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Inclusion of rare exocrine tumor patients on clinical studies of pancreatic cancer. Study registrations on clinicaltrials.gov over the last two years (from 8/2020 through 8/2022) were searched for those that were interventional, enrolled adults, and included the term pancreas cancer, resulting in identification of 425 records. Eliminating those specific for PNET, carcinoid syndrome or endocrine tumors resulted in 405 entries. 267 of these were specific for pancreas cancer and did not include other tumor types. After exclusion of those evaluating screening regimens, diagnostic procedures (imaging, molecular profiling), interventional procedures (endoscopy, surgery, anesthesia), and psychological, dietary, or lifestyle modification, 214 studies testing medical interventions were identified. The percentage of clinical studies specific for pancreas cancer that allow only PDAC patients versus any exocrine pancreatic cancer patient are depicted.
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Pancreatic cancer is an aggressive malignancy with increasing incidence. Pancreatic ductal adenocarcinoma (PDAC) accounts for > 90% of pancreatic cancer diagnoses, while other exocrine tumors are much rarer. In this review, we have focused on two rare cancers of the exocrine pancreas: adenosquamous carcinoma of the pancreas (ASCP) and pancreatic ac...
Citations
... Pancreatic ductal adenocarcinoma (PDAC) represents almost 90% of all pancreatic cancers (Skorupan et al., 2023). Pancreatic cancer is among the top three leading causes of cancerrelated deaths in both sexes in the USA (Siegel et al., 2023), with almost the same number of new cases and deaths reported annually. ...
Pancreatic ductal adenocarcinoma (PDAC) is poised to be a leading cause of cancer-related deaths. Despite developing new treatment strategies, patient outcomes have not significantly improved. Chemoresistance has been implicated as a major contributor to ineffective treatments observed with studies suggesting combination therapy targeting multiple pathways. This study explored dysregulated genes in tumours of PDAC patients to identify targets which could be used effectively in combination with conventional therapy against cancer cells.
In this study, PCR arrays were used for gene expression profiling of tumours obtained from South African PDAC patients to identify key differentially expressed pathways and potentially new therapeutic target genes. SPP1 was selected and RNA interference was used to knock the gene down. Migration and apoptosis assays were used to evaluate the effect of the knockdown, alone and in combination with gemcitabine, on a pancreatic cancer cell line, MIA PaCa-2. Proteomic analysis using SWATH-MS was used to demonstrate potential molecular mechanisms linked to the morphological and phenotypical effects observed with treatment.
We demonstrated several genes linked to the growth factor and signal transduction signalling pathways, and identified SPP1 as a target. We observed that by combining SPP1 knockdown with conventional chemotherapy, gemcitabine, resulted in a synergistic effect, leading to an enhanced early apoptotic response. A decline of migratory and invasive capabilities of MIA PaCa-2 cells was observed upon subjecting the cancer cells to SPP1 reduction and gemcitabine treatment. Furthermore, proteomic analyses uncovered several pathways that were dysregulated by the combination therapy including both pro-and anti-tumorigenic ones.
The study findings indicate that SPP1 could be a potential therapeutic target for PDAC, and the possible synergistic effects observed when SPP1 knockdown was combined with gemcitabine treatment suggest a potential avenue for developing more effective treatments for PDAC while exploring tumour cell adaptation for survival.
... In their nature, these factors align rare cancers more closely with other oncological conditions than with rare genetic disorders. Moreover, for many rare cancers, treatment alternatives often overlap with those available for common cancer types [67,68]. However, the OD price tags, often higher than innovative non-orphan products, distinguish significantly rare cancers [44,69]. ...
Simple Summary
In this study, we investigate the availability and access to orphan drugs for rare cancers in Bulgaria, aiming to address the urgent need for improved treatment access for this vulnerable population. By comparing data from European and national sources, we aimed to assess the availability, delays, and budgetary impact of these drugs. Our findings reveal significant disparities in their access and highlight the pressing need for targeted policies to address these inequalities. This research contributes valuable insights into the challenges faced by rare cancer patients and we call for focused efforts at both the European and national levels to ensure equitable access to treatment.
Abstract
Rare cancers are defined by an annual incidence of fewer than 6 per 100,000. Bearing similarities to rare diseases, they are associated with substantial health inequalities due to diagnostic complexity and delayed access to innovative therapies. This situation is further aggravated in Southeastern European countries like Bulgaria, where limited public resources and expertise underscore the need for additional policy and translational research on rare cancers. This study aimed to explore the availability and access to orphan drugs for rare cancers in Bulgaria for the period of 2020–2023. We cross-compared data from both the European Union and national public sources to evaluate the number of available and accessible orphan drugs for rare cancers, the delay from market authorization to reimbursement, the dynamics of public expenditures, and regional disparities in access across the country. We juxtaposed the main characteristics of oncological and non-oncological orphan drugs as well. Only 15 out of 50 oncological orphan drugs that were authorized by the European Medicine Agency were accessible for rare cancer patients in Bulgaria. The median delay between market authorization and inclusion in the Bulgarian Positive Drug List was 760 days. The total expenditures for all orphan drugs for rare cancers amounted to EUR 74,353,493 from 2020 to 2023. The budgetary impact of this group rose from 0.24% to 3.77% of total public medicinal product expenditures for the study period. Rare cancer patients represent a vulnerable population that often faces limited to no access to treatment. We call for targeted European and national policies to address this major inequality.
... Unlike the more common pancreatic ductal adenocarcinoma, PACC is characterized by its unique histopathological features, predominantly composed of acinar cells that closely resemble normal pancreatic acinar tissue. [4] Despite its infrequency, PACC poses significant diagnostic and therapeutic challenges due to its ability to mimic other pancreatic neoplasms both clinically and radiologically. The distinct molecular and genetic alterations underlying PACC further differentiate it from other pancreatic tumours [5], highlighting the need for a comprehensive understanding of its pathogenesis for the development of targeted therapeutic strategies. ...
Pancreatic cancer accounts for less than 5% of all cancers. And the rarest type of them all is the pancreatic acinar cell carcinoma accounting for less than 0.05% of all cancers. Acinar cell carcinomas are highly aggressive neoplasms, with a median DFS (Disease Free State) for patients with localized disease and metastatic disease of 47 and 14 months, respectively, and an overall 5-year survival rate ranging from 36.2% to 72.8% in surgically resected individuals. A 21-year old man presented with non-specific symptoms like progressive abdominal pain, weight loss, nausea and vomiting, melena, weakness, anorexia. Patient was a smoker and consumed moderate amounts of alcohol. There was no family history of gastrointestinal disease. Examinations including enhanced abdominal and pelvic CT scans, chest X-ray, abdominal ultrasound, tumour markers, liver and renal function and coagulation function were performed. With the imaging, the differential diagnosis could be well-differentiated pancreatic endocrine neoplasms, solid pseudopapillary neoplasms, mixed acinar neoplasms and pancreatoblastomas. He was referred to surgical oncology for tumour resection. The following day, a modified laparoscopic Whipple (pylorus preserving pancreaticoduodenectomy) was performed. The reason being, aggressive surgical resection with negative margins is associated with long-term survival. Negative margins were obtained in the pancreatectomy specimen. Post operative histological analysis revealed abundant material with cells depicting varying degrees of acinar differentiation and lack ductal and endocrine cells. The aspirates contained mostly cohesive fragments forming acini, cellular cords or solid nests of neoplastic epithelium. The neoplastic cells did not show the compact, orderly lobular “bunch of grapes” arrangement of normal epithelium.
... Owing to the rarity of PACC, data regarding PACC-specific treatment outcomes is limited. Because the standard treatment of unresectable PACC has not been established, systemic chemotherapy for PACC is derived from the treatment of PDAC, including FFX and GEM plus nab-paclitaxel combination therapy (GnP) (11,12,100,(117)(118)(119). In previous studies on patients with advanced PACC, GEM-containing regimens have shown poorer treatment outcomes than fluoropyrimidine-containing regimens (11,12,118). ...
... OS tended to be better in patients who received a platinumcontaining or irinotecan-containing regimen than in patients who did not (11). PACC generally responds favourably to FFX, and some patients achieve a complete response (57,116,(119)(120)(121)(122). ...
Pancreatic acinar cell carcinoma is a rare form (0.2–4.3%) of pancreatic neoplasm with unique clinical and molecular characteristics, which largely differ from pancreatic ductal adenocarcinoma. Pancreatic acinar cell carcinoma occurs more frequently in males and can occur in children. Serum lipase is elevated in 24–58% of patients with pancreatic acinar cell carcinoma. Pancreatic acinar cell carcinomas tend to be large at diagnosis (median tumour size: ~5 cm) and are frequently located in the pancreas head. Radiologically, pancreatic acinar cell carcinoma generally exhibits a solid appearance; however, necrosis, cystic changes and intratumoral haemorrhage can occur in larger lesions. Immunostaining is essential for the definitive diagnosis of pancreatic acinar cell carcinoma. Compared with pancreatic ductal adenocarcinoma, pancreatic acinar cell carcinoma has a more favourable prognosis. Although radical surgery is recommended for patients with pancreatic acinar cell carcinoma who do not have distant metastases, the recurrence rate is high. The effectiveness of adjuvant therapy for pancreatic acinar cell carcinoma is unclear. The response to FOLFIRINOX is generally favourable, and some patients achieve a complete response. Pancreatic acinar cell carcinoma has a different genomic profile compared with pancreatic ductal adenocarcinoma. Although genomic analyses have shown that pancreatic acinar cell carcinoma rarely has KRAS, TP53 and CDKN2A mutations, it has a higher prevalence of homologous recombination-related genes, including BRCA1/2 and ATM, than pancreatic ductal adenocarcinoma, suggesting high sensitivity to platinum-containing regimens and PARP inhibitors. Targeted therapies for genomic alternations are beneficial. Therefore, genetic testing is important for patients with pancreatic acinar cell carcinoma to choose the optimal therapeutic strategy.
... Pancreatic acinar cell carcinoma (PACC) represents just 0.2-2% of all pancreatic malignancies in adults and is generally characterized as having a better prognosis [88,89]. Randomized trials are missing, though it seems that FOLFIRINOX might be the preferred first-line regimen [90][91][92][93]. ...
... Molecular testing for all PACC patients for somatic mutations should be considered as these occur at higher incidences and are frequently actionable. Further, a higher rate of MSI-H/dMMR has been described in PACC [88]. ...
... Adenosquamous carcinoma of the pancreas (ASCP) comprises 0.38-10% of exocrine pancreatic cancers [88,94,95] and is considered more aggressive than PDAC. According to the limited retrospective studies, there is no preferred regimen in a first-line setting, and both FOLFIRINOX and gemcitabine/nab-paclitaxel have shown efficacy [88,96,97]. ...
Pancreatic cancer (PDAC) is one of the most aggressive solid tumors and is showing increasing incidence. The aim of our review is to provide practical help for all clinical oncologists and to summarize the current management of PDAC using a simple “ABC method” (A—anatomical resectability, B—biological resectability and C—clinical conditions). For anatomically resectable PDAC without any high-risk factors (biological or conditional), the actual standard of care is represented by surgery followed by adjuvant chemotherapy. The remaining PDAC patients should all be treated with initial systemic therapy, though the intent for each is different: for borderline resectable patients, the intent is neoadjuvant; for locally advanced patients, the intent is conversion; and for metastatic PDAC patients, the intent remains just palliative. The actual standard of care in first-line therapy is represented by two regimens: FOLFIRINOX and gemcitabine/nab-paclitaxel. Recently, NALIRIFOX showed positive results over gemcitabine/nab-paclitaxel. There are limited data for maintenance therapy after first-line treatment, though 5-FU or FOLFIRI after initial FOLFIRINOX, and gemcitabine, after initial gemcitabine/nab-paclitaxel, might be considered. We also dedicate space to special rare conditions, such as PDAC with germline BRCA mutations, pancreatic acinar cell carcinoma and adenosquamous carcinoma of the pancreas, with few clinically relevant remarks.
Pancreatic acinar cell carcinoma (PACC) is a rare cancer with no specific treatment. The treatment and chemotherapy for PACC are selected according to pancreatic ductal adenocarcinoma (PDAC). Herein, we describe a recurrent PACC case of an older adult patient. The patient was treated with systemic chemotherapy, chemoradiotherapy, and maintenance therapy based on the pathologic germline BRCA2 variant, resulting in long-term survival. The pathogenic BRCA variant is detected more frequently in patients with PACC than in those with PDAC. The BRCA variant significantly impacts treatment selection and prognosis; therefore, early genomic analysis is recommended when treating PACC.
