Why is pancreatic cancer so aggressive?

The term pancreatic cancer is synonymously used for pancreatic ductal adenocarcinoma (PDAC) - one of the most aggressive of all cancers. Accounting for >80% of pancreatic cancers, PDAC is currently the third leading cause of cancer related deaths in USA and is projected to become second leading cause by 2025. The overall 5-year survival in PDAC for localized cancer (no spread beyond pancreas) is 37%, regional cancer (spread to nearby structures or regional lymph nodes) is 12% and for metastatic cancer (spread to distant parts of body such as liver, lungs of bones) the 5-year survival is 3%.

However, PDAC is not the only type of cancer pancreas and there are several other types of cancers arising from the pancreas. In a recent study using National Cancer Database of USA, survival analysis of different histologic types of pancreatic cancers reported median overall survival of 20.2 months for PDAC. In contrast median survival for cystic mucinous neoplasms with an associated invasive carcinoma was 52.6 months while median survival was not reached for neuroendocrine tumors, with 5-year overall survival rates of 84%¹. For this reason, biological behavior of PDAC is considered to be entirely different and more aggressive in comparison to other malignant pancreatic tumors.

The biological factors responsible for this aggressive nature of PDAC are not fully understood.

This article briefly summarizes some of the proposed mechanisms responsible for aggressive nature of PDAC.

Metastasis (i.e. spread to distant organs such as liver, lung or bone) is the most common cause of death in cancer patients. This holds particularly true for PDAC because most of the patients are diagnosed late with metastasis. The factors that may be responsible for this aggressive nature of PDAC may include

·         Late diagnosis

·         Early metastasis

·         Minimally effective systemic therapy

The proposed time for progression from the initiating event that began pancreatic cancer genesis until development of the cancer clone is an average of 11.7 years. Further it takes an average of 6.8 years for development of metastatic subclones and patients dying an average of 2.7 years later. Unfortunately, most patients with PDAC are diagnosed late towards the end of this 21-year average time span, indicating that the poor prognosis may be due to late diagnosis in the natural history of the disease².

Many studies have proposed that epithelial to mesenchymal transition (EMT) contributes to early dissemination of cancer cells and plays important role in invasion and metastasis of PDAC³. Several EMT inducing transcription factors such as Snail, Twist and Zeb1 have been studied. For the sake of simplicity, the current discussion is restricted to recently proposed Zeb1 factor which controls ability of cells to migrate and survive in early embryonic development. The Zeb 1 is blocked in normal cells but its re-activation in cancer cells leads to early dissemination of cancer cells throughout the body and quick adaptation of these cancer cells to the changing conditions in their new environment.  This leads to easier dissemination of cancer cells and early development of metastases⁴.  

In summary, PDAC is associated with limited survival with current therapies and further improvement in survival is likely to come with advancements either in diagnostic modalities for early detection of cancer or effective systemic therapy i.e. chemotherapy / immunotherapy, against metastases.

References

1.       Pokrzywa CJ, Abbott DE, Matkowskyj KA et al. Natural History and Treatment Trends in Pancreatic Cancer Subtypes. J Gastrointest Surg. 2019

2.       S Yachida and CA Iacobuzio-Donahue. Evolution and dynamics of pancreatic cancer progression. Oncogene 2013

3.       Zheng X, Carstens JL, Kim J et al. EMT program is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015

4.       Krebs AM, Mitschke J, Lasierra Losada M, Schmalhofer O et al. The EMT activator ZEB1 is a key factor for cellular plasticity and promotes metastasis in pancreatic cancer. Nat Cell Biol 2017

Authors:

Dr Nitin Vashistha, MS, FIAGES, FACS

Dr Dinesh Singhal, MS, FACS, DNB (Surg Gastro)

Department of Surgical Gastroenterology,
Max Super Speciality Hospital, Saket, New Delhi, India
E mail: gi.cancer.india@gmail.com

www.gicancerindia.com