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Immunotherapy-based monotherapy treatment in metastatic pancreatic ductal adenocarcinoma (mPDAC) has shown limited benefit outside of the mismatch repair deficiency setting, while safety and efficacy of combining dual-checkpoint inhibitor immunotherapy with chemotherapy remains uncertain. Here, we present results from the CCTG PA.7 study (NCT02879318), a randomized phase II trial comparing gemcitabine and nab-paclitaxel with and without immune checkpoint inhibitors durvalumab and tremelimumab in 180 patients with mPDAC. The primary endpoint was overall survival. Secondary endpoints included progression-free survival and objective response rate. Results of the trial were negative as combination immunotherapy did not improve survival among the unselected patient population ( p  = 0.72) and toxicity was limited to elevation of lymphocytes in the combination immunotherapy group ( p  = 0.02). Exploratory baseline circulating tumor DNA (ctDNA) sequencing revealed increased survival for patients with KRAS wildtype tumors in both the combination immunotherapy ( p  = 0.001) and chemotherapy ( p  = 0.004) groups. These data support the utility of ctDNA analysis in PDAC and the prognostic value of ctDNA-based KRAS mutation status. Metastatic pancreatic ductal adenocarcinoma (mPDAC) has limited therapeutic options and is associated with a poor prognosis. Here the authors report the results of a randomized phase II trial showing that combining checkpoint inhibitors (durvalumab and tremelimumab) with chemotherapy (gemcitabine and nab-paclitaxel) does not improve survival compared to chemotherapy alone in patients with mPDAC.

Human pluripotent stem cells can be differentiated into exocrine pancreas progenitor organoids, allowing studies of development and pancreatic cancer modeling. There are few in vitro models of exocrine pancreas development and primary human pancreatic adenocarcinoma (PDAC). We establish three-dimensional culture conditions to induce the differentiation of human pluripotent stem cells into exocrine progenitor organoids that form ductal and acinar structures in culture and in vivo. Expression of mutant KRAS or TP53 in progenitor organoids induces mutation-specific phenotypes in culture and in vivo . Expression of TP53 R175H induces cytosolic SOX9 localization. In patient tumors bearing TP53 mutations, SOX9 was cytoplasmic and associated with mortality. We also define culture conditions for clonal generation of tumor organoids from freshly resected PDAC. Tumor organoids maintain the differentiation status, histoarchitecture and phenotypic heterogeneity of the primary tumor and retain patient-specific physiological changes, including hypoxia, oxygen consumption, epigenetic marks and differences in sensitivity to inhibition of the histone methyltransferase EZH2. Thus, pancreatic progenitor organoids and tumor organoids can be used to model PDAC and for drug screening to identify precision therapy strategies.

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/m 2 ) 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/m 2 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. G-quadruplex stabilizers, including CX-5461, exhibit synthetic lethality with loss of BRCA1/2 in preclinical models. Here the authors report the results of a phase I study of CX-5461 in patients with solid tumors enriched for DNA-repair deficiencies.

The CCTG PA.7 study was a randomized phase II trial comparing chemotherapy with and without dual immune checkpoint inhibition in patients with metastatic pancreatic ductal adenocarcinoma (mPDAC). In follow-up to the published primary results of the trial, the analysis herein focused on long-term survival and exploratory analysis.Plasma sequencing analysis identified concurrent mutations in DNA damage repair genes BRCA1, POLE, ATM and FANCA in 18/173 (10.40%) of patients, and presence of two or more mutations in these genes was associated with overall survival benefit for patients receiving immunotherapy (median overall survival 26.2 vs. 9.7 months; hazard ratio, 0.34; 95% CI, 0.16–0.68; p = 0.001; interaction p = 0.003). Partial response was observed in 7/11 (63.64%) patients with concurrent DNA damage repair gene mutations in the immunotherapy arm. As a prospective study in PDAC identifying a potential biomarker beyond mismatch repair deficiency for benefit from immunotherapy, these data highlight an actionable subgroup of mPDAC. The CCTG PA.7 randomized phase II trial compared chemotherapy with and without dual immune checkpoint inhibition in patients with metastatic pancreatic ductal adenocarcinoma. Here, the authors report long-term survival and exploratory analysis of the CCTG PA.7 trial, identifying a pattern of mutations linked to improved immunotherapy response.

Over a decade of sequencing-based genomics research has unveiled a diverse somatic mutation landscape across patients with pancreatic ductal adenocarcinoma (PDAC), and the identification of druggable mutations has aligned with the development of novel targeted therapeutics. However, despite these advances, direct translation of years of PDAC genomics research into the clinical care of patients remains a critical and unmet need. Technologies that enabled the initial mapping of the PDAC mutation landscape, namely whole-genome and transcriptome sequencing, remain overly expensive in terms of both time and financial resources. Consequentially, dependence on these technologies to identify the relatively small subset of patients with actionable PDAC alterations has greatly impeded enrollment for clinical trials testing novel targeted therapies. Liquid biopsy tumor profiling using circulating tumor DNA (ctDNA) generates new opportunities by overcoming these challenges while further addressing issues particularly relevant to PDAC, namely, difficulty of obtaining tumor tissue via fine-needle biopsy and the need for faster turnaround time due to rapid disease progression. Meanwhile, ctDNA-based approaches for tracking disease kinetics with respect to surgical and therapeutic interventions offer a means to elevate the current clinical management of PDAC toward higher granularity and accuracy. This review provides a clinically focused summary of ctDNA advances, limitations, and opportunities in PDAC and postulates ctDNA sequencing technology as a catalyst for evolving the clinical decision-making paradigm of this disease.

Background Programmed cell death 1 (PD1) inhibitors have recently shown promising anti-cancer effects in a number of solid tumor types. A predictive biomarker to this class of drugs has not been clearly identified; however, overexpression of the PD1 ligand (PD-L1) has shown particular promise in lung adenocarcinoma. In this study, we explore the staining characteristics, prevalence, and clinico-molecular correlates of PD-L1 overexpression in pancreatic ductal adenocarcinoma (PDAC). Methods A tissue microarray (TMA) was constructed from cases of resected PDAC. PD-L1 immunohistochemistry (IHC) was performed using the SP142 primary antibody. Immunohistochemical assessment for deficient mismatch repair status (MMRd), CD3 and CD8 were performed. All biomarkers were assessed independently by two anatomical pathologists and consensus achieved on all cases. Survival analysis was performed using three thresholds (> = 1%, >5% and >10%) for tumor cell membrane staining. Results Two-hundred fifty-two cases were included in the TMA and evaluable by IHC. Thirty-one (12%), 17 (7%), 12(5%) cases were positive at percentage cut offs of >0, >5, and >10% respectively. Increased PD-L1 expression was associated with inferior prognosis ( p  = 0.0367). No statistically significant association was identified between PD-L1 status and MMR status or tumor infiltrating lymphocytes. Conclusions This data suggests that there is an inverse relationship between PD-L1 expression and disease specific survival times in resected PDAC. Consequently, this association may represent a phenotype where increased PD-L1 expression has an effect on tumor biology and could therefore identify a subgroup where PD1 blockade could have enhanced effectiveness.

Comparing the outcomes from Lanreotide and Octreotide LAR in a subset of digestive system cancers using a British Columbia Cohort: This study looked at how two medications—Octreotide LAR and Lanreotide—are used to treat people with neuroendocrine tumors (NETs) in the small bowel and pancreas in British Columbia, Canada. These drugs help slow the growth of tumors, but no direct comparisons have been made between them in clinical trials. Using healthcare records, this study compared how often each drug was used, how well they worked, and how often doses were increased or switched. Lanreotide was more often used in more aggressive tumors and was linked to longer survival. Dose increases were similar between the two drugs, but fewer patients needed extra short-acting medication with Lanreotide. Most switches between medications were due to side effects.

Deficiencies in DNA mismatch repair have been associated with inferior response to 5-FU in colorectal cancer. Pancreatic ductal adenocarcinoma is similarly treated with pyrimidine analogs, yet the predictive value of mismatch repair status for response to these agents has not been examined in this malignancy. A tissue microarray with associated clinical outcome, comprising 254 resected pancreatic ductal adenocarcinoma patients was stained for four mismatch repair proteins (MLH1, MSH2, MSH6 and PMS2). Mismatch repair deficiency and proficiency was determined by the absence or presence of uniform nuclear staining in tumor cells, respectively. Cases identified as mismatch repair deficient on the tissue microarray were confirmed by immunohistochemistry on whole slide sections. Of the 265 cases, 78 (29%) received adjuvant treatment with a pyrimidine analog and 41 (15%) showed a mismatch repair-deficient immunoprofile. Multivariable disease-specific survival in the mismatch repair-proficient cohort demonstrated that adjuvant chemotherapy, regional lymph-node status, gender, and the presence of tumor budding were significant independent prognostic variables ( P ≤0.04); however, none of the eight clinico-pathologic covariates examined in the mismatch repair-deficient cohort were of independent prognostic significance. Univariable assessment of disease-specific survival revealed an almost identical survival profile for both treated and untreated patients with a mismatch repair-deficient profile, while treatment in the mismatch repair-proficient cohort conferred a greater than 10-month median disease-specific survival advantage over their untreated counterparts ( P =0.0018). In this cohort, adjuvant chemotherapy with a pyrimidine analog conferred no survival advantage to mismatch repair-deficient pancreatic ductal adenocarcinoma patients. Mismatch repair immunoprofiling is a feasible predictive marker in pancreatic ductal adenocarcinoma patients, and further prospective evaluation of this finding is warranted.

Background The impact of palliative resection of the primary tumor on outcomes in patients with metastatic colorectal cancer (mCRC) remains unclear. The primary objective of this study was to evaluate the association between palliative resection and overall survival (OS) in a population-based cohort of mCRC. Methods Patients diagnosed with mCRC between 2006 and 2008 and treated at the BC Cancer Agency were reviewed. Survival analysis was conducted using Kaplan–Meier methods. Cox proportional hazards regression models were fitted to evaluate the relationship between palliative resection and OS while controlling for potential confounders, such as age, gender, Eastern Cooperative Oncology Group status, carcinoembryonic antigen level, primary tumor location, metastatic site and number, and receipt of systemic therapy. To adjust for the heterogeneity and selection bias between the group that underwent palliative resection and the group that did not, a propensity score–matched analysis was also performed. Results A total of 517 patients were included. Among these cases, 378 (73 %) patients underwent palliative resection of their primary tumor, and 139 (27 %) patients did not. A total of 327 patients (63 %) were treated with palliative chemotherapy. Palliative resection was associated with a longer median OS (17.9 vs. 7.9 months) and more favorable unadjusted and adjusted hazard ratios (HRs) for death (HR 0.46, 95 % CI 0.37–0.56, p  < 0.0001 and HR 0.56, 95 % CI 0.40–0.78, p  = 0.0007, respectively) when compared with no resection. In a propensity score–matched analysis, prognosis was also more favorable in the resected group ( p  = 0.0017). Conclusions In this cohort of mCRC patients, palliative resection of the primary tumor was associated with improved OS.

There is emerging evidence about the predictive role of homologous recombination deficiency (HRD), but this is less defined in gastrointestinal (GI) and thoracic malignancies. We reviewed whole genome (WGS) and transcriptomic (RNA-Seq) data from advanced GI and thoracic cancers in the Personalized OncoGenomics trial (NCT02155621) to evaluate HRD scores and single base substitution (SBS)3, which is associated with BRCA1/2 mutations and potentially predictive of defective HRD. HRD scores were calculated by sum of loss of heterozygosity, telomeric allelic imbalance, and large-scale state transitions scores. Regression analyses examined the association between HRD and time to progression on platinum (TTPp). We included 223 patients with GI ( n  = 154) or thoracic ( n  = 69) malignancies. TTPp was associated with SBS3 ( p  < 0.01) but not HRD score in patients with GI malignancies, whereas neither was associated with TTPp in thoracic malignancies. Tumors with g BRCA1/2 mutations and a somatic second alteration exhibited high SBS3 and HRD scores, but these signatures were also present in several tumors with germline but no somatic second alterations, suggesting silencing of the wild-type allele or BRCA1/2 haploinsufficiency. Biallelic inactivation of an HR gene, including loss of XRCC2 and BARD1 , was identified in BRCA1/2 wild-type HRD tumors and these patients had prolonged response to platinum. Thoracic cases with high HRD score were associated with high RECQL5 expression ( p  ≤ 0.025), indicating another potential mechanism of HRD. SBS3 was more strongly associated with TTPp in patients with GI malignancies and may be complementary to using HRD and BRCA status in identifying patients who benefit from platinum therapy.