引领胰腺癌的革命

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胰腺癌是第4位th leading cause of cancer death in western countries and the 7th 全球癌症死亡的主要原因, largely due to the complexities in its biology and management.1,2,3 It also has one of the worst survival rates of all ‘common’ cancers, with only 9% of patients with advanced (metastatic) disease surviving more than five years after diagnosis.4 Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer (accounting for 85% of cases)5, compared with pancreatic neuroendocrine tumours (PNETs) which are far less common and account for around 4% of cases.6

PDAC是最具侵袭性的癌症之一.7  Due to the diversity of genetic mutations and dense connective tissue that forms the pancreas, PDAC is also one of the most chemo-resistant and radio-resistant type of cancer.1,8 PDAC has an extremely poor prognosis with only ~20% of patients surviving one-year at all stages of the disease.9 The causes of pancreatic cancer are still not well understood, 尽管某些危险因素，比如吸烟, diabetes, obesity and chronic pancreatitis have been identified.2

多亏了专门的科学研究, there have been positive developments to better manage this high morbidity cancer. To understand why pancreatic cancer presents such an intricate and complex challenge, we must first understand the crucial role that the pancreas plays in regulating bodily functions.  

胰腺——给身体带来平衡

扩大信息图表

The pancreas itself is a gland organ located in the abdomen near the liver. The pancreas plays a dual role in regulating bodily functions10,11:

  • 内分泌系统——胰腺分泌激素, including the blood sugar-regulating hormones insulin and glucagon, 直接进入血液
  • Exocrine system – the pancreas secretes enzymes into the digestive tract through a duct into the duodenum, which is responsible for breaking down food and absorbing nutrients.

胰腺肿瘤

Pancreatic cancer is classified into two main tumour types – depending on whether the tumour forms in the exocrine cells, 或者内分泌细胞. 

PNETs, 俗称“胰岛细胞肿瘤”, are a rare type of cancer that form in the endocrine cells.12 PNETs have a better prognosis, compared to more common types of cancer.10

Exocrine tumours account for 96% of pancreatic cancers 最常见的是PDAC.5,13 PDAC develops from the cells which line the ducts in the pancreas. 这些导管输送消化液, 包含酶, into the main pancreatic duct and then into the first part of the small intestine.9

As this disease has the potential to spread quickly and symptoms often do not present until the disease is at an advanced stage, more than 50% of pancreatic cancer patients are diagnosed when the disease has already spread to other organs in the body – for these patients the average survival is less 不到一年.5,14

There are multiple reasons for the potentially quick spread of this disease, including the close proximity of major blood vessels in the pancreas, 哪些容易被癌细胞入侵.15 因为PDAC症状是非特异性的, 诊断是非常有挑战性的, 这大大降低了存活的几率. 这导致PDAC被称为“沉默的杀手.’16

扩大信息图表

A limited treatment landscape highlights urgent unmet need

从历史上看, patients with advanced pancreatic cancer have faced poor outcomes due to the aggressive nature of the disease and limited treatment advancements compared to other tumour types, particularly lagging behind other common cancers with regards to precision therapy.2,4,17,18

Only approximately 20% of patients with advanced disease are eligible for surgery, due to the metastatic (advanced) stage of their cancer at the time of diagnosis, while treatment options including chemotherapy and radiotherapy are often limited.19,20 The high burden of symptoms in advanced pancreatic cancer presents further challenges, as symptoms can interfere with treatment efficacy and quality of life.21

Pancreatic cancer – is it possible this difficult disease could be biomarker-driven?

We have already come a long way in understanding what biomarker status means for cancers such as breast, prostate, ovarian, 肺和胃, 举几个例子. 随着基因组分析技术的出现, 选择性分子靶向治疗, biomarkers have now been shown to play an increasingly important role in the clinical management of pancreatic cancer patients.22

In PDAC, some tumour suppressor genes (which actively prevent the formation of cancer) are commonly mutated resulting in aggressive tumour growth.23 这些基因, 包括BRCA1/2, PRSS1和CDKN2A, are just some of the predictive biomarkers for metastatic pancreatic cancer, and have uses far beyond diagnosis; they may also be used to predict potential treatment outcomes and help identify familial risk of developing PDAC.5,24

Targeted cancer therapies are drugs that interfere with specific molecules involved in cancer cell growth and survival. 了解靶向治疗是如何起作用的, it’s important to understand the mechanisms of cancer cells.25

The BRCA1/2 genes form part of the DNA damage response (DDR), or a process through which various pathways work to repair DNA damage. 当BRCA基因发生突变时, 阻碍DDR修复进程, 患癌症的风险也会增加.26 Around 5-10% of patients with familial PDAC and 3% of patients with sporadic PDAC are predicted to harbour a germline BRCA mutation. Knowing whether a patient carries this mutation may be used to help identify suitable treatment options.27

癌细胞的DNA损伤程度很高, loss of one or more DNA repair pathways increased DNA replication stress. These properties may be exploited as potential therapeutic targets. By researching agents that can target these particular dependencies, treatments may actively target a fundamental feature of cancer cells and turn this against itself, 导致癌细胞死亡.27

For more information on exploiting cancer-specific DDR-dependencies 点击这里

The future for pancreatic cancer research and development

The prevalence of pancreatic cancer will continue to increase if we do not achieve further breakthroughs in diagnosis and treatment. Current strategies to improve treatment outcomes focus on earlier detection through screening and biomarker testing with more effective, 有针对性的治疗.28,29

BRCA-mutated metastatic pancreatic cancer is a devastating difficult-to-treat disease with critical unmet needs, 但随着基因检测的不断创新, 生物标志物的使用, 潜在的靶向治疗和持续的研究, we are making progress in helping to change patients’ prognoses.30 AstraZeneca is committed to driving this progression and we strongly believe that to increase the pace at which progress is made in pancreatic cancer survival, we must push forward as a community to help raise awareness of unmet needs, and to activate change where we know improvements can be made.

参考文献

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