Long-term Survivors Of Pancreatic Cancer Research Articles

A Somatic BRCA2-Mutated Pancreatic Adenocarcinoma With Sustained Exceptional Response to Modified FOLFIRINOX.

Homologous recombination repair (HRR) pathway deficiency opens multiple therapeutic avenues within pancreatic cancer. Patients with HRR deficiency-associated gene mutations such as BRCA1, BRCA2, and PALB2 are more susceptible to platinum-based chemotherapies and in those with somatic BRCA mutations, PARP inhibitor therapy prolongs progression-free survival. The case discussed herein illustrates the therapeutic opportunities offered through the identification of HRR deficiency in pancreatic cancer, as well as the challenges associated with treatment and prevention of central nervous system metastases in long-term survivors of pancreatic cancer.

Quality of Life and Gastrointestinal Symptoms in Long-term Survivors of Pancreatic Cancer Following Pancreatoduodenectomy.

To describe long-term quality of life (QOL) and gastrointestinal (GI) symptoms in patients who underwent pancreatoduodenectomy for pancreatic cancer in the modern era. As advances in pancreatic cancer management improve outcomes, it is essential to assess long-term patient-reported outcomes after surgery. Patients who underwent curative intent pancreatoduodenectomy for pancreatic cancer between January 2011 and June 2019 from a single center were identified. Patients alive ≥3 years after surgery were considered long-term survivors (LTS). LTS who were alive in June 2022 received a 55-question survey to assess their QOL (EORTC-QLQ-C30) and GI symptoms (EORTC-PAN26 and Problem Areas in Diabetes Questionnaire). Responses were compared against population norms. Clinicodemographic characteristics in LTS versus non-LTS and survey completion were compared. Six hundred seventy-two patients underwent pancreatoduodenectomy for pancreatic cancer; 340 were LTS. One hundred thirty-seven patients of the 238 eligible to complete the survey responded (response rate: 58%). Compared to the US general population, LTS reported significantly higher QOL (75 vs 64; P <0.001), less nausea/vomiting, pain, dyspnea, insomnia, appetite loss, and constipation, but more diarrhea (all P <0.001). Most patients (n=136/137, 99%) reported experiencing postoperative GI symptoms related to pancreatic insufficiency (n=71/135, 53%), reflux (n=61/135, 45%), and delayed gastric emptying (n=31/136, 23%). Most patients (n=113/136, 83%) reported that digestive symptoms overall had little to no impact on QOL, and 91% (n=124/136) would undergo surgery again. Despite known long-term complications following pancreatoduodenectomy, cancer survivors appear to have excellent QOL. Specific long-term gastrointestinal symptoms data should be utilized for preoperative education and follow-up planning.

Outcomes of surgical resection for pulmonary metastasis from pancreatic cancer.

As the number of long-term survivors of pancreatic cancer is expected to increase thanks to recent advances in multidisciplinary treatment and earlier diagnoses of pancreatic cancer, we are likely to encounter more cases of postoperative pulmonary nodules. We analyzed the clinical course and prognosis of resection of pulmonary metastases from pancreatic cancer to clarify the prognostic implication of pulmonary metastasectomy for pancreatic cancer. We retrospectively analyzed 35 patients who underwent resection of lung metastases after pancreatic cancer surgery. Short- and long-term outcomes and factors associated with the prognosis were analyzed. The observation period was 20 (range, 1-101)months, with 3- and 5-year survival rates of 88.3% and 64.5% from pancreatectomy and 44.1% and 28.3% from lung resection, respectively. A univariate analysis revealed that a period from pancreatic cancer resection to pulmonary nodule shadow detection of < 15months was associated with a significantly lower overall survival from pancreatic resection than a longer period. Conversely, histological type, stage, size of lung metastases, and resection technique were not associated with the overall survival. A long-term prognosis may be expected in some cases with a disease-free interval of ≥ 15months. Our findings suggest that the disease-free interval may influence the prognosis.

P-94 Overview of clinicopathological and prognostic factors for long-term survivors of pancreatic cancer from a multicenter study of 532 patients

P-94 Overview of clinicopathological and prognostic factors for long-term survivors of pancreatic cancer from a multicenter study of 532 patients

Percutaneous transsplenic venous embolization of elevated jejunal varices after pancreaticoduodenectomy: A case report

Recent advances in chemotherapy and radiotherapy have led to an increase in the number of long-term survivors of pancreatic cancer. However, this has also increased the number of patients suffering from ectopic varices and bleeding owing to left-sided portal hypertension and thrombocytopenia caused by splenomegaly after pancreaticoduodenectomy combined with resection of the splenic vein. A 65-year-old woman with varices of the elevated jejunum due to left sided portal hypertension after pancreaticoduodenectomy had repeated melena, which started about 1 year before admission. We describe the first reported case of percutaneous transsplenic venous embolization using metallic coils, which successfully achieved hemostasis of refractory bleeding from the elevated jejunal varices after pancreaticoduodenectomy.

Quality of life and gastrointestinal symptoms in long-term survivors of pancreatic cancer

Background: As advances in the management of pancreatic cancer result in improve outcomes, it is essential to assess the quality of life (QOL) and gastrointestinal (GI) symptoms for the growing number of long-term survivors.

Immunoediting Removes High-Quality Neoantigens in Pancreatic Cancer.

Recurrent tumors in long-term survivors of pancreatic cancer have less high-quality neoantigens.

Neoantigen quality predicts immunoediting in survivors of pancreatic cancer.

Cancer immunoediting1 is a hallmark of cancer2 that predicts that lymphocytes kill more immunogenic cancer cells to cause less immunogenic clones to dominate a population. Although proven in mice1,3, whether immunoediting occurs naturally in human cancers remains unclear. Here, to address this, we investigate how 70 human pancreatic cancers evolved over 10 years. We find that, despite having more time to accumulate mutations, rare long-term survivors of pancreatic cancer who have stronger T cell activity in primary tumours develop genetically less heterogeneous recurrent tumours with fewer immunogenic mutations (neoantigens). To quantify whether immunoediting underlies these observations, we infer that a neoantigen is immunogenic (high-quality) by two features—‘non-selfness’ based on neoantigen similarity to known antigens4,5, and ‘selfness’ based on the antigenic distance required for a neoantigen to differentially bind to the MHC or activate a T cell compared with its wild-type peptide. Using these features, we estimate cancer clone fitness as the aggregate cost of T cells recognizing high-quality neoantigens offset by gains from oncogenic mutations. With this model, we predict the clonal evolution of tumours to reveal that long-term survivors of pancreatic cancer develop recurrent tumours with fewer high-quality neoantigens. Thus, we submit evidence that that the human immune system naturally edits neoantigens. Furthermore, we present a model to predict how immune pressure induces cancer cell populations to evolve over time. More broadly, our results argue that the immune system fundamentally surveils host genetic changes to suppress cancer.

Longitudinal Changes in Body Composition of Long-Term Survivors of Pancreatic Head Cancer and Factors Affecting the Changes.

Previous studies on changes in body composition of pancreatic cancer patients have only focused on short-term survivors. We studied longitudinal body composition changes and factors affecting them in long-term survivors by analyzing many abdominal computed tomography images using artificial intelligence technology. Of 302 patients who survived for >36 months after surgery were analyzed. Multivariate logistic regression analysis for factors affecting body composition changes and repeated-measures analysis of variance to observe differences in the course of change according to each factor were performed. In logistic analysis, preoperative sarcopenia and recurrence were the main factors influencing body composition changes at 1 and 3 years after surgery, respectively. In changes of longitudinal body composition, the decrease in body composition was the greatest at 3–6 months postoperatively, and the preoperative status did not recover even 3 years after surgery. Especially, males showed a greater reduction in skeletal muscle (SKM) after surgery than females (p < 0.01). In addition, SKM (p < 0.001) and subcutaneous adipose tissue (p < 0.05) mass rapidly decreased in case of recurrence. In conclusion, long-term survivors of pancreatic cancer did not recover their preoperative body composition status, and preoperative sarcopenia and recurrence influenced body composition changes.

P-106 Descriptive study of long-term survivors with advanced pancreatic cancer

Advanced pancreatic cancer (PC) has a grim prognosis, with a 5-year survival rate less than 5%. Long-term survivors with advanced PC are not defined and the literature on the subject is scarce and based mainly in isolated clinical cases. In the post-hoc analysis of the MPACT study, 4% of patients treated with gemcitabine plus nab-paclitaxel (GNP) lived more than 3 years (1). In the PRODIGE study, 18.6% of patients had a survival over 18 months (2). A surgical series describes 2% of survivors > 5 years (3). We present characteristics of long-term survivors of PC, as well as tumor characteristics, treatments, and results obtained. This observational and descriptive study of patients with advanced PC in the province of Huelva, in the period between 2012 and 2020, considered long-term survivors (> 2.5 years). Statistical analysis was performed using the IBM SPSS Statistics 22 program. 8 patients were selected, 7 metastatic and 1 locally advanced. 75% males, median age 64 years. 87.5% with ECOG 1 were not diabetic and had not previously presented hepatitis or pancreatitis. 62.5% smoked and 25% had excessive alcohol consumption. No patient had a family history of cancer. 87.5% were diagnosed in stage IV and 12.5 in stage III. Histological grade 2 in 87.5%, and vascular-lymphatic invasion in 50%. 75% were located in the body and body/tail. At diagnosis, 37.5% had elevated lactate dehydrogenase (LDH) and 12.5% had decreased albumin levels. 50% showed elevation of Ca 19.9 and the neutrophil-lymphocyte ratio (NLR) was higher than 3 in 37.5%. 50% of patients had ≥ 2 affected organs (12.5% > 3 organs). 37.5% liver metastases, 12.5%, peritoneal metastases, 50% lung metastases, 50% lymph node metastases. A biliary stent was placed in 25%. No patient had thrombosis during the course of the disease. 50% of patients underwent surgery and received neoadjuvant/adjuvant therapies. 62.5% received radiotherapy. 62.5% patients received first-line GNP treatment. 37.5% patients showed a complete response (CR) and 50% a partial response (PR) as the best response (BR) to the first-line treatment. The median progression-free survival (PFS1) was 15.5 months (95% CI; 13.7 - 17.2). 62.5% received GNP in the second-line treatment, as a new regimen or retreatment. The BR to the second-line treatment: 37.5% PR. The median progression-free survival (PFS2) was 5.29 months (95% CI; 1.15 - 9.42). 62.5% of the patients received third-line treatment. 37.5% capecitabine-oxaliplatin, 12.5% irinotecan and 12.5% GNP. The BR to the third-line: 25% PR and 37.5% stable disease (SD). The median overall survival (OS) was 40.5 months (95% CI; 38.53 - 42.48). 3 patients are still alive with a median follow-up of 31.4 months. We highlight in our series the unusual evolution with a median OS greater than 3 years, as well as the high percentage of complete responses and the high efficiency with retreatments. We must investigate the molecular characteristics to explain these results. We believe it is the first European series of patients with long-term survivors of PC with promising results including only advanced disease.

Immunomodulation in Pancreatic Cancer

Simple SummaryPancreatic cancer is an aggressive disease that has few options for treatment. Immune checkpoint blockers have been revolutionary in specific cancer types yet have not shown promise in pancreatic cancers. This review discusses components of the immune system needed for successful anti-tumor responses against pancreatic cancer and how these mechanisms can be exploited to develop new therapeutic strategies.Pancreatic cancer has a high mortality rate, and its incidence is increasing worldwide. The almost universal poor prognosis of pancreatic cancer is partly due to symptoms presenting only at late stages and limited effective treatments. Recently, immune checkpoint blockade inhibitors have drastically improved patient survival in metastatic and advanced settings in certain cancers. Unfortunately, these therapies are ineffective in pancreatic cancer. However, tumor biopsies from long-term survivors of pancreatic cancer are more likely to be infiltrated by cytotoxic T-cells and certain species of bacteria that activate T-cells. These observations suggest that T-cell activation is essential for anti-tumor immunity in pancreatic cancers. This review discusses the immunological mechanisms responsible for effective anti-tumor immunity and how immune-based strategies can be exploited to develop new pancreatic cancer treatments.

Abstract IA31: Measuring the emergence of non-self in tumors

Abstract Molecules generated by mutational and epigenetic processes in tumors have been associated with recognition of tumors by the innate and adaptive immune system. For example, neoantigens have been implicated in response to checkpoint blockade therapies. Likewise, the display of pathogen-associated patterns by nucleic acids unsilenced by epigenetic alterations have been implicated in activation of the innate immune system. Here we determine molecular features which place a tumor at a selective advantage or disadvantage, and how these selective pressures depend on the tumor’s environment. We have proposed general frameworks to address these questions. In the case of tumor neoantigens, we present a fitness model of candidate immunogenic neoantigens distributed across a tumor’s subclonal structure in a given microenvironment. We show how our approach can be used to characterize response to checkpoint-blockade therapies and apply it to the general problem of immune-driven tumor evolution in a unique cohort of long-term survivors of pancreatic cancer. In the case of immunostimulatory RNA, we proposed a method of calculating entropic forces for determining the likelihood of tumoral RNA being recognized as pathogen-associated and characterizing classes of pathogen mimicry. Citation Format: Marta Luksza, Alexander Solovyov, Nicolas Vabret, Vinod Balachandran, Nadeem Riaz, Vladimir Makarov, Matthew D. Hellmann , Alexandra Snyder, Samuel Funt, Romain Remark, Miriam Merad, Sacha Gnjatic, Dean F. Bajorin, Jonathan Rosenberg, Steven Leach, Arnold J. Levine, Timothy A. Chan, Nina Bhardwaj, Jedd Wolchock, Benjamin D. Greenbaum. Measuring the emergence of non-self in tumors [abstract]. In: Proceedings of the Fourth CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; Sept 30-Oct 3, 2018; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2019;7(2 Suppl):Abstract nr IA31.

Long-Term Survivors of Pancreatic Cancer: A California Population-Based Study.

Pancreatic cancer continues to carry a poor prognosis with survival rates that have had minimal improvement over the past 4 decades. We report a population-based, comprehensive analysis of long-term survivors of pancreatic adenocarcinoma diagnosed in the diverse population of California. Data from the California Cancer Registry were used to evaluate long-term survival. A total of 70,442 patients diagnosed with pancreatic adenocarcinoma between 1988 and 2009 were identified. Logistic regression was used to identify factors associated with achieving 5-year survival. The overall 5-year survival was 2.5%, with minimal incremental improvements throughout the 3 decades. Age, stage, degree of differentiation, and surgical resection were associated with 5-year survival. Furthermore, younger age and receiving care at a National Cancer Institute-designated cancer center were similarly correlated with 5-year survival regardless of surgical intervention. In addition, we identified stage, differentiation, and adjuvant chemotherapy as significant factors for long-term survival in surgically resected patients. In the unresectable patients, Asian/Pacific islanders and Hispanics were significantly more likely to reach the 5-year milestone than non-Hispanic whites. Although pancreatic cancer mortality remains high, our study highlights baseline characteristics, treatment, biological factors, and ethnicity that are associated with long-term survival. These findings may serve as a springboard for further investigation.

Identification of unique neoantigen qualities in long-term survivors of pancreatic cancer.

Pancreatic ductal adenocarcinoma is a lethal cancer with fewer than 7% of patients surviving past 5 years. T-cell immunity has been linked to the exceptional outcome of the few long-term survivors, yet the relevant antigens remain unknown. Here we use genetic, immunohistochemical and transcriptional immunoprofiling, computational biophysics, and functional assays to identify T-cell antigens in long-term survivors of pancreatic cancer. Using whole-exome sequencing and in silico neoantigen prediction, we found that tumours with both the highest neoantigen number and the most abundant CD8+ T-cell infiltrates, but neither alone, stratified patients with the longest survival. Investigating the specific neoantigen qualities promoting T-cell activation in long-term survivors, we discovered that these individuals were enriched in neoantigen qualities defined by a fitness model, and neoantigens in the tumour antigen MUC16 (also known as CA125). A neoantigen quality fitness model conferring greater immunogenicity to neoantigens with differential presentation and homology to infectious disease-derived peptides identified long-term survivors in two independent datasets, whereas a neoantigen quantity model ascribing greater immunogenicity to increasing neoantigen number alone did not. We detected intratumoural and lasting circulating T-cell reactivity to both high-quality and MUC16 neoantigens in long-term survivors of pancreatic cancer, including clones with specificity to both high-quality neoantigens and predicted cross-reactive microbial epitopes, consistent with neoantigen molecular mimicry. Notably, we observed selective loss of high-quality and MUC16 neoantigenic clones on metastatic progression, suggesting neoantigen immunoediting. Our results identify neoantigens with unique qualities as T-cell targets in pancreatic ductal adenocarcinoma. More broadly, we identify neoantigen quality as a biomarker for immunogenic tumours that may guide the application of immunotherapies.

Morbidity among long-term survivors after pancreatoduodenectomy for pancreatic adenocarcinoma.

Because pancreatoduodenectomy for pancreatic adenocarcinoma is focused on disease-free and overall survival, morbidity among long-term survivors is not well described. This study sought to evaluate outcomes for long-term survivors of pancreatic cancer after pancreatoduodenectomy. The authors identified 29 patients from their prospectively collected database of patients with pancreatic adenocarcinoma who had undergone pancreatoduodenectomy and were without evidence of disease during at least 3 years of follow-up evaluation. Demographics, treatment, and pathologic characteristics were collected for review. Data with regard to long-term sequelae also were collected, focusing on those complications requiring additional procedures and on the development of metachronous cancers. The median follow-up period was 83 months, with 62 % of patients still alive. All patients received an R0 resection, and 34 % of the patients had N1 disease. For 42 % of the patients, no significant subsequent sequelae occurred. In the four remaining patients (14 %), ascites developed, requiring repeated paracentesis or Denver shunt, with a median time to development (MTD) of 63 months. Six patients (21 %) experienced a biliary stricture requiring stent placement (MTD, 56 months). One patient experienced portal venous thrombosis requiring a venous stent (MTD, 52 months), and four patients (14 %) experienced clinically significant ulcers (MTD, 52 months). With regard to metachronous cancers, two patients experienced subsequent lymphomas (MTD, 92 months). Long-term survivors among patients who undergo pancreatoduodenectomy for pancreatic adenocarcinoma can experience significant late sequelae, which often manifest more than 3 years after surgery. As such, continued follow-up evaluation and counseling are warranted.

Morbidity in long-term survivors after pancreatoduodenectomy for pancreatic adenocarcinoma.

307 Background: Because the focus of pancreatoduodenectomy for pancreatic adenocarcinoma is placed on disease-free and overall survival, morbidity in long-term survivors is not well described. We sought to evaluate outcomes of long-term survivors of pancreatic cancer after pancreatoduodenectomy. Methods: We identified 30 patients from our prospectively collected database of patients with pancreatic adenocarcinoma who had undergone pancreatoduodenectomy, and who were without evidence of disease with at least 40 months of follow-up. Demographics, treatment and pathologic characteristics were collected for review. Data with regards to long-term sequelae were also collected, particularly those complications requiring additional procedures and the development of metachronous cancers. Results: The median length of follow up was 83 months, with 60% of patients still alive. Half the patients were male, and the median age at diagnosis was 70 years. With regard to treatment, 80% of patients received chemoradiation, with half of these patients receiving it in the neoadjuvant setting. All patients received an R0 resection, although two patients required at least partial resection of the superior mesenteric or portal veins. Thirty-three percent of patients had N1 disease. Forty-four percent of patients did not have any significant subsequent sequelae. In the remainder, four patients (13%) developed ascites requiring repeated paracentesis or Denver shunt, with median time to development (MTD) of 63 months. Six patients (20%) developed a biliary stricture requiring stent placement (MTD 56 months), one patient developed portal venous thrombosis requiring a venous stent (MTD 52 months), and 3 patients (10%) experienced clinically significant gastric anastomotic ulcers (MTD 47 months). With regards to metachronous cancers, 2 patients developed subsequent lymphomas (MTD 92 months). Conclusions: Long-term survivors of patients who undergo pancreatoduodenectomy for pancreatic adenocarcinoma can develop significant late sequelae, which often can manifest more than three to five years after surgery. Continued follow-up and counseling is warranted.

Defective DNA Mismatch Repair in Long-Term (≥3 Years) Survivors with Pancreatic Cancer

Background/Aims: Defective DNA mismatch repair (MMR) in pancreatic cancer, reported in up to 13% of sporadic pancreatic cancers, may predict a good prognosis. To determine if long-term survival in pancreatic cancer could be attributed to defective DNA MMR, we ascertained its prevalence in 35 pancreatic cancer patients who survived ≧3 years after surgery. Methods: We performed immunohistochemistry (IHC) for MMR proteins hMLH1, hMSH2, and hMSH6 in all 35 tumors and microsatellite instability (MSI) studies in 34/35 tumors using 10 microsatellite markers in paired normal and tumor DNA. Defective DNA MMR was defined as absence of protein expression on IHC and/or MSI in ≧30% of markers studied. Results: On IHC, 3/35 (8.6%) tumors had defective DNA MMR. All 3 had absent expression of a DNA MMR protein (hMLH1 in 2 and hMSH2) and 2/3 also had MSI; the third could not be tested. Definitely 2, and probably all 3 patients had hereditary nonpolyposis colon cancer as determined by clinical and genetic profiles. Conclusion: Defective DNA MMR is uncommon in long-term survivors of pancreatic cancer and does not account for the survival benefit in those with sporadic pancreatic cancer.

PANCREATIC CANCER: The Bigger Picture

Despite accurate diagnosis, better radiologic techniques, and safer surgery, long-term survival after surgical therapy for pancreatic cancer is disappointing. Median survival following pancreaticoduodenal resection is 12 to 15 months independent of surgical expertise, hospital size, or technical factors. Subsets of favorable tumors and longer survival times after surgery have been defined and include: small tumor size and low-grade lesions, tumor-free margins, and absence of nodal, venous, or perineural invasion; however, long-term survivors of pancreatic cancer may have none of these favorable features, and their tumors commonly manifest the most adverse tumor prognostic features. The converse that small-sized, histologically favorable tumors result in long-term survivors, also is not true. Five-year survival rates average 5% or less after all resections. In a large series in which 118 pancreatic resections were performed in 684 evaluated patients over a 6-year period, there were 12 5-year survivors, 5 of whom died in the sixth year. A report of 10-year survivors after surgery numbered 13 patients. The best actual 5-year survival rate was reported by Trede et al. Of the 37, 5-year survivors from a cohort of 118 patients, more than half died of cancer. This far exceeds any other actual survival rate and may be explained by a smaller tumor size. Farnell et al reported a 5-year survival rate difference (i.e., actuarial survival) in a subset of 174 resected patients with adenocarcinoma without perineural or duodenal invasion and with negative nodes (23% versus 6.8%), respectively. An impressive, large series of 616 patients with resected adenocarcinoma of the pancreas who underwent PDR (85%), distal pancreatectomy (9%), and total pancreatectomy (6%), has been reported. The mortality rate was 2.1%, and postoperative complications occurred in 30%. The five-year survival rate was 15%. The author's best result was observed among 20 initially "unresectable" patients who were treated with chemoradiation therapy, followed by tumor extirpation. Among the 18 surgical survivors there are seven five-year survivors, three of whom are in their tenth year of survival. They are discussed in the article by Cooperman et al ("Long-term Follow-up...") elsewhere in this issue.