Pancreatic ductal adenocarcinoma (PDAC) is among the cancer types with poorest prognosis and survival rates primarily due to resistance to standard-of-care therapies, including gemcitabine (GEM) and olaparib. Particularly, wild-type (wt)BRCA tumours, the most prevalent in PDAC, are more resistant to DNA-targeting agents like olaparib, restraining their clinical application. Recently, we disclosed a monoterpene indole alkaloid derivative (BBIT20) as a new inhibitor of homologous recombination (HR) DNA repair with anticancer activity in breast and ovarian cancer. Since inhibition of DNA repair enhances the sensitivity of cancer cells to chemotherapy, we aimed to investigate the anticancer potential of BBIT20 against PDAC, particularly carrying wtBRCA.

In vitro and in vivo PDAC models, particularly human cell lines (including GEM-resistant PDAC cells), patient-derived organoids and xenograft mice of PDAC were used to evaluate the anticancer potential of BBIT20, alone and in combination with GEM or olaparib. Disruption of the BRCA1-BARD1 interaction by BBIT20 was assessed by co-immunoprecipitation, immunofluorescence and yeast two-hybrid assay.

The potent antiproliferative activity of BBIT20, superior to olaparib, was demonstrated in PDAC cells regardless of BRCA status, by inducing cell cycle arrest, apoptosis, and DNA damage, while downregulating HR. The disruption of DNA double-strand breaks repair by BBIT20 was further reinforced by non-homologous end joining (NHEJ) suppression. The inhibition of BRCA1-BARD1 heterodimer by BBIT20 was demonstrated in PDAC cells and confirmed in a yeast two-hybrid assay. In GEM-resistant PDAC cells, BBIT20 showed potent antiproliferative, anti-migratory and anti-invasive activity, overcoming GEM resistance by inhibiting the multidrug resistance P-glycoprotein, upregulating the intracellular GEM-transporter ENT1, and downregulating GEM resistance-related microRNA-20a and GEM metabolism enzymes as RRM1/2. Furthermore, BBIT20 did not induce resistance in PDAC cells. It inhibited the growth of patient-derived PDAC organoids, by inducing apoptosis, repressing HR, and potentiating olaparib and GEM cytotoxicity. The enhancement of olaparib antitumor activity by BBIT20 was confirmed in xenograft mice of PDAC. Notably, it hindered tumour growth and liver metastasis formation, improving survival of orthotopic xenograft mice of PDAC. Furthermore, its potential as a stroma-targeting agent, reducing fibrotic extracellular matrix and overcoming desmoplasia, associated with an enhancement of immune cell response by depleting PD-L1 expression in tumour tissues, renders BBIT20 even more appealing for combination therapy, particularly with immunotherapy.

These findings underscore the great potential of BBIT20 as a novel multifaceted anticancer drug candidate for PDAC treatment.

Tandem duplicator phenotype (TDP) consists of distinct genomic rearrangements where tandem duplications are randomly distributed. In this study, we characterized the prevalence and outcomes of TDP in a large series of prospectively sequenced tumors from patients with pancreatic ductal adenocarcinomas (PDAC). Whole-genome sequencing (WGS) was performed in 530 PDAC cases from the PanCuRx Initiative, COMPASS and PanGen/POG trials in Canada. Of 530 cases, 52 were identified as TDP (9.8%; 13 resected, 39 advanced). Etiological subgroups of TDP included BRCA1 (n = 9), CCNE1 (n = 4), and unknown (n = 39). Presence of TDP was not prognostic in resected specimens (p = 0.77) compared with non-HRD and non-TDP cases, described as typicals. In advanced cases, when stratified for only classical subtype cases, platinum therapy was correlated with longer response in non-BRCA1 TDP vs. typicals (p = 0.0036). There was no difference in overall survival between TDP and typicals (p = 0.5).TDP represents a potential novel targetable subgroup for chemotherapy selection in PDAC.

A woman in her 60s presented with persistent abdominal pain and jaundice. She had a history of BRCA1 gene mutation and was previously treated for triple-negative early breast cancer. Abdominal ultrasound and CT scan of the abdomen revealed a mass around the pancreatic head. Magnetic resonance cholangiopancreatography showed a dilated common bile duct and a normal pancreatic duct. Liver function improved after endoscopic retrograde cholangiopancreatography and biliary stent placement. Staging CT confirmed no distant metastasis. The patient underwent Whipple's procedure to remove the pancreatic lesion. Histology from the resection confirmed carcinosarcoma with positive margins, along with lymphovascular, perineural and nodal involvement. She was offered adjuvant chemotherapy with a combination of Folinic acid, 5-fluorouracil, Oxaliplatin and Irinotecan (FOLFIRINOX). Due to derangement in liver enzymes after one cycle of chemotherapy, an MRI scan confirmed liver metastasis. The same chemotherapy regimen was continued in a palliative setting, initially showing a partial response to the liver metastases, but subsequently resulting in a long-term complete radiological response. Pancreatic carcinosarcoma is a rare type of cancer with no clear consensus on the appropriate management. In this case, FOLFIRINOX palliative chemotherapy led to long-term disease control. Future studies on molecular profiling may provide insights for genotype-driven, personalised treatment strategies for similar cases.

Mutations in BRCA1 and/or BRCA2 (BRCAm) and other homologous recombination repair genes (HRRm) are associated with several cancers. We evaluated the prevalence and association with overall survival (OS) of somatic BRCAm and HRRm among patients with advanced solid tumors.

We used deidentified data from the AACR GENIE Biopharma Collaborative dataset derived from patients with tumors genotyped using next-generation sequencing between 1 January 2014 and 31 December 2017. Eligible patients were aged ≥18 years diagnosed with non-small-cell lung, colorectal, breast, bladder, prostate, or pancreatic cancer, with documented BRCA/HRR somatic mutation status. The primary analysis was OS (censored at the start of poly[ADP ribose] polymerase inhibitors [PARPi]/immunotherapy) after initiation of second-line therapy since most patients had sequencing after first-line therapy.

Among eligible patients, 242/7022 (3.4%) had BRCAm and 477/5474 (8.7%) had HRRm. Adjusted OS HRs (95% CI) for the primary analysis (using the initiation of second-line therapy as index date) were 0.79 (0.61-1.03) with/without BRCAm (n = 116/n = 3394) and 0.83 (0.69-0.99) with/without HRRm (n = 247/n = 2656); in sensitivity analysis of patients with stage IV disease, HRs were 0.97 (0.68-1.38) with/without BRCAm (n = 58/n = 1847) and 0.92 (0.73-1.18) with/without HRRm (n = 132/n = 1488).

Overall, BRCAm and HRRm did not show a strong association with OS, with a trend toward longer OS among patients receiving standard second-line therapies excluding PARPi/immunotherapy.

PARP inhibitors (PARPi) have been licensed for the maintenance therapy of patients with metastatic pancreatic cancer carrying pathogenic germline BRCA1/2 mutations. However, mutations in BRCA1/2 are notably rare in pancreatic cancer.

There is a significant unmet clinical need to broaden the utility of PARPi.

RNA sequencing was performed to screen potential targets for PARPi sensitivity. The synthetic lethal effects were verified in patient-derived xenograft (PDX), xenograft and patient-derived organoid models. Mechanisms were explored via LC‒MS/MS, coimmunoprecipitation, laser microirradiation, immunofluorescence, the homologous recombination (HR) or non-homologous end joining (NHEJ) reporter system, in situ proximity ligation assay and live-cell time-lapse imaging analyses.

Targeting protein for Xenopus kinesin-like protein 2 (TPX2) is an exploitable vulnerability. TPX2 was downregulated in PDX models sensitive to PARPi, and TPX2 inhibition conferred synthetic lethality to PARPi both in vitro and in vivo. Mechanistically, TPX2 functions in a cell cycle-dependent manner. In the S/G2 phase, ATM-mediated TPX2 S634 phosphorylation promotes BRCA1 recruitment to double-strand breaks (DSBs) for HR repair, whereas non-phosphorylated TPX2 interacts with 53BP1 to recruit it for NHEJ. The balance between phosphorylated and non-phosphorylated TPX2 determines the DSB repair pathway choice. During mitosis, TPX2 phosphorylation enhances Aurora A activity, promoting mitotic progression and chromosomal stability. Targeting TPX2 S634 phosphorylation with a cell-penetrating peptide causes genomic instability and mitotic catastrophe and enhances PARPi sensitivity. Additionally, the inhibition of TPX2 or S634 phosphorylation combined with gemcitabine further sensitised pancreatic cancer to PARPi.

Our findings revealed the dual-functional significance of TPX2 in controlling DNA DSB repair pathway choice and mitotic progression, suggesting a potential therapeutic strategy involving PARPi for patients with pancreatic cancer.

Pancreatic cancer arising in the context of BRCA predisposition may benefit from poly(ADP-ribose) polymerase inhibitors. We analyzed real-world data on the impact of olaparib on survival in metastatic pancreatic cancer patients harboring germline BRCA mutations in Italy, where olaparib is not reimbursed for this indication.

Clinico/pathological data of pancreatic cancer patients with documented BRCA1-2 germline pathogenic variants who had received first-line chemotherapy for metastatic disease were collected from 23 Italian oncology departments and the impact of olaparib exposure on overall survival (OS) was analyzed.

Of 114, 53 BRCA-mutant pancreatic cancer patients had received olaparib for metastatic disease. OS was significantly longer in patients who were exposed to olaparib (hazard ratio [HR] 0.568, 95% confidence interval [CI] 0.351-0.918, log-rank p = 0.02) in any setting/line of treatment; similar results were obtained for patients who received olaparib as maintenance treatment (in any line of treatment), patients who had stage IV disease at diagnosis, and patients who did not experience progressive disease as their best response to first-line chemotherapy. Exposure to olaparib in the first-line maintenance setting after platinum-based chemotherapy, however, did not significantly impact survival. At multivariate analysis, CA19.9 levels at diagnosis and response to first-line chemotherapy were independently prognostic; however, when response to chemotherapy was excluded, any exposure to olaparib was a significant independent predictor of longer OS, together with CA19.9 levels.

The real-world data presented here support the use of olaparib for metastatic disease in germline BRCA-mutant pancreatic cancer patients, as it may significantly prolong survival.

Germline genetic testing (GT) is recommended for all patients with pancreatic ductal adenocarcinoma (PDAC), but the traditional clinical genetics infrastructure is limited in addressing the unique needs of this population. We describe the integration of point of care (POC) GT into routine clinical practice for all patients with PDAC at an academic medical center.

We developed a clinical POC workflow that leverages electronic health record (EHR) tools and behavioral nudges to enhance the sustainability and scalability of our previously described research-based POC model. For each of the research and clinical POC cohorts, we calculated the percentage of eligible patients who underwent GT. We used Wilcoxon rank-sum and Pearson's chi-squared tests to compare patients who did and did not undergo GT. We conducted surveys among oncology clinicians to evaluate the acceptability, appropriateness, and feasibility of the clinical POC model.

The research POC cohort included 905 patients, of whom 694 (76.7%) underwent GT. The clinical POC cohort included 148 patients, of whom 126 (85.1%) underwent GT. Patients who underwent GT in the research POC cohort were significantly younger (median age, 67.0 v 70.9 years; P = .031) and more likely to be White (82.1% v 68.7%; P < .001) and commercially insured (41.8% v 28.0%; P < .001) compared with those who did not; there were no significant differences between GT groups in the clinical POC cohort. Oncology clinicians found the clinical POC model to be acceptable (mean 4.4/5), appropriate (4.6/5), feasible (4.0/5), and have a positive impact on their patients (4.9/5).

A clinical POC model leveraging EHR tools and behavioral nudges is acceptable, appropriate, feasible, and associated with a >85% GT rate among patients with PDAC.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a 5-year survival rate of 12%. It has two major molecular subtypes: classical and basal, regulated by the master transcription factors (MTFs) GATA6 and ΔNp63, respectively.

This study sought to uncover the transcriptional regulatory mechanisms controlling PDAC subtype identity.

We integrated primary tumour single-cell RNA-seq, patient-derived xenograft RNA-seq and multispectral imaging to identify MTF-dependent, subtype-specific markers. We created subtype-specific fluorescent reporter systems and conducted drug screenings to find actionable targets. We analysed chromatin accessibility (ATAC-seq), genome-wide occupancy (ChIP-seq) for epigenetic status (H3K27ac), MTFs (GATA6, ΔNp63), RNA polymerase II (Pol II), H3K4me3-anchored chromatin topology (HiChIP) and nascent RNA capture sequencing (PRO-seq). Additionally, we used nuclease-dead Cas9 (dCas9) to manipulate transcriptional regulatory mechanisms.

Our approach identified glucocorticoid receptor (GR) agonists as agents that suppress the classical transcriptional programme by interacting with GATA6. GATA6 regulates classical-specific transcription through promoter-proximal pause release. Depletion of GATA6 increased Pol II occupancy at GATA6-bound enhancers and transcriptional start sites, stabilising enhancer-promoter interactions. Artificially inducing pausing at GATA6-bound enhancers with dCas9 abrogated target gene expression and induced pausing at both the enhancer and target gene promoter. Conversely, in basal PDAC ΔNp63 promotes Pol II recruitment and stabilises enhancer-promoter interactions.

This study provides new insights into the transcriptional control and role of GR agonists in controlling PDAC molecular subtype identity.

The prognosis for patients with pancreatic ductal adenocarcinoma (PDAC) is poor. Secondary brain metastasis (Br-M) occurs in less than 1% of patients. Clinical characteristics and molecular alterations have not been characterized in this rare patients' subset.

The Foundry software platform was used to retrospectively query electronic health records for patients with Br-M secondary to PDAC from 2005 to 2023; clinical, molecular, and overall survival (OS) data were analyzed.

Br-M was diagnosed in 44 patients with PDAC. Median follow-up was 78 months; median OS from initial PDAC diagnosis was 47 months. Median duration from PDAC diagnosis to Br-M detection was 24 months; median OS from Br-M diagnosis was 3 months. At Br-M diagnosis, 82% (n = 36) of patients had elevated CA19-9. Lung was the most common preexisting metastatic location (71%) with Br-M, followed by liver (66%). Br-M were most frequently observed in the frontal lobe (34%, n = 15), cerebellar region (23%, n = 10), and leptomeninges (18%, n = 8). KRAS mutations were detected in 94.1% (n = 16) of patients who had molecular data available (n = 17) with KRASG12V being the most frequent subtype 47% (n = 8); KRASG12D in 29% (n = 5); KRASG12R in 18% (n = 3). Patients who underwent Br-M surgical resection (n = 5) had median OS of 8.6 months, while median OS following stereotactic radiosurgery only (n = 11) or whole-brain radiation only (n = 20) was 3.3 and 2.8 months, respectively.

Br-M is a late PDAC complication, resulting in an extremely poor prognosis especially in leptomeningeal disease. KRAS was mutated in 94.1% of the patients and the KRASG12V subtype was prevalent.

Background: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of approximately 13% for advanced stages. While the majority of PDAC cases are sporadic, a significant subset is attributable to hereditary and familial predispositions, accounting for approximately 25% of cases. This article synthesizes recent advancements in the understanding, detection, and management of hereditary pancreatic cancer (PC). Results: Our review highlights the critical role of genetic testing (GT) in identifying high-risk individuals (HRIs), with germline pathogenic variants (PVs) found in up to 20% of hereditary PDAC cases. Since the implementation of next-generation sequencing (NGS) panels in 2014, detection capabilities have been significantly enhanced. HRIs can be included in screening programs that facilitate the early detection of PDAC. Early detection strategies, including the use of microribonucleic acid (miRNAs) signatures and novel imaging techniques like hyperpolarized 13C-magnetic resonance spectroscopy (MRS) have shown promising results. The identification of germline pathogenic variants (PVs) or mutations in homologous recombination (HR) genes plays a predictive role in the response to various treatments, prolonging patient survival. Discussion: Universal germline testing for PDAC, as recommended by the National Comprehensive Cancer Network (NCCN), is now a standard practice, facilitating the identification of at-risk individuals and enabling targeted surveillance and intervention. Multidisciplinary management, integrating genetic counseling, imaging, and gastrointestinal services, is essential for optimizing outcomes. Conclusions: Advances in genetic testing and biomarker research are transforming the landscape of hereditary PC management. Early detection and personalized treatment strategies are pivotal in improving survival rates. Ongoing multi-institutional research efforts are crucial for validating biomarkers and developing preventive measures, ultimately aiming to reduce the burden of this aggressive cancer.

The lifetime risk of pancreatic cancer in women with a germline mutation in BRCA1 and BRCA2 is not well established. In an international prospective cohort of female carriers of BRCA1 and BRCA2 mutations, the cumulative incidence of pancreatic cancer from age 40 until 80 years was estimated.

A total of 8295 women with a BRCA1 or BRCA2 mutation were followed for new cases of pancreatic cancer. Subjects were followed from the date of baseline questionnaire or age 40 years (whichever came last) until a new diagnosis of pancreatic cancer, death from another cause, or date of last follow-up.

Thirty-four incident pancreatic cancer cases were identified in the cohort. The annual risk of pancreatic cancer between age 40 and 80 years was 0.04% for BRCA1 carriers and 0.09% for BRCA2 carriers. Via the Kaplan-Meier method, the cumulative incidence from age 40 to 80 years was 2.2% (95% CI, 1.1%-4.3%) for BRCA1 carriers and 2.7% (95% CI, 1.3%-5.4%) for BRCA2 carriers. Only two of the 34 cases reported a first-degree relative with pancreatic cancer (hazard ratio, 4.75; 95% CI, 1.13-19.9; p = .03). Risk factors for pancreatic cancer included alcohol intake and a history of diabetes. The 5-year survival rate for the 34 cases was 8.8%.

The lifetime risk of pancreatic cancer is approximately 2% in women with a BRCA1 mutation and 3% for women with a BRCA2 mutation. The poor survival in hereditary pancreatic cancer underscores the need for novel antitumoral strategies.

Chemotherapy resistance is the main reason of treatment failure in gastric cancer (GC). However, the mechanism of oxaliplatin (OXA) resistance remains unclear. Here, we demonstrate that extracellular mechanical signaling plays crucial roles in OXA resistance within GC. We selected OXA-resistant GC patients and analyzed tumor tissues by single-cell sequencing, and found that the mitochondrial content of GC cells increased in a biosynthesis-independent manner. Moreover, we found that the increased mitochondria of GC cells were mainly derived from mesenchymal stromal cells (MSCs), which could repair the mitochondrial function and reduce the levels of mitophagy in GC cells, thus leading to OXA resistance. Furthermore, we investigated the underlying mechanism and found that mitochondrial transfer was mediated by mechanical signals of the extracellular matrix (ECM). After OXA administration, GC cells actively secreted ECM in the tumor microenvironment (TEM), increasing matrix stiffness of the tumor tissues, which promoted mitochondria to transfer from MSCs to GC cells via microvesicles (MVs). Meanwhile, inhibiting the mechanical-related RhoA/ROCK1 pathway could alleviate OXA resistance in GC cells. In summary, these results indicate that matrix stiffness could be used as an indicator to identify chemotherapy resistance, and targeting mechanical-related pathway could effectively alleviate OXA resistance and improve therapeutic efficacy.

Pancreatic ductal adenocarcinoma (PDAC) is the most aggressive and invasive type of pancreatic cancer and is expected to soon become the second leading cause of cancer-associated death. The high mortality rate is due to the clinical features that allow asymptomatic progression to advanced stages, a period when current therapeutic treatments have limited efficacy. To address these challenges, researchers are focused on identifying new molecular and circulating markers for early PDAC detection and precision medicine. In this mini-review, we report the most well-known and recently identified molecular and circulating biomarkers. This study aimed to emphasize the need for continued innovative research to develop diagnostic algorithms and therapies to improve the management of patients with PDAC.

Pancreatic adenocarcinoma remains a malignancy with a grim prognosis and scarce personalized treatment options. Pathogenic variants of DNA damage repair (DDR) genes are emerging as molecular targets, as they confer a higher sensitivity to DNA-damaging agents. This study aimed at assessing the activity of chlorambucil as salvage therapy in metastatic pancreatic cancer patients bearing a germline pathogenetic variant or variant of uncertain significance on a DDR-related gene.

Platinum-pretreated metastatic pancreatic cancer patients harbouring a germline variant on a DDR gene received chlorambucil at a daily oral dose of 6 mg/m2 for 42 every 56 days for the first cycle and for 14 every 28 days for the following cycles, until disease progression or unacceptable toxicity. The primary endpoint was 6-month progression-free survival rate (PFS-6). Median progression-free survival (PFS) and overall survival (OS) were secondarily described.

Twenty patients were enrolled between December 2020 and September 2022. PFS-6 was 5%, median PFS and OS were 1.6 months and 3.0 months, respectively. Grade-3 adverse events were observed in 25% of patients, while no Grade-4 toxicity was reported.

Single agent chlorambucil did not show sufficient signal of activity to warrant its further investigation in metastatic pancreatic cancer patients bearing a DDR-related germline alteration.

Pancreatic adenocarcinoma (PDAC) is predicted to become the second leading cause of cancer deaths by 2030 and this is mostly due to therapy failure. Limited treatment options and resistance to standard-of-care (SoC) therapies makes PDAC one of the cancer types with poorest prognosis and survival rates [1,2]. Pancreatic tumors are renowned for their poor response to therapeutic interventions including targeted therapies, chemotherapy and radiotherapy. Herein, we review hallmarks of therapy resistance in PDAC and current strategies aiming to tackle escape mechanisms and to re-sensitize cancer cells to therapy. We will further provide insights on recent advances in the field of drug discovery, nanomedicine, and disease models that are setting the ground for future research.

The efficacy and safety of conversion surgery (CS) after FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP) chemotherapy in patients with initially unresectable pancreatic cancer (PC) remains unclear.

This multicenter retrospective cohort study enrolled patients, between 2014 and 2018, with initially locally advanced or metastatic PC who were considered candidates for CS following FOLFIRINOX or GnP chemotherapy. They were classified into surgery (207 patients [194 resection and 13 exploratory laparotomy only]) and continued chemotherapy (10 patients, control) groups. The primary endpoint was overall survival (OS) from the day of diagnosis of potentially curative resection on imaging studies, with an expected hazard ratio (HR) of 0.7.

OS in the surgery group was longer than that in the control group (HR, 0.47; 95% confidence interval [CI]: 0.24-0.93). The median OS was 34.4 (95% CI: 27.9-43.4) and 19.8 (95% CI: 14.9-31.1) months in the surgery and control groups, respectively. The Clavien-Dindo grade ≥ IIIa postoperative complication and in-hospital mortality rates were 19.6% and 0.5%, respectively. Multivariate analysis revealed that preoperative chemotherapy duration was not associated with OS.

CS, following a favorable response to FOLFIRINOX or GnP chemotherapy, improved initially unresectable PC prognosis (specifically, OS), regardless of the chemotherapy duration.

Familial pancreatic cancer (FPC) represents a significant yet underexplored area in pancreatic cancer research. Basic research efforts are notably limited, and when present, they are predominantly centered on the BRCA1 and BRCA2 mutations due to the scarcity of other genetic variants associated with FPC, leading to a limited understanding of the broader genetic landscape of FPC. This review examines the current state of FPC research, focusing on the molecular mechanisms driving pancreatic ductal adenocarcinoma (PDAC) progression. It highlights the role of homologous recombination (HR) and its therapeutic exploitation via synthetic lethality with PARP inhibitors in BRCA1/2-deficient tumors. The review discusses various pre-clinical models of FPC, including conventional two-dimensional (2D) cell lines, patient-derived organoids (PDOs), patient-derived xenografts (PDXs), and genetically engineered mouse models (GEMMs), as well as new advancements in FPC research.

Identification of homologous recombination deficiency (HRD) remains a challenge in advanced pancreatic cancer (APC). We investigated the utility of circulating tumour DNA (ctDNA) profiling in the assessment of BRCA1/2 and ATM mutation status and treatment selection in APC.

We analysed clinical and ctDNA data of 702 patients with APC enroled in GOZILA, a ctDNA profiling study using Guardant360.

Inactivating BRCA1/2 and ATM mutations were detected in 4.8% (putative germline, 3.7%) and 4.4% (putative germline, 0.9%) of patients, respectively. Objective response (63.2% vs. 16.2%) and PFS (HR 0.55, 95% CI 0.32-0.93) on platinum-containing chemotherapy were significantly better in patients with putative germline BRCA1/2 (gBRCA) mutation than those without. In contrast, putative gBRCA mutation had no impact on the efficacy of gemcitabine plus nab-paclitaxel. In 2 patients treated with platinum-containing therapy, putative BRCA2 reversion mutations were detected. Three of seven patients with somatic BRCA mutations responded to platinum-containing therapy, while only one of four with putative germline ATM mutations did. One-third of somatic ATM mutations were in genomic loci associated with clonal haematopoiesis.

Comprehensive ctDNA profiling provides clinically relevant information regarding HRD status. It can be a practical, convenient option for HRD screening in APC.

A 54-year-old man with resectable pancreatic cancer and abnormally high levels of carbohydrate antigen 19-9 (CA19-9) underwent 6 months of platinum-based chemotherapy. This treatment substantially reduced the primary tumor size and normalized CA19-9 levels. Subsequently, radical surgery was conducted. However, eight months post-surgery, CA19-9 levels re-elevated, and lymph-node recurrence was observed. The patient underwent treatment with poly(adenosine diphosphate ribose) polymerase inhibitors (PARPi) following the detection of frameshift L1904fs*5 via BRACAnalysis CDx. This mutation revealed a stop codon, leading to the inactivation of the BRCA function. Additionally, the patient tested positive for a mutation in the breast cancer susceptibility gene 2 (BRCA2). Two months after starting PARPi, there was evidence of tumor shrinkage. Nevertheless, 5 months later, CA19-9 levels increased again, and new metastatic tumors in the liver were identified. Genomic profiling test (FoundationOne CDx) of surgically resected specimens revealed a BRCA2 pL1908fs*2 mutation, indicating its location in the cis position on the same allele as the germline BRCA2 mutation. The pL1908fs*2 deletion, alongside the original L1904fs*5, resulted in three deletions, equating to one amino acid deletion. This deletion ultimately reversed the stop codon, leading to the restoration of BRCA2 functionality. Despite treatment with PARPi for postoperative recurrence, a sustained response was not achieved owing to BRCA reversion mutations. It is essential to acknowledge the rarity of BRCA reversion mutations, which limit the effectiveness of PARPi.

Pancreatic ductal adenocarcinoma (PDAC) has a known poor prognosis. For a select group, those with BRCA mutations, frontline platinum-based therapy and poly (ADPribose) polymerase inhibitors are options that can potentially lead to survival benefit.

We present 2 cases of patients with BRCAmutated pancreatic cancer with liver metastases that achieved a remarkable long-term complete remission on platinum-based chemotherapy.

Germline testing for BRCA is important in PDAC because it influences treatment choices that impact survival. Complete responses with chemotherapy alone are rarely observed in metastatic PDAC, but may be seen upon treatment with platinum-based therapy.

Pancreatic ductal adenocarcinoma (PDAC), a leading cause of cancer mortality in the United States, presents significant treatment challenges due to its late diagnosis and poor prognosis. Despite advances, the five-year survival rates remain dismally low, with only a fraction of patients eligible for potentially curative surgical interventions. This review aims to comprehensively examine the current landscape of targeted therapies in PDAC, focusing on recent developments in precision medicine approaches. We explore various molecular targets, including KRAS mutations, DNA damage repair deficiencies, mismatch repair pathway alterations, and rare genetic fusions. The review discusses emerging therapies, such as PARP inhibitors, immune checkpoint inhibitors, and novel targeted agents, like RET and NTRK inhibitors. We analyze the results of key clinical trials and highlight the potential of these targeted approaches in specific patient subgroups. Recent developments in PDAC research have emphasized precision oncology, facilitated by next-generation sequencing and the identification of genetic and epigenetic alterations. This approach tailors treatments to individual genetic profiles, improving outcomes and reducing side effects. Significant strides have been made in classifying PDAC into various subtypes, enhancing therapeutic precision. The identification of specific mutations in genes like KRAS, along with advancements in targeted therapies, including small molecule inhibitors, offers new hope. Furthermore, emerging therapies targeting DNA repair pathways and immunotherapeutic strategies also show promising results. As research evolves, integrating these targeted therapies with conventional treatments might improve survival rates and quality of life for PDAC patients, underscoring the shift towards a more personalized treatment paradigm.

Germline breast cancer susceptibility gene (gBRCA) mutation in patients with pancreatic cancer (PC) is not common in clinical practice. Therefore, factors that efficiently show gBRCA mutations and the real-world outcomes of olaparib maintenance therapy have not been fully established. In the present study, we clarified the indicators for the effective detection of gBRCA mutation and the efficacy and safety of olaparib as maintenance therapy.

We retrospectively analyzed 84 patients with PC who underwent gBRCA testing (BRACAnalysis, Myriad Genetics, Salt Lake City, UT, USA) at our institute between January 2021 and March 2022. For each patient, clinical data were extracted from medical records.

The median patient age was 64 y (29-85 y), and 41 patients (48.8%) were male. The gBRCA mutations were identified in 10 (11.9%) patients; two patients had BRCA1 mutation and eight had BRCA2 mutation. All patients with gBRCA mutation had a family history of any cancer, and eight of them had a family history of Hereditary Breast and Ovarian Cancer syndrome (HBOC)-related cancer. The gBRCA mutation rate was higher for patients with PC with a family history of HBOC-related cancer compared to that in patients with PC having a family history of other cancers and no family history of cancer (22.9% vs. 4.1%; P = 0.014). In our study, eight out of 10 patients with gBRCA-positive PC received olaparib after platinum-based chemotherapy. The best responses to platinum-based chemotherapy included a complete response in one patient (12.5%) and a partial response in seven patients (87.5%). The median duration of treatment with platinum-based chemotherapy plus olaparib was 17.5 months (8-87 months), and the duration of treatment with olaparib maintenance therapy was 11 months (1-30 months). During olaparib maintenance therapy, three patients showed no disease progression. One of these three patients underwent conversion surgery after receiving olaparib for 12 months.

The gBRCA testing should be considered proactively, especially in patients with PC with a family history of HBOC-related cancer.

In this editorial accompanying manuscript the by Klatte and colleagues, Drs Singh, and Nipp review the data behind universal germline testing in pancreatic adenocarcinoma, and review possible reasons for and solutions continued inadequate rates of germline testing in our community. Making germline testing for all patients with pancreatic adenocarcinoma is critical and will require cross-disciplinary collaboration and innovation.

We aimed to characterize the initial healthcare journey of metastatic pancreatic ductal adenocarcinoma (mPDAC) patients in Portugal, including healthcare provision and factors affecting therapeutic decisions, namely BRCA mutations testing.

This is a descriptive cross-sectional, web-based survey using a convenience sampling approach. Portuguese oncologists and pathologists that routinely work with mPDAC patients from the different geographical regions and settings were invited to participate in the study via email (December 2020). Descriptive statistical analyses were performed, with categorical variables reported as absolute and relative frequencies, and continuous variables with non-normal distribution as median and interquartile range (IQR) (Stata v.15.0).

Seventy physicians participated in the study (43 oncologists, 27 pathologists). According to the responses, a median of 28 patients per center (IQR 12-70) was diagnosed with PDAC in the previous year; 22 of them referring (IQR 8-70) to mPDAC. The pointed median time from patients' first hospital admission until disease diagnosis/staging is between 2 and 4 weeks. Endoscopic ultrasound with fine-needle biopsy is available in most hospitals (86%). Around 50% of physicians request BRCA testing; the assessment of additional biomarkers besides BRCA is requested by 40% of professionals. Half of them stated that BRCA testing should be requested earlier-upon histological diagnosis, especially because the median time for results is of 4.0 weeks (IQR 4-8). PARP inhibitors such as olaparib, when available, would be the therapy of choice for most oncologists (71%) if no disease' progression occurs after 4 months. Treatments' selection is usually grounded on clinical criteria (e.g., performance status, liver function). Around 45% of patients use FOLFIRINOX/mFOLFIRINOX as the first-line therapy. Gemcitabine + nab-paclitaxel is used by 35% of patients as the second-line therapy.

Physicians in Portugal support the increasing role of patient-tailored treatments in mPDAC, whose selection should be grounded on tumoral subtyping and molecular profiling. Further efforts to develop multidisciplinary teams, standardized clinical practice, and optimize the implementation of new target therapies are needed.

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, with a 5-year overall survival rate of 10%. In November 2018, NCCN recommended that all patients with PDAC receive genetic counseling (GC) and germline testing regardless of family history. We hypothesized that patients with PDAC were more likely to be referred for testing after this change to the guidelines, regardless of presumed predictive factors, and that compliance would be further improved following the implementation of a hereditary cancer clinic (HCC).

We conducted a single-institution retrospective analysis of patients diagnosed with PDAC from June 2017 through December 2021 at University of California, Irvine. We compared rates of genetics referral among patients in different diagnostic eras: the 18-month period before the NCCN Guideline change (pre-NCCN era: June 2017 through November 2018), 14 months following the change (post-NCCN era: December 2018 through January 2020), and 18 months after the creation of an HCC (HCC era: June 2020 through December 2021). Family and personal cancer history, genetics referral patterns, and results of GC were recorded. Data were compared using chi-square, Fisher exact, and multivariate analyses.

A total of 335 patients were treated for PDAC (123 pre-NCCN, 109 post-NCCN, and 103 HCC) at University of California, Irvine. Demographics across groups were comparable. Prior to the guideline changes, 30% were referred to GC compared with 54.7% in the post-NCCN era. After the implementation of the HCC, 77.4% were referred to GC (P<.0001). The odds ratio (OR) for referral to GC among patients with a positive family history of cancer progressively decreased following the change (pre-NCCN era: OR, 11.90 [95% CI, 3.00-80.14]; post-NCCN era: OR, 3.39 [95% CI, 1.13-10.76]; HCC era: OR, 3.11 [95% CI, 0.95-10.16]).

The 2018 updates to the NCCN Guidelines for PDAC recommending germline testing for all patients with PDAC significantly increased GC referral rates at our academic medical center. Implementation of an HCC further boosted compliance with guidelines.

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.

Introduction: Pancreatic cancer is the most fatal cancer type in the world. Its high mortality is mostly correlated to the absence of symptoms and the difficulty in early diagnosis, which in the majority of the cases occurs when the disease has already spread metastasis. Nowadays, tests that could predict early diagnosis are not available yet and the number of prognostic tests is limited. Hence, there is an urgent need for biomarkers capable of detecting early development or the rapid progression of the disease. Patients and Methods: DNA methylation represents the most frequent epigenetic event among tumor suppressor genes that are involved in various carcinogenic pathways. In the recent study we have tried to evaluate, for the first time, the prognostic value of BRCA1 and BRCA2 methylation in the cell-free DNA of pancreatic cancer patients. Using methylation-specific real-time PCR we examined the methylation status of BRCA1 and BRCA2 in 55 patients with operable and 50 patients with metastatic pancreatic cancer. In the operable disease setting, BRCA1 was found to be methylated in 33/55 (63.5%) patients examined while BRCA2 was also highly methylated in 31/55 (56.3%). In the metastatic disease, BRCA1 was found to be methylated in 26/50 (52%) while BRCA2 was found methylated in 23/50 (46%). Results: All control samples were negative for BRCA1 orBRCA2 promoter methylation. Patients with operable pancreatic cancer and a methylated BRCA1 and BRCA2 promoter status had a statistically significant poorer outcome as compared with patients with a non-methylated one (p=0.012 and p=0.001, respectively). Conclusion: In this study plasma methylation of BRCA1 and BRCA2 represents a frequent event in both the operable as well as in the metastatic setting. BRCA1 and BRCA2 methylation was significant and correlated with decreased survival in patients with operable pancreatic cancer. A larger cohort of patients is required to further explore the potential of these findings as well as to investigate whether BRCA1/2 methylation in plasma could serve as a potential prognostic biomarker in pancreatic cancer.

Pancreatic acinar cell carcinoma is a rare form (0.2-4.3%) of pancreatic neoplasm with unique clinical and molecular characteristics, which largely differ from pancreatic ductal adenocarcinoma. Pancreatic acinar cell carcinoma occurs more frequently in males and can occur in children. Serum lipase is elevated in 24-58% of patients with pancreatic acinar cell carcinoma. Pancreatic acinar cell carcinomas tend to be large at diagnosis (median tumour size: ~5 cm) and are frequently located in the pancreas head. Radiologically, pancreatic acinar cell carcinoma generally exhibits a solid appearance; however, necrosis, cystic changes and intratumoral haemorrhage can occur in larger lesions. Immunostaining is essential for the definitive diagnosis of pancreatic acinar cell carcinoma. Compared with pancreatic ductal adenocarcinoma, pancreatic acinar cell carcinoma has a more favourable prognosis. Although radical surgery is recommended for patients with pancreatic acinar cell carcinoma who do not have distant metastases, the recurrence rate is high. The effectiveness of adjuvant therapy for pancreatic acinar cell carcinoma is unclear. The response to FOLFIRINOX is generally favourable, and some patients achieve a complete response. Pancreatic acinar cell carcinoma has a different genomic profile compared with pancreatic ductal adenocarcinoma. Although genomic analyses have shown that pancreatic acinar cell carcinoma rarely has KRAS, TP53 and CDKN2A mutations, it has a higher prevalence of homologous recombination-related genes, including BRCA1/2 and ATM, than pancreatic ductal adenocarcinoma, suggesting high sensitivity to platinum-containing regimens and PARP inhibitors. Targeted therapies for genomic alternations are beneficial. Therefore, genetic testing is important for patients with pancreatic acinar cell carcinoma to choose the optimal therapeutic strategy.