|Year : 2016 | Volume
| Issue : 2 | Page : 41-47
The Role of Precision Medicine in Pancreatic Cancer: Challenges for Targeted Therapy, Immune Modulating Treatment, Early Detection, and Less Invasive Operations
Khaled Kyle Wong1, Zhirong Qian2, Yi Le3
1 Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
2 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
3 Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
|Date of Submission||14-Feb-2016|
|Date of Acceptance||16-Apr-2016|
|Date of Web Publication||29-Apr-2016|
Dr. Yi Le
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA 02115
Source of Support: None, Conflict of Interest: None
Pancreatic cancer is one of the most lethal types of cancer due to its heterogeneous nature and the difficulty of detecting lesions in the pancreas during the early stages of tumorigenesis. Until recently, progress has been slow in developing methods to detect pancreatic lesions early. However, recent advances in genetics, biomarkers, imaging, and surgical procedures have aided the early detection of such lesions before the incurable metastatic disease state. Precision medicine has benefited pancreatic cancer patients in such areas as genetics, more targeted approaches to therapy, immunotherapy advances, and the discovery of more ideal biomarkers. In this review, the various studies and trials in these areas were reviewed to illustrate the promise of precision medicine.
Keywords: Biomarkers, cancer antigen 19-9, immunotherapy, laparoscopy, microRNA
|How to cite this article:|
Wong KK, Qian Z, Le Y. The Role of Precision Medicine in Pancreatic Cancer: Challenges for Targeted Therapy, Immune Modulating Treatment, Early Detection, and Less Invasive Operations. Cancer Transl Med 2016;2:41-7
|How to cite this URL:|
Wong KK, Qian Z, Le Y. The Role of Precision Medicine in Pancreatic Cancer: Challenges for Targeted Therapy, Immune Modulating Treatment, Early Detection, and Less Invasive Operations. Cancer Transl Med [serial online] 2016 [cited 2019 May 25];2:41-7. Available from: http://www.cancertm.com/text.asp?2016/2/2/41/181434
| Introduction|| |
Pancreatic cancer, also known as pancreatic ductal adenocarcinoma (PDA), is one of the most lethal types of cancer because it is difficult to detect at an early stage and find an effective treatment.  Although pancreatic cancer is not highly prevalent in the general population, it is commonly diagnosed in people over the age of 40. It is estimated that about 53,070 new cases will occur in the United States in 2016.  Nevertheless, patients diagnosed with pancreatic cancer have an unacceptably low 5-year survival rate - slightly < 5%.  A recent study reported that by 2020, pancreatic cancer-related mortality will catch up with the mortality rate of colon cancer, and by 2030, it will be the second most common cancer-related death after lung carcinoma although its incidence will not increase significantly to exceed the five most common cancers.  Because of the low frequency of people developing pancreatic cancer relative to other types of cancers such as colorectal cancer, it is not feasible to conduct population-based screening for early detection of pancreatic cancer.  However, other methods such as precision medicine should be considered for early detection and optimal treatment of pancreatic cancer.
By definition, precision medicine is a treatment targeted to an individual on the basis of various factors such as genetic, biomarker, phenotypic, or psychosocial characteristics.  In the context of cancer treatment, technology advances and increased molecular understanding of the etiology of pancreatic cancer have allowed the precision medicine to impact patients. Discovery of common genetic mutations that drive different cancers such as KRAS has facilitated the development of more individualized drugs targeting relevant mutations found in each tumor type.  The application of precision medicine advances can minimize unnecessary side effects present in broad, traditional treatment,  improve clinical outcomes, and reduce rates of toxicity,  and antibiotic resistance.  We review the latest findings in pancreatic cancer genetics, targeted approaches in PDA therapy, immunotherapy, biomarkers of early detection, advances in imaging technology, and less invasive operations.
| Overview of Pancreatic Cancer|| |
One of the obstacles in the management of pancreatic cancer is the detection of cancer in a later, often metastatic, stage in which the cancer is unresectable. In fact, 80% of the patients diagnosed with pancreatic cancer have unresectable tumors, which is the result of metastasis.  Even though 20% of pancreatic cancer patients undergo surgical resection and therefore have an improved survival rate, many nevertheless face recurrence of pancreatic cancer. 
Since the 1990s, gemcitabine has been the preferred treatment for pancreatic cancer. More recently, various types of combination chemotherapy such as nab-paclitaxel with gemcitabine, or FOLFIRINOX (5-fluorouracil, leucovorin, irinotecan, and oxaliplatin), with/without gemcitabine have been used to increase the response rate, especially in patients who have metastatic pancreatic cancer.  However, this type of intensive treatment frequently has negative side effects including but not limited to Grade 3-4 toxicities: cytopenias, diarrhea, and neutropenic fever. 
Discovery of common gene mutations has facilitated progress in precision medicine. The most common mutation is found in the KRAS oncogene, occurring in over 90% of patients diagnosed with pancreatic cancer; this mutation is commonly located on codon 12 of exon 1 and sometimes located on codons 13 and 61. , Other common mutations include the inactivation of the tumor suppressor genes CDKN2A and TP53, found in 70% of invasive PDAs.  In addition, the SMAD4 gene, a tumor-suppressor gene that is involved in the signal transduction of tumor growth factor β (TGF-β), is altered in 50% of PDAs. ,,
Despite increased characterization of the molecular changes in pancreatic cancer, progress in improving outcomes in the clinic has been slow due to the complexity of pancreatic cancer. We have learned that pancreatic cancer is genetically heterogeneous; in other words, pancreatic cancer is an aggregate of multiple diseases involving various mutations. 
| Genetic Alterations as Therapeutic Targets|| |
The genetics of PDA could provide a roadmap to targeted therapy. Specifically, multiple pathways that are genetically dysregulated in PDA could serve as targets of therapy. In general, the genetic features of disease provide the basis for considering relatively simple approaches for targeted treatment of cancer. Conventionally, it is easy to envision how a specific activating genetic event can be targeted. 
Findings from next-generation sequencing analyses
The molecular characterization of PDA has lagged behind that of other tumor types. One reason is that PDA is often dominated by desmoplastic stroma, which makes analyses of tumor epithelial cells difficult. Researchers have used several approaches to circumvent issues of tumor cellularity. To date, approximately > 300 PDA genomes/exomes have been sequenced. Like many cancers, while the established mutations, such as KRAS and TP53, occur at high frequency, there are a plethora of genetic alterations beyond the canonical KRAS, TP53, CDKN2A, and SMAD4 spectrum. Sequence analyses of PDAs have identified significant mutations in TGFBR2, KDM6A, AXIN1, ACVR1B, PIK3CA RNF43, GNAS, ATM, GLI3, ARID1A, and RBM10. , In addition to mutations within genes, many cancer cells contain copy number alterations, which support the biologic significance of a given genetic alteration.  Computational approaches can identify regions of significant deletion or amplification in tumor cells.  In the case of PDA, this includes many known tumor suppressors, such as CDKN2A and SMAD4, and oncogenes such as MYC and CCND1. , Interestingly, many of the mutations are in genes whose products participate in the same pathways. Sequencing studies have identified the KRAS, TGFB, TP53, MYC, chromatin remodeling, DNA repair, cell cycle, WNT-β-catenin, and Notch signaling pathways, which might be targeted therapeutically.
KRAS-methyl ethyl ketone pathway
Because most PDAs have activating KRAS mutations, the pathway is an obvious choice for targeting. The National Cancer Institute has a new program specifically directed toward developing KRAS inhibitors.  However, to date, no inhibitor of KRAS has been brought to clinical application. In fact, there have been multiple attempts to target effector pathways downstream of KRAS, for example, methyl ethyl ketone (MEK) signaling. Multiple potent MEK inhibitors have been developed and have activity in models of PDA. , However, in a series of clinical trials, the MEK inhibitors CI-1040A and AZD6244 as single agents were not effective in patients whose disease progressed on prior therapy. , These findings reveal the challenges of targeting a single pathway in PDA. Recently, there are a number of mutant KRAS-directed trials to test various MEK targeted combinations in patients with PDAs.
PIK3CA signaling pathway
PIK3CA, another downstream signal mediator of receptor tyrosine kinases, initiates the Akt-mammalian target of rapamycin (mTOR) pathway. Studies suggest that activation of PIK3CA occurs during the early phase of pancreatic carcinogenesis and is detectable in intraductal papillary mucinous neoplasm (IPMN) lesions.  Given the potential antiapoptotic effect along with growth stimulus potential, the impact of PIK3CA on pancreatic carcinogenesis might be more significant. However, it is not clear whether mutant PIK3CA is a good therapeutic target. While preclinical studies provided promising results following inhibition of the PIK3CA/Akt/mTOR pathway, clinical trials have not shown a significant benefit with the oral mTOR inhibitors.  Although the results of clinical trials have disappointed clinical investigators, this is still an active area of investigation, due to the finding that PI3K inhibitors can augment the activity of MEK inhibitors, suggesting a rational combination treatment strategy.
Tumor growth factor β/SMAD signaling pathway
Because of the frequent loss of SMAD4, TGFBR2, and other elements of the pathway, approaches to therapeutically target the loss of TGF-β signaling in PDA cells could be useful. However, TGF-β signaling is a very complex signaling network and the role of the TGF-β pathway in cellular homeostasis varies by genetic profile of the cancer cell.  TGF-β signaling acts as a tumor suppressor gene in nonmalignant clones  and also cross-talks with oncogenic signaling pathways.  The data regarding the role of SMAD4 in pancreatic cancer are also controversial. An ongoing trial will evaluate the role of loss of SMAD4 as a biomarker for more aggressive tumor biology and will correlate genotype with clinical outcome and the use of radiation therapies that may enhance locoregional disease control (NCT01921751). More translational and clinical studies are required to identify potential benefit of TGF-β inhibition in pancreatic cancer.
TP53 and CDKN2A
TP53 has been identified to be mutated in 40-75% of pancreatic adenocarcinoma cases.  Somatic TP53 mutations occur at a later stage of tumor development unlike early KRAS oncogene activation.  Given the critical effect of TP53-related pathways on pancreatic cancers, reactivation of TP53 has been interrogated in preclinical studies. , Although there have been many promising results from preclinical studies, clinical development of agents designed to reactivate TP53 has been slow.
CDKN2A encodes the p16ink4a protein, which is a major inhibitor of CDK4/CDK6 and CyclinD1 complex, which promotes a signal for cell cycle progression. Silencing of the tumor suppressor gene CDKN2A due to mutation or deletion has been shown in more than 50% of pancreatic cancers. Highly potent CDK4/6 inhibitors have been developed including LEE-011 (Ribociclib), PD-0332991 (Palbociclib), and LY2835219 (Abemaciclib).  A preclinical study showed suppression of pancreatic cancer cells growth in vitro and in vivo after being treated by a CDK4/6 inhibitor.  Drug screens have identified mTOR, insulin-like growth factor 1 receptor, and MEK inhibitors as effective agents, in combination with CDK4/6 inhibitors, in models of PDA. , Although CDK4/6 inhibitors are not currently in clinical trials for the treatment of PDA, it is likely that the number of trials investigating the effects of the CDK4/6 combination in patients with PDA will increase.
Notch signaling has essential functions in the development and differentiation of cells and tissues in many organs and is activated by direct cellular surface interaction. The Notch pathway has a crucial role in many human malignancies such as lung, breast cancer as well as pancreatic cancer.  Notch pathway activity is associated with chemoresistance and metastasis. , Overexpression of Notch signaling components in pancreatic tumors has been associated with poor outcomes for patients. Notch signaling is required for pancreatic tumor progression and metastasis in mouse models,  so pancreatic cancer is considered to be relatively dependent on Notch signaling. Collectively, suppression of notch has potential for therapeutic efficacy. The Notch signaling pathway can be inhibited pharmacologically with inhibitors of gamma-secretase, antibodies, and other mechanisms.  Tarextumab, an antibody against NOTCH2 and NOTCH3, is currently being tested in a randomized, placebo-controlled, Phase II trial (NCT01647828), in combination with gemcitabine and nab-paclitaxel in untreated patients with metastatic pancreatic adenocarcinoma.  There is also evidence indicating that chemotherapy resistance might be reversed by targeted inhibition of the Notch pathway.  Together, all evidence suggests that targeting the Notch signaling pathway is a viable therapeutic strategy.
Chromatin instability and DNA repair
A proportion of PDAs was known to contain either germline or somatic mutations in BRCA1 or BRCA2. Recent sequencing studies identified subtypes of PDA characterized by chromosomal instability, probably due to BRCA deficiency or similar deficits in DNA repair. , A recent study reported that some patients with chromosomal instability indicative of BRCA deficiency have exceptional responses to platinum-based regimens. 
| Immune Environment|| |
Regulatory T cells (T reg ) cells are generally defined as CD4 + CD25 + FoxP3 + cells that inhibit immune responses by secreting suppressive cytokines such as interleukin 10 and TGF-β.  Higher levels of T reg cells have been associated with poor prognosis in PDA. , T reg cells are a crucial component of the tumor immunosuppressive network in the tumor microenvironment. , Natural killer (NK) cells are usually decreased and functionally impaired in PDA, even in the early stages of disease such as pancreatic intraepithelial neoplasias. High levels of NK cells lead to a better prognosis. , The M2 (anti-inflammatory) subtype of macrophages has immunosuppressive activities and has been associated with a poor prognosis;  PDA is a hypoxic environment with a dense stroma, which constitutes 90% of the tumor volume. It is suggested that the desmoplastic stroma could help create an immunosuppressive microenvironment. 
| Immune Modulating Treatment|| |
Because the potential of tumors to alter their genetic code and generate potent antigens, immunotherapy is becoming an integral part of precision medicine. The ability of cancer cells to evade immune surveillance has become a major focus of attention in the field of cancer research.  However, in many cancers, this immune response fails to eradicate the cancer cells, and tumor continues to grow in part via immune editing processes. Recent research identified targetable peptides that are responsible for the failure of an immune response such as programmed death-1 (PD-1) receptor and ligand (PD-L1).  PD-L1 antibody has been assessed in early safety studies with notable activity in solid tumors  and is currently being investigated in pancreatic cancer in a Phase I study (NCT01693562). Other immune modulating agents targeting PD-1, CTLA-4, CXCR4, and indoleamine 2,3-dioxygenase are also currently under investigation in pancreatic adenocarcinoma for safety and clinical activity in Phase I and Phase II studies. In one study, antibodies against PD-L1 did not have a signal of sufficient activity in 14 patients with pancreatic cancer.  However, this study was too small to conclude that this strategy does not work in PDA. This result however suggests there is further opportunity for combining checkpoint inhibitors with other modalities such as vaccines. Another promising approach is the use of a CD40 agonist antibody, which has been tested in combination with gemcitabine and has some clinical responses in a clinical trial. ,
| Discovery of More Ideal Biomarkers of Early Detection|| |
Cancer antigen 19-9
Over the years, the biomarker cancer antigen 19-9 (CA 19-9), a sialylated Lewis blood antigen, has been widely used for the diagnosis and management of pancreatic cancer. , However, there are limitations to CA 19-9 such as its poor sensitivity of about 41-86% and poor specificity of about 33-100%.  Furthermore, there is a higher false-positive elevation in the presence of jaundice, which further affects the specificity of such a biomarker.  Thus, more ideal biomarkers are needed to facilitate the detection of pancreatic cancer and tailor a specific treatment based on the specific mutations and responses of the individual. ,
A recent study identified the serum protein MIC-1 as a more sensitive biomarker than CA 19-9. Briefly, this biomarker is found in 90% of the patients with resectable pancreatic cancer, whereas only 62% of the patients with resectable pancreatic cancer have elevated levels of CA 19-9. 
There are other biomarkers that are more ideal than CA 19-9 due to the high specificity, high sensitivity, short half-life, cost-effectiveness, and accuracy. Notably, such biomarkers are found in the serum,  pancreatic juice, stools, and saliva. 
In the past 5 years, an explosion of microRNA (miRNA) research has occurred as has much of the work related to pancreatic cancer precursors such as IPMNs.  miRNAs have tissue-specific expression patterns, can be reliably and reproducibly measured in tissue and biological fluids because of their small size and stability, and can regulate hundreds of cancer-related genes and pathways. More than 1000 miRNAs are known; some are tumor suppressors, whereas others are oncogenes. Due to their stability, miRNAs are detectable in blood, plasma, and tumor tissues. 
To find biomarkers for early diagnosis of pancreatic cancer, Kojima et al. examined miRNA expression in 571 blood samples: 150 from healthy patients, 100 with pancreatic cancer, 98 with biliary tract cancer, 21 with nonmalignant pancreatic or biliary disorders, and 202 with other cancers. Among 100 pancreatic cancer patients, they found 81 miRNAs for pancreatic cancer and 66 for biliary tract cancer that had statistically significantly different expression from that of the healthy control group. Between both groups, 55 were common for both cancer types, making it difficult to find only pancreatic cancers. Eight miRNAs achieved sensitivity for pancreatic cancer of 80.3%, specificity of 97.6%, and accuracy of 91.6%, in contrast to CA 19-9 and carcinoembryonic antigen. 
With more sensitive and specific biomarkers, earlier and more specific detection of pancreatic lesions is possible. For instance, in the Individualized Molecular Pancreatic Cancer Therapy trial, biopsies were performed in high-risk patients to extract genomic data as a means to guide treatment decisions such as prescribing precision medicine. 
| Advances in Imaging Technology|| |
The technology to precisely measure, monitor, and diagnose tumor progression and regression is essential to affirm the success of precision medicine. According to Chang et al.,  there is a 10-year period between the occurrence of cancer-related mutations and the development of the nonmetastatic founder cell. The goal of imaging technology is the detection of pancreatic lesions and neoplasia that are early enough to be resectable; currently, 80% of the patients diagnosed with pancreatic cancer have unresectable tumors as aforementioned. Through the advances in imaging technology, smaller pancreatic lesions with relatively higher sensitivity and accuracy are detected at earlier stages of cancer development. However, early detection of pancreatic lesions and neoplasia are not yet optimal, for imaging still fails to accurately detect any lesion smaller than one centimeter.  Nevertheless, smaller lesions are increasingly being detected at higher accuracy using approaches including but not limited to the endoscopic ultrasonography (EUS), computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance cholangiopancreatography (MRCP), each of which has its advantages and disadvantages. ,
The EUS can detect lesions as small as 2-3 mm  with greater depth, greater contrast, and greater sensitivity than other imaging procedures such as the CT or MRI. Furthermore, the EUS has an accuracy of 92%, rendering this imaging procedure to be quite beneficial in characterizing the vessels of lesions and identifying the stage of the tumor with greater accuracy.  One drawback is that it is an invasive procedure. 
The CT, usually the multidetector CT, provides high-resolution views of pancreatic tumors and the neighboring areas. However, the CT has a sensitivity of only 68-77% and an accuracy of about 77% when detecting lesions that are < 2 cm in size. ,
The MRI with MRCP is generally noninvasive, provides excellent contrast, and provides a sensitivity of 100% and an accuracy of 98%. Furthermore, it provides a sensitivity of 88%. In other words, this imaging procedure is relatively accurate, and similar to the CT, sensitivity and accuracy declines when detecting lesions < 1 cm. 
Advances in imaging technology provide the tools to not only detect pancreatic lesions with greater accuracy, sensitivity, and specificity but also detect such lesions earlier with respect to the development of pancreatic cancer.  Through early detection, there is potential in determining the outcome of pancreatic cancer through sufficient time and optimal treatment. In other words, such screening for early detection can potentially allow the patient to avoid under detection, overtreatment, and unnecessary side effects by tailoring the specific remedy for optimal treatment. 
| Less Invasive Operations: Approach with Robotics and Laparoscopy|| |
Typically, pancreatic tumors are categorized as either resectable, unresectable, or borderline resectable.  To perform a biopsy on such tumors, potentially invasive surgery is needed. However, advances in surgical techniques have made the surgeries less invasive, notably using the laparoscopic and robotic techniques. In fact, these less invasive surgical techniques reduce morbidity and mortality rates.  Laparoscopy is a less invasive approach for patients with pancreatic cancer. However, this technique has a few limitations such as a two-dimensional view, a lack of dexterity, and poor ergonomics. 
Recently, robotic surgery has been developed, which is a more optimal approach than laparoscopy. Compared with laparoscopy, robotic surgery is less invasive and results in fewer hospital days for patients.  In addition, robotic surgery overcomes some of the limitations laparoscopy have, as robotic surgery uses three-dimensional vision, has higher resolution cameras and microinstruments,  has more dexterity, and has better ergonomics. However, this approach in surgery is more expensive, takes longer, and is not quite necessary for simpler surgical operations such as distal pancreatectomy. According to studies investigated by Del Chiaro and Segersvard,  robotic surgery lasts for about 522 min and costs 7000 USD more than other surgical operations on pancreatic tumors. Nevertheless, robotic surgery is considered a feasible alternative due to the advanced technology and accuracy. 
Less invasive surgery such as laparoscopic and robotic surgery is one of the advances in surgery for pancreatic cancer. Through such surgery, patients experience decreased intraoperative blood loss and fewer complications. With fewer complications, simpler and more direct treatment can be prescribed, thereby underscoring the progress of precision medicine. 
Single-gene mutations have already influenced surgical decision-making in breast, colorectal, and thyroid cancer.  However, the direct and indirect influences of genomic profiling on surgery in pancreatic cancer have not been fully investigated.
| Conclusion|| |
With the advent of more specific and sensitive biomarkers, advances in imaging techniques, and advances in less invasive surgical operations, pancreatic lesions can be detected earlier. Through early detection, the severity of pancreatic cancer upon diagnosis is reduced and the chances of resection of the pancreas tumor are higher. Furthermore, such sensitivity and precision of technology allows specific and individualized treatment that reduces the side effects found in broad range, traditional medicine such as gemcitabine.
Progress in technology for detection and treatment has been made over the years, but further understanding and discovery of biomarkers, surgical procedures, and imaging techniques should be considered to ultimately differentiate tumor cells and accurately prescribe treatment based on a very specific biomarker found during the evolutionary stages of pancreatic cancer.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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