Some pancreatic cancer patients (hereinafter referring just to those with ductal adenocarcinoma of the pancreas) have substantially better outcomes than the majority. In the paper now reviewed by this blog entry (link at the end of this article) as published in the October 2016 issue of Endocrine-related Cancer journal, the French authors summarize surveillance, prognosis and treatment options for pancreatic cancer patients that are ONLY ASSOCIATED with BRCA2 genetic mutations. They also identify characteristics of other patients with pancreatic cancer who may benefit from the same or similar treatment regimens. What we can learn from pancreatic cancer BRCA2 treatment successes may be able to be applied to other pancreatic cancer patients, even possibly providing for further rates of improved outcomes.
The encouraging results for these pancreatic cancer patients were paved by earlier breast and ovarian cancer studies noting improved survival of patients carrying BRCA1 and BRCA2 mutations treated with platinum-based chemotherapy (here and here) and PARP inhibitor therapy (here). Individual case reports for those with pancreatic cancer (here and here) showed similar connections between platinum chemotherapy and more positive treatment outcomes. Around the same time, treatment selection evaluated a tumor’s genetic mutations in addition to the site of origin. More rigorous studies followed, strengthening the connection and uncovering additional mutation types that might benefit from these types of therapy for pancreatic cancer.
The Beginnings of an Era of More Effective BRCA2 Pancreatic Cancer Treatment
Recent genome-wide studies of pancreatic tumors identified four distinct mutational subtypes of pancreatic cancer. Most BRCA2 pancreatic cancer patients appear to fall into the ‘unstable’ subtype comprising 14% of all pancreatic tumors in the study. ‘Unstable’ tumors have large number of chromosomal rearrangements, pointing to a broken DNA homologous recombination (HR) repair mechanism. The authors note that mutations in other Fanconi pathway genes such as BRCA1, FANC-C, FANC-G, ATM, and PALB2 may also be sensitive to platinum chemotherapies and PARP inhibitors (in vivo study on FANCC/FANCG, in vitro study on PALB2). Reliably effective treatments for pancreatic cancer are generally elusive, but these treatments in patients with pancreatic cancer who carry certain genetic mutations may offer increasing promise.
Eventually, secondary mutations in heavily treated BRCA2 pancreatic cancer may cause resistance to platinum chemotherapy (here). Depending upon how the secondary mutations restored BRCA function, PARP inhibitors may still be effective (here).
Germline (inherited) BRCA2 mutations account for around 5% of all pancreatic cancer (here). Germline mutations in BRCA1, PALB2, ATM, FANC-C and FANC-G are less prevalent. Mutations in these same genes also account for 10-15% of all sporadic (non-inherited) pancreatic cancer (here and here). Patients in both of these groups may be in a position to benefit from platinum and PARP inhibitor treatments.
Familial Pancreatic Cancer
The authors in the study at hand discuss familial pancreatic cancer in much detail, recommending screening for high-risk individuals. Familial pancreatic cancer families consist of BRCA2 carriers with ≥1 first-degree relative with pancreatic cancer, or anyone with ≥2 blood relatives with pancreatic cancer. The authors postulate that Endoscopic Ultrasound (EUS) and MRI are the most effective screening methods (here), but both can offer a potential high risk of overtreatment when benign cystic lesions are mistaken for malignant tumors (here). Prophylactic surgery in individuals at high risk for familial pancreatic cancer was not recommended due to high mortality and medical complication rates.
In familial pancreatic cancer, BRCA2 appears to be a major player. But in 80-85% of familial pancreatic cancer, no germline mutation has yet been identified. Registries exist to document and help identify the causes of familial pancreatic cancer. Participation in these registries does not necessarily provide for early detection, but may lead to improved population-wide understanding of the genetic and environmental aspects of pancreatic cancer.
More effective treatments (platinum chemotherapy and PARP inhibitors) exist for pancreatic cancer patients with BRCA2 mutations. These treatments may also benefit those with BRCA1, PALB2, ATM, FANC-C or FANC-G mutations. Half of all pancreatic cancer patients with BRCA2 mutations do not meet genetic testing criteria (here), implying that more could be benefitting from these treatments but are unaware of their status. Thus, it is important to draw the attention of patients and professionals to this important and even critical information.
Gemcitabine Confers Comparable FOLFIRINOX Pancreatic Cancer Survival in Those with High hENT1 Levels
The drug gemcitabine is generally well tolerated, but its efficacy for pancreatic cancer (ductal adenocarcinoma of the pancreas) when used as a solitary chemotherapy is now understood to not be as great as that of use in combination with Abraxane, or as that of the four-drug chemotherapy combination regimen – FOLFIRINOX. However these combination chemotherapy regimens for pancreatic cancer tend to carry more frequent and severe adverse effects.
Gemcitabine is a hydrophilic nucleoside analog, and consequently must be carried by cell membrane transporters to penetrate the hydrophobic cell wall in order to initiate its cytotoxic anti-pancreatic-tumor activity. The main membrane carrier for gemcitabine is considered to be hENT1 (human equilibrative nucleoside transporter 1). Past retrospective studies with gemcitabine used as adjuvant therapy for pancreatic cancer, though somewhat conflicting, generally appear to suggest that increased levels of hENT1 may be associated with a greater than expected survival advantage.
The authors, from the Università Cattolica del Sacro Cuore in Rome, Italy, conducted a retrospective analysis to better understand the relationship between hENT1 expression as an indicator of gemcitabine chemotherapy outcomes in pancreatic cancer. And more specifically, to determine the survival characteristics in pancreatic cancer of the less toxic monotherapy as compared to the generally more efficacious but more toxic combination regimen of FOLFIRINOX, especially in terms of those pancreatic cancer patients demonstrating hyperexpression of hENT1. The results of this study were published in the October 2016 issue of Clinical & Translational Oncology (the official journal of the Federation of Spanish Oncology Societies and of the National Cancer Institute of Mexico).
The researchers reviewed the records of 149 patients with locally advanced and metastatic pancreatic cancer who had been treated in their institution from 2009 until 2013. They found that 70 of patients’ records were evaluable (36 FOLFIRINOX and 34 gemcitabine monotherapy). The authors also found that 31 patients had stored pancreatic cancer tumor tissue with enough RNA to evaluate hENT1 levels. The median overall survival was significantly longer in duration in the FOLFIRINOX as compared to the gemcitabine group (11 months vs. 8 months). Also, the FOLFIRINOX arm showed a statistically greater incidence of Grade 3 and 4 adverse effects over gemcitabine, especially neutropenia, diarrhea, and sensory neuropathy. These outcomes were seen as consistent with what has come to be expected in the treatment of pancreatic cancer.
The authors now did something very clever. They assayed hENT1 levels from pancreatic tissue in three healthy controls. In this manner, they established a median hENT1 level which served as a border for the purposes of the remainder of the study. Results found to lie below this median level were assumed to represent low hENT1 expression, and those above this cut-off were assumed to be hyperexpression of hENT1.
Of the 31 patients who had pancreatic tissue for analysis, 12 were classified as having low hENT1 levels, and 19 patients were found to carry hENT1 hyperexpression. Seven of the hENT1 hyperexpressors had received FOLFIRINOX; twelve received gemcitabine. Seven of the hENT1 hypoexpressors had received FOLFIRINOX, five received gemcitabine.
The key finding of this study is that within the hENT1 hyperexpressors in pancreatic cancer there was no statistical difference in overall survival and in progression free survival between the FOLFIRINOX and the gemcitabine monotherapy groups. (OS FOLFIRINOX 8.5 months; gemcitabine 7 months). Further, the overall survival of the 12 hENT1 hyperexpressors treated with gemcitabine was significantly greater than the 5 hypoexpressors treated with gemcitabine (8 months vs. 2 months). The FOLFIRINOX expression subgroups with pancreatic cancer did not show any statistical difference in survival.
In the discussion section of the paper, the authors note the small sample size as a possible limitation of the study. The implications of these results certainly appear to be worth future replication attempts with a much larger study population. The identification of those pancreatic cancer patients who might do as well with less toxic gemcitabine monotherapy over combination chemotherapy could confer a considerable quality of life benefit.
Dale O’Brien, MD
In two separate studies, Boston researchers (primarily) have discovered and begun to characterize the intriguing and likely important finding that protein metabolites found in human serum are elevated typically years before the diagnosis of pancreatic cancer (ductal adenocarcinoma of the pancreas) is established. The implications of this discovery have cast a new light on the early development of pancreatic cancer.
The central finding is that amino acids in the proteinogenic class known as branched-chain amino acids appear to be elevated in serum most often years prior to the diagnosis of pancreatic cancer. Specifically, these metabolic factors are the three amino acids isoleucine, leucine, and valine.
The research team for the initial study was led by scientists from the Dana-Farber Cancer Institute (and other Harvard institutions) and MIT. Also included among these scientists were those from other American universities and Canada. The results from this primary paper were published in the October 2014 issue of NATURE Medicine journal. The researchers gained access to blood samples that had been earlier collected (at least two years) from about 1,500 people in other medical tracking studies. They analyzed these samples for more than 100 metabolites and discovered 15 that were present in those people who eventually were diagnosed with pancreatic cancer as compared with matched controls (p ≤ 0.05). On further inspection, the remarkable probabilities of the noted three branched-chain amino acid elevations were determined as significant at p ≤ 0.0006 in those later diagnosed with pancreatic cancer.
The branched-chain amino acid elevations were most strongly noted during the period between two to five years before the diagnosis of pancreatic cancer, and the range was 2 to 25 years prior. The median duration between the branched-chain amino acid elevations and the diagnosis of pancreatic cancer was 8.7 years.
The causation of amino acid elevations is not fully clear. Circulation serum branched-chain amino acid elevations are seen in obese individuals and in those with insulin resistance. Subsequent tests by the researchers using mice did not appear to find a relationship between the elevated branched-chain amino acid levels and diabetes mellitus or with pancreatitis. There did again appear to be a relationship between the elevated amino acid levels and early pancreatic cancer, though this was essentially only seen in mice with Kras associated pancreatic cancer tumors. The authors note that unlike other amino acids, branched-chain amino acids are not regulated by the liver. That the levels are typically determined by dietary intake, tissue metabolism, and the breakdown of muscle and other bodily proteins. Further mice studies appeared to indicate that the early elevated branched-chain amino acid load associated with later pancreatic cancer may be related to muscle catabolism.
The second related study included some of the same aforementioned researchers, comprised primarily of Boston located scientists mainly from Harvard and MIT institutions. This work, published in the September 2016 issue of the journal Science (American Association for the Advancement of Science), built on an aspect of the earlier study to further explicate the tissue context related to tumor development by determining and comparing metabolic use patterns of branched-chain amino acids in pancreatic cancer as compared to non-small lung cancer. The authors note that both pancreatic cancer and non-small cell lung cancer often include mutations of Kras and p53, but that each of these tumors use branched-chain amino acids differently. NSCLC utilizes these amino acids as a nitrogen source (thus, increased uptake), whereas pancreatic cancer demonstrates diminished uptake of branched-chain amino acids. The differences in the levels of branched-chain amino acids between these tumors were shown to be at least in part metabolically based though enzyme variation. The different amino acid levels in these two tumor types appear to hold in mice as well as humans. The authors conclude that tissue origin appears to determine how tumors fulfil their metabolic needs.
The finding and explication related to elevations of branched-chain amino acids in serum years prior to the diagnosis of pancreatic cancer has to be judged as highly significant. It is not clear at this point the direction that this line of inquiry will assume, but one hopes that it continues and that the final destination will lead to the earlier diagnosis of pancreatic cancer.
Dale O’Brien, MD