Search

Survival outcomes after pancreatectomy for pancreatic ductal adenocarcinoma may be biased by right-censoring. We herein analyzed a large dataset with no censored events for up to 5 years and dynamically investigated the impact of known prognostic factors, accounting for unobserved tumor characteristics.Consecutive patients undergoing pancreatectomy from 2000 to July 2015 were included. The 1- to 5-year empirical survival rates were calculated, and factors associated with long-term survival (≥5 years) were analyzed using multivariable models. Dynamic analyses of survival and recurrence were conducted through landmarking, and the contribution of unobserved heterogeneity was estimated using frailty models.The study population included 1,048 patients. The median follow-up was 30.4 months in the whole cohort and 97.2 months in survivors. The median survival was 30.4 months, with empirical 1- to 5-year rates of 85.5%, 59.6%, 43.2%, 32.1%, and 27.5%. A favorable pathological profile was associated with 5-year survival, albeit 25.7% of long-survivors received an R1 resection, and 28.8% had N2 disease. The median recurrence-free survival was 17.2 months. At landmark analyses, baseline prognostic lost strength over time, with no independent predictors of survival being identified in the sets of patients alive at 4 and 5 years. There was a significant amount of unobserved heterogeneity in the early postoperative period.The 5-year post-pancreatectomy empirical survival was 27.5%. Dynamic analyses showed a time-varying structure of prognostic variables and a substantial impact of unobserved tumor characteristics that may drive the disease course under the selective pressure of surgical resection and adjuvant chemotherapy.

FOXD2-AS1 is known to promote the development of several cancers. However, its role in pancreatic adenocarcinoma (PAAD) is unclear.Expression of FOXD2-AS1 and miR-30a-3p in PAAD patients was analyzed with RT-qPCR. A follow-up study was performed to analyze the prognostic value of FOXD2-AS1 for PAAD. Overexpression assays were performed to analyze the crosstalk between FOXD2-AS1 and miR-30a-3p. Cell invasion and migration were analyzed by transwell assays.Analysis of the TCGA dataset revealed that FOXD2-AS1 was upregulated in PAAD tissues compared to the non-cancer tissues (1.89 vs. 0.2 TPM), indicating potential involvement of FOXD2-AS1 in PAAD. Our own data also showed FOXD2-AS1 was overexpressed in PAAD. Moreover, high FOXD2-AS1 levels predicted poor survival. It is predicted that miR-30a-3p can bind FOXD2-AS1, while their overexpression did not affect each other's expression. Correlation analysis revealed a significant correlation between FOXD2-AS1 and COX-2. In addition, FOXD2-AS1 overexpression increased COX-2 level, while miR-30a-3p played an opposite role. FOXD2-AS1 and COX-2 overexpression increased PAAD cell invasion and migration. MiR-30a-3p played an opposite role and inhibited the effects of FOXD2-AS1 and COX-2 overexpression.FOXD2-AS1 may promote PAAD cell invasion and migration by sponging miR-30a-3p to upregulate COX-2.

Background Timely surgical resection in patients with suspected or diagnosed pancreas adenocarcinoma is an essential part of care. We hypothesized that longer surgical wait time was associated with worse oncologic outcomes. Methods A retrospective cohort of patients (N = 144) with resectable pancreas adenocarcinoma was divided into four wait time groups ( 12 weeks), defined from the time of diagnosis on cross-sectional imaging. Overall and recurrence-free survival were analyzed using the Kaplan–Meier method and Cox proportional hazards regression. A higher rate of conversion to palliative bypass in patients waiting over 4 weeks was observed and further analyzed using post-hoc multivariate regression. Results On multivariable analysis, longer wait time was associated with improved overall (HR 0.49, 95% CI: 0.28–0.85) and recurrence-free survival (HR 0.29, 95% CI: 0.15–0.56) in >12 weeks compared to Conclusion Wait time over 8 weeks was associated with a higher rate of palliative bypass. There was an improvement in overall and recurrence-free survival in patients who waited over 12 weeks, likely due to selection bias.

CA extern Simple Summary Treatment of pancreas ductal adenocarcinoma (PDAC) remains challenging due to the late stage of presentation, limited efficacy of cytotoxic chemotherapies, and aggressive tumor biology. Novel therapeutic targets are desperately needed. The voltage-gated potassium channel, Kv1.3, is one such unique target. It has been extensively studied in many cancers but less is known in pancreas cancer. In this study, we evaluated the tissue expression of Kv1.3 in resected PDAC and tumor inhibition using novel Kv1.3 inhibitors developed by our group (PCARBTP and PAPTP) with cytotoxic chemotherapies. We found that Kv1.3 is expressed in early stage, non-metastatic, resectable pancreas cancer specimens. Treatment with novel mitochondrial Kv1.3 inhibitors resulted in 95% reduced tumor growth when combined with cytotoxic chemotherapies. This near complete eradication of tumors using this treatment strategy shows that Kv1.3 represents an innovative therapeutic target for pancreas cancer therapy. Pancreas ductal adenocarcinoma (PDAC) is one the most aggressive cancers and associated with very high mortality, requiring the development of novel treatments. The mitochondrial voltage-gated potassium channel, Kv1.3 is emerging as an attractive oncologic target but its function in PDAC is unknown. Here, we evaluated the tissue expression of Kv1.3 in resected PDAC from 55 patients using immunohistochemistry (IHC) and show that all tumors expressed Kv1.3 with 60% of tumor specimens having high Kv1.3 expression. In Pan02 cells, the recently developed mitochondria-targeted Kv1.3 inhibitors PCARBTP and PAPTP strongly reduced cell survival in vitro. In an orthotopic pancreas tumor model (Pan02 cells injected into C57BL/6 mice) in immune-competent mice, injection of PAPTP or PCARBTP resulted in tumor reductions of 87% and 70%, respectively. When combined with clinically used Gemcitabine plus Abraxane (albumin-bound paclitaxel), reduction reached 95% and 80% without resultant organ toxicity. Drug-mediated tumor cell death occurred through the p38-MAPK pathway, loss of mitochondrial membrane potential, and oxidative stress. Resistant Pan02 clones to PCARBTP escaped cell death through upregulation of the antioxidant system. In contrast, tumor cells did not develop resistance to PAPTP. Our data show that Kv1.3 is highly expressed in resected human PDAC and the use of novel mitochondrial Kv1.3 inhibitors combined with cytotoxic chemotherapies might be a novel, effective treatment for PDAC.

The poor prognosis of pancreatic ductal adenocarcinoma (PDAC) is frequently associated to high treatment resistance. Gemcitabine (GEM) alone or in combination is the most used chemotherapy for unresecable PDACs. Here we studied whether modulated electro-hyperthermia (mEHT), a non-invasive complementary treatment, can support the effect of GEM on PDAC cells in vitro. The LD20 for the GEM-resistant Panc1 cells proved to be 200× higher than for the drug-sensitive Capan1. The mEHT alone caused significant apoptosis in Capan1 cultures as confirmed by the elevated SubG1 phase cell fraction and increased number of cleaved Caspase-3 positive cells 48 h after treatment, with an additive effect when GEM was used after hyperthermia. These were accompanied by reduced number of G1, S, and G2/M phase cells and elevated expression of the cyclin-dependent kinase inhibitor p21waf1 protein. In GEM-resistant Panc1 cells, an initial apoptosis was detected by flow cytometry 24 h after mEHT ± GEM treatment, which however diminished by 48 h at persistent number of cleaved Caspase-3 positive tumor cells. Though GEM monotherapy reduced the number of tumor progenitor colonies in Capan1 cell line, an additive colony inhibitory effect of mEHT was observed after mEHT + GEM treatment. The heat shock induced Hsp27 and Hsp70 proteins, which are known to sensitize PDAC cells to GEM were upregulated in both Capan1 and Panc1 cells 24 h after mEHT treatment. The level of E-Cadherin, a cell adhesion molecule, increased in Capan1 cells after mEHT + GEM treatment. In conclusion, in GEM-sensitive PDAC cells mEHT treatment alone induced cell death and cell cycle inhibition and improved GEM efficiency in combination, which effects were milder and short-term up to 24 h in the GEM-resistant Panc1 cells. Our data further support the inclusion of hyperthermia, in particular of mEHT, into the traditional oncotherapy regimens of PDAC.

Background: Ovarian metastases (OM) of pancreatic adenocarcinoma (PA) (OM-PA) can mimic primary ovarian mucinous carcinoma (POMC) on imaging and histology. These metastases are often symptomatic and not highly chemosensitive, so that oophorectomy may be considered. Aims: The aims of this study were to compare the characteristics of OM-PA and POMC, and discuss the role of surgery. Patients and Methods: Clinical, imaging, and histological data of patients with OM-PA and POMC (2000–2017) in three tertiary centers were reviewed. Twenty-six genes were analyzed by next generation sequencing (NGS) on both primary PA and OM-PA. Results: Twenty-two women with OM-PA ( n = 13, 11 with surgical resection) or POMC ( n = 9) were selected. OM-PA were smaller than POMC ( p = 0.02); imaging, histological, and immunohistochemistry data did not clearly differentiate OM-PA from POMC in 12 of 22 cases (54%). Seven PA/OM-PA pairs were analyzed, and a concordant KRAS mutation was identified in all cases. In four OM-PA, concordant mutations were also found in TP53 ( n = 3), SMAD4 ( n = 1), MET ( n = 1), and PDGFRA ( n = 1) genes. The aim of oophorectomy in 11 OM-PA was for antalgic ( n = 6) or curative ( n = 5) intent. Pain improved in 4/6 of the former patients, but 2/6 had significant morbidity, and 2/6 died of rapid tumor progression. After oophorectomy, median progression-free and overall survivals were 6 (0–11) and 8 months (1–131), respectively. Conclusion: Analysis of mutation profiles in both primary PA and ovarian tumors, especially KRAS, can help to determine the pancreatic origin of OM-PA. Surgical resection of OM-AP in highly selected patients may improve pelvic symptoms but may also cause significant morbidity. The benefit to survival requires further studies.

Introduction To assess the prognostic significance of postoperative changes in immune status represented by total lymphocyte count (TLC) and neutrophil-to-lymphocyte ratio (NLR) in resectable pancreatic cancer. Methods Patients who underwent curative pancreatectomy for pancreatic adenocarcinoma were divided into high and low groups according to cut-off values of TLC, and NLR measured preoperatively, immediately after surgery, and 1- or 6-month after surgery. Oncologic outcomes were compared between the two groups at different times, and prognostic roles of TLC and NLR were evaluated. Results Of 193 patients, the median follow-up time was 22 months, and median survival was 18 months. Their immunologic status deteriorated within 3-4 days after the operation and recovered after that. At 1- and 6-month postoperatively, overall survival rates were significantly lower in the group with high NLR (> 2.535 and > 3.21, respectively) and low TLC (< 1.66 × 109/L and < 1.62 × 109/L, respectively). In multiple regression analysis, elevated NLR at postoperative 1- and 6-month and decreased TLC at postoperative 1-month were significant prognosis predictors. Conclusions Changes in immune status such as decreased TLC and elevated NLR at postoperative 1- and 6-month are effective prognostic predictors after curative pancreatectomy in patients with pancreatic adenocarcinoma.

Targeting the rich extracellular matrix of desmoplastic tumors has been successfully shown to normalize collagen and hyaluronan levels and re-engineer intratumoral mechanical forces, improving tumor perfusion and chemotherapy. As far as targeting the abundant cancer-associated fibroblasts (CAFs) in desmoplastic tumors is concerned, while both pharmacologic inhibition of the sonic-hedgehog pathway and genetic depletion of fibroblasts have been employed in pancreatic cancers, the results between the two methods have been contradictory. In this study, we employed vismodegib to inhibit the sonic-hedgehog pathway with the aim to i) elucidate the mechanism of how CAFs depletion improves drug delivery, ii) extent and evaluate the potential use of sonic-hedgehog inhibitors to breast cancers, and iii) investigate whether sonic-hedgehog inhibition improves not only chemotherapy, but also the efficacy of the most commonly used breast cancer nanomedicines, namely Abraxane® and Doxil®. We found that treatment with vismodegib normalizes the tumor microenvironment by reducing the proliferative CAFs and in cases the levels of collagen and hyaluronan. These modulations re-engineered the solid and fluid stresses in the tumors, improving blood vessel functionality. As a result, the delivery and efficacy of chemotherapy was improved in two models of pancreatic cancer. Additionally, vismodegib treatment significantly improved the efficacy of both Abraxane and Doxil in xenograft breast tumors. Our results suggest the use of vismodegib, and sonic hedgehog inhibitors in general, to enhance cancer chemo- and nanotherapy. © 2017 Elsevier B.V. 261 105 112 105-112

Oxidative stress (OS) is associated with many diseases ranging from cancer to neurodegenerative disorders. Nuclear factor-erythroid 2 p45-related factor 2 (Nrf2) is one of the most effective cytoprotective controller against OS. Modulation of Nrf2 pathway constitutes a remarkable strategy in the antineoplastic treatments. A big number of Nrf2-antioxidant response element activators have been screened for use as chemo-preventive drugs in OS associated diseases like cancer even though activation of Nrf2 happens in a variety of cancers. Research proved that hyperactivation of the Nrf2 pathway produces a situation that helps the survival of normal as well as malignant cells, protecting them against OS, anticancer drugs, and radiotherapy. In this review, the modulation of the Nrf2 pathway, anticancer activity and challenges associated with the development of an Nrf2-based anti-cancer treatment approaches are discussed.

Rexin-G is a replication-incompetent retroviral vector displaying a cryptic SIG-binding peptide for targeting abnormal Signature (SIG) proteins in tumors and encoding a dominant-negative human cyclin G1 construct. Herein we report on the safety and antitumor activity of escalating doses of Rexin-G in gemcitabine-refractory pancreatic adenocarcinoma, with one 10-year survivor. For the safety analysis (n = 20), treatment-related grade 1 adverse events included fatigue (n = 6), chills (n = 2), and headache (n = 1), with no organ damage and no DLT. No patient tested positive for vector-neutralizing antibodies, antibodies to gp70, replication-competent retrovirus (RCR), or vector integration into genomic DNA of peripheral blood lymphocytes (PBLs). For the efficacy analysis (n = 15), one patient achieved a complete response (CR), two patients had a partial response (PR), and 12 had stable disease (SD). Median progression-free survival (PFS) was 2.7, 4.0, and 5.6 months at doses 0–I, II, and III, respectively. Median overall survival (OS) and 1-year OS rate at dose 0–I were 4.3 months and 0%, and at dose II–III they were 9.2 months and 33.3%. To date, one patient is still alive with no evidence of cancer 10 years after the start of Rexin-G treatment. Taken together, these data suggest that Rexin-G, the first targeted gene delivery system, is uniquely safe and exhibits significant antitumor activity, for which the FDA granted fast-track designation. Keywords: gene therapy, cell cycle control, 10-year cancer-free survivor, pancreas adenocarcinoma, cyclin G1 inhibitor, retrovector, tumor targeting, targeted gene delivery, CCNG1

Pancreatic adenocarcinoma (PDAC) remains one of the most lethal cancers today and is expected to be the second cause of cancer death in the coming decade. Multiple factors including rising incidence, late stage at presentation, disease aggression and ineffective treatment strategies contribute to poor 5-year survival rates estimated at 8-11% in North America and European countries (1,2). Today, we are beginning to see advances as we more accurately define tumor stage to provide better assessments for treatment and understand distinct molecular subgroups used to optimize therapeutic strategies. Molecular profiling of PDAC can uncover specific targets but can also allow for more refined approaches with our standard chemotherapeutics. Understanding how we can further interrogate the tumor microenvironment, metabolic pathways and illicit immune responses in this ‘cold’ tumor will further improve our treatment options. Many exciting opportunities will be discussed at this meeting. Despite multiple large phase III trials, the most prominent advances in recent years have come from combination chemotherapy regimens showing modest improvements in survival and quality of life parameters over single agent gemcitabine in the first-line metastatic setting. The current standards are either modified (m) FOLFIRINOX or the doublet of nab-paclitaxel plus gemcitabine (GnP), however both still result in median survivals of less than 1 year. As no studies have compared these 2 regimens head to head for efficacy, and aside from a known germline pathogenic variant in BRCA1/2, patient selection for either regimen is driven by performance status and/or patient preference for toxicity, schedule and drug-delivery. Exploring biomarkers or molecular profiling that may predict differential responses to chemotherapy upfront are key to advancing the field (3, 4) as only 50-60 % of patients with PDAC are well enough to move to second-line metastatic strategies (5). For example, the trial ‘Pancreatic Adenocarcinoma Signature Stratification for treatment (PASS-01)’, launching this year will evaluate the 2 standard regimens in fit first-line metastatic patients but will also explore high content molecular profiling, chemotherapy signatures, patient derived organoid models and other putative biomarkers to predict responses to chemotherapy and hypothesize alternatives(4). Building on first line systemics, the recent focus adds new agents to the better tolerated GnP standard. Targeting stroma in PDAC is a significant area of research including strategies aimed at targeting the desmoplastic architecture to decrease tumor pressure and vascular compression, thus improving drug delivery to cancer cells. We recently saw the negative data from the phase III HALO 301 trial. (6) This randomized double-blinded phase III trial compared PEGPH20 plus GnP to GnP for patients with hyaluronan (HA)-high metastatic adenocarcinoma following a promising randomized phase II trial in this enriched population. The primary endpoint of OS was not met with a median OS of 11.2 and 11.5 months (HR 1.00, p=0.096). There was a higher response rate in the experimental arm but with no improvement in duration of response, PFS or OS. The authors discuss potential reasons for this failure including underestimating the complexity of the the fibro-inflammatory infiltrate in the TME. While pre-clinical data demonstrated that desmoplastic stroma may limit the movement of systemic agents to the TME, there is also evidence from other studies that stromal elements may restrain PDAC progression (7). Finally, the IHC assay for HA has some reliability concerns and indeed less data when used to evaluate metastatic biopsies rather than the primary. Insights will no doubt arise from this disappointing result. Other important negative trials reported in the past year include the RESOLVE trial which added ibrutinib (BTK inhibitor) to GnP with a median survival favoring the control (8). The CanStemIIIP trial evaluating the stem cell agent napabucasin added to GnP was closed for futility on an interim analysis (press release Jul 2019) More promising, strategies combining immunotherapy to chemotherapy are pending and may show subsets that benefit (9) as is the anticipated anti-mitichondrial drug, devimistat added to mFOLFIRINOX in the first-line setting (10). Further progress is being made with PDAC deficient in homologous recombination repair (HRD). The sum of data supports a better survival seen when BRCA-1/2 cases are treated with a platinum salt. A retrospective study demonstrated a median survival of 2.4 years vs 1.5 years when metastatic HRD mutated patients were treated with a platinum vs another chemo regimen (11). Potentially this population represents approximately 10% of patients and therefore justifies germline and somatic testing as the result affects chemotherapy choice. Maintenance therapy after platinum-based chemotherapy control was studied in the landmark POLO phase III trial. Patients with germline BRCA1/2 were randomized 2:1 to PARP inhibitor olaparib or placebo after a minimum of 16 weeks of platinum-based chemotherapy with response or stable disease. The primary endpoint was met with a PFS of 7.4 vs 3.8 months (HR 0.53, p=0.0038) (12). Unfortunately, no improvement in OS was seen at 18.9 vs 18.1 months (HR 0.91, p=0.68). This trial does stand as a proof of principal biomarker-selected strategy, rather rare in oncology and appears to be changing practice for some pancreas cancer patients. Recent ASCO guidelines were updated to acknowledge that in this specific population in the maintenance setting after platinum- based chemotherapy, options include continuing the active chemotherapy or switching to olaparib (13). The KRAS WT group is a distinct entity that can harbor rare but highly druggable fusions such as NTRK, NRG1, ALK as well as alterations in BRAF (14,15). ASCO guidelines recently updated recommendations for therapy after failure of first-line chemotherapy highlighting treatment with larotrectinib or entrectinib in the presence of an NTRK fusion (13). Similarly, rare subsets testing positive for mismatch repair-deficiency could be considered for pembrolizumab (13). Clearly one the most significant advances for pancreatic cancer patients in recent times was the striking benefit seen with 6 months of adjuvant mFOLFIRINOX over adjuvant gemcitabine in the PRODIGE24-CCTG PA6 trial (16). In selected patients post resection (R0 or R1) median disease-free survival was 21.6 vs 12.8 months (HR 0.58, p The scope for improving patient outcomes by sequencing chemotherapy with surgery is striking. Yet older population data suggest that only 50% of patients receive any adjuvant chemotherapy, likely due to a combination of post-op frailty plus nihilism towards the benefits of chemotherapy. Hopefully, this is now changing. Also, there is strong traction to study therapy in the neoadjuvant setting to improve deliverability of the chemo, higher R0 resections, a testing of chemosensitivity and better selection for surgery. Recent presentation of SWOG S1505 demonstrated similar efficacy of either neoadjuvant mFOLFIRINOX or GnP (18) but leaves the door open for trials comparing neoadjuvant to adjuvant strategies. In addition, optimizing the best pre-operative regimens in high risk populations such as borderline and locally advanced patients with the potential to convert to a R0 resection is a high priority including the addition of chemoradiation, and newer local techniques such as SBRT. As integrated somatic and germline profiling becomes standard, we will increasingly see targeted approaches for subsets of patients. However, we will require more innovative approaches leveraging our understanding of the interplay between TME, metabolic profiles and microbioata. Never have efforts been more focused for success in pancreas cancer. References 1) Huang L et al. Stratified survival of resected and overall pancreatic cancer patients in Europe and the USA in the early twenty-first century: a large, international population-based study. BMC Med 2018 2) Bray F et al. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries . CA Cancer J Clin2018 3) O'Kane GM et al. GATA6 Expression Distinguishes Classical and Basal-like Subtypes in Advanced Pancreatic Cancer. Clin Cancer Res 2020. 4) NCT04469556 Pancreatic Adenocarcinoma Signature Stratification for treatment (PASS-01) 5) Walker EJ and Ko AH. Beyond first-line chemotherapy for advanced pancreatic cancer: an expanding array of therapeutic options? World J of Gastro. 2014 6) Van Cutsem E et al. Randomized Phase III Trial of Pegvorhyaluronidase alfa with nab-Paclitaxel Plus Gemcitabine for Patients with Hyaluronan-High Metastatic Adenocarcinoma. J Clin. Onc. 2020 7) Sinn M et al. a-smooth muscle actin expression and desmoplastic stromal reaction in pancreatic cancer: results from the CONKO-001study. Br J Cancer 2014 8) Tempero M et al. ESMO 21st World Congress in GI, Jul 2019. 9) Renouf D et al. The Canadian cancer Trials group PA.7 trial: results from the safety run in of a randomized phase II of gemcitabine and nab-paclitaxel vs gemcitabine, nab-paclitaxel, durvalumab and tremelimumab as 1st-line therapy in metastatic pancreatic adenocarcinoma. J Clin Onc 2018. 10) ClinicalTrials.gov ID: NCT03504423 11) Pishvaian M et al. Outcomes in pancreatic adenocarcinoma patients with genetic alterations in DNA damage repair (DDR) pathways: results from the Know Your Tumor (KYP) program. J Clin Onc 2019 12) GolanT et al. Maintenance Olaparib for germline BRCA-mutated metastatic pancreatic cancer. N Engl. J Med 2019 381:317-327 13) Davendra PS et al. Metastatic Pancreatic Cancer: ASCO guideline update. J Clin Oncol. Aug 5, 2020. 14) Pishvaian MJ et al. Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial. Lancet Oncol 2020. 15) Aguirre AJ et al. Real-time Genomic Characterization of Advanced Pancreatic Cancer to Enable Precision Medicine. Cancer Discov 2018. 16) Conroy T et al. FOLFIRINOX or gemcitabine as adjuvant therapy for pancreas cancer. N Engl J Med. 2018. 17) Tempero MA et al. APACT: phase III, multicenter, international, open-label, randomized trial of adjuvant nab-paclitaxel plus gemcitabine (nab-P/G) vs gemcitabine (G) for surgically resected pancreatic adenocarcinoma. DOI: 10.1200/JCO.2019.37.15_suppl.4000 Journal of Clinical Oncology 37,2019. 18) Sohal D et al. SWOG S1505; Results of perioperative chemotherapy with mFOLFIRINOX versus gemcitabine/nab-paclitaxel for resectable pancreatic ductal adenocarcinoma. ASCO 2020. Virtual Scientific Program. Abstract 4504. Citation Format: Jennifer J Knox. Clinical advances in pancreas adenocarcinoma [abstract]. In: Proceedings of the AACR Virtual Special Conference on Pancreatic Cancer; 2020 Sep 29-30. Philadelphia (PA): AACR; Cancer Res 2020;80(22 Suppl):Abstract nr IA-08.

Introduction: Homologous recombination deficiency (HRD) is an emerging biomarker for DNA-damage-response (DDR)-targeted therapies in pancreatic cancer (PDAC). There are different methods available to identify HRD in other cancers, however these have not been evaluated comprehensively in PDAC for their response prediction to first-line platinum-based therapies (1L-platinum). Methods: Patients with advanced (stage 3-4) PDAC who had germline and somatic MSK-IMPACT were included. We evaluated genetic methods for HRD and their association with clinical outcomes on 1L-platinum or 1L-non-platinum therapies. Homologous recombination (HR)-genes included: ATM, BAP1, BARD1, BLM, BRCA1, BRCA2, BRIP1, CHEK2, FAM175A, FANCA, FANCC, NBN, PALB2, RAD50, RAD51, RAD51C, RTEL1. We evaluated the status of pathogenic HR-gene mutations (HRm): (1) germline vs. somatic HRm; (2) core HRm (cHRm) (BRCA1, BRCA2, PALB2) vs. non-core (ncHRm); (3) zygosity (monoallelic vs. biallelic HRm). Additionally, HRD genetic signatures using large-scale state transition (LST) and signature 3 (Sig3) were evaluated. Results: Two-hundred and sixty-two patients with advanced PDAC who received care at Memorial Sloan Kettering were included. There was no difference in overall survival (OS) for patients with either germline or somatic HRm, hence they were analyzed together as HRD. Median [95% CI] follow-up among surviving patients (n=75) was 21.9 [1.4-57.0] months, median OS was 15.5 [14.6-19] months, and median progression-free survival (PFS) was 7 [6.1-8.1] months. The effect of HRD on PFS was dependent on whether the patient received 1L-platinum or not. After controlling for stage at diagnosis, patients with HRD had a reduced risk of progression or death compared to patients without HRD when treated with 1L-platnium (HR: 0.44 [95%CI: 0.29-0.67], p Conclusion: Patients who have PDAC with HRD defined by HRm had better OS irrespective of 1L-platinum, although they had better PFS when treated with 1L-platinum compared to 1L-non-platinum. Among methods to identify HRD, pathogenic HR-gene mutations remain the standard when using a targeted-sequencing approach. Further investigation is warranted. Citation Format: Wungki Park, Jiapeng Chen, Joanne F. Chou, Christine Iacobuzio-Donague, Nadeem Riaz, Eileen M. O'Reilly. Genetic algorithms to identify homologous recombination deficiency (HRD) in pancreas adenocarcinoma [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3557.