Pancreatic cancer

Pancreatic cancers can arise from either the exocrine or the endocrine parenchyma. The vast majority come from exocrine tissue and can arise from ductal epithelium, acinar cells or connective tissue. They are predominantly malignant tumours.

Neuroendocrine tumours, which behave differently to those arising from the exocrine compartment, will not be discussed further in this article.

Ductal adenocarcinomas are the most common type of pancreatic cancer, accounting for over 80% of cases, and can range from well differentiated to poorly differentiated, with different morphological variants described. Other types of pancreatic cancer include adenosquamous carcinomas and acinar cell carcinomas.

Cystic neoplasms, which may be detected incidentally on imaging, can include serous cystadenoma, intraductal papillary mucinous neoplasm and mucinous cystic neoplasm. Of these, the mucinous lesions have the potential for malignant progression.

In the UK, there are around 10,500 new cases of pancreatic cancer diagnosed each year, making it the 10th most common cancer. Most cases occur in older patients, with a mean age of onset of over 70 years. Life expectancy is poor, in part due to the fact that many diagnoses occur at a later stage.

While a small proportion of patients will have a family history of pancreatic or other cancers, only a minority of cases are linked to constitutional (germline) genetic variants. These are discussed in more detail later in this article. Other risk factors include smoking, obesity and excess alcohol consumption.

While known pancreatic cancer susceptibility syndromes only explain a small number of familial pancreatic cancer cases, for those with an affected first-degree relative the risk of developing the disease is 62%–76% higher than that of the general population.

Somatic (tumour) genetics and pancreatic cancer

The majority of cases of pancreatic cancer are caused by somatic (tumour) variants acquired during an individual’s lifetime, affecting genes that control DNA repair mechanisms or cell growth and division. Somatic variants arise in the tumour, and are not present constitutionally; this means that they are not present in the germline and cannot be passed on to offspring.

Types of somatic (tumour) variants commonly found in pancreatic tumours include:

• mutational activation of oncogenes, with KRAS variants found in over 90% of pancreatic cancers;
• inactivation of tumour suppressor genes, including TP53, CDKN2A and SMAD4; and
• inactivation of genes responsible for DNA damage repair, such as BRCA2, ATM, MLH1 and MSH2. Note that while the majority of variants occurring in DNA damage repair genes are somatic (tumour-only) in origin, a small but significant proportion of pancreatic cancer is caused by underlying constitutional (germline) pathogenic variants in a DNA repair gene.

Constitutional (germline) genetics and pancreatic cancer

A small proportion of cases of pancreatic cancer (under 10%) have an underlying inherited genetic cause. Patients with an underlying hereditary cancer predisposition may be affected at younger-than-expected ages, or may have a family history of pancreatic cancer or related cancers.

• Pathogenic variants in BRCA1, BRCA2 and PALB2 affect DNA repair.
• BRCA1 and BRCA2 variants are known to be associated with hereditary breast and ovarian cancers, but individuals with variants in these genes are also at increased risk of developing pancreatic cancer – particularly those with a BRCA2 variant. These genes are involved in homologous recombination and double-stranded DNA break repair (the PALB2 protein interacts with BRCA1 and BRCA2 proteins during DNA repair).
• ATM pathogenic variants come in many forms. Biallelic variants in ATM are associated with a rare progressive neurological condition known as ataxia telangiectasia. Individuals with heterozygous (monoallelic) variants in ATM have increased risks of certain cancers, including breast, prostate and pancreatic cancer. Breast cancer risk is greatest for those with truncating variants, or the recurrent missense variant c.7271T>G (p.Val2424Gly), but genotype-specific pancreatic cancer risk estimates have yet to be determined. Considering all variants, the relative risk of pancreatic cancer in individuals with monoallelic ATM variants has been estimated to be 4.5%–9.5%, with cumulative lifetime risk estimated to be 5%–14%.
• Peutz-Jeghers syndrome is caused by a constitutional (germline) variant in the STK11 gene. The condition is characterised by the development of benign hamartomatous polyps in the gastrointestinal tract, mucocutaneous pigmentation of the buccal and perianal mucosae and fingertips (typically evident in childhood and fading over time), and multi-organ cancer predisposition. Lifetime pancreatic cancer risk in individuals with Peutz-Jeghers is estimated to be 11%–36%.
• Lynch syndrome is caused by inactivating variants in one of the DNA mismatch repair (MMR) genes: MLH1, MSH2, MSH6, PMS2 or EPCAM. It is predominantly associated with the development of colorectal and endometrial cancers, but there is also an increased risk of other cancers, including pancreatic cancer. The cumulative incidence of pancreatic cancer is highest for individuals with MLH1-associated Lynch syndrome (at 3.3%–12.3%) when compared to Lynch syndrome caused by pathogenic variants in other MMR genes (0%–5.2%).
• Familial atypical multiple mole melanoma (FAMMM) syndrome is caused by constitutional (germline) pathogenic variants in CDKN2A or, less commonly, in CDK4. Patients with this condition are predisposed to developing atypical naevi and are at high risk of melanoma. FAMMM is associated with a risk of pancreatic cancer that is 13 to 38 times higher than that of the general population.
• Hereditary pancreatitis is most commonly associated with variants in the PRSS1 gene, although it has also been linked to variants in other genes. PRSS1-associated hereditary pancreatitis is inherited in an autosomal dominant manner, but autosomal recessive, oligogenic and polygenic forms also exist. The risk associated with underlying genetic predisposition may be further modified by environmental or lifestyle factors. Chronic inflammation, associated with hereditary pancreatitis, is a risk factor for the development of pancreatic cancer.

• In cases of metastatic pancreatic cancer that are MMR deficient or microsatellite instability high, nivolumab immunotherapy can be used as a treatment instead of chemotherapy.
• If a BRCA1 or BRCA2 variant (either constitutional (germline) or somatic (tumour)) is identified in an individual with pancreatic cancer, it may have implications for the treatment of their current cancer. At present, PARP inhibitors are not approved by NICE for treatment of BRCA-mutation-positive metastatic pancreatic cancer.
• If a constitutional (germline) variant is identified in a pancreatic cancer predisposition gene, there are implications for management of the patient’s own future cancer risk, as well as that of their relatives. For more information, see Results: Patient with pancreatic cancer and a constitutional (germline) pathogenic BRCA variant.

For clinicians

• Cancer Research UK: Pancreatic cancer statistics
• NICE: Pancreatic cancer in adults: Diagnosis and management

References:

• Ducreux M, Cuhna AS, Caramella C and others. ‘Cancer of the pancreas: ESMO clinical practice guidelines for diagnosis, treatment and follow-up’. Annals of Oncology 2015: volume 26, supplement 5, pages V56–V68. DOI: 10.1093/annonc/mdv295

For patients

• Cancer Research UK: Pancreatic cancer
• Macmillan Cancer Support: Pancreatic cancer
• Pancreatic Cancer UK: What is pancreatic cancer?