Virtual Care for Patients with Advanced Well Differentiated Gastroenteropancreatic Neuroendocrine Tumor (GEP-NET).

INTRODUCTION: The COVID-19 pandemic resulted in an unprecedent shift towards virtual cancer care, including the care of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). The aim of this study was to evaluate the use of virtual care for GEP-NETs during the COVID-19 pandemic at a high-volume academic cancer center. METHODS: This retrospective, observational study performed at the Ottawa Hospital Cancer Center in Canada evaluated adult patients with GEP-NETs seen in consultation by medical oncology between 1 June 2019 and 31 December 2022. Demographic, clinicopathologic, cancer treatment and visit data were collected. Univariable and multivariable analyses assessed the relationship between patient characteristics and virtual care use. RESULTS: A total of 103 patients with well-differentiated GEP-NETS were included. Overall, 18/103 (17.5%) consults and 594/781 (76.1%) follow-ups were performed virtually. All consultation visits returned to in-person assessment by 2022, while 67.0% and 41.4% follow-ups remained virtual in 2022 and 2023, respectively. The year of follow-up, sex, employment and Charlston comorbidity index were associated with virtual follow-up use in the multivariable analysis. DISCUSSION: Virtual care remained a predominant method of GEP-NET patient assessment in the peri-pandemic period. These results highlight an opportunity to improve access to subspecialty neuroendocrine cancer care through the continued use of virtual care.

Transverse Colon Primary Tumor Location as a Biomarker in Metastatic Colorectal Cancer: A Pooled Analysis of CCTG/AGITG CO.17 and CO.20 Randomized Clinical Trials.

PURPOSE: Sidedness is prognostic and predictive of anti-EGFR efficacy in metastatic colorectal cancer (mCRC). Transverse colon has been historically excluded from several analyses of sidedness and the optimal division between left- and right-sided colorectal cancer is unclear. We investigated transverse colon primary tumor location as a biomarker in mCRC. EXPERIMENTAL DESIGN: Pooled analysis of CCTG/AGITG CO.17 and CO.20 trials of cetuximab in chemotherapy-refractory mCRC. Outcomes of patients with RAS/BRAF wild-type (WT) mCRC from CO.17 and KRAS WT mCRC from CO.20 were analyzed according to location. RESULTS: A total of 553 patients were analyzed, 32 (5.8%) with cancers from the transverse, 101 (18.3%) from right, and 420 from (75.9%) left colon. Transverse mCRC failed to reach significant benefit from cetuximab versus best supportive care (BSC) for overall survival [OS; median, 5.9 vs. 2.1 months; HR, 0.63; 95% confidence interval (CI), 0.28-1.42; P=0.26] and progression-free survival (PFS; median, 1.8 vs. 1.3 months; HR, 0.57; 95% CI, 0.26-1.28; P=0.16). Analyzing exclusively patients randomized to cetuximab, right-sided and transverse had comparable outcomes for OS (median, 5.6 vs. 5.9 months; HR, 0.82; 95% CI, 0.50-1.34; P=0.43) and PFS (median, 1.9 vs. 1.8 months; HR, 0.78; 95% CI, 0.49-1.26; P=0.31). Patients with left-sided mCRC had superior outcomes with cetuximab compared with transverse for OS (median, 9.7 vs. 5.9 months; HR, 0.42; 95% CI, 0.27-0.67; P=0.0002) and PFS (median, 3.8 vs. 1.8 months; HR, 0,49; 95% CI, 0.31-0.76; P=0.001). Location was not prognostic in patients treated with BSC alone. CONCLUSIONS: Transverse mCRC has comparable prognostic and predictive features with right-sided mCRC.

Rural versus urban outcomes following transcatheter aortic valve implantation: The importance of the heart team.

BACKGROUND: Rural patients face known healthcare disparities and worse cardiovascular outcomes compared to urban residents due to inequitable access and delayed care. Few studies have assessed rural-urban differences in outcomes following Transcatheter Aortic Valve Implantation (TAVI). We compared short-term post-TAVI outcomes between rural and urban patients. METHODS: We performed a retrospective analysis of n = 413 patients who underwent TAVI at our large academic medical center, between 2011 and 2020 (rural/urban patients = 93/320. Rural/urban males = 53/173). Primary outcomes were all-cause mortality and cardiovascular mortality. Secondary outcomes included stroke/transient ischemic attack, myocardial infarction, atrial fibrillation, acute kidney injury, bleeding, vascular complications, and length of stay. RESULTS: The mean age in years was 77 [IQR 70-82] for rural patients and 78 [IQR 72-84] for urban patients. Baseline characteristics were similar between groups, except for a greater frequency of active smokers and diabetics as well as a greater body mass index in the rural group. There were no statistically significant differences in all-cause or cardiovascular mortality between the groups. There was also no statistically significant difference in secondary outcomes. CONCLUSION: Rural and urban patients had no statistically significant difference in all-cause mortality or cardiovascular mortality following TAVI. Given its minimally invasive nature and quality-centric, multidisciplinary care provided by the TAVI Heart Teams, TAVI may be the preferred modality for the treatment of severe aortic stenosis in rural populations.

Eastern Canadian Gastrointestinal Cancer Consensus Conference 2023.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2023 was held in Quebec City, Quebec 2-4 February 2023. The purpose of the conference was to develop consensus statements on emerging and evolving treatment paradigms. Participants included Canadian medical oncologists, radiation oncologists, pathologists and surgical oncologists from across Ontario, Quebec, and the Atlantic provinces. Consensus statements were developed following rapid review presentations and discussion of available literature. The recommendations proposed here represent the consensus opinions of physicians involved in the care of patients with gastrointestinal malignancies who participated in this meeting.

A Practical Guide for the Systemic Treatment of Biliary Tract Cancer in Canada.

Biliary tract cancers (BTC) are rare and aggressive tumors with poor prognosis. Radical surgery offers the best chance for cure; however, most patients present with unresectable disease, and among those receiving curative-intent surgery, recurrence rates remain high. While other locoregional therapies for unresectable disease may be considered, only select patients may be eligible. Consequently, systemic therapy plays a significant role in the treatment of BTC. In the adjuvant setting, capecitabine is recommended following curative-intent resection. In the neoadjuvant setting, systemic therapy has mostly been explored for downstaging in borderline resectable tumours, although evidence for its routine use is lacking. For advanced unresectable or metastatic disease, gemcitabine-cisplatin plus durvalumab has become the standard of care, while the addition of pembrolizumab to gemcitabine-cisplatin has also recently demonstrated improved survival compared to chemotherapy alone. Following progression on gemcitabine-cisplatin, several chemotherapy combinations and biomarker-driven targeted agents have been explored. However, the optimum regimen remains unclear, and access to targeted agents remains challenging in Canada. Overall, this article serves as a practical guide for the systemic treatment of BTC in Canada, providing valuable insights into the current and future treatment landscape for this challenging disease.

Small Bowel Neuroendocrine Tumors-10-Year Experience of the Ottawa Hospital (TOH).

(1) Aim: The prevalence and incidence of small bowel NETs have increased significantly over the past two decades. This study aims to report the 10-year experience of SB-NET management at a regional cancer center in Canada. (2) Materials and methods: We conducted a retrospective study of the clinical and pathological data of patients diagnosed with biopsy-proven SB-NET at The Ottawa Hospital (TOH), Ottawa, Canada between 2011 and 2021. We report the clinicopathological characteristics of these patients, as well as their outcomes data, including survival rates. (3) Results: Between 2011 and 2021, a total of 177 SB-NET cases were identified with 51% (n = 91) of cases being males. The most common sites of the tumors were the ileum 53% (n = 94), followed by the duodenum 9% (n = 16) and jejunum 7% (n = 12). Approximately 24% (n = 42) of the patients had symptoms for over six months prior to diagnosis and 18% (n = 32) had functioning SB-NET during the course of the disease. The majority of patients had locally advanced or metastatic disease at the time of presentation with stage III, and stage IV representing 42% (n = 75), and 41% (n = 73) respectively. The majority of patients 84% (n = 148) had well-differentiated histology. One hundred twenty patients underwent surgical resection of the primary tumor including 28 patients (16%) with limited metastatic disease. A total of 21 patients (18%) had recurrence after curative surgery. A total of 62 patients (35%) received first-line somatostatin analog (SSA) therapy for unresectable disease and seven patients had PRRT after progression on SSA. Five years OS was 100%, 91%, 97%, and 73% for stages I, II, III, and IV respectively. In univariate analysis, carcinoid symptoms, T stage, and differentiation were significant predictors for worse overall survival, but not RFS. (4) Conclusions: Compared to published historical controls, our study suggests improvement in the 5-year survival rate of SB-NETs over the last 10 years.

Adjuvant Chemotherapy and Radiotherapy in Resected Pancreatic Ductal Adenocarcinoma: A Systematic Review and Clinical Practice Guideline.

Pancreatic cancer is the seventh leading cause of cancer deaths worldwide, accounting for 4.7% of all cancer deaths, and is expected to climb significantly over the next decade. The purpose of this systematic review and guidance document was to synthesize the evidence surrounding the role of adjuvant treatment (chemotherapy and chemoradiation therapy [CRT], and stereotactic body radiation therapy [SBRT]) in resected pancreatic ductal adenocarcinoma (PDAC). Systematic literature searches of MEDLINE, EMBASE, and 11 guideline databases were conducted. Both direct and indirect comparisons indicate adjuvant chemotherapy offers a survival advantage over surgery alone. The optimal regimens recommended are mFOLFIRINOX with alternative options of gemcitabine plus capecitabine, gemcitabine alone, or S-1 (which is not available in North America). Trials comparing a CRT strategy to modern chemotherapy regimens are lacking. However, current evidence demonstrates that the addition of CRT to chemotherapy does not result in a survival advantage over chemotherapy alone and is therefore not recommended. Trials evaluating SBRT in PDAC are also lacking. SBRT should only be used within a clinical trial or multi-institutional registry.

Real world use of lanreotide in neuroendocrine tumors.

Background: Treatment for metastatic neuroendocrine tumors (NETs) is often with somatostatin analogues (SSA) such as lanreotide in the first-line setting. Real world use of lanreotide in Canada is not well studied. Methods: We performed a retrospective chart review of 69 patients to study real world use of lanreotide at our centre. Results: Lanreotide was the first-line of systemic treatment in 60 patients. Watch-and-wait was a common strategy and was seen in 31 patients. SSA switch strategy was seldom applied. Majority of patients on lanreotide had low-grade NETs. Standard starting dose of lanreotide 120 mg every 28 days was used in 66 patients. Dose escalation to 120 mg every 21 days occurred in 7 patients. The primary intention for treatment was tumor control in 32 patients, and both tumor and symptom control in 34 patients. Median time on treatment was 21.6 months. Conclusions: Overall, our findings were in keeping with current guidelines. It will be interesting to assess how clinical practice evolves in the future and to determine the role of dose escalation for disease control.

Zanidatamab, a novel bispecific antibody, for the treatment of locally advanced or metastatic HER2-expressing or HER2-amplified cancers: a phase 1, dose-escalation and expansion study.

BACKGROUND: HER2-targeted therapies have substantially improved outcomes for patients with HER2-positive breast and gastric or gastro-oesophageal junction cancers. Several other cancers exhibit HER2 expression or amplification, suggesting that HER2-targeted agents can have broader therapeutic impact. Zanidatamab is a humanised, bispecific monoclonal antibody directed against two non-overlapping domains of HER2. The aim of this study was to evaluate the safety and anti-tumour activity of zanidatamab across a range of solid tumours with HER2 expression or amplification. METHODS: This first-in-human, multicentre, phase 1, dose-escalation and expansion trial included patients aged 18 years and older, with a life expectancy of at least 3 months, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and locally advanced or metastatic, HER2-expressing or HER2-amplified solid tumours of any kind who had received all available approved therapies. The primary objectives of part 1 were to identify the maximum tolerated dose, optimal biological dose, or recommended dose of zanidatamab; all patients were included in the primary analyses. Part 1 followed a 3 + 3 dose-escalation design, including different intravenous doses (from 5 mg/kg to 30 mg/kg) and intervals (every 1, 2, or 3 weeks). The primary objective of part 2 was to evaluate the safety and tolerability of zanidatamab monotherapy in solid tumours. This trial is registered with ClinicalTrials.gov (NCT02892123), and parts 1 and 2 of the trial are complete. Part 3 of the study evaluates the use of zanidatamab in combination with chemotherapy and is ongoing. FINDINGS: Recruitment took place between Sept 1, 2016, and March 13, 2021. In Part 1 (n=46), no dose-limiting toxicities were detected and the maximum tolerated dose was not reached. The recommended dose for part 2 (n=22 for biliary tract cancer; n=28 for colorectal cancer; and n=36 for other HER2-expressing or HER2-amplified cancers excluding breast or gastro-oesophageal cancers; total n=86) was 20 mg/kg every 2 weeks. The most frequent treatment-related adverse events in part 1 of the study were diarrhoea (24 [52%] of 46 patients; all grade 1-2) and infusion reactions (20 [43%] of 46 patients; all grade 1-2). The most frequent treatment-related adverse events in part 2 of the study were diarrhoea (37 [43%] of 86 patients; all grade 1-2 except for one patient) and infusion reactions (29 [34%] of 86 patients; all grade 1-2). A total of six grade 3 treatment-related adverse events were reported in four (3%) of 132 patients. In part 2, 31 (37%; 95% CI 27·0-48·7) of 83 evaluable patients had a confirmed objective response. There were no treatment-related deaths. INTERPRETATION: These results support that HER2 is an actionable target in various cancer histologies, including biliary tract cancer and colorectal cancer. Evaluation of zanidatamab continues in ongoing studies. FUNDING: Zymeworks.

Integrative analysis of KRAS wildtype metastatic pancreatic ductal adenocarcinoma reveals mutation and expression-based similarities to cholangiocarcinoma.

Oncogenic KRAS mutations are absent in approximately 10% of patients with metastatic pancreatic ductal adenocarcinoma (mPDAC) and may represent a subgroup of mPDAC with therapeutic options beyond standard-of-care cytotoxic chemotherapy. While distinct gene fusions have been implicated in KRAS wildtype mPDAC, information regarding other types of mutations remain limited, and gene expression patterns associated with KRAS wildtype mPDAC have not been reported. Here, we leverage sequencing data from the PanGen trial to perform comprehensive characterization of the molecular landscape of KRAS wildtype mPDAC and reveal increased frequency of chr1q amplification encompassing transcription factors PROX1 and NR5A2. By leveraging data from colorectal adenocarcinoma and cholangiocarcinoma samples, we highlight similarities between cholangiocarcinoma and KRAS wildtype mPDAC involving both mutation and expression-based signatures and validate these findings using an independent dataset. These data further establish KRAS wildtype mPDAC as a unique molecular entity, with therapeutic opportunities extending beyond gene fusion events.

Asymptomatic Aorto-Atrial Fistula Secondary to Surgical Repair of Ascending Aortic Dissection: When to Do Nothing.

Secondary aorto-atrial fistula is a rare but potentially life-threatening complication of ascending aortic dissection surgical repair. Secondary aorto-atrial fistulas commonly lead to symptomatic heart failure requiring emergent repair. We present a rare case of secondary aorto-atrial fistula after surgical repair of aortic dissection that remained asymptomatic for a decade. (Level of Difficulty: Intermediate.).

Tumor Biomarker Testing for Metastatic Colorectal Cancer: a Canadian Consensus Practice Guideline.

The systemic therapy management of metastatic colorectal cancer (mCRC) has evolved from primarily cytotoxic chemotherapies to now include targeted agents given alone or in combination with chemotherapy, and immune checkpoint inhibitors. A better understanding of the pathogenesis and molecular drivers of colorectal cancer not only aided the development of novel targeted therapies but led to the discovery of tumor mutations which act as predictive biomarkers for therapeutic response. Mutational status of the KRAS gene became the first genomic biomarker to be established as part of standard of care molecular testing, where KRAS mutations within exons 2, 3, and 4 predict a lack of response to anti- epidermal growth factor receptor therapies. Since then, several other biomarkers have become relevant to inform mCRC treatment; however, there are no published Canadian guidelines which reflect the current standards for biomarker testing. This guideline was developed by a pan-Canadian advisory group to provide contemporary, evidence-based recommendations on the minimum acceptable standards for biomarker testing in mCRC, and to describe additional biomarkers for consideration.

Takotsubo Cardiomyopathy Secondary to Cryptococcal Meningoencephalitis in a Patient With Multiple Sclerosis.

Takotsubo or stress-induced cardiomyopathy is described as reversible left ventricular dysfunction that develops following a stressful emotional or physical event primarily occurring in postmenopausal females. Many physiologic triggers have been identified in the pathogenesis of Takotsubo cardiomyopathy, including diseases which affect the central nervous system such as traumatic brain injuries, hemorrhagic and ischemic strokes, epilepsy, and central nervous system infections, including meningitis and encephalitis; however, there are very few published case reports of Takotsubo cardiomyopathy in the setting of fungal meningoencephalitis. We present a unique case of Takotsubo cardiomyopathy secondary to Cryptococcus neoformans meningoencephalitis in a middle-aged female with a history of multiple sclerosis who was taking immunosuppressive therapy.

Results of the phase I CCTG IND.231 trial of CX-5461 in patients with advanced solid tumors enriched for DNA-repair deficiencies.

CX-5461 is a G-quadruplex stabilizer that exhibits synthetic lethality in homologous recombination-deficient models. In this multicentre phase I trial in patients with solid tumors, 40 patients are treated across 10 dose levels (50-650 mg/m2) to determine the recommended phase II dose (primary outcome), and evaluate safety, tolerability, pharmacokinetics (secondary outcomes). Defective homologous recombination is explored as a predictive biomarker of response. CX-5461 is generally well tolerated, with a recommended phase II dose of 475 mg/m2 days 1, 8 and 15 every 4 weeks, and dose limiting phototoxicity. Responses are observed in 14% of patients, primarily in patients with defective homologous recombination. Reversion mutations in PALB2 and BRCA2 are detected on progression following initial response in germline carriers, confirming the underlying synthetic lethal mechanism. In vitro characterization of UV sensitization shows this toxicity is related to the CX-5461 chemotype, independent of G-quadruplex synthetic lethality. These results establish clinical proof-of-concept for this G-quadruplex stabilizer. Clinicaltrials.gov NCT02719977.

A phase II trial of GSK2256098 and trametinib in patients with advanced pancreatic ductal adenocarcinoma.

Background: Mitogen-activated protein kinase kinase (MEK) is activated by mutated KRAS in >90% of pancreatic ductal adenocarcinoma (PDAC). MEK and focal adhesion kinase (FAK) are frequently co-activated in PDAC providing a rationale for combining trametinib, an oral allosteric MEK1/2 inhibitor, with GSK2256098, an oral FAK inhibitor. Methods: Advanced PDAC patients whose disease progressed after first line palliative chemotherapy were treated with GSK2256098 250 mg twice daily and trametinib 0.5 mg once daily orally. The primary endpoint was clinical benefit (CB; complete response, partial response, or stable disease ≥24 weeks). Twenty-four patients were planned to enroll using a 2-stage minimax design (P0=0.15, P1=0.40; alpha =0.05, power 0.86). The combination would be considered inactive if 2/12 or fewer patients achieved CB at the end of stage 1, and would be considered active if >7/24 response-evaluable patients achieved CB by the end of stage 2. Serial blood samples were collected for circulating tumor DNA (ctDNA) mutation profiling. Results: Sixteen patients were enrolled and 11 were response evaluable. Of those 11, 10 had progressive disease as best tumor response and one had stable disease for 4 months. No treatment related grade ≥3 adverse events (AEs) were observed. The median progression free survival (PFS) was 1.6 (95% CI: 1.5-1.8) months and the median overall survival (OS) was 3.6 (95% CI: 2.7-not reached) months. One response-inevaluable patient achieved clinical stability for 5 months with reduction in CA19-9 and ctDNA levels with a MAP2K1 treatment resistance mutation detected in ctDNA at clinical progression. Conclusions: The combination of GSK2256098 and trametinib was well tolerated but was not active in unselected advanced PDAC.

Oral magnesium supplements for cancer treatment-induced hypomagnesemia: Results from a pilot randomized trial.

BACKGROUND AND AIMS: Optimal management of cancer treatment-induced hypomagnesemia (hMg) is not known. We assessed the feasibility of using a novel pragmatic clinical trials model to compare two commonly used oral Mg replacement strategies. METHODS: Patients with grade 1 to 3 hMg while receiving either platinum-based chemotherapy or epidermal growth factor receptor inhibitors (EGFRI) were randomized to oral magnesium oxide (MgOx) or oral magnesium citrate (MgCit). The trial methodology utilized the integrated consent model. Feasibility would be successful if; accrual rate was ≥5 patients a month and if measures of patient and physician engagement, were > 50%. Secondary endpoints included; comparison of Mg levels, cardiac arrhythmias, and rates of treatment delay/hospitalizations. RESULTS: From July 2016 to December 2017, an average of 1 patient a month was accrued. All 15 eligible and approached patients consented to participate in the study (100% engagement) and 7/15 were randomized to MgOx and 8/15 to MgCit. The percentage of physicians who approached patients for the study was 4 of 6 (66.6% engagement). The mean slope of change in Mg (mmol/L/day) was 0.0022 (95% CI: -0.0001 to 0.0044) for MgOx and 0.0006 (95% CI, -0.0012 to 0.0024) for MgCit (P = .2123). Three patients (20%) required IV magnesium while on the study (2 MgCit and 1 MgOx). Grade 1 diarrhea occurred in 3 patients in the MgCit arm. CONCLUSION: Despite oral magnesium tolerability and meeting most of its feasibility endpoints, this study did not meet its target accrual rate. Alternative designs would be necessary for a definitive efficacy study.

Avoidance of ST-Segment-Elevation Myocardial Infarction Treatment for >1 Week Due to COVID-19 Fears.

During the coronavirus disease 2019 (COVID-19) pandemic, social distancing guidelines have negatively affected the care-seeking behavior of patients with chronic medical conditions, including those with cardiovascular disease. We report the case of a 60-year-old man with vague gastrointestinal symptoms who waited more than 1 week to seek treatment for fear of COVID-19 infection. On presentation at another hospital, he was found to have had an anterior myocardial infarction, and he underwent percutaneous coronary intervention to stent an occluded proximal left anterior descending coronary artery. Subsequently, the patient experienced refractory cardiogenic shock and, during his transfer to our hospital, refractory ventricular tachycardia, which ultimately proved fatal.

Eastern Canadian Gastrointestinal Cancer Consensus Conference 2019.

The annual Eastern Canadian Gastrointestinal Cancer Consensus Conference 2019 was held in Morell, Prince Edward Island, 19-21 September 2019. Experts in medical oncology, radiation oncology, and surgical oncology who are involved in the management of patients with gastrointestinal malignancies participated in presentations and discussion sessions for the purpose of developing the recommendations presented here. This consensus statement addresses multiple topics in the management of anal, colorectal, biliary tract, and gastric cancers, including: radiotherapy and systemic therapy for localized and advanced anal cancer; watch and wait strategy for the management of rectal cancer; role of testing for dihydropyrimidine dehydrogenase (DPD) deficiency prior to commencement of fluoropyrimidine therapy; radiotherapy and systemic therapy in the adjuvant and unresectable settings for biliary tract cancer; and radiotherapy and systemic therapy in the perioperative setting for early-stage gastric cancer.

BRCA mutated pancreatic cancer: A change is coming.

Pancreatic cancer remains a leading cause of cancer-related death with few available therapies for advanced disease. Recently, patients with germline BRCA mutations have received increased attention due to advances in the management of BRCA mutated ovarian and breast tumors. Germline BRCA mutations significantly increase risk of developing pancreatic cancer and can be found in up to 8% of patients with sporadic pancreatic cancer. In patients with germline BRCA mutations, platinum-based chemotherapies and poly (ADP-ribose) polymerase inhibitors are effective treatment options which may offer survival benefits. This review will focus on the molecular biology, epidemiology, and management of BRCA-mutated pancreatic cancer. Furthermore, we will discuss future directions for this area of research and promising active areas of research.

Subtype-Discordant Pancreatic Ductal Adenocarcinoma Tumors Show Intermediate Clinical and Molecular Characteristics.

PURPOSE: RNA-sequencing-based subtyping of pancreatic ductal adenocarcinoma (PDAC) has been reported by multiple research groups, each using different methodologies and patient cohorts. "Classical" and "basal-like" PDAC subtypes are associated with survival differences, with basal-like tumors associated with worse prognosis. We amalgamated various PDAC subtyping tools to evaluate the potential of such tools to be reliable in clinical practice. EXPERIMENTAL DESIGN: Sequencing data for 574 PDAC tumors was obtained from prospective trials and retrospective public databases. Six published PDAC subtyping strategies (Moffitt regression tools, clustering-based Moffitt, Collisson, Bailey, and Karasinska subtypes) were used on each sample, and results were tested for subtype call consistency and association with survival. RESULTS: Basal-like and classical subtype calls were concordant in 88% of patient samples, and survival outcomes were significantly different (P < 0.05) between prognostic subtypes. Twelve percent of tumors had subtype-discordant calls across the different methods, showing intermediate survival in univariate and multivariate survival analyses. Transcriptional profiles compatible with that of a hybrid subtype signature were observed for subtype-discordant tumors, in which classical and basal-like genes were concomitantly expressed. Subtype-discordant tumors showed intermediate molecular characteristics, including subtyping gene expression (P < 0.0001) and mutant KRAS allelic imbalance (P < 0.001). CONCLUSIONS: Nearly 1 in 6 patients with PDAC have tumors that fail to reliably fall into the classical or basal-like PDAC subtype categories, based on two regression tools aimed toward clinical practice. Rather, these patient tumors show intermediate prognostic and molecular traits. We propose close consideration of the non-binary nature of PDAC subtypes for future incorporation of subtyping into clinical practice.