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.

Precision medicine for pancreatic cancer: Characterizing the clinico-genomic landscape and outcomes of KRAS G12C-mutated disease.

BACKGROUND: Mutated KRAS is the most common oncogene alteration in pancreatic cancer (PDAC), and KRAS G12C mutations (KRAS G12Cmut) are observed in 1-2%. Several inhibitors of KRAS G12C have recently demonstrated promise in solid tumors, including PDAC. Little is known regarding clinical, genomics and outcome data of this population. METHODS: Patients with PDAC and KRAS G12Cmut were identified at Memorial Sloan Kettering Cancer Center (MSK), and via the AACR Project GENIE database. Clinical, treatment, genomic and outcomes data were analysed. A cohort of patients at MSK with non-G12C KRAS PDAC was included for comparison. RESULTS: Among 3,571 patients with PDAC, 39 with KRAS G12Cmut were identified (1.1%). Median age was 67 years, 56% were female. Median BMI was 29.2 kg/m2, 67% had a smoking history. Median OS 13 months (9.4, not reached (NR)) for stage IV, and 26 months (23, NR) for stage I-III. Complete genomic data (via AACR GENIE) was available for N = 74. 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 PDAC, ARID1A co-mutations were more frequent in KRAS G12Cmut (P < .05). OS did not differ between KRAS G12Cmut and non-G12C KRAS PDAC. Germline pathogenic variants were identified in 17%. N = 2 received KRAS G12C-directed therapy. CONCLUSION: PDAC and KRAS G12Cmut may be associated with a distinct clinical phenotype. Genomic features are similar to non-G12C KRAS-mutated PDAC, although enrichment of ARID1A co-mutations was observed. Targeting of KRAS G12C in PDAC provides a precedent for broader KRAS targeting in PDAC.

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.

Advances in Systemic Therapy in Pancreatic Cancer.

Substantial progress has been made toward understanding biology and developing new therapies for pancreatic ductal adenocarcinoma (PDAC). In this review, new insights from genomic profiling, as well as implications for treatment and prognosis, are discussed. New standards of care approaches with a focus on drug therapies are discussed for the treatment of resectable and advanced PDAC. The role of targeted and immune therapies remains limited; cohorts likely to benefit from these approaches are discussed. Promising, preliminary results regarding experimental therapies are reviewed.

Prior irinotecan exposure does not preclude benefit to liposomal irinotecan in patients with metastatic pancreatic ductal adenocarcinoma.

BACKGROUND: Subgroup analyses of the NAPOLI-1 study identified that among patients who were irinotecan naïve prior to entering the clinical trial, a survival benefit was observed between the study arm and control arm. This treatment benefit was not observed among those previously exposed to irinotecan. This study sought to understand the impact of prior exposure to irinotecan on clinical outcomes among patients treated with liposomal irinotecan in the real-world setting. METHODS: This retrospective observational study utilized a nationwide electronic health record (EHR)-derived deidentified database. Data for adult patients with mPDAC treated with liposomal irinotecan-based regimens between January 2016 and October 2020 were analyzed. Patient characteristics, overall survival (OS), and progression-free survival (PFS) were assessed. Cox proportional hazard methods were used to calculate hazard ratios (HRs). HRs were adjusted for demographics and relevant clinical covariates. RESULTS: Six hundred and seventy-five patients with mPDAC treated with a liposomal irinotecan-based regimen were included. The unadjusted OS HR was 1.3 (95% CI: 1.1-1.6, p < 0.001) and unadjusted PFS was HR 1.4 (95% CI: 1.2-1.7, p < 0.001). After adjustment for baseline characteristics, the adjusted OS HR was 1.0 (95% CI: 0.8-1.3, p = 0.8836) and the adjusted PFS HR was 1.1 (95% CI: 0.8-1.4, p = 0.5626). CONCLUSIONS: Prior irinotecan was not found to be a significant predictor of patient outcomes in those later treated with liposomal irinotecan. Thus, the results may inform the rationale for utilizing liposomal irinotecan combination therapy following prior irinotecan exposure in mPDAC, in particular where the prior irinotecan exposure was more distant in time.

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.

ChemoSensitivity Assay Guided Metronomic Chemotherapy Is Safe and Effective for Treating Advanced Pancreatic Cancer.

Cytotoxic chemotherapy remains the mainstay of treatment for advanced pancreatic adenocarcinoma (PDAC). Emerging studies support metronomic chemotherapy (MCT) as effective, challenging established paradigms of dosing and schedules. The blood-based ChemoSensitivity Assay has been shown to predict response and survival in advanced PDAC patients treated with standard chemotherapy. The current study combines these concepts for a highly personalized treatment approach. This was a retrospective analysis; a pilot (n = 50) and validation cohort (n = 45) were studied. The ChemoSensitivity Assay was performed at baseline and during therapy; results were correlated to drugs administered and patient outcomes. MCT was administered based on the assay results at the treating physician's discretion. Patients in the pilot cohort experienced favorable survival compared with historical controls (median overall survival (mOS) 16.8 mo). Patients whose treatment closely matched the ChemoSensitivity Assay predictions experienced longer median time on lines of therapy (5.3 vs. 3.3 mo, p = 0.02) and showed a trend for longer mOS (20.9 vs. 12.5 mo, p = 0.055) compared with those not closely matched. These findings were confirmed in the validation cohort. Overall, patients treated with MCT closely matching Assay results experienced a remarkable mOS of 27.7 mo. ChemoSensitivity profiling-guided MCT is a promising approach for personalized therapy in advanced PDAC.

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).

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.

Pharmacologically controlling protein-protein interactions through epichaperomes for therapeutic vulnerability in cancer.

Cancer cell plasticity due to the dynamic architecture of interactome networks provides a vexing outlet for therapy evasion. Here, through chemical biology approaches for systems level exploration of protein connectivity changes applied to pancreatic cancer cell lines, patient biospecimens, and cell- and patient-derived xenografts in mice, we demonstrate interactomes can be re-engineered for vulnerability. By manipulating epichaperomes pharmacologically, we control and anticipate how thousands of proteins interact in real-time within tumours. Further, we can essentially force tumours into interactome hyperconnectivity and maximal protein-protein interaction capacity, a state whereby no rebound pathways can be deployed and where alternative signalling is supressed. This approach therefore primes interactomes to enhance vulnerability and improve treatment efficacy, enabling therapeutics with traditionally poor performance to become highly efficacious. These findings provide proof-of-principle for a paradigm to overcome drug resistance through pharmacologic manipulation of proteome-wide protein-protein interaction networks.

Real-world prognostic factors for survival among treated patients with metastatic pancreatic ductal adenocarcinoma.

BACKGROUND: Many real-world studies of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) are restricted to single centers, limiting the generalizability of their insights. This study aimed to identify important population-based predictors for survival in patients diagnosed with mPDAC in a broader setting. METHODS: Data between 1 January 2017 and 31 December 2019 were extracted from the Flatiron Health EHR database. Treatment-specific predictive models were generated for patients treated with first-line gemcitabine+nab-paclitaxel (GNP), FOLFIRINOX, gemcitabine monotherapy (gem-mono), and second-line liposomal irinotecan-based regimens. The holdout method was used for cross-validation. Age at diagnosis, sex, BMI, smoking status, and ECOG performance score were included in all models with additional demographic, clinical characteristics, and hematological function assessed for inclusion. RESULTS: Of the 3625 patients, 43% received GNP, 26% received FOLFIRINOX, 7% received gem-mono, and 23% received other regimens; 40% (n = 1448) advanced to the second line. Among all first-line patients, the following were included in the final model: prior surgery, white blood cell (WBC) counts, serum albumin (SA), liver function tests (LFTs), serum bilirubin, serum carbohydrate antigen 19-9, and ascites. Models for patients receiving specific therapies differed from the overall model, GNP (ascites removed), FOLFIRINOX (stage at initial diagnosis added), and gem-mono (LFTs omitted). Alkaline phosphatase (ALP), SA, and WBC counts were important predictors of survival among patients treated with second-line liposomal irinotecan. Across all regimens, the strongest predictors of survival were ECOG score, SA, and ALP. CONCLUSIONS: In this real-world study of patients with mPDAC, important population prognostic factors of survival were identified in a large cohort of patients receiving systemic treatment.

Clinical Outcomes Among Patients With Metastatic Pancreatic Ductal Adenocarcinoma Treated With Liposomal Irinotecan.

BACKGROUND: The NAPOLI-1 trial demonstrated that liposomal irinotecan in combination with fluorouracil (5-FU) and leucovorin (LV) prolonged survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) previously treated with gemcitabine-based therapy. Real-world data on clinical outcomes associated with liposomal irinotecan in NAPOLI-1-based regimens is needed to further substantiate this. METHODS: This real-world, retrospective chart review study included patients with mPDAC who received NAPOLI-1-based regimens from six academic centers in the United States. Liposomal irinotecan initiation defined the index date. Overall survival (OS) and progression-free survival (PFS) were assessed with Kaplan-Meier methodology. RESULTS: There were 374 patients evaluated; median age was 68 years, and 51% were female. Among 326 patients with baseline ECOG information, approximately 74% had ECOG score <2. Liposomal irinotecan was administered as a doublet with 5-FU in a NAPOLI-1-based regimen in the first line (1L; 16%), 2L (42%), and 3L+ (42%) of the metastatic setting. For patients treated in 1L, 2L, and 3L+, median [95% confidence interval (CI)] OS was 8.0 [5.1, 11.2], 7.3 [5.3, 8.8], and 4.6 [4.0, 5.7] months, and median [95% CI] PFS was 4.2 [2.2, 6.6], 3.0 [2.6, 3.7], and 2.0 [1.7, 2.2] months, respectively. CONCLUSIONS: Patients in a real-world setting treated with NAPOLI-1-based liposomal irinotecan doublet regimens at academic centers were older with poorer performance status compared to trial patients yet had similar outcomes and efficacy. Furthermore, liposomal irinotecan was frequently used in the 3L+ setting where no treatment has been approved and provided clinical benefit.

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.

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.

Conformation-Specific Inhibitory Anti-MMP-7 Monoclonal Antibody Sensitizes Pancreatic Ductal Adenocarcinoma Cells to Chemotherapeutic Cell Kill.

Matrix metalloproteases (MMPs) undergo post-translational modifications including pro-domain shedding. The activated forms of these enzymes are effective drug targets, but generating potent biological inhibitors against them remains challenging. We report the generation of anti-MMP-7 inhibitory monoclonal antibody (GSM-192), using an alternating immunization strategy with an active site mimicry antigen and the activated enzyme. Our protocol yielded highly selective anti-MMP-7 monoclonal antibody, which specifically inhibits MMP-7's enzyme activity with high affinity (IC50 = 132 ± 10 nM). The atomic model of the MMP-7-GSM-192 Fab complex exhibited antibody binding to unique epitopes at the rim of the enzyme active site, sterically preventing entry of substrates into the catalytic cleft. In human PDAC biopsies, tissue staining with GSM-192 showed characteristic spatial distribution of activated MMP-7. Treatment with GSM-192 in vitro induced apoptosis via stabilization of cell surface Fas ligand and retarded cell migration. Co-treatment with GSM-192 and chemotherapeutics, gemcitabine and oxaliplatin elicited a synergistic effect. Our data illustrate the advantage of precisely targeting catalytic MMP-7 mediated disease specific activity.

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.

Leptomeningeal disease in pancreas ductal adenocarcinoma: A manifestation of longevity.

BACKGROUND: /Objectives: Pancreatic adenocarcinoma (PDAC) metastatic to the leptomeninges is a rare and lethal event. Leptomeningeal disease (LMD) research is limited in PDAC, and insights into clinical descriptors, possible disease predictors, and treatment strategies is necessitated. METHODS: Memorial Sloan Kettering databases were queried with Institutional Review Board approval to identify patients with LMD and PDAC treated between January 2000 and June 2020. Medical record review was used to abstract clinical, genomic, pathologic, and radiographic data. Overall survival was calculated from date of PDAC diagnosis to date of death. Previously published literature on LMD from PDAC was reviewed. RESULTS: Four patients with LMD from PDAC were identified, two males and two females. Age at diagnosis ranged from 57 to 68 years. All four patients had predominant lung metastasis and a relatively low burden of intra-abdominal disease. Somatic testing indicated alterations typical of PDAC and no PDAC defining pathogenic germline mutations were identified. An extended clinical course prior to LMD diagnosis was observed in all patients, ranging from 16 to 148 months. Upon diagnosis of LMD, three patients elected for supportive care and one patient received a limited course of craniospinal radiation. The median survival following diagnosis of LMD was 1.6 months (range 0.5-2.8 months). CONCLUSIONS: LMD from PDAC is a rare occurrence that may be more frequent in patients with lung metastasis and/or a more indolent clinical course. Following diagnosis of LMD, prognosis is poor, and survival is short. New treatment strategies for this manifestation of PDAC are needed.