Salvage Ablative Radiotherapy for Isolated Local Recurrence of Pancreatic Adenocarcinoma following Definitive Surgery.

Introduction: The rate of isolated locoregional recurrence after surgery for pancreatic adenocarcinoma (PDAC) approaches 25%. Ablative radiation therapy (A-RT) has improved outcomes for locally advanced disease in the primary setting. We sought to evaluate the outcomes of salvage A-RT for isolated locoregional recurrence and examine the relationship between subsequent patterns of failure, radiation dose, and treatment volume. Methods: We conducted a retrospective analysis of all consecutive participants who underwent A-RT for an isolated locoregional recurrence of PDAC after prior surgery at our institution between 2016 and 2021. Treatment consisted of ablative dose (BED10 98-100 Gy) to the gross disease with an additional prophylactic low dose (BED10 < 50 Gy), with the elective volume covering a 1.5 cm isotropic expansion around the gross disease and the circumference of the involved vessels. Local and locoregional failure (LF and LRF, respectively) estimated by the cumulative incidence function with competing risks, distant metastasis-free and overall survival (DMFS and OS, respectively) estimated by the Kaplan-Meier method, and toxicities scored by CTCAE v5.0 are reported. Location of recurrence was mapped to the dose region on the initial radiation plan. Results: Among 65 participants (of whom two had two A-RT courses), the median age was 67 (range 37-87) years, 36 (55%) were male, and 53 (82%) had undergone pancreaticoduodenectomy with a median disease-free interval to locoregional recurrence of 16 (range, 6-71) months. Twenty-seven participants (42%) received chemotherapy prior to A-RT. With a median follow-up of 35 months (95%CI, 26-56 months) from diagnosis of recurrence, 24-month OS and DMFS were 57% (95%CI, 46-72%) and 22% (95%CI, 14-37%), respectively, while 24-month cumulative incidence of in-field LF and total LRF were 28% (95%CI, 17-40%) and 36% (95%CI 24-48%), respectively. First failure after A-RT was distant in 35 patients (53.8%), locoregional in 12 patients (18.5%), and synchronous distant and locoregional in 10 patients (15.4%). Most locoregional failures occurred in elective low-dose volumes. Acute and chronic grade 3-4 toxicities were noted in 1 (1.5%) and 5 patients (7.5%), respectively. Conclusions: Salvage A-RT achieves favorable OS and local control outcomes in participants with an isolated locoregional recurrence of PDAC after surgical resection. Consideration should be given to extending high-dose fields to include adjacent segments of at-risk vessels beyond direct contact with the gross disease.

Morbidity and mortality in patients with stage IV pancreatic adenocarcinoma and acute cholangitis: Outcomes and risk prognostication.

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.

Deep Learning Model for Tumor Type Prediction using Targeted Clinical Genomic Sequencing Data.

Tumor type guides clinical treatment decisions in cancer, but histology-based diagnosis remains challenging. Genomic alterations are highly diagnostic of tumor type, and tumor type classifiers trained on genomic features have been explored, but the most accurate methods are not clinically feasible, relying on features derived from whole genome sequencing (WGS), or predicting across limited cancer types. We use genomic features from a dataset of 39,787 solid tumors sequenced using a clinical targeted cancer gene panel to develop Genome-Derived-Diagnosis Ensemble (GDD-ENS): a hyperparameter ensemble for classifying tumor type using deep neural networks. GDD-ENS achieves 93% accuracy for high-confidence predictions across 38 cancer types, rivalling performance of WGS-based methods. GDD-ENS can also guide diagnoses on rare type and cancers of unknown primary, and incorporate patient-specific clinical information for improved predictions. Overall, integrating GDD-ENS into prospective clinical sequencing workflows could provide clinically-relevant tumor type predictions to guide treatment decisions in real time.

Deep Learning Model for Tumor Type Prediction using Targeted Clinical Genomic Sequencing Data.

Tumor type guides clinical treatment decisions in cancer, but histology-based diagnosis remains challenging. Genomic alterations are highly diagnostic of tumor type, and tumor type classifiers trained on genomic features have been explored, but the most accurate methods are not clinically feasible, relying on features derived from whole genome sequencing (WGS), or predicting across limited cancer types. We use genomic features from a dataset of 39,787 solid tumors sequenced using a clinical targeted cancer gene panel to develop Genome-Derived-Diagnosis Ensemble (GDD-ENS): a hyperparameter ensemble for classifying tumor type using deep neural networks. GDD-ENS achieves 93% accuracy for high-confidence predictions across 38 cancer types, rivalling performance of WGS-based methods. GDD-ENS can also guide diagnoses on rare type and cancers of unknown primary, and incorporate patient-specific clinical information for improved predictions. Overall, integrating GDD-ENS into prospective clinical sequencing workflows has enabled clinically-relevant tumor type predictions to guide treatment decisions in real time.

Personalized RNA neoantigen vaccines stimulate T cells in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) is lethal in 88% of patients1, yet harbours mutation-derived T cell neoantigens that are suitable for vaccines 2,3. Here in a phase I trial of adjuvant autogene cevumeran, an individualized neoantigen vaccine based on uridine mRNA-lipoplex nanoparticles, we synthesized mRNA neoantigen vaccines in real time from surgically resected PDAC tumours. After surgery, we sequentially administered atezolizumab (an anti-PD-L1 immunotherapy), autogene cevumeran (a maximum of 20 neoantigens per patient) and a modified version of a four-drug chemotherapy regimen (mFOLFIRINOX, comprising folinic acid, fluorouracil, irinotecan and oxaliplatin). The end points included vaccine-induced neoantigen-specific T cells by high-threshold assays, 18-month recurrence-free survival and oncologic feasibility. We treated 16 patients with atezolizumab and autogene cevumeran, then 15 patients with mFOLFIRINOX. Autogene cevumeran was administered within 3 days of benchmarked times, was tolerable and induced de novo high-magnitude neoantigen-specific T cells in 8 out of 16 patients, with half targeting more than one vaccine neoantigen. Using a new mathematical strategy to track T cell clones (CloneTrack) and functional assays, we found that vaccine-expanded T cells comprised up to 10% of all blood T cells, re-expanded with a vaccine booster and included long-lived polyfunctional neoantigen-specific effector CD8+ T cells. At 18-month median follow-up, patients with vaccine-expanded T cells (responders) had a longer median recurrence-free survival (not reached) compared with patients without vaccine-expanded T cells (non-responders; 13.4 months, P = 0.003). Differences in the immune fitness of the patients did not confound this correlation, as responders and non-responders mounted equivalent immunity to a concurrent unrelated mRNA vaccine against SARS-CoV-2. Thus, adjuvant atezolizumab, autogene cevumeran and mFOLFIRINOX induces substantial T cell activity that may correlate with delayed PDAC recurrence.

Genomic Biomarkers Associated with Response to Induction Chemotherapy in Patients with Localized Pancreatic Ductal Adenocarcinoma.

PURPOSE: There is increasing use of neoadjuvant chemotherapy in the management of localized pancreatic ductal adenocarcinoma (PDAC), yet there are few validated biomarkers to guide therapy selection. We aimed to determine whether somatic genomic biomarkers predict response to induction FOLFIRINOX or gemcitabine/nab-paclitaxel. EXPERIMENTAL DESIGN: This single-institution cohort study included consecutive patients (N = 322) with localized PDAC (2011-2020) who received at least one cycle of FOLFIRINOX (N = 271) or gemcitabine/nab-paclitaxel (N = 51) as initial treatment. We assessed somatic alterations in four driver genes (KRAS, TP53, CDKN2A, and SMAD4) by targeted next-generation sequencing, and determined associations between these alterations and (1) rate of metastatic progression during induction chemotherapy, (2) surgical resection, and (3) complete/major pathologic response. RESULTS: The alteration rates in driver genes KRAS, TP53, CDKN2A, and SMAD4 were 87.0%, 65.5%, 26.7%, and 19.9%, respectively. For patients receiving first-line FOLFIRINOX, SMAD4 alterations were uniquely associated with metastatic progression (30.0% vs. 14.5%; P = 0.009) and decreased rate of surgical resection (37.1% vs. 66.7%; P < 0.001). For patients receiving induction gemcitabine/nab-paclitaxel, alterations in SMAD4 were not associated with metastatic progression (14.3% vs. 16.2%; P = 0.866) nor decreased rate of surgical resection (33.3% vs. 41.9%; P = 0.605). Major pathologic response was rare (6.3%) and not associated with type of chemotherapy regimen. CONCLUSIONS: SMAD4 alterations were associated with more frequent development of metastasis and lower probability of reaching surgical resection during neoadjuvant FOLFIRINOX but not gemcitabine/nab-paclitaxel. Confirmation in a larger, diverse patient cohort will be important before prospective evaluation of SMAD4 as a genomic biomarker to guide treatment selection.

Stereotactic ablative radiation for pancreatic cancer on a 1.5 Telsa magnetic resonance-linac system.

Purpose: Ablative radiation therapy (A-RT) appears to improve outcomes in locally advanced pancreatic cancer (LAPC) yet requires solutions for respiratory and digestive motion. We report outcomes of A-RT for pancreatic cancer using 1.5 T MR-adaptive treatment delivery. Methods: Between March 2020 and July 2021, we treated 30 patients with pancreatic cancer with 50 Gy in 5 fractions (biologically effective dose [BED10] = 100 Gy10) using a novel compression belt workflow and remote planning on the Unity 1.5 T MR linac system. Cumulative incidence of progression was computed from A-RT initiation with death as a competing risk. Overall (OS) and progression-free survival (PFS) were calculated using Kaplan Meier methods. Results: Of 30 patients, most (73 %) were locally advanced, 4 (13 %) were metastatic, 2 (7 %) were medically inoperable, and 2 (7 %) were locally recurrent. Most (73 %) received FOLFIRINOX prior to A-RT. Median follow-up times from diagnosis and A-RT were 17.6 (IQR 15.8-23.1) and 11.5 months (IQR 9.7-16.1), respectively. Cumulative incidences at 1-year of local and distant progression were 19.3 % (95 %CI 6.7-36.8 %) and 47.4 % (95 %CI 26.7-65.6 %), respectively. Median OS from diagnosis and A-RT were not reached. One-year OS from diagnosis and A-RT were 96.4 % (95 %CI 77.2-99.5 %) and 80.0 % (95 %CI 57.3-91.4 %), respectively. Median and 1-year PFS were 10.1 months (95 %CI 4.4-14.4) and 39.7 % (95 %CI 20.3-58.5 %), respectively. No grade 3 + toxicities were observed. Conclusions: A-RT using the 1.5 T Unity MR Linac resulted in promising LC and OS with no severe toxicity in patients with LAPC despite radiosensitive organs adjacent to the target volumes. Longer follow-up is needed to assess long-term outcomes.

Methylation Analyses Reveal Promoter Hypermethylation as a Rare Cause of "Second Hit" in Germline BRCA1-Associated Pancreatic Ductal Adenocarcinoma.

BACKGROUND AND OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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.

Ordered and deterministic cancer genome evolution after p53 loss.

Although p53 inactivation promotes genomic instability1 and presents a route to malignancy for more than half of all human cancers2,3, the patterns through which heterogenous TP53 (encoding human p53) mutant genomes emerge and influence tumorigenesis remain poorly understood. Here, in a mouse model of pancreatic ductal adenocarcinoma that reports sporadic p53 loss of heterozygosity before cancer onset, we find that malignant properties enabled by p53 inactivation are acquired through a predictable pattern of genome evolution. Single-cell sequencing and in situ genotyping of cells from the point of p53 inactivation through progression to frank cancer reveal that this deterministic behaviour involves four sequential phases-Trp53 (encoding mouse p53) loss of heterozygosity, accumulation of deletions, genome doubling, and the emergence of gains and amplifications-each associated with specific histological stages across the premalignant and malignant spectrum. Despite rampant heterogeneity, the deletion events that follow p53 inactivation target functionally relevant pathways that can shape genomic evolution and remain fixed as homogenous events in diverse malignant populations. Thus, loss of p53-the 'guardian of the genome'-is not merely a gateway to genetic chaos but, rather, can enable deterministic patterns of genome evolution that may point to new strategies for the treatment of TP53-mutant tumours.

Circulating tumor and invasive cell expression profiling predicts effective therapy in pancreatic cancer.

BACKGROUND: Pancreatic adenocarcinoma (PDAC) remains a refractory disease; however, modern cytotoxic chemotherapeutics can induce tumor regression and extend life. A blood-based, pharmacogenomic, chemosensitivity assay using gene expression profiling of circulating tumor and invasive cells (CTICs) to predict treatment response was previously developed. The combination regimen of 5-fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) and gemcitabine/nab-paclitaxel (G/nab-P) are established frontline approaches for treating advanced PDAC; however, there are no validated biomarkers for treatment selection. A similar unmet need exists for choosing second-line therapy. METHODS: The chemosensitivity assay was evaluated in metastatic PDAC patients presenting for frontline treatment. A prospective study enrolled patients (n = 70) before receiving either FOLFIRINOX or G/nab-P at a 1:1 ratio. Six milliliters of peripheral blood was collected at baseline and at time of disease progression. CTICs were isolated, gene-expression profiling was performed, and the assay was used to predict effective and ineffective chemotherapeutic agents. Treating physicians were blinded to the assay prediction results. RESULTS: Patients receiving an effective regimen as predicted by the chemosensitivity assay experienced significantly longer median progression-free survival (mPFS; 7.8 months vs. 4.2 months; hazard ratio [HR], 0.35; p = .0002) and median overall survival (mOS; 21.0 months vs. 9.7 months; HR, 0.40; p = .005), compared with an ineffective regimen. Assay prediction for effective second-line therapy was explored. The entire study cohort experienced favorable outcomes compared with historical controls, 7.1-month mPFS and 12.3-month mOS. CONCLUSIONS: Chemosensitivity assay profiling is a promising tool for guiding therapy in advanced PDAC. Further prospective validation is under way (clinicaltrials.gov NCT03033927).

Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients.

Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression.

Induction FOLFIRINOX for patients with locally unresectable pancreatic ductal adenocarcinoma.

OBJECTIVES: Patients with locally advanced pancreatic adenocarcinoma (PDAC) receive induction chemotherapy with or without radiation, with the goal of R0 resection and improving survival. Herein, we evaluate the outcomes of patients who presented with Stage III PDAC and received induction FOLFIRINOX. METHODS: An institutional database was queried for consecutive patients who received induction FOLFIRINOX for locally unresectable PDAC between 2010 and 2016. Clinical and radiographic parameters were assessed pre- and posttreatment, and clinical outcomes were evaluated. RESULTS: There were 200 patients who met the inclusion criteria. The median number of cycles of FOLFIRINOX was 8, 70% (n = 140) received radiation, and 18% (n = 36) underwent resection. Median overall survival (OS) in resected patients was 36 months (95% confidence interval [CI]: 24-56), and this group had improved OS compared to patients that did not undergo resection (hazard ratio (95% CI): 0.41 (0.26-0.64), p < 0.001). Patients (n = 112) who did not progress on induction therapy but remained unresectable had a median OS of 23.9 months (95% CI: 21.1-25.4). CONCLUSION: Nearly 20% of patients with locally advanced PDAC responded sufficiently to induction FOLFIRINOX to undergo resection, which was associated with improved OS compared to patients that did not undergo resection. Patients with stable disease who remain unresectable represent a group of patients with locally advanced PDAC who may benefit from optimization of additional nonoperative treatment.

Pancreas cancer and BRCA: A critical subset of patients with improving therapeutic outcomes.

BACKGROUND: Patients with germline/somatic BRCA1/BRCA2 mutations (g/sBRCA1/2) comprise a distinct biologic subgroup of pancreas ductal adenocarcinoma (PDAC). METHODS: Institutional databases were queried to identify patients who had PDAC with g/sBRCA1/2. Demographics, clinicopathologic details, genomic data (annotation sBRCA1/2 according to a precision oncology knowledge base for somatic mutations), zygosity, and outcomes were abstracted. Overall survival (OS) was estimated using the Kaplan-Meier method. RESULTS: In total, 136 patients with g/sBRCA1/2 were identified between January 2011 and June 2020. Germline BRCA1/2 (gBRCA1/2) mutation was identified in 116 patients (85%). Oncogenic somatic BRCA1/2 (sBRCA1/2) mutation was present in 20 patients (15%). Seventy-seven patients had biallelic BRCA1/2 mutations (83%), and 16 (17%) had heterozygous mutations. Sixty-five patients with stage IV disease received frontline platinum therapy, and 52 (80%) had a partial response. The median OS for entire cohort was 27.6 months (95% CI, 24.9-34.5 months), and the median OS for patients who had stage IV disease was 23 months (95% CI, 19-26 months). Seventy-one patients received a poly(adenosine diphosphate ribose) polymerase (PARP) inhibitor (PARPi), and 52 received PARPi monotherapy. For maintenance PARPi, 10 patients (36%) had a partial response, 12 (43%) had stable disease, and 6 (21%) had progression of disease as their best response. Six patients (21%) received maintenance PARPi for >2 years. For those with stage IV disease who received frontline platinum, the median OS was 26 months (95% CI, 20-52 months) for biallelic patients (n = 39) and 8.66 months (95% CI, 6.2 months to not reached) for heterozygous patients (n = 4). The median OS for those who received PARPi therapy was 26.5 months (95% CI, 24-53 months) for biallelic patients (n = 25) and 8.66 months (95% CI, 7.23 months to not reached) for heterozygous patients (n = 2). CONCLUSIONS: g/sBRCA1/2 mutations did not appear to have different actionable utility. Platinum and PARPi therapies offer therapeutic benefit, and very durable outcomes are observed in a subset of patients who have g/sBRCA1/2 mutations with biallelic status.

Noninvasive Detection of Polyclonal Acquired Resistance to FGFR Inhibition in Patients With Cholangiocarcinoma Harboring FGFR2 Alterations.

PURPOSE: Fibroblast growth factor receptor (FGFR) 2 alterations, present in 5%-15% of intrahepatic cholangiocarcinomas (IHC), are targets of FGFR-directed therapies. Acquired resistance is common among patients who respond. Biopsies at the time of acquired resistance to targeted agents may not always be feasible and may not capture the genetic heterogeneity that could exist within a patient. We studied circulating tumor DNA (ctDNA) as a less invasive means of potentially identifying genomic mechanisms of resistance to FGFR-targeted therapies. MATERIALS AND METHODS: Serial blood samples were collected from eight patients with FGFR-altered cholangiocarcinoma for ctDNA isolation and next-generation sequencing (NGS) throughout treatment and at resistance to anti-FGFR-targeted therapy. ctDNA was sequenced using a custom ultra-deep coverage NGS panel, incorporating dual index primers and unique molecular barcodes to enable high-sensitivity mutation detection. RESULTS: Thirty-one acquired mutations in FGFR2, 30/31 located in the kinase domain, were identified at resistance in six of eight patients with detectable ctDNA. Up to 13 independent FGFR2 mutations were detected per patient, indicative of striking genomic concordance among resistant subclones. CONCLUSION: ctDNA could be an effective means to longitudinally monitor for acquired resistance in FGFR2-altered IHC. The numerous acquired genetic alterations in FGFR2 suggest frequent polyclonal mechanisms of resistance that cannot be detected from single-site tissue biopsies.

Local Control and Survival After Induction Chemotherapy and Ablative Radiation Versus Resection for Pancreatic Ductal Adenocarcinoma With Vascular Involvement.

OBJECTIVE: We sought to compare overall survival (OS) and disease control for patients with localized pancreatic ductal adenocarcinoma (PDAC) treated with ablative dose radiotherapy (A-RT) versus resection. SUMMARY BACKGROUND DATA: Locoregional treatment for PDAC includes resection when possible or palliative RT. A-RT may offer durable tumor control and encouraging survival. METHODS: This was a single-institution retrospective analysis of patients with PDAC treated with induction chemotherapy followed by A-RT [≥98 Gy biologically effective dose (BED) using 15-25 fractions in 3-4.5 Gy/fraction] or pancreatectomy. RESULTS: One hundred and four patients received A-RT (49.8%) and 105 (50.2%) underwent resection. Patients receiving A-RT had larger median tumor size after induction chemotherapy [3.2 cm (undetectable-10.9) vs 2.6 cm (undetectable-10.7), P < 0.001], and were more likely to have celiac or hepatic artery encasement (48.1% vs 11.4%, P <0.001), or superior mesenteric artery encasement (43.3% vs 9.5%, P < 0.001); however, there was no difference in the degree of SMV/PV involvement (P = 0.123). There was no difference in locoregional recurrence/progression at 18-months between A-RT and resection; cumulative incidence was 16% [(95% confidence interval (CI) 10%-24%] versus 21% (95% CI 14%-30%), respectively (P= 0.252). However, patients receiving A-RT had a 19% higher 18-month cumulative incidence of distant recurrence/progression [58% (95% CI 48%-67%) vs 30% (95% CI 30%-49%), P= 0.004]. Median OS from completion of chemotherapy was 20.1 months for A-RT patients (95% CI 16.4-23.1 months) versus 32.9 months (95% CI 29.7-42.3 months) for resected patients (P < 0.001). CONCLUSION: Ablative radiation is a promising new treatment option for PDAC, offering locoregional disease control similar to that associated with resection and encouraging survival.

Treatment patterns and survival in patients with early-onset pancreatic cancer.

BACKGROUND: Pancreatic cancer is uncommon in patients younger than 50 years, although its incidence is increasing. This study characterizes treatment utilization for early-onset pancreatic cancer (EOPC) versus average-age-onset pancreatic cancer (AOPC) and identifies factors associated with failure to receive treatment. METHODS: The National Cancer Data Base (NCDB) was queried for patients with EOPC (age < 50 years) or AOPC (age ≥ 50 years) from 2004 to 2016. Multinomial regression was used to compare utilization (single modality vs multimodal treatment with or without surgery vs no treatment) between EOPC and AOPC. Kaplan-Meier methods were used to estimate overall survival (OS). RESULTS: Of 248,634 patients, 15,710 (6.3%) had EOPC. There were more male patients (56% vs 50%), non-White patients, and privately insured patients (61% vs 30%) with EOPC versus AOPC, without notable differences in clinical stage distribution. Patients with EOPC received more chemotherapy (38% vs 29%), surgery (9% vs 6.9%), chemoradiation (12% vs 9.2%), and multimodal treatment (21% vs 15%). The odds of receiving multimodal curative therapy were significantly higher for patients with EOPC versus patients with AOPC after adjustments for confounders (odds ratio, 3.89; 95% confidence interval [CI], 3.66-4.15; P < .001). Nineteen percent of patients with EOPC, in contrast to 39% of patients with AOPC, received no treatment. Patients with AOPC more frequently declined chemotherapy (15% vs 9.5%). One-year OS was higher for EOPC versus AOPC across each stage (0/I/II, 72% [95% CI, 71%-74%] vs 53% [95% CI, 53%-54%]; III, 48% [95% CI, 45%-50%] vs 38% [95% CI, 37%-38%]; IV, 25% [95% CI, 24%-26%] vs 15% [95% CI, 15%-15%]) and treated patients (0/I/II, 75% [95% CI, 74%-77%] vs 64% [95% CI, 63%-64%]; III, 51% [95% CI, 49%-54%] vs 47% [95% CI, 47%-48%]; IV, 29% [95% CI, 28%-31%] vs 23% [95% CI, 23%-24%]). CONCLUSIONS: Patients with EOPC receive more oncologic therapy than patients with AOPC, although the intensity, type, and duration of chemotherapy are not available in the NCDB; however, 19% and 39%, respectively, receive no therapy. Underutilization may explain suboptimal oncologic outcomes. Efforts to improve access and treatment utilization in all age groups are warranted.

Early-Onset Pancreas Cancer: Clinical Descriptors, Genomics, and Outcomes.

BACKGROUND: Recent evidence suggests a rising incidence of cancer in younger individuals. Herein, we report the epidemiologic, pathologic, and molecular characteristics of a patient cohort with early-onset pancreas cancer (EOPC). METHODS: Institutional databases were queried for demographics, treatment history, genomic results, and outcomes. Overall survival from date of diagnosis was estimated using Kaplan-Meier method. RESULTS: Between 2008 and 2018, 450 patients with EOPC were identified at Memorial Sloan Kettering. Median overall survival was 16.3 (95% confidence interval [CI] = 14.6 to 17.7) months in the entire cohort and 11.3 (95% CI = 10.2 to 12.2) months for patients with stage IV disease at diagnosis. Of the patients, 132 (29.3% of the cohort) underwent somatic testing; 21 of 132 (15.9%) had RAS wild-type cancers with identification of several actionable alterations, including ETV6-NTRK3, TPR-NTRK1, SCLA5-NRG1, and ATP1B1-NRG1 fusions, IDH1 R132C mutation, and mismatch repair deficiency. A total of 138 patients (30.7% of the cohort) underwent germline testing; 44 of 138 (31.9%) had a pathogenic germline variant (PGV), and 27.5% harbored alterations in cancer susceptibility genes. Of patients seen between 2015 and 2018, 30 of 193 (15.5%) had a PGV. Among 138 who underwent germline testing, those with a PGV had a reduced all-cause mortality compared with patients without a PGV controlling for stage and year of diagnosis (hazard ratio = 0.42, 95% CI = 0.26 to 0.69). CONCLUSIONS: PGVs are present in a substantial minority of patients with EOPC. Actionable somatic alterations were identified frequently in EOPC, enriched in the RAS wild-type subgroup. These observations underpin the recent guidelines for universal germline testing and somatic profiling in pancreatic ductal adenocarcinoma.

Association of Ablative Radiation Therapy With Survival Among Patients With Inoperable Pancreatic Cancer.

IMPORTANCE: Surgical resection has been considered the only curative option for patients with pancreatic cancer. Nonoperative local treatment options that can provide a similar benefit are needed. Emerging radiation techniques that address organ motion have enabled curative radiation doses to be given in patients with inoperable disease. OBJECTIVE: To determine the association of hypofractionated ablative radiation therapy (A-RT) with survival for patients with locally advanced pancreatic cancer (LAPC) treated with a novel radiation planning and delivery technique. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included 119 consecutive patients treated with A-RT between June 2016 and February 2019 and enrolled in a prospectively maintained database. Patients were treated with a standardized technique within a large academic cancer center regional network. All patients with localized, unresectable, or medically inoperable pancreatic cancer with tumors of any size and less than 5 cm luminal abutment with the primary tumor were eligible. INTERVENTIONS: Ablative RT (98 Gy biologically effective dose) was delivered using standard equipment. Respiratory gating, soft tissue image guidance, and selective adaptive planning were used to address organ motion and limit the dose to surrounding luminal organs. MAIN OUTCOMES AND MEASURES: The primary outcome was overall survival (OS). Secondary outcomes included incidence of local progression and progression-free survival. RESULTS: Between 2016 and 2019, 119 patients (59 men, median age 67 years) received A-RT, including 99 with T3/T4 and 53 with node-positive disease, with a median carbohydrate antigen 19-9 (CA19-9) level greater than 167 U/mL. Most (116 [97.5%]) received induction chemotherapy for a median of 4 months (0.5-18.4). Median OS from diagnosis and A-RT were 26.8 and 18.4 months, respectively. Respective 12- and 24-month OS from A-RT were 74% (95% CI, 66%-83%) and 38% (95% CI, 27%-52%). Twelve- and 24-month cumulative incidence of locoregional failure were 17.6% (95% CI, 10.4%-24.9%) and 32.8% (95% CI, 21.6%-44.1%), respectively. Postinduction CA19-9 decline was associated with improved locoregional control and survival. Grade 3 upper gastrointestinal bleeding occurred in 10 patients (8%) with no grade 4 to 5 events. CONCLUSIONS AND RELEVANCE: This cohort study of patients with inoperable LAPC found that A-RT following multiagent induction therapy for LAPC was associated with durable locoregional tumor control and favorable survival. Prospective randomized trials in patients with LAPC are warranted.

Phase 1 cohort expansion study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced mesothelioma.

BACKGROUND LY3023414 is a selective, ATP competitive inhibitor of class I PI3K isoforms, mTORC1/2 and DNA-PK. A Phase 1 dose escalation, 200 mg twice daily (BID) of LY3023414 was the determined recommended phase 2 dose (RP2D). We report the antitumor activity and safety of LY3023414 monotherapy in patients with advanced mesothelioma.METHODS Patients enrolled had advanced malignant pleural or peritoneal mesothelioma with measurable disease, ECOG PS 0-1, were refractory or ineligible to receive standard therapies. Patients received LY3023414 200 mg BID. This dose expansion cohort is intended to evaluate preliminary antitumor activity of LY3023414 by overall response rate. Safety, tolerability and pharmacokinetics were assessed. Biomarkers associated with treatment response was an exploratory endpoint. RESULTS Forty-two patients received LY3023414 for a median duration of 11.2 weeks (range: 1.1-53.0). One patient had a confirmed partial response (PR) (ORR 2.4%). Three patients had an unconfirmed PR. Seventeen patients had stable disease (SD) (DCR 43%). Most common adverse events (AEs) included fatigue (43%), nausea (43%), decreased appetite (38%), vomiting (33%), and diarrhea (29%). AEs were mostly mild or moderate. Grade ≥ 3 AEs were reported for 21% of patients with fatigue as the most frequent event (10%). Alterations of BAP1 were identified in 11/19 patients as the most common molecular aberration, followed by SETD2 and NF2 alterations. No obvious pattern of genetic changes/mutations in single genes or pathways was associated with anti-tumor activity. CONCLUSION LY3023414 monotherapy (200 mg BID) demonstrated an acceptable and manageable safety profile with limited single-agent activity in patients with advanced mesothelioma. ClinicalTrials.gov identifier: NCT01655225; Date of registration: 19 July 2012.