Adenocarcinomas of the ampulla of Vater are relatively rare, accounting for only 0.2% of gastrointestinal cancers [17
]. Perhaps due to their location and propensity to present with jaundice at an early resectable stage, these tumors are more likely to be resectable at the time of diagnosis than are pancreatic cancers [18
]. Furthermore, in comparison to pancreatic cancer, resected ampullary cancers are associated with better 5-year survival rates of 34 to 61% [19
]. Surgical series have demonstrated the factors affecting survival include completeness of surgical resection and nodal status. Surgical treatment for ampullary cancer and cancers in the head of the pancreas are similar in that surgeons perform a pancreaticoduodenectomy. Thereafter, the treatments may diverge. There is no clear consensus on the role of or the optimal regimen for adjuvant chemotherapy in ampullary cancers. Similarly, in part due to its relative rarity, there is no clear standard chemotherapeutic regimen for recurrent or metastatic ampullary cancer.
A better understanding of molecular oncogenesis and the emergence of targeted agents will likely lead to improved treatment outcomes in this and other cancers. Our study used whole genome sequencing to analyze the genome of a resected ampullary carcinoma. We found expected as well as novel aberrations. We found an activating mutation in KRAS
codon 12. KRAS
mutations are common in ampullary cancer although the 25 to 37% incidence appears to be lower than the approximately 95% rate of KRAS
mutation seen in pancreatic adenocarcinomas [13
]. Furthermore, similar to what is seen in colonic adenomas, KRAS
mutations occur in benign ampullary adenomas, suggesting activating mutations of KRAS
are relatively early events in the progression toward cancer and the mutation does not appear to affect prognosis [14
]. This tumor also demonstrated a somatic nonsynonymous mutation in SMAD4
(mothers against decapentaplegic homolog 4), which has been observed previously in 50% of ampullary cancers but infrequently in bile duct cancers [24
The most notable gene deletion we found was a focal deletion of a region in chromosome 10 including the PTEN
tumor suppressor gene (phosphate and tensin homologue deleted on chromosome 10). Cowden's syndrome is characterized by a germline mutation in the PTEN
gene resulting in loss of function. This syndrome is characterized by noncancerous hamartomas of the skin and mucous membranes and affected patients have in increased risk of tumors of the breast, thyroid, uterus and gastrointestinal tract. Benign tumors of the ampulla of Vater have been reported in patients with Cowden's syndrome but are not a common feature within cancers of the ampulla. Loss of PTEN expression by immunohistochemisty has been associated with liver metastases and poor prognosis in colon cancer [25
]. In a large-scale survey of the genomic aberrations of pancreatic cancers, PTEN
deletions were not seen, although small deleterious coding mutations were detected [26
]. We can conclude that despite their anatomic location in proximity to the pancreas, ampullary cancers are distinct entities from adenocarcinoma of the pancreas and bile duct cancers and thus should be treated as a different entity.
To that end, the loss of PTEN
expression is important not only in the pathogenesis but because it exposes a potential therapeutic target (Figure ). The PTEN
protein product is an inhibitor of phosphoinositide 3-kinase (PI3K) and downstream signaling through AKT. Phosphorylation of Akt results in phosphorylation of several target proteins involved in regulation of key cellular functions, including cell proliferation, glucose metabolism, protein translation, and cell survival [27
]. Additionally, activation of the PI3K pathway has been linked to activation of mammalian target of rapamycin (mTOR), although the mechanism is not yet fully elucidated [28
]. The presence of a deletion in PTEN
in this ampullary cancer would be predicted to release from inhibition activation of the PI3K/mTOR pathway. Consequently, one can infer that an agent that is a dual PI3K/mTOR inhibitor, such as NVP-BEZ235, would be an attractive therapeutic option for our patient should his disease recur [29
]. NVP-BEZ235 and other agents like it have been shown in vitro
to inhibit growth of cancer cells with activating mutations of PI3K and are all under clinical development [30
]. In the case presented here, however, the tumor carries both a KRAS
activating mutation and complete inactivation of PTEN
, supporting dual activation of both the MEK/ERK and the PI3K/AKT axes (Figure ). The inhibition of only one axis may not be sufficient for effective treatment as there is likely to be compensatory activity from the other activated axis.
Figure 3 Simplified map and interactions of the phosphoinositide 3-kinase (PI3K) and RAS pathways highlighting the genomic aberrations (-, loss of function mutation, *gain of function mutation) identified in a cancer of the ampulla of Vater and the putative therapeutic (more ...)
Our group reported the beneficial results seen in a clinical trial on patients with refractory solid tumors whose chemotherapy was chosen based on analysis of tumor biopsies using immunohistochemistry and expression arrays [31
]. New technologies such as applied herein have made high-throughput whole-genome sequencing a more rapid and cost-effective process in a manner not possible with older technologies such as Sanger sequencing. The prospect is raised, therefore, that one may soon be able to apply whole-genome sequencing to the analysis of an individual patient's tumor to guide an informed choice of a therapeutic regimen. This type of personalized or precision medicine has only begun to be studied. Several limitations remain before this whole-genome sequencing methodology can be widely applied, including the need for improved and standardized bioinformatic analysis, along with reliable and rapid methods for validation of genomic findings and cost. Furthermore, if a target is found, one must have access to an agent and, in many cases, such agents may not be approved for clinical use. Thus, we must begin to understand the links between genomic profile and drug context in early drug development. This is amplified even more where there is evidence to support combination therapies.