reviewed for completeness of documentation of involvement of the 45 sites. For patients who underwent neoadjuvant chemotherapy based on diagnostic laparoscopy findings or underwent primary debulking surgery with suboptimal resection, the EMR was reviewed to identify surgically established sites of disease that were unresectable or challenging to resect. Gynecologic oncology surgeons were electronically surveyed. RESULTS. The mean report turnaround time was 29.8 minutes for simple structured reports versus 54.5 minutes for synoptic reports (p < .001). A mean of 17.6 of 45 sites (range, four to 43 sites) were mentioned by simple structured reports versus 44.5 of 45 sites (range, 39-45) for synoptic reports (p < .001). Forty-three patients had surgically established unresectable or challenging-to-resect disease; involvement of anatomic site(s) with such disease was mentioned in 37% (11/30) of simple structured reports versus 100% (13/13) of synoptic reports (p < .001). All eight surveyed gynecologic oncology surgeons completed the survey. CONCLUSION. A synoptic report improved completeness of pretreatment CT reports in patients with advanced ovarian cancer, including for established sites of unresectable or challenging-to-resect disease. CLINICAL IMPACT. The findings indicate the role of disease-specific synoptic reports in facilitating referrer communication and potentially guiding clinical decision-making.