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Brandon G Smaglo, Michael J PishvaianLombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USAAbstract: The management of metastatic pancreatic adenocarcinoma is a challenge for medical oncologists because of both the aggressive nature of the disease and the relative paucity of effective systemic treatments with activity against this type of tumor. In the effort to discover new agents and combinations that may augment the therapeutic arsenal available for the management of this cancer, early phase clinical trials have been performed using ixabepilone, an epothilone B analog, with promising results. Targeting the microtubule system with certain taxanes in the management of pancreatic adenocarcinoma has been validated; ixabepilone also targets the microtubule system, interfering with it in an alternate manner from the taxane mechanism. Ixabepilone has demonstrated activity in cancers that have become taxane-resistant as well as those that never had any demonstrable taxane susceptibility. The available data for the use of ixabepilone in the management of pancreatic adenocarcinoma are limited but promising. Single-arm studies have demonstrated both clinical efficacy and tolerable toxicity for the use of ixabepilone as monotherapy. The trial data available for ixabepilone used as a part of combination therapy are similar: it has been paired with chemotherapy (carboplatin, irinotecan) and biologic therapy (dasatinib, sunitinib) at the Phase I level to treat solid tumors in general, again with tolerable side effects and a suggestion of benefit. A single Phase II study has evaluated combination therapy with ixabepilone in the management of patients with pancreatic cancer, pairing it with cetuximab with clinical benefit. Although these trials are promising with regard to addition of ixabepilone to the slim armamentarium for management of pancreatic cancer, further work is still to be done. Importantly, this work bears the burden of not only validating the clinical benefit of ixabepilone, but also of determining whether this benefit is enhanced in any way by combination therapy, and where ixabepilone fits in the sequence of management for patients with metastatic pancreatic cancer.Keywords: ixabepilone, pancreatic cancer, microtubules

Purpose: The EXTEND trial tested the hypothesis that adding comprehensive metastasis-directed therapy (MDT) to chemotherapy would improve progression-free survival (PFS) over chemotherapy alone among patients with oligometastatic pancreatic ductal adenocarcinoma (PDAC)., Methods: EXTEND (ClinicalTrials.gov identifier: NCT03599765) is a multicenter, phase II basket trial randomly assigning patients with ≤five metastases 1:1 to MDT plus systemic therapy versus systemic therapy. Disease progression was defined by radiologic criteria (RECIST v1.1), clinical progression, or death. The primary end point was PFS in the per-protocol population, evaluated after all patients achieved at least 6 months of follow-up. Exploratory end points included systemic immune response measures., Results: Between March 19, 2019, and February 13, 2023, 41 patients were randomly assigned and 40 were eligible for the primary analysis of PFS (19 patients in the MDT arm; 21 patients in the control arm). At a median follow-up time of 17 months, the median PFS time was 10.3 months (95% CI, 4.6 to 14.0) in the MDT arm versus 2.5 months (95% CI, 1.7 to 5.1) in the control arm. PFS was significantly improved by the addition of MDT to systemic therapy ( P = .030 for stratified log-rank test) with a hazard ratio of 0.43 (95% CI, 0.20 to 0.94). No grade ≥3 or greater adverse events related to MDT were observed. Systemic immune activation events were associated with MDT and correlated with improved PFS., Conclusion: This study supports the addition of MDT to systemic therapy for patients with oligometastatic PDAC. Induction of systemic immunity is a possible mechanism of benefit. These results warrant confirmatory trials to refine treatment strategy and provide external validation.

Objectives: Acinar cell carcinoma (ACC) accounts for about 1% of pancreatic cancers. The molecular and clinical features of ACC are less characterized than those of pancreatic ductal adenocarcinoma. Methods : We retrospectively evaluated the clinical and molecular features of ACC patients who underwent germline and/or somatic molecular testing at The University of Texas MD Anderson Cancer Center from 2008 to 2022 and two cases from 2023-2024 who underwent RNA and TME analysis by Boston Gene. Patient information was extracted from our institutional database with the approval of the Institutional Review Board. Results: We identified 16 patients with available molecular testing results. Fourteen patients had metastatic disease, one had borderline resectable disease, and one had localized resectable disease at diagnosis. Fifteen patients were wild type for KRAS (one patient had unknown KRAS status). Somatic/germline mutations of DNA damage repair genes ( BRCA1/2 , PALB2 , and ATM ) were present in 5 of 12 patients tested for these genes. One patient was found to have RET fusion and responded favorably to selpercatinib for over 42 months. The median overall survival (OS) was 24 months for patients with metastatic disease. One of the additional two cases who underwent BostonGene testing was found to have NTRK1 fusion. RNA and TME analysis by Boston Gene of the two cases reported immune desert features and relatively lower RNA levels of CEACAM5, CD47, CD74, and MMP1 and higher RNA levels of CDH6 compared with PDAC.

Background: 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., Materials and Methods: 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., Results: 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., Conclusion: 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., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Pancreatic ductal adenocarcinoma is characterised by low immunogenicity and an immunosuppressive tumour microenvironment. LOAd703, an oncolytic adenovirus with transgenes encoding TMZ-CD40L and 4-1BBL, lyses cancer cells selectively, activates cytotoxic T cells, and induces tumour regression in preclinical models. The aim of this study was to evaluate the safety and feasibility of combining LOAd703 with chemotherapy for advanced pancreatic ductal adenocarcinoma., Methods: LOKON001 was a non-randomised, phase 1/2 study conducted at the Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA, and consisted of two arms conducted sequentially; the results of arm 1 are presented here. In arm 1, patients 18 years or older with previously treated or treatment-naive unresectable or metastatic pancreatic ductal adenocarcinoma were treated with standard 28-day cycles of intravenous nab-paclitaxel 125 mg/m 2 plus gemcitabine 1000 mg/m 2 (up to 12 cycles) and intratumoural injections of LOAd703 every 2 weeks. Patients were assigned using Bayesian optimal interval design to receive 500 μL of LOAd703 at 5 × 10 10 (dose 1), 1 × 10 11 (dose 2), or 5 × 10 11 (dose 3) viral particles per injection, injected endoscopically or percutaneously into the pancreatic tumour or a metastasis for six injections. The primary endpoints were safety and treatment-emergent immune response in patients who received at least one dose of LOAd703, and antitumour activity was a secondary endpoint. This study was registered with ClinicalTrials.gov, NCT02705196, arm 2 is ongoing and open to new participants., Findings: Between Dec 2, 2016, and Oct 17, 2019, 23 patients were assessed for eligibility, leading to 22 patients being enrolled. One patient withdrew consent, resulting in 21 patients (13 [62%] men and eight [38%] women) assigned to a dose group (three to dose 1, four to dose 2, and 14 to dose 3). 21 patients were evaluable for safety. Median follow-up time was 6 months (IQR 4-10), and data cutoff was Jan 5, 2023. The most common treatment-emergent adverse events overall were anaemia (96 [8%] of 1237 events), lymphopenia (86 [7%] events), hyperglycaemia (70 [6%] events), leukopenia (63 [5%] events), hypertension (62 [5%] events), and hypoalbuminaemia (61 [5%] events). The most common adverse events attributed to LOAd703 were fever (14 [67%] of 21 patients), fatigue (eight [38%]), chills (seven [33%]), and elevated liver enzymes (alanine aminotransferase in five [24%], alkaline phosphatase in four [19%], and aspartate aminotransferase in four [19%]), all of which were grade 1-2, except for a transient grade 3 aminotransferase elevation occurring at dose 3. A maximum tolerated dose was not reached, thereby establishing dose 3 as the highest-evaluated safe dose when combined with nab-paclitaxel plus gemcitabine. Proportions of CD8 + effector memory cells and adenovirus-specific T cells increased after LOAd703 injections in 15 (94%) of 16 patients for whom T-cell assays could be performed. Eight (44%, 95% CI 25-66) of 18 patients evaluable for activity had an objective response., Interpretation: Combining LOAd703 with nab-paclitaxel plus gemcitabine in patients with advanced pancreatic ductal adenocarcinoma was feasible and safe. To build upon this novel chemoimmunotherapeutic approach, arm 2 of LOKON001, which combines LOAd703, nab-paclitaxel plus gemcitabine, and atezolizumab, is ongoing., Funding: Lokon Pharma, the Swedish Cancer Society, and the Swedish Research Council., Competing Interests: Declaration of interests BLM has received salary support from Lokon Pharma for serving as principal investigator for LOKON001 (payments made to Baylor College of Medicine). EKR has received payments from Lokon Pharma for serving as a scientific advisor. BGS has received consulting fees for participating on pancreatic cancer advisory boards for Ipsen Pharmaceuticals. WA, MO, KP, SJ, and JJ have been paid standard physician's fees by Lokon Pharma to perform LOAd703 injections for LOKON001 (payments made to Baylor College of Medicine). AB received salary support from Lokon Pharma for serving as clinical trial coordinator for LOKON001 (payments made to Baylor College of Medicine). AML has received financial support from Lokon Pharma to perform laboratory correlative studies (payments made to Baylor College of Medicine). LCS is employed by Lokon Pharma, has stock and ownership interests in AstraZeneca, and holds patents and other intellectual property at Alligator. JW, EE, and JL-J are employed by Lokon Pharma. GJU has received salary support from Lokon Pharma for helping with the conceptualisation of LOKON001 (payments made to Uppsala University); has received consulting fees from Alligator Bioscience, Boehringer Ingelheim, and SeqCure Immunology AB; has received honoraria from Novartis, Pierre Fabre, Merck, and Bristol Myers Squibb for lectures; and has received payments from Novartis, Sanofi, Pierre Fabre, Merck, and Bristol Myers Squibb for participating in advisory boards. BG has received salary support from Lokon Pharma for performing regulatory work for LOKON001 (payments made to Baylor College of Medicine) and has served as a consultant for Lokon Pharma (payments made through QB Regulatory Consulting, owned by BG). SGH has received salary support from Lokon Pharma for serving as the primary statistician for LOKON001 (payments made to Baylor College of Medicine). MKB has received consulting fees from and participated in data safety monitoring boards for Marker Therapeutics and Turnstone Biologics, and has stock in Turnstone Biologics and AlloVir. ASIL is employed by and receives research funding from Lokon Pharma and has leadership roles and ownership interests in Lokon Pharma. MW declares no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Objective: We aimed to determine if advances in neoadjuvant therapy affected recurrence patterns and survival outcomes after pancreatectomy for pancreatic ductal adenocarcinoma (PDAC)., Background: Data are limited on how modern multimodality therapy affects PDAC recurrence and post-recurrence survival., Methods: Patients who received neoadjuvant therapy followed by curative-intent pancreatectomy for PDAC during 1998-2018 were identified. Treatments, recurrence sites and timing, and survival were compared between patients who completed neoadjuvant therapy and pancreatectomy in 1998-2004, 2005-2011, and 2012-2018., Results: The study included 727 patients (203, 251, and 273 in the 1998-2004, 2005-2011, and 2012-2018 cohorts, respectively). Use of neoadjuvant induction chemotherapy increased over time, and regimens changed over time, with >80% of patients treated in 2012-2018 receiving FOLFIRINOX or gemcitabine with nab-paclitaxel. Overall, recurrence sites and incidence (67.5%, 66.1%, and 65.9%) remained stable, and 85% of recurrences occurred within 2 years of surgery. However, compared to earlier cohorts, the 2012-2018 cohort had lower conditional risk of recurrence in postoperative year 1 and higher risk in postoperative year 2. Overall survival increased over time (median, 30.6, 33.6, and 48.7 mo, P < 0.005), driven by improved post-recurrence overall survival (median, 7.8, 12.5, and 12.6 mo; 3-year rate, 7%, 10%, and 20%; P < 0.005)., Conclusions: We observed changes in neoadjuvant therapy regimens over time and an associated shift in the conditional risk of recurrence from postoperative year 1 to postoperative year 2, although recurrence remained common. Overall survival and post-recurrence survival remarkably improved over time, reflecting improved multimodality regimens for recurrent disease., Competing Interests: Conflicts of Interest and Source of Funding: The authors have no conflicts of interest related to the design or execution of this study. The authors have no financial relationships related to the design or execution of this study. Supported in part by the NIH/NCI under award number P30CA016672. SHC is supported by National Institutes of Health T32 CA 009599 and the MD Anderson Cancer Center support grant (P30 CA016672)., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The relevance of KRAS mutation alleles to clinical outcome remains inconclusive in pancreatic adenocarcinoma (PDAC). We conducted a retrospective study of 803 patients with PDAC (42% with metastatic disease) at MD Anderson Cancer Center. Overall survival (OS) analysis demonstrated that KRAS mutation status and subtypes were prognostic (p < 0.001). Relative to patients with KRAS wildtype tumors (median OS 38 months), patients with KRAS G12R had a similar OS (median 34 months), while patients with KRAS Q61 and KRAS G12D mutated tumors had shorter OS (median 20 months [HR: 1.9, 95% CI 1.2-3.0, p = 0.006] and 22 months [HR: 1.7, 95% CI 1.3-2.3, p < 0.001], respectively). There was enrichment of KRAS G12D mutation in metastatic tumors (34% vs 24%, OR: 1.7, 95% CI 1.2-2.4, p = 0.001) and enrichment of KRAS G12R in well and moderately differentiated tumors (14% vs 9%, OR: 1.7, 95% CI 1.05-2.99, p = 0.04). Similar findings were observed in the external validation cohort (PanCAN's Know Your Tumor® dataset, n = 408)., (© 2024. The Author(s).)

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy for which multiagent chemotherapy is the mainstay of treatment resulting in limited survival and symptomatic benefit. Treatment with immune checkpoint inhibitors (ICI) has proven effective in a growing number of solid tumors but has yet to show clinical benefit in patients with PDAC. Given the growing number of ICI-based clinical trials in development for patients with PDAC and lack of clinical benefit thus far with ICI-based therapies in these patients, we sought to (1) determine the outcomes of patients with PDAC treated with ICI-based therapies as part of an early phase clinical trial, (2) validate the utility of established prognostic scoring systems, and (3) identify novel prognostic factors in an attempt to better identify patients that would benefit from enrollment onto an ICI-based early phase clinical trial., Methods: We conducted a single-center retrospective analysis of patients with advanced PDAC who were treated with ICI-based therapy as part of an early-phase clinical trial., Results: Patients were only able to stay on study for a limited time due to disease progression and/or a change in performance status and had a poor overall survival. Established prognostic scoring systems were not effective in predicting outcomes in this patient population, but factors such as pre-treatment albumin neutrophil to lymphocyte ratio (NLC) may be helpful in patient selection., Conclusions: This study underscores the need for larger studies to help identify patient and tumor intrinsic factors that predict response to ICI-based therapies in patients with PDAC., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The relevance of KRAS mutation alleles to clinical outcome remains inconclusive in pancreatic adenocarcinoma (PDAC). We conducted a retrospective study of 803 PDAC patients (42% with metastatic disease) at MD Anderson Cancer Center. Overall survival (OS) analysis demonstrated that KRAS mutation status and subtypes were prognostic (p<0.001). Relative to patients with KRAS wildtype tumors (median OS 38 months), patients with KRAS G12R had a similar OS (median 34 months), while patients with KRAS Q61 and KRAS G12D mutated tumors had shorter OS (median 20 months [HR: 1.9, 95% CI 1.2-3.0, p=0.006] and 22 months [HR: 1.7, 95% CI 1.3-2.3, p<0.001], respectively). There was enrichment of KRAS G12D mutation in metastatic tumors (34% vs 24%, OR: 1.7, 95% CI 1.2-2.4, p=0.001) and enrichment of KRAS G12R in well and moderately differentiated tumors (14% vs 9%, OR: 1.7, 95% CI 1.05-2.99, p=0.04). Similar findings were observed in the external validation cohort (PanCAN's Know Your Tumor ® dataset, n=408)., Competing Interests: Additional Declarations: There is a conflict of interest Dan Zhao is an advisory board member for Affini-T and she has clinical trial contract with CARsgen and Mirati. Disclosures and Competing interests: This data has not been previously presented. COI disclosures pending from authors.

Real-world evidence regarding the value of integrating genomic profiling (GP) in managing cancer of unknown primary (CUP) is limited. We assessed this clinical utility using a prospective trial of 158 patients with CUP (October 2016-September 2019) who underwent GP using next-generation sequencing designed to identify genomic alterations (GAs). Only 61 (38.6%) patients had sufficient tissue for successful profiling. GAs were seen in 55 (90.2%) patients of which GAs with US Food and Drug Administration-approved genomically matched therapy were seen in 25 (40.9%) patients. A change in therapy was recommended and implemented (primary endpoint of the study) in 16 (10.1%) and 4 (2.5%) patients of the entire study cohort, respectively. The most common reason for inability to implement the profiling-guided therapy was worsening of performance status (56.3%). Integrating GP in management of CUP is feasible but challenging because of paucity of tissue and aggressive natural history of the disease and requires innovative precision strategies., (© The Author(s) 2023. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Purpose: Pembrolizumab significantly improves clinical outcomes in advanced/metastatic microsatellite instability high (MSI-H)/deficient mismatch repair (dMMR) solid tumors but is not well studied in the neoadjuvant space., Methods: This is a phase II open-label, single-center trial of localized unresectable or high-risk resectable MSI-H/dMMR tumors. Treatment is pembrolizumab 200 mg once every 3 weeks for 6 months followed by surgical resection with an option to continue therapy for 1 year followed by observation. To continue on study, patients are required to have radiographic or clinical benefit. The coprimary end points are safety and pathologic complete response. Key secondary end points are response rate and organ-sparing at one year for patients who declined surgery. Exploratory analyses include interrogation of the tumor immune microenvironment using imaging mass cytometry., Results: A total of 35 patients were enrolled, including 27 patients with colorectal cancer and eight patients with noncolorectal cancer. Among 33 evaluable patients, best overall response rate was 82%. Among 17 (49%) patients who underwent surgery, the pathologic complete response rate was 65%. Ten patients elected to receive one year of pembrolizumab followed by surveillance without surgical resection (median follow-up of 23 weeks [range, 0-54 weeks]). An additional eight did not undergo surgical resection and received less than 1 year of pembrolizumab. During the study course of the trial and subsequent follow-up, progression events were seen in six patients (four of whom underwent salvage surgery). There were no new safety signals. Spatial immune profiling with imaging mass cytometry noted a significantly closer proximity between granulocytic cells and cytotoxic T cells in patients with progressive events compared with those without progression., Conclusion: Neoadjuvant pembrolizumab in dMMR/MSI-H cancers is safe and resulted in high rates of pathologic, radiographic, and endoscopic response, which has implications for organ-sparing strategies.

Despite aggressive adjuvant management, a high percentage of patients who undergo appropriate surgical resection for pancreatic cancer will see their cancer recur and thus will not be cured. An important paradigm shift to achieve better outcomes has been therapy sequence, with neoadjuvant chemotherapy preceding surgery. Patients with a borderline resectable cancer, or patients with a resectable cancer but who have other high-risk features, are ideal candidates to consider for neoadjuvant chemotherapy. Among the high-risk features, a baseline elevated CA 19-9 concentration can be particularly useful, as its response trend during neoadjuvant chemotherapy can offer important insights into the prognosis after surgery. When selecting a neoadjuvant chemotherapy regimen, response data available for the use of FOLFIRINOX and gemcitabine and nabpaclitaxel in the metastatic setting support their use in this space. FOLFIRINOX is perhaps the preferred regimen, given its proven adjuvant benefit and possibly its superior tumor response rate; still, patient tolerance and thus ability to complete recommended treatment must be carefully considered. This review presents the evidence supporting neoadjuvant chemotherapy for resectable pancreatic cancer, the factors to consider when making such a recommendation, the selection of specific regimens, and our institutional approach using these tools.

Objective: To characterize associations between carbohydrate antigen 19-9 (CA19-9) dynamics during neoadjuvant therapy (NT) and survival for patients with pancreatic ductal adenocarcinoma (PDAC)., Background: Although normalization of CA19-9 during NT is associated with improved outcomes following PDAC resection, we hypothesize that CA19-9 dynamics during NT can improve prognostication., Methods: Characteristics for patients with PDAC undergoing NT (July 2011-October 2018) with ≥3 CA19-9 results (bilirubin<2mg/dL) were collected and grouped by CA19-9 dynamics. Nonproducers (<1 U/ml) were excluded, and normal was ≤35 U/ml. Postresection survival was compared among groups., Results: Of 431 patients, 166 had eligible CA19-9 values. Median baseline CA19-9 was 98 U/ml. Overall 2-year postresection recurrence-free survival (RFS) and overall survival (OS) were 37% and 63%, respectively. Patients with normalization (53%) had improved 2-year RFS (47% vs. 28%, P = 0.01) and OS (75% vs. 49%, P = 0.01). CA19-9 dynamics during NT were analyzed by shape, direction, and normalization creating response types ("A-B-C-D-E"). Type A was "Always" decreasing to normalization, B "Bidirectional" with eventual normalization, C "Consistently" normal, D any "Decrease" without normalization, and E "Elevating" without normalization. Types A and B responses were associated with the longest postresection 2-year RFS (51% and 56%) and OS (75% and 92%, respectively) whereas Types D and E had the worst outcomes. After adjusting for node-positivity, perineural invasion, and margin-positivity, CA19-9 response types were independently associated with both RFS and OS, and predicted outcomes are better than CA19-9 normalization alone (likelihood ratio test RFS P < 0.001, OS P = 0.01)., Conclusions: This novel A-B-C-D-E classification of CA19-9 dynamics during NT was associated with postresection outcomes more precisely than CA19-9 normalization alone., Competing Interests: The authors report no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Perineural invasion is a frequent histological finding in pancreatic adenocarcinoma. However, perineural invasion by intraductal papillary mucinous neoplasm (IPMN), a precursor lesion of pancreatic adenocarcinoma, has not been reported so far. We report a unique case of perineural invasion by IPMN in a 60-year-old female who underwent pancreatoduodenectomy for high-risk features of IPMN. Histological evaluation showed increased nerve density in the connective tissue of IPMN with multiple foci of perineural invasion by IPMN. In addition, there was a discrete 2 mm focus of invasive carcinoma that did not show perineural invasion. Chemotherapy was started and the patient is disease-free at 29 months follow up. The case illustrates previously unreported neuroplastic alterations and neutrotropism in benign neoplastic component of a malignant IPMN., (© 2022 by the Association of Clinical Scientists, Inc.)

Background: Cancer of unknown primary (CUP) presenting as bone-predominant (BCUP) or lymph node-only disease (LNCUP) represents two clinically distinct subsets of nonvisceral CUP. These present a diagnostic challenge with a large differential of putative primary cancers and defy the "one-treatment-fits-all" approach., Materials and Methods: We identified patients with BCUP (n = 29) and LNCUP (n = 63) using a prospectively collected CUP database and tumor registry of patients seen at MD Anderson Cancer Center between 2001 to 2017. Clinicopathological characteristics, treatments, and outcomes were abstracted. A control group of non-BCUP/LNCUP cases (n = 443) from the database was used for comparison. Kaplan-Meier method was used to estimate overall survival and compared using log-rank test., Results: In this cohort, 64% and 60% patients had disseminated disease at diagnosis and 39% and 23% had Culine poor-risk disease in BCUP and LNCUP, respectively. Median overall survival (OS) for BCUP was 14.5 months and for LNCUP was 32.6 months. For BCUP, gemcitabine plus platinum was the most common initial chemotherapy (54%). For LNCUP, carboplatin plus paclitaxel was the most common initial chemotherapy (38%). Radiation was given to 74% of patients with BCUP and 37% of those with LNCUP. On multivariate analysis, poor-risk Culine group (hazard ratio [HR], 1.76; p < .001) and high neutrophil-to-lymphocyte ratio (HR, 2.38, p < .001) were associated with worse OS., Conclusion: BCUP and LNCUP are rare subsets within CUP with varying prognosis. Poor-risk Culine group and high neutrophil-to-lymphocyte ratio are associated with poor survival. Select patients with limited metastases can have long-term survival with aggressive multimodality treatment. Careful clinicopathological review can facilitate chances of site-directed therapy., Implications for Practice: Cancer of unknown primary (CUP) rarely presents as bone-predominant (BCUP) or lymph node-only (LNCUP) disease. This article describes a cohort of each and compares with a larger CUP cohort. Patients with BCUP have unique issues with fractures and pain, often receiving radiation. Overall survival of 14.5 months was similar to a larger CUP comparison cohort. Patients with LNCUP had improved overall survival at 32.6 months, with longer survival in patients without disseminated disease. Culine poor-risk group and neutrophil-to-lymphocyte ratio were associated with worse overall survival. Tips regarding diagnosis and management of these rare malignant subsets are provided., (© 2021 The Authors. The Oncologist published by Wiley Periodicals LLC on behalf of AlphaMed Press.)

Purpose: Up to 17% of patients with pancreatic ductal adenocarcinoma (PDAC) harbor pathogenic (germline or somatic) mutations in a homologous recombination, DNA damage response and repair (HR-DDR) gene, such as BRCA1/2 , or PALB2 . Platinum-based chemotherapy, or treatment with PARP inhibitors are of particular benefit in these patients. However, there may be even greater benefit when platinums and PARP inhibitors are combined., Patients and Methods: We performed a single-arm, open-label, phase I/II study of the PARP inhibitor, veliparib, with 5-fluorouracil (no 5FU bolus) and oxaliplatin (FOLFOX) for patients with metastatic PDAC. Thirty-one patients were enrolled in a phase I dose escalation of veliparib (40 mg to 250 mg twice a day, days 1-7 of each 14-day cycle), to identify the recommended phase II dose (RP2D) of veliparib for the combination. Another 33 patients were enrolled in two parallel phase II trials to assess the objective response rate (ORR) in untreated or in previously treated patients. If available, germline or somatic testing was collected to identify pathogenic HR-DDR mutations., Results: The combination of veliparib and FOLFOX was tolerable at a RP2D of veliparib of 200 mg twice a day. The primary endpoint for both phase II cohorts was met, and the ORR overall was 26%. There was greater activity in platinum-naïve patients, and those who harbored a pathogenic HR-DDR mutation. Specifically, the ORR of HR-DDR mutated, platinum-naïve patients was 57%., Conclusions: The combination of veliparib and FOLFOX was safe for patients with metastatic PDAC and showed promising activity particularly in patients with platinum-naïve disease that harbors a pathogenic HR-DDR mutation., (©2020 American Association for Cancer Research.)

Background: Multimodality therapy (MMT) is recommended for patients with resectable gastric cancer, but no single approach has been established as standard. Little is presently known about current national practice patterns and sequencing of MMT., Methods: Retrospective cohort study of patients with gastric cancer aged 18 to 80 y in the National Cancer Database (2006-2014) with ≥T2 and/or node-positive disease (i.e., stage Ib to III) treated with MMT. Clinical nodal staging accuracy was ascertained among those treated with upfront surgery by comparing clinical and pathologic nodal staging. Multivariable Cox regression was used to evaluate the association between overall risk of death and MMT approach (i.e., radiation used versus not and treatment sequence)., Results: Among 5817 patients, 16.1% received perioperative MMT, 50.6% preoperative only, and 33.3% postoperative only. The sensitivity, specificity, positive predictive value, and negative predictive values of clinical nodal staging were 68.4%, 88.8%, 91.1%, and 62.7%, respectively. Current clinical nodal staging modalities understage 37.3% of clinically node-negative patients. Over time, radiation utilization decreased (74.3% in 2006 versus 53.9% in 2014; trend test, P < 0.001), perioperative MMT increased (8.9% versus 22.2%%; trend test, P < 0.001), and postoperative MMT decreased (43.1% versus 21.0%; trend test, P < 0.001). Neither type of MMT nor treatment sequence is associated with risk of death., Conclusions: One-third of patients with gastric cancer who are candidates to receive MMT are treated with upfront surgery. Given the high false negative rate of clinical nodal staging and high noncompletion rate of postoperative treatment, efforts should be directed at improving and optimizing preoperative therapy utilization., (Published by Elsevier Inc.)

Objective: To determine the association between neoadjuvant chemotherapy and chemoradiation therapy on completeness of pathologic response and to assess the impact of primary tumor versus nodal response on survival after esophagectomy., Methods: Patients aged 18 to 80 years in the National Cancer Data Base (2006-2016) with clinically staged, locally advanced (cT2-4 or cN+) esophageal adenocarcinoma who underwent an R0 esophagectomy after neoadjuvant chemotherapy or chemoradiation therapy were included. Multivariable Cox proportional hazards regression models were constructed to assess the association between treatment response and survival., Results: Among 2870 patients, there was a significant dose-response association between completeness of response and overall survival: no response (reference), partial response (hazard ratio [HR], 0.81; 95% confidence interval [CI], 0.72-0.91), and complete response (HR, 0.55; 95% CI, 0.47-0.65). Compared with neoadjuvant chemotherapy alone, neoadjuvant chemoradiation was associated with higher pathologic primary tumor (33.9% vs 21.3%; P < .001) and pathologic nodal response rates (55.9% vs 32.7%; P < .001). Both a primary and nodal response were associated with improved survival. However, among patients with a primary but no nodal response, primary tumor response was not associated with risk of death (HR, 0.88; 95% CI, 0.69-1.11). In contrast, among patients who had a nodal but no primary response, the survival benefit of a nodal response was maintained (HR, 0.66; 95% CI, 0.58-0.76)., Conclusions: Pathologic nodal (rather than primary tumor) response to neoadjuvant therapy is associated with improved survival. These data suggest a need to optimize neoadjuvant strategies associated with more complete nodal response rates and to consider more aggressive adjuvant treatment for patients with residual nodal disease after esophagectomy., (Copyright © 2018 The American Association for Thoracic Surgery. All rights reserved.)

Background: Pathologically positive lymph nodes (ypN+) after preoperative chemotherapy are associated with poor survival in patients with gastric cancer. Little is known about the association between response to preoperative therapy and the benefit of postoperative therapy. Methods: This retrospective cohort study of the National Cancer Database included patients with clinically node-positive (cN+) gastric cancer treated with preoperative therapy followed by surgery (2006-2014). Preoperative treatment modality was categorized as the inclusion of radiation therapy (RT) or chemotherapy alone. Pretreatment clinical and pathologic stages were used to determine pathologic treatment response rates. The association between overall risk of death and preoperative treatment, disease response, and adjuvant therapy use was evaluated using multivariable Cox regression. Results: Preoperative RT was used in 53.6% of 1,976 patients with cN+ gastric cancer, (74.3% cardia and 10.1% noncardia). The nodal response rate was 38.9% and was higher with RT than with chemotherapy alone (cardia, 46.0% vs 29.1%; P <.001; noncardia, 43.8% vs 31.9%; P =.06). Preoperative RT was associated with an approximate 2-fold increase in the odds of pathologic response compared with chemotherapy. Overall, use of adjuvant therapy was not associated with a decreased risk of death. A primary tumor response with residual nodal disease was not associated with survival (hazard ratio [HR], 1.03; 95% CI, 0.66-1.60). However, a nodal response with residual primary disease was significantly associated with survival (HR, 0.54; 95% CI, 0.44-0.65). Conclusions: More than one-third of node-positive gastric cancers showed pathologic nodal response with preoperative treatment. RT is associated with a higher response than chemotherapy. Patients with ypN+ disease have worse survival, regardless of whether they receive postoperative therapy. Future gastric cancer trials should evaluate the role of preoperative RT and individualize postoperative therapy use., (Copyright © 2019 by the National Comprehensive Cancer Network.)

Background: For locally advanced rectal cancer, response to neoadjuvant radiation has been associated with improved outcomes but has not been well characterized in general practice. The goals of this study were to describe disease response rates after neoadjuvant treatment and to evaluate the association between disease response and survival., Materials and Methods: Retrospective cohort study of patients aged 18-80 y with clinical stage II and III rectal adenocarcinoma in the National Cancer Database (2006-2012). All patients underwent radical resection after neoadjuvant treatment. Treatment responses were defined as follows: no tumor response; intermediate-T and/or N downstaging with residual disease; and complete-ypT0N0. Multivariable, multinomial regression was used to evaluate the association between neoadjuvant radiation use and disease response. Multivariable Cox regression was used to evaluate the association between disease response and overall risk of death., Results: Among 12,024 patients, 12% had a complete and 30% an intermediate response. Neoadjuvant chemotherapy alone was less likely to achieve an intermediate (relative risk ratio: 0.70 [0.56-0.88]) or a complete response (relative risk ratio: 0.59 [0.41-0.84]) relative to neoadjuvant radiation. Tumor response was associated with improved 5-y overall survival (complete = 90.2%, intermediate = 82.0%, no response = 70.5%; log-rank, P < 0.001). Complete and intermediate pathologic responses were associated with decreases in risk of death (hazard ratio: 0.40 [0.34-0.48] and 0.63 [0.57-0.69], respectively) compared to no response. Primary tumor and nodal response were independently associated with decreased risk of death., Conclusions: Neoadjuvant radiation is associated with treatment response, and pathologic response is associated with improved survival. Pathologic response may be an early benchmark for the oncologic effectiveness of neoadjuvant treatment., (Published by Elsevier Inc.)

Despite its declining incidence, gastric cancer (GC) remains a leading cause of cancer-related deaths worldwide. A multimodal approach to GC is critical to ensure optimal patient outcomes. Pretherapy fine resolution contrast-enhanced cross-sectional imaging, endoscopic ultrasound and staging laparoscopy play an important role in patients with newly diagnosed ostensibly operable GC to avoid unnecessary non-therapeutic laparotomies. Currently, margin negative gastrectomy and adequate lymphadenectomy performed at high volume hospitals remain the backbone of GC treatment. Importantly, adequate GC surgery should be integrated in the setting of a multimodal treatment approach. Treatment for advanced GC continues to expand with the emergence of additional lines of systemic and targeted therapies.

The optimal adjuvant management of patients with resectable gastric cancer remains a therapeutic challenge. Although the benefit of adjuvant therapy for these patients is clearly established, recurrence and mortality rates remain high despite such treatment. Moreover, surgical comorbidities and treatment toxicities result in high rates of failure to complete treatment after surgery. Two divergent approaches to adjuvant treatment have emerged as standard: postoperative chemoradiotherapy and perioperative chemotherapy. Because these approaches have never been compared directly, recommendations for adjuvant treatment require multidisciplinary discussion. During this discussion, the characteristics of the symptoms, the histology, location, and stage of the tumor, and the feasibility of the patient's completing all recommended therapy may be considered. In our own practice, we favor perioperative chemotherapy for patients with asymptomatic, proximal, higher-stage disease and adjuvant chemoradiotherapy for patients with symptomatic, distal, lower-stage disease. Herein, we summarize the available data for approaches to the adjuvant treatment of gastric cancer, with special consideration of the characteristics of the patients enrolled in the various studies. We also describe how we developed our paradigm for recommending a particular approach to adjuvant treatment for each patient.

Gastroesophageal adenocarcinomas represent one of the top five most common types of cancer worldwide. Despite significant advancement, it is still not known which first-line chemotherapy option is best matched to an individual patient. The vast advances in molecular biology have led to the discovery of many potential predictive biomarkers, such as HER-2 neu, thymidylate synthase (TS), excision repair cross-complementation group 1 (ERCC1), and topoisomerase-1 (TOPO1). These markers could allow us to select treatment based on an individual's tumor profile, resulting in an improvement of outcome. Our report highlights two patients with metastatic gastric cancer that achieved an exceptional response with traditional therapy and provides insights into the future perspectives of molecular profile-directed chemotherapy.

The curative surgical resection of metastatic disease in patients with stage IV colorectal cancer with a limited tumor burden is standard of care. However, the role for neoadjuvant medical therapy and the ideal composition of that therapy are not established. Several neoadjuvant medical therapies, including standard advanced colorectal cancer chemotherapy regimens-such as folinic acid, fluorouracil (5-FU), and oxaliplatin (FOLFOX); folinic acid, 5-FU, and irinotecan (FOLFIRI); and folinic acid, 5-FU, oxaliplatin, and irinotecan (FOLFOXIRI)-have been evaluated, as has the addition of the biologic agents bevacizumab, panitumumab, and cetuximab. Those patients who are immediate surgical candidates do not seem to benefit from a neoadjuvant medical approach and should proceed directly to surgical resection. Those patients who are not surgical candidates at presentation can in some instances achieve a conversion of disease to a curable state with systemic therapy. Here, we review the studies that have explored different treatment regimens, therapeutic sequencing, and biologic inclusions for the treatment of these patients, with neoadjuvant intent. We also describe how we have established our own treatment paradigm for the management of potentially curable metastatic colorectal cancer.

Anal squamous cell carcinoma (ASCC) is a rare, HPV-associated malignancy typically diagnosed in early stages and definitively treated with chemoradiation. In situations where patients exhibit metastatic or recurrent disease, treatment options are severely limited. In this study, molecular alterations were identified that could be used to aid in therapeutic decisions for patients with metastatic or recurrent anal squamous cell carcinoma. Specimens from patients with this cancer were tested via a multiplatform profiling service (Caris Life Sciences, Phoenix, AZ) consisting of gene sequencing, protein expression by immunohistochemistry, and gene amplification with in situ hybridization. Utilizing these techniques, novel treatment strategies that could be explored were identified, including potential benefit with anti-EGFR therapies, immune checkpoint inhibitors, topoisomerase inhibitors, and taxanes. The frequency of overexpression of proteins that mark resistance to chemotherapeutic drugs, such as MRP1 (chemotherapy efflux pump), ERCC1 (resistance to platinum-based chemotherapy), and thymidylate synthase (resistance to fluoropyrimidines) were also identified, suggesting a lack of benefit. This multiplatform strategy could be explored for its potential to generate a personalized treatment selection for patients with advanced ASCC, provide a guide for future therapeutic development for this cancer, and be extended to other rare cancer types as well.

Biotherapeutics are attractive anti-cancer agents due to their high specificity and limited toxicity compared to conventional small molecules. Antibodies are widely used in cancer therapy, either directly or conjugated to a cytotoxic payload. Peptide therapies, though not as prevalent, have been utilized in hormonal therapy and imaging. The limitations associated with unmodified forms of both types of biotherapeutics have led to the design and development of novel structures, which incorporate key features and structures that have improved the molecules' abilities to bind to tumor targets, avoid degradation, and exhibit favorable pharmacokinetics. In this review, we highlight the current status of monoclonal antibodies and peptides, and provide a perspective on the future of biotherapeutics using novel constructs., (© 2015, The American College of Clinical Pharmacology.)

Immunoconjugates are specific, highly effective, minimally toxic anticancer therapies that are beginning to show promise in the clinic. Immunoconjugates consist of three separate components: an antibody that binds to a cancer cell antigen with high specificity, an effector molecule that has a high capacity to kill the cancer cell, and a linker that will ensure the effector does not separate from the antibody during transit and will reliably release the effector to the cancer cell or tumour stroma. The high affinity antibody-antigen interaction allows specific and selective delivery of a range of effectors, including pharmacologic agents, radioisotopes, and toxins, to cancer cells. Some anticancer molecules are not well tolerated when administered systemically owing to unacceptable toxicity to the host. However, this limitation can be overcome through the linking of such cytotoxins to specific antibodies, which mask the toxic effects of the drug until it reaches its target. Conversely, many unconjugated antibodies are highly specific for a cancer target, but have low therapeutic potential and can be repurposed as delivery vehicles for highly potent effectors. In this Review, we summarize the successes and shortcomings of immunoconjugates, and discuss the future potential for the development of these therapies.

Inhibition of tumor angiogenesis has emerged as an important therapeutic component in the management of metastatic colorectal cancer. Three anti-angiogenic agents are currently approved in this clinical setting: bevacizumab, ziv-aflibercept, and regorafenib. Bevacizumab, a monoclonal antibody that targets the angiogenesis-driving ligand vascular endothelial growth factor A (VEGF-A), is the only anti-angiogenic agent approved in first-line therapy for metastatic colorectal cancer, where it can be used in combination with intravenous 5-fluorouracil-containing chemotherapy regimens. In conjunction with second-line chemotherapies, bevacizumab also has anti-cancer activity, both for the management of metastatic colorectal cancer in patients who received it as a part of their first line therapy and for those who are naïve to it. Ziv-aflibercept also has demonstrated clinical activity in conjunction with the chemotherapeutic regimen FOLFIRI in the second line management of patients with metastatic colorectal cancer; it functions by binding VEGF-A to the vascular endothelial growth factor proteins VEGF-B and PIGF (placental growth factor). Regorafenib, which inhibits multiple tyrosine kinases, including the VEGF receptors, has proven clinical benefit in the management of patients with metastatic colorectal cancer refractory to all other therapies. For patients' whose cancers are refractory to all other therapies, there is also evidence for the use of bevacizumab with fluoropyrimidine monotherapy, but only in the bevacizumab-naïve patient subset. Presently, it is not clear if any one agent as more activity in a particular line of therapy than another, has greater efficacy when paired with a particular chemotherapy backbone, or if a particular patient subset is more likely to benefit from these agents. Given the present benefit and tolerance data, an anti-angiogenic agent should be considered in all lines of therapy in the management of metastatic colorectal cancer, with the evidence for the use of these agents in each specific line of therapy and in specific chemotherapeutic combinations driving agent selection.

Chemotherapy is proven to play a central role in the adjuvant management of pancreatic cancer. A number of studies have validated its small but significant survival benefit to patients following surgical resection, but many questions about the optimal adjuvant chemotherapeutic management of pancreatic cancer still persist. Currently, the benefits of both the chemotherapeutic agents gemcitabine and 5-fluorouracil have been validated as adjuvant options, with a preference for gemcitabine emerging based on its greater tolerability. Methods to individualize the selection of an adjuvant agent based on an individual tumor's characteristics are being explored, and additional novel agents and regimens are actively being investigated. In the studies that established chemotherapy's adjuvant benefit, a controversy simultaneously developed as to the role of the concurrent use of adjuvant radiation therapy in addition to chemotherapy, leading to the development of a conflicting consensus on how to adjuvantly manage pancreatic cancer patients. Chemotherapy given concurrently with radiation therapy has emerged as the preferred adjuvant approach in the United States, whereas chemotherapy alone is preferred in Europe. In addition to the debate over modality, a separate debate of treatment timing has emerged from studies of neoadjuvant therapy, which has demonstrated a survival benefit in the management of pancreatic cancer, but has not been directly compared with postsurgical adjuvant therapy. This review discusses the evidence for chemotherapy in the adjuvant management of pancreatic cancer, including both the choice of agent and value of concurrent radiation therapy, as well as future directions with novel agents and regimens, techniques of response prediction, and timing to postsurgical adjuvant versus neoadjuvant therapy.