Systemic treatment of pancreatic cancer revisited


Abstract

Pancreatic cancer is considered to be one of the most aggressive cancers. For unknown reasons, the incidence of pancreatic cancer is slowly rising and so too are mortality rates. Over 75% of patients are diagnosed with locally advanced disease or with metastases; and more than 95% of patients have metastases at diagnosis or will develop metastases during their follow-up. Despite recent improvements in the therapy of pancreatic cancer, initially with demonstration of the activity of the FOLFIRINOX regimen and subsequently the approval of nab-paclitaxel in combination with gemcitabine, prognosis remains poor and the 5-year survival rate is less than 5%. To date, neither personalized medicine nor immunotherapy, the 2 recent revolutions of cancer treatment, have delivered major positive results in the treatment of pancreatic cancer; and it is especially clear that immune checkpoint inhibitors will not become a major tool in the treatment of pancreatic cancer. There are many ongoing studies, including those exploring combinations of chemotherapy with immunotherapy. Vaccines or T cells modified with a chimeric antigen receptor (CAR-T cells) could also play a role in the treatment of cancer in the future. The aim of this review is to discuss recent improvements in standard of care, major obstacles to overcome, recent results of new treatment combinations, and the most interesting innovative approaches.

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Selecting chemotherapy for pancreatic cancer: Far away or so close?


Abstract

Pancreatic cancer is a lethal disease with a very poor prognosis. In contrast to treatments for many other tumor types, cytotoxic agents are still the first-line drugs for pancreatic cancer in both the palliative and adjuvant settings. Some progress has been made in recent years, but most large phase 3 studies have not shown significant improvements in survival. Because the available drugs and regimens are limited in both type and effect, the selection of chemotherapy based on clinicopathologic characteristics may be consequential for pancreatic cancer. In the present report, we focused on 7 landmark clinical trials for pancreatic cancer. We observed that FOLFIRINOX (oxaliplatin, irinotecan, fluorouracil, and leucovorin) and NG (nab-paclitaxel and gemcitabine), 2 first-line regimens, exerted opposite effects on metastatic pancreatic cancer patients with different baseline carbohydrate antigen 19-9 (CA19-9) levels. This suggested that not only the performance status but possibly also CA19-9 levels should be considered when making a therapeutic choice for patients with advanced pancreatic cancer. Moreover, we found that patients with a diagnosis of pancreatic cancer who have undergone a surgical resection with a negative margin (R0) may benefit more from fluorouracil and/or oral prodrugs of fluorouracil-based adjuvant therapy than from gemcitabine. Conversely, gemcitabine or gemcitabine-based regimens may be more effective for patients with a positive resection margin (R1). Based on these findings, we propose flowcharts for selecting chemotherapy for both advanced and resected pancreatic cancer. Furthermore, we present possible mechanisms and interpretations underlying the selection of chemotherapy for pancreatic cancer and propose the tumor burden as a key variable in this process. Regardless of the possible bias and exact treatment selection process, this study offers an opportunity to improve patient outcomes by using agents currently used in the therapy of pancreatic cancer. Although these conclusions are based on indirect evidence, we provide insights and possibilities to drive the selection of chemotherapy for pancreatic cancer.

Saving Steve Jobs


Second Opinions Are Critical: Learn how Steve Jobs fought cancer with the right diagnosis, extending life expectancy when Apple needed him the most.

The trouble with misfits, as Steve Jobs would say, was that they refused to comply. As an entrepreneur who pioneered successive revolutions in personal computing & portable devices, Jobs will always be remembered as an aggressive creator and visionary innovator, who never settled for what the world believed to be a norm.

Of course – we know him as the man who famously put a thousand songs in your pocket and gave the world exceptionally efficient and beautiful gadgets; we have admired his ideas on life and debated endlessly about his arguments. We have smiled at his antics and shed tears at his interpretation of Gandhi. But there is another story – one that runs parallel to his tales of entrepreneurial excellence, and sadly, the one that gets misrepresented the most.

As is the case with volatile urban legends, it is widely speculated that Steve Jobs outlived the general life expectancy of a terminal pancreatic cancer patient. He was diagnosed, after all, in 2003!

Myth: Steve Jobs Had Pancreatic Cancer.

It is common knowledge that Jobs was never too vocal about personal issues. At the helm of a publicly traded computing giant however, he was answerable to his board, shareholders, and members of the Apple tribe. Even so, Steve usually refrained from focusing on the specifics of his diagnosis, which led many to believe that he suffered from pancreatic cancer.

However, there is a general consensus within the medical fraternity that pancreatic cancer (Adenocarcinoma) would have translated into an expedited death, shortly after his diagnosis was confirmed in 2003. What really allowed Jobs to live reasonably well for the next 8 years, was an accurate diagnosis.

Pancreatic Cancer vs Neuroendocrine Cancer

Among a very few instances where Jobs decided to throw some light to his diagnosis, he referred to his affliction as a “hormonal imbalance” as opposed to your regular, run-of-the-mill Pancreatic Cancer.

In a convocation speech at Stanford University in 2005 (now popular, thanks to YouTube), Jobs reflected back on the discovery of a tumor in his pancreas in 2003, and the initial reaction of his doctors who were almost certain at the time, that it was an ‘incurable’ type of cancer, giving him a probable life expectancy of 3 to 6 months.
 

I lived with that diagnosis all day. Later that evening I had a biopsy, where they stuck an endoscope down my throat, through my stomach and into my intestines, put a needle into my pancreas and got a few cells from the tumor. I was sedated, but my wife, who was there, told me that when they viewed the cells under a microscope the doctors started crying because it turned out to be a very rare form of cancer that is curable with surgery. I had the surgery, and I’m fine now.

-Steve Jobs, Stanford Convocation, 2005

It is confirmed today, that Jobs suffered from Neuroendocrine Cancer. Due to a lack of clear public understanding and widespread awareness about the disease (It is reported that as few as 10 cancer specialists in the world fully understood Neuroendocrine Cancer in 2001), its symptoms were often mistaken for Pancreatic Cancer, Irritable Bowel Syndrome or Crohn’s Disease.

While most forms of pancreatic cancer arise from pancreatic cells, neuroendocrine tumors arise from hormone-producing islet cells that happen to be in the pancreas. Unlike regular pancreatic cancer, where patients are likely to die within weeks or months after diagnosis, neuroendocrine cancer grows slow, and can be controlled and contained with an early, accurate diagnosis.

Fact: Steve Jobs Had Access To Specialists.

Following his surgery, Jobs lived for 8 more years, and during this time, administrative responsibilities at Apple were gradually handed down to the right personnel.

It isn’t hard to understand that a man of Jobs’ stature had access to the absolute best that the medicare industry had to offer at the time, and that his diagnosis and subsequent surgery were accelerated by the availability of dedicated on-call specialists whenever required. In other words, Jobs didn’t have to worry about the credibility of the treatment he was receiving.

Sadly, though – misdiagnosis and incorrect treatments result in a huge number of deaths around the world today.

Not everyone can afford to deploy medical resources like Steve Jobs did, and yet – as many as 1,000 patients are diagnosed with Neuroendocrine cancer each year in the United States alone.

With the right push and timely access to specialists, they can be treated well, treated right, and allowed the same life expectancy extensions as Jobs enjoyed, if not more.

Question: Doesn’t limited access make you vulnerable to an incorrect diagnosis?

Plagued by the deplorable condition of state-sponsored and privately-distributed health insurance providers and non-availability of surplus funds, most cancer patients in the world today have their options severely limited to standard-issue procedures for diagnosis and treatment. While rare cases such as Neuroendocrine tumors require special analysis, it is still extremely common to find misinterpretations of its symptoms.

The general population still doesn’t have enough access to specialists. Even if they go to general physicians and hospitals, they get referred to standard procedures such as chemotherapy and radiation therapy. In fact, credible and qualified second opinions were really hard to source, until a new wave of internet-enabled services made it possible to connect patients with specialists and multidisciplinary panels of oncologists.

The Onco.com Advantage

At Onco.com, we offer single consultations with domestic & international oncologists, as well as a tumor-board review for advanced cases, for patients who wish to have their ongoing cancer treatment reviewed. In a reference that Jobs would have probably humored, we are trying to intervene as an ‘Autocorrect’ service for cancer treatments around the world, with the availability of an unbiased consultation/treatment being our top priority.

Any patient, irrespective of the stage of their diagnosis/treatment, can send us their existing medical data and receive an accurate analysis of their treatment, and we will revert with any necessary course corrections, as well as suggestions about possible clinical trial engagements that can really make a difference. Not being affiliated to any hospital or treatment centre allows us to be focused only on the right advice for cancer patients, and lets us push forward into a world where everyone has access to the the diagnostic advantages that helped Steve Jobs live for 8 more years.

References & Bibliography

  1. Reference: Neuroendocrine Tumor Research Foundation
  2. Reference: An article that first appeared in Charlotte Observer
  3. Reference: National Cancer Institute – cancer.gov PDQ on Islet Cell Tumors

Adding Enzyme to Chemo Combo Improves Outcomes in Pancreatic CA


Adding pegvorhyaluronidase alfa (PEGPH20) to nanoparticle albumin-bound paclitaxel (Abraxane) plus gemcitabine (Gemzar) boosted progression-free survival (PFS) in patients with untreated metastatic pancreatic ductal adenocarcinoma (mPDA), researchers said.

In the phase II HALO-202 trial, PFS was significantly improved with the combined regimen (6 months versus 5.3 months; HR 0.73, 95% CI 0.53 to 1.00, P=0.049), according to Sunil Hingorani, MD, PhD, of the Fred Hutchinson Cancer Research Center in Seattle, and colleagues.

However, the largest PFS increase was seen in patients with excessive hyaluronan (HA) in their tumors who were treated with the triple combination (PAG) compared to those treated with the dual combo (AG), (9.2 months versus 5.2 months; HR 0.51, 95% CI 0.26 to 1.00, P=0.048), the researchers reported online in the Journal of Clinical Oncology.

The objective response rate was also higher in patients with HA-high tumors treated with PAG versus AG (45% versus 31%), as was the median overall survival (11.7 versus 9.7 months).

“This highlights the importance of patient selection for targeted therapies,” they wrote. “Although further investigation in a larger cohort is warranted, these results clearly support the therapeutic potential of PAG treatment in patients with HA-high mPDA.”

Currently, AG is the first-line standard of care for patients with mPDA. When HA accumulates in the tumor, however, it elevates interstitial pressure and impairs perfusion. Preclinical studies have demonstrated that the pegylated recombinant human hyaluronidase PEGPH20 degrades HA, improving drug delivery.

“Pancreas cancers have been notoriously resistant to virtually all forms of chemical and radiotherapies with a particularly notable disconnect between the ability to kill these cells in a dish versus in a patient,” Hingorani told MedPage Today.

“This randomized phase II trial provides further rationale supporting a compelling explanation for at least part of this resistance, namely very high interstitial concentrations of hyaluronan,” he continued. “These data also support the use of tumor HA as a potential predictive biomarker for patient selection in the ongoing, global phase III study of PAG versus AG in patients with HA-high PDA.”

The HALO-202 trial was conducted in two stages. In stage 1 (March 2013 to April 2014), 146 patients were randomized 1:1 to receive PAG or AG — but researchers observed an imbalance in thromboembolic events early in the study. The trial was subsequently put on hold and 29 patients receiving PAG continued treatment with AG alone. Seven of these patients went back on PEGPH20 therapy when stage 2 of the trial started (August 2014 to February 2016) with an amended protocol.

In stage 2, patients with thromboembolic events were excluded, enoxaparin (Lovenox) prophylaxis was initiated in both arms, and an additional 133 patients were randomized 2:1 to PAG or AG. A primary safety endpoint for thrombolic events was added to determine the efficacy of enoxaparin prophylaxis, and any patient who experienced such an event had to discontinue PEGPH20.

Of the total 279 patients enrolled, 84 (34%) had HA-high tumors.

Each 4-week cycle consisted of 3 weeks on and 1 week off treatment. During cycle 1, PEGPH20 (3 mg/kg) was administered intravenously twice weekly and this was reduced to once weekly during subsequent cycles. AG was administered at standard doses: nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2.

The combination had a manageable toxicity profile and anti-coagulant prophylaxis with enoxaparin reduced thromboembolic event rates in both treatment arms (14% PAG versus 10% AG), they reported.

There were also significant differences in the rates of treatment-related grade 3/4 adverse events between the PAG and AG treatment arms. The most common AEs included muscle spasms (13% PAG versus 1% AG), neutropenia (29% versus 18%), and myalgia (5% versus 0%).

In the phase III trial currently underway, Hingorani predicted that outcomes will “only be as good as the companion drugs that are given along with the enzyme [PEGPH20].” Although standard chemotherapies are unlikely to achieve a cure in the metastatic setting, the approach could potentially produce the kind of meaningful and durable responses seen with treatment for other non-curable cancers, he said.

“If we can at least have the opportunity to increase longevity, we can give patients and their families some time to adjust to the reality of their diagnosis,” Hingorani said.

Limitations of the study include the relatively small number of patients with HA-high tumors available for evaluation of enoxaparin prophylaxis. There were 49 patients with HA-high tumors in the PAG arm and 35 in the AG arm. Discontinuation rates during the temporary clinical hold also precluded robust statistical analyses of overall survival and objective response rate by HA level, the study authors said.

How obesity contributes to, blocks treatment of pancreatic cancer


Investigators have discovered the mechanism by which obesity increases inflammation and desmoplasia — an accumulation of connective tissue — in the most common form of pancreatic cancer and also identify a treatment strategy that may inhibit the process.
 Massachusetts General Hospital (MGH) investigators have discovered the mechanism by which obesity increases inflammation and desmoplasia — an accumulation of connective tissue — in the most common form of pancreatic cancer. In their report published online in Cancer Discoverythe researchers describe how interactions among fat cells, immune cells and connective tissue cells in obese individuals stimulate a microenvironment that promotes tumor progression while blocking the response to chemotherapy. They also identify a treatment strategy that may inhibit the process.

“We evaluated the effects of obesity on numerous aspects of tumor growth, progression and treatment response in several animal models of pancreatic ductal adenocarcinoma and confirmed our findings in samples from cancer patients,” says Dai Fukumura, MD, PhD, of the Steele Laboratory of Tumor Biology in the MGH Department of Radiation Oncology, the study’s co-senior author. “Along with finding that tumors from obese mice or patients exhibited elevated levels of adipocytes or fat cells and of desmoplasia, both of which fuel tumor progression and interfere with treatment response, we also identified the underlying cause.”

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death worldwide, and more than half of patients diagnosed with PDAC are overweight or obese. Among patients with PDAC, obesity more than doubles the already high risk of death. Previous research by the MGH team and others has shown that PDAC is characterized by elevated desmoplasia — with an overproduction of extracellular matrix tissue by pancreatic stellate cells — which both promotes the survival and migration of cancer cells and blocks the penetration of chemotherapy drugs into tumors. Obesity itself is known to contribute to desmoplasia, with the expansion of fat tissue leading to inflammation and fibrosis and an accumulation of fat within the normal pancreas, which also causes inflammation.

The team’s experiments revealed that the elevated desmoplasia in obese mouse models of PDAC was caused by activation of pancreatic stellate cells through the antiogensin II type-1 receptor (AT1) signaling pathway. This activation was promoted by production of interleukin-1 beta (IL-1ß) both by fat cells and by the immune cells called neutrophils within and around tumors. Inhibiting AT1 signaling with losartan, which is used clinically to treat hypertension, reduced obesity-associated desmoplasia and tumor growth and increased the response to chemotherapy in the obese mouse model but not in normal weight animals. Analysis of tumors from human PDAC patients revealed increased desmoplasia and fat deposits only in samples from obese patients, and data from more than 300 patients showed that excess weight was associated with a reduction in patients’ response to chemotherapy.

João Incio, MD, PhD, of the Steele lab, lead author of the study, says, “Understanding the way that obesity affects pancreatic cancer may help us identify biomarkers — such as body weight and increased levels of tumor fibrosis — that could identify patients for whom AT1 blockers or IL-1ß antibodies would be most beneficial. Since FDA-approved versions of both agents are readily available, this strategy could be readily translated into the clinic. In addition, incorporating body weight into the design of preclinical studies could better account for the lack of response to conventional chemotherapeutical drugs.”

Co-senior author Rakesh K. Jain, PhD, director of the Steele Laboratory, adds, “With the majority of pancreatic cancer patients being overweight or obese at diagnosis, uncovering potential therapeutic targets within the mechanisms associating obesity with poor cancer prognoses is the first step towards developing remedies that could disrupt this association and significantly improve patient outcome. Targeting inflammation and fibrosis holds the promise to improve the clinical outcome of this major group of cancer patients.”

Pancreatic Cancer: Chemoradiotherapy vs Chemo Alone


Adding radiation to chemotherapy does not improve overall survival in comparison with chemotherapy alone in patients with locally advanced pancreatic cancer with controlled disease after 4 months of induction therapy, according to results from the phase 3 randomized clinical trial LAP07. The findings werepublished online May 4 in the Journal of the American Medical Association.

The study also found that adding the targeted agent erlotinib (Tarceva, Osi Pharmaceuticals, Inc) to gemcitabine (Gemzar, Eli Lilly and Company) does not increase overall survival in comparison with gemcitabine alone.

 “The overall survival was better than expected, confirming the efficacy of this strategy using induction chemotherapy first. Survival after chemoradiation was not inferior to chemotherapy,” study author Florence Huguet, MD, of the Department of Radiotherapy, Tenon Hospital, Paris, France, wrote in an email to Medscape Medical News.

“Chemoradiation and chemotherapy remain two reasonable options in patients with disease control after 4 months of chemotherapy,” she added.

There is no consensus concerning the best treatment strategy for locally advanced pancreatic cancer, Dr Huguet explained. Such tumors are not resectable because of invasion into adjacent structures. Although these patients do not yet have metatastic disease, they are at risk for local progression and metatastasis. Such patients usually receive induction chemotherapy followed by chemoradiation (fluorouracil or capecitabine [Xeloda, F. Hoffman/La Roche, Ltd] plus radiation) if the disease has not progressed.

Chemoradiation has the potential to decrease distant metastases and convert inoperable tumors into resectable ones. However, results from at least five randomized, controlled trials that compared chermoradiotherapy with chemotherapy have been conflicting. Some retrospective studies, though, have suggested a survival advantage for patients who receive induction therapy followed by chemoradiotherapy.

Previous studies have also suggested that adding erlotinib to gemcitabine may increase survival. However, the results, though statistically significant, have not proved to be clinically meaningful.

Study Details

The LAP07 trial was an international, open-label, unblinded phase 3 randomized trial that included 449 adults with stage III locally advanced pancreatic cancer. Enrollment occurred between 2008 and 2011 in 80 centers in France, Australia, New Zealand, Belgium, and Sweden.

 Researchers first randomly assigned 223 patients to 1000 mg/m2 of gemcitabine alone once a week and 219 patients to 1000 mg/m2 of weekly gemcitabine plus 100 mg/day of oral erlotinib. They then randomly assigned patients who were without disease progression after 4 months of induction therapy to receive two additional months of the same chemotherapy (n = 136) or chermoradiotherapy (54 Gy, 30 daily fractions over 6 weeks) plus capecitabine 800 mg/m2 twice a day (n = 133).

An interim analysis conducted after 221 patients died (109 in the chemoradiotherapy group and 112 in the chemotherapy group) led to early cessation of the trial due to futility.

Over a median overall follow-up of 36.7 months, median overall survival rates in the chemotherapy and chemoradiotherapy groups were similar (16.5 months vs 15.2 months, respectively; hazard ratio [HR], 1.03; P = .83). Likewise, progression-free survival rates were similar in the two groups (HR, 0.78, 95% confidence interval [CI], 0.61 – 1.01; P = .06).

In the group that received gemcitabine alone, median overall survival was similar to that of the group that received gemcitabine plus erlotinib (13.6 months vs 11.9 months, respectively; HR, 1.19; P = .09). Progression-free survival rates were also similar for the two groups (HR, 1.12; 95% CI, 0.92 – 1.36; P = .26).

The group that received gemcitabine plus erlotinib experienced significantly more grade 3 or 4 anemia (P = .05), febrile neutropenia (P = .03), diarrhea (P = .006), and acneiform rash (P = .007) compared with the group that received gemcitabine alone.

The chemoradiotherapy group showed no increase in grade 3 or 4 toxicity except for nausea. In addition, this group experienced less local progression than the group that received chemotherapy alone (32% vs 46%; P = .03), and progression-free survival was increased, resulting in a longer treatment-free period (6.1 months vs 3.7 months; P = .02).

“This could translate into a better quality of life, which is in favor of chemoradiation,” Dr Huguet pointed out, “On the other hand, radiation therapy is more expensive and time consuming for the patients.”

The study included a radiation therapy quality assurance and quality control component to ensure delivery of protocol-compliant radiation therapy. Evaluations showed that 32% of participants received radiation per protocol, 50% had minor deviations, and 18% had major deviations. Major deviations were mainly with regard to variations from the planned schedule. These deviations did not significantly affect overall survival.

The study did not employ the most optimal drugs for chemotherapy ― FOLFIRINOX (leucovorin/fluorouracil/irinotecan/oxaliplatin) and gemcitabine-nab-paclitaxel ― because the trial began in 2005, before these regimens came into use.

 Using these more effective regimens could improve the results, Dr Huguet speculated. Also, new radiation techniques, such as intensity-modulated radiation therapy and image-guided radiation therapy, may allow for dose escalation and better sparing of organs at risk.

“These two axes of development should be explored in the future,” she concluded.

Progress, but Not Precision

The results represent progress, but the goal of precision medicine was not achieved, Deborah Schrag, MD, MPH, of the Dana Farber Cancer Institute, Boston, Massachusetts, and associate editor of JAMA, writes in a linked editorial.

 “The trial does not include information about the molecular correlates of response,” she said in an email to Medscape Medical News. “It is quite plausible that there is heterogeneity in response and that some tumors are especially responsive to radiation.”

Research is currently underway to identify molecular signatures of tumors that are particularly responsive to radiation or chemotherapy, she noted.

Asked about the clinical implications of the new findings, Dr Schrag wrote: “Chemoradiation need not be a component of standard care based on the LAP07 study results. However, it is also important to realize that radiation was not inferior to continued chemotherapy.”

 In her editorial, she points out that pancreatic cancer is one of the most difficult-to-treat tumor types and that little progress has been made. “Pancreas cancer mortality rates have not substantially declined over the past decade, and the incidence is increasing in low- and middle-resource countries,” she notes.

“If cancer is the emperor of all maladies, then pancreatic adenocarcinoma is the ruthless dictator of all cancers,” she comments.

Diabetes drug may slow growth of pancreatic cancer.


Researchers including those of Indian-origin may have uncovered a novel mechanism behind the ability of the diabetes drug metformin to inhibit the progression of pancreatic cancer.

Researchers found that metformin decreases the inflammation and fibrosis characteristic of the most common form of pancreatic cancer.

The findings indicate that this beneficial effect may be most prevalent in overweight and obese patients.

The study by researchers at Massachusetts General Hospital (MGH) in US focused on pancreatic ductal adenocarcinoma, the most common form of pancreatic cancer.

Half of those diagnosed with this form of pancreatic cancer are overweight or obese, and up to 80 per cent have type 2 diabetes or are insulin resistant.

Diabetic patients taking metformin – a common medication for type 2 diabetes – have a reduced risk of developing pancreatic cancer; and among patients who develop the tumour,    those taking the drug may have a reduced risk of death.

However, previously the mechanism of metformin’s action against pancreatic cancer was unclear, and no potential biomarkers of response to metformin had been reported.

The researchers first found that levels of hyaluronan, a component of the extracellular matrix, were 30 per cent lower in tumour samples from overweight or obese patients who were taking metformin to treat diabetes than in those who did not take the drug.

In an obese animal model of pancreatic cancer, those that received metformin had reduced expression of both hyaluronan  and collagen-1 and fewer activated pancreatic stellate cells    (PSCs).

Studies in cultured cells identified the signalling pathway by which metformin reduces the production of  hyaluronan and collagen-1 by PSCs and also prevents the recruitment of tumour-associated macrophages, which increase  the inflammatory environment.

In obese mouse models, researchers including Rakesh K  Jain and Priya Suboj from MGH found that metformin treatment  reduced levels of tumour-associated macrophages by 60 per cent and reduced expression of genes involved in remodelling the  extracellular matrix of tumour tissue.

The tumours of animals treated with metformin also had reductions in a metastasis-associated change in cellular characteristics called epithelial to mesenchymal transition(EMT) and in the overall level of metastasis.

These tumour-related effects of metformin appear to be independent of the drug’s effects on metabolic pathways involved in glucose metabolism and body weight.

“We found that metformin alleviates desmoplasia – an accumulation of dense connective tissue and tumour-associated immune cells that is a hallmark of pancreatic cancer – by inhibiting the activation of the pancreatic stellate cells  that produce the extracellular matrix and by reprogrammingimmune cells to reduce inflammation,” said Dai Fukumura from MGH.

Urine Proteins Point to Early-Stage Pancreatic Cancer


Raising hopes for a simple, noninvasive, inexpensive, and easily repeatable test for pancreatic cancer, scientists at Barts Cancer Institute, Queen Mary University, have developed a three-protein biomarker panel that can screen urine samples to identify pancreatic cancer when it is still in its early stages. The panel, the scientists say, has already demonstrated better than 90% accuracy. Moreover, it readily distinguishes between pancreatic cancer and chronic pancreatitis, conditions that are easily mistaken for each other.

The scientists settled on just three proteins after conducting proteomic analyses of 488 urine samples—192 from patients with pancreatic ductal adenocarcinoma (PDAC), 92 from patients with chronic pancreatitis, 87 from healthy volunteers, and 117 samples from patients with other benign and malignant liver and gall bladder conditions.

The urine samples were subjected to assays using GeLC-MS/MS (in-gel tryptic digestion followed by liquid chromatography-tandem mass spectrometry) andELISA. Initially, around 1,500 proteins were identified, with approximately half being common to both male and female volunteers. Of these, three proteins—LYVE1, REG1A, and TFF1—were selected for closer examination.

Each of the three proteins was elevated in urine samples from PDAC patients, but not in urine samples from healthy patients. Patients suffering from chronic pancreatitis had significantly lower levels than cancer patients.

Combining the three proteins, the scientists discovered, yielded a robust panel. The panel’s performance was described August 3 in the journal Clinical Cancer Research, in an article entitled, “Identification of a Three-Biomarker Panel in Urine for Early Detection of Pancreatic Adenocarcinoma.”

“When comparing PDAC with healthy urine specimens, the resulting areas under the receiver-operating characteristic curves (AUC) of the panel were 0.89 in the training (70% of the data) and 0.92 in the validation (30% of the data) datasets,” wrote the authors. “When comparing PDAC stage I–II with healthy urine specimens, the panel achieved AUCs of 0.90 and 0.93 in the training and validation datasets, respectively.”

At present, noninvasive biomarkers for early detection of PDAC are not available. The biomarker panel established by the Barts Cancer Institute scientists, however, shows promise.

“We’ve always been keen to develop a diagnostic test in urine as it has several advantages over using blood. It’s an inert and far less complex fluid than blood and can be repeatedly and non-invasively tested,” said lead researcher Tatjana Crnogorac-Jurcevic, M.D., Ph.D. “It took a while to secure proof of principle funding in 2008 to look at biomarkers in urine, but it’s been worth the wait for these results. This is a biomarker panel with good specificity and sensitivity, and we’re hopeful that a simple, inexpensive test can be developed and in clinical use within the next few years.”

The team is hoping to conduct further tests on urine samples from people in high-risk groups, to further validate the study findings. Dr. Crnogorac-Jurcevic is also keen to access samples of urine collected from volunteers over a period of 5–10 years. By examining samples from donors who went on to develop pancreatic cancer, this longitudinal information will allow the researchers to see if the three-biomarker signature is present during the latency period—the time between the genetic changes that will cause the cancer to develop and the clinical presentation.

With few specific symptoms even at a later stage of the disease, more than 80% of people with pancreatic cancer are diagnosed when the cancer has already spread. This means they are not eligible for surgery to remove the tumor—currently the only potentially curative treatment.

Patients are usually diagnosed when the cancer is already at a terminal stage, but if diagnosed at stage II, the survival rate is 20%, and at stage I, the survival rate for patients with very small tumors can increase up to 60%. It is hoped that with early detection, the survival rate for pancreatic cancer will improve. At present, only about 3% of patients found to have pancreatic cancer survive more than five years.

GI Needle Biopsies Do Not Spread Cancer, Study Suggests


Pancreatic cancer research has picked up the pace, with an urgency sparked by the realization that by 2030 this tumor type will be the second most deadly cancer in the United States (after lung cancer) and will kill more Americans than breast, prostate, or colorectal cancer.

Three new research approaches were highlighted here at a press briefing during the American Association for Cancer Research (AACR) special conference, Pancreatic Cancer: Innovations in Research and Treatment. They include a new panel of pancreatic cancer blood biomarkers for use in a blood test to aid earlier diagnosis, a new monoclonal antibody that “uncloaks” tumors for immune destruction and is about to be tested in humans, and the use of gemcitabine to strengthen the punch of a radioactive antibody. This combination of gemcitabine with a radioactive antibody (clivatuzumab tetraxetan with yttrium-90 [90Y], under development by Immunomedics), prolongs survival for at least some patients with metastatic pancreatic cancer, and is now being tested in an ongoing phase 3 trial.

Blood Test May Reduce the Need for Invasive Testing

Late diagnosis is one reason why fewer than 20% of patients with pancreatic cancer survive for more than 1 year, and only 6% survive for 5 years.

Only about 10% of pancreatic cancers are diagnosed while the disease is still localized, when there is a better chance of treatment.
With the aim of improving the early diagnosis rate, a team lead by Ayumu Taguchi, PhD, MD, is developing a blood test that would identify patients who have cancer from those who have other conditions. The blood test combines the known pancreatic cancer biomarker CA 19-9 (which has limited accuracy) with 3 new pancreatic cancer biomarkers.

“Our current imaging approaches to pancreatic cancer detection are not amenable to use in a widespread screening program. A biomarker-based method could be used much more broadly. The goal of our research was to develop a panel of biomarkers that could be used for diagnosis of early-stage pancreatic cancer,” Dr. Taguchi said during a press conference at the meeting. He is assistant professor at The University of Texas MD Anderson Cancer Center in Houston and collaborated on this project with researchers from the Fred Hutchinson Cancer Research Center (Seattle, Washington), the University of California San Francisco, and the University of Utah School of Medicine (Salt Lake City).

The team reported that about 90% of the time, the biomarker panel accurately distinguished individuals with pancreatic cancer from those who were healthy, had chronic pancreatitis, or had pancreatic cysts. Dr. Taguchi suggested that this biomarker panel, which requires validation in larger studies, might greatly reduce the number of patients who would have to undergo extremely invasive pancreatic cancer screening procedures, in part because it had a high negative predictive value (98% ability to determine when a patient had chronic pancreatitis or benign pancreatic cysts rather than early-stage cancer).

The researchers first studied candidate biomarkers plus CA19-9 in a training set of blood plasma samples from 138 patients with pancreatic cancer and 81 controls (52 healthy persons and 29 patients with chronic pancreatitis), then tested the most promising combination in an independent cohort of plasma samples from 42 patients with early-stage pancreatic cancer, 50 healthy controls, 29 patients with chronic pancreatitis, and 14 patients with benign pancreatic cysts.

“We need to further validate our panel using larger numbers of samples collected before diagnosis of early-stage pancreatic cancers. However, we are hopeful that we can develop a panel that will have clinical application,” Dr. Taguchi said.
During the press conference, moderator Andrew M. Lowy, MD, professor of surgery at the University of California, San Diego, said, “There is a great need for us to improve therapies for pancreatic cancer and our ability to detect and prevent pancreatic cancer.” However, Dr. Lowy cautioned that the biomarker panel would probably not be used for routine mass screening because the incidence of pancreatic cancer is so low that there would likely be too many false-positive results.

Anti-CD47 Antibody Strips the Veil From Pancreatic Cancer Cells

Many types of cancer cells hide behind a scrim of CD47 protein, which renders them less visible to the immune system. Monoclonal antibody Hu5F9 strips away that veil and could potentially make many types of cancer subject to removal by normal immune surveillance processes.

Geoffrey W. Krampitz, MD, described work with Hu5F9 that showed tumor regression in preclinical models of pancreatic neuroendocrine tumors and of pancreatic ductal adenocarcinoma. Dr. Krampitz is a doctoral candidate in the laboratory of Irving L. Weissman, MD, director of the Institute for Stem Cell Biology and Regenerative Medicine at Stanford University School of Medicine and the Ludwig Center for Cancer Stem Cell Research in California.

Hu5F9 appears to be active against the subset of “tumor initiating cells” responsible for tumor development, metastasis, and recurrence, as well as against other tumor cells, Dr. Krampitz said. CD47 is expressed at high levels in many types of cancer and functions as what Dr. Krampitz called a “do not kill” flag to protect cancers from removal by passing macrophages. “Every single cancer we have looked at highly expresses CD47 on its cell surface,” Dr. Krampitz said.

The researchers tested the anti-CD47 antibody in 3 lines of research, all of which showed impressive efficacy against pancreatic neuroendocrine cancers and against pancreatic ductal adenocarcinomas.

“One treatment model involved injecting very well-characterized pancreatic cancer cell lines into mice either orthotopically or heterotopically and then treating with anti-CD47. In most of those mice we saw complete elimination of the tumor. In genetic mouse models of pancreatic cancer, colon cancer, and other types of cancer treated with an antibody against mouse CD47, we have seen decreased tumor burden, elimination of metastases, and prolongation of survival. Most important, when we took patients’ tumors from the operating room and put them into immunocompromised mice to create a xenograft of a human tumor, anti-CD47 produced complete elimination of tumors, reduction of metastases, and prolongation of survival,” Dr. Krampitz said at the press conference.

The studies included tumor samples from 39 patients with pancreatic neuroendocrine tumors (19 of which contained tumor-initiating cells) and from 39 patients with pancreatic ductal adenocarcinoma, the most common type of pancreatic cancer.

Dr. Krampitz said that anti-CD47 will be further characterized in an upcoming paper. He explained that most cells have CD47 on their surface but lose CD47 expression as they age or become damaged, which leads to their elimination by macrophages. Pancreatic neuroendocrine tumors, pancreatic ductal adenocarcinomas, and many other cancer types appear to have high-jacked that signal in a “false flag” strategy to avoid removal by the immune system. Blocking CD47 apparently makes these cancer cells once more visible to normal immune surveillance.

Clinical safety trials with anti-CD47 are expected to begin later this year.”Right now we are looking at the safety profile of anti-CD47 in monkeys,” Dr Krampitz said. Toxicity concerns with anti-CD47 include removal of healthy cells (particularly red blood cells) that normally express CD47 to prevent autoimmune removal.

The monoclonal antibody clivatuzumab tetraxetan, weaponized with a dose of radioactive 90Y, targets the MUC5ac protein found on the surface of most pancreatic cancer cells, but not on normal cells. Final phase Ib clinical trial data presented by Vincent J. Picozzi Jr, MD, director of the Pancreas Center of Excellence at the Virginia Mason Medical Center’s Digestive Disease Institute, Seattle, Washington, showed that adding a low “radiosensitizing” dose of gemcitabine further softened the pancreatic cancer’s cellular defenses and significantly increased treatment impact.

90Y-clivatuzumab tetraxetan with gemcitabine is being tested against placebo with gemcitabine for metastatic pancreatic cancer in the phase III PANCRIT-1 trial. The phase III trial opened in January 2014, and Dr. Picozzi said at the press conference that (on the basis of experience with the phase Ib study), researchers expect rapid accrual and hope to complete the study in 2015.

The phase Ib trial included 58 patients, all of whom had metastatic pancreatic cancer and had received at least 2 prior therapies. All patients received 6.5 mCi/m 90Y-clivatuzumab tetraxetan for 3 weeks, divided into multiple smaller doses per cycle. After randomization, half of the patients (group A; n = 29) also received low-dose gemcitabine (200 mg/m2), weekly for 1 week and then in combination with the radioimmunotherapy for 3 weeks in each cycle. Patients received treatment for up to 9 cycles, with 4-week delays in between.

Twenty-seven of 29 patients in group A received at least 1 cycle of the combination, and 12 patients completed 2 or more cycles of treatment. In the other group (group B), 26 patients completed at least 1 cycle of treatment with the antibody alone, and 11 patients completed 2 or more cycles of treatment.

Median overall duration of survival was similar for patients who completed only 1 treatment cycle (3.9 months for group A and 2.8 months for group B) but was significantly longer with combination therapy among patients who completed 2 or more treatment cycles (7.9 months for group A and 3.4 months for group B; P = .004). Two patients in group A had partial responses by RECIST (response evaluation criteria in solid tumors) criteria, and 3 patient in group A are still being observed 11 to 17 months after the beginning of treatment.

The only clinically significant adverse effects were cytopenias (mainly thrombocytopenia), which were “mostly transient and manageable with infrequent hematologic support and little evidence of increased infection or bleeding,” Dr. Picozzi reported.

“We found that 90Y-clivatuzumab tetraxetan, when used with low-dose gemcitabine, is a safe, low-side-effect therapy that can prolong survival for at least some patients with metastatic pancreatic cancer, even when no chemotherapy options exist,” Dr. Picozzi concluded.

Time for Pancreatic Cancer Research to Catch Up?

“The projections for deaths from pancreatic and liver cancers are startling,” said Lynn Matrisian, PhD, MBA, vice president of scientific and medical affairs at the Pancreatic Cancer Action Network (PCAN), which supported the study that predicted the high rate of pancreatic cancer death by 2030.

“This study is a call to action to the scientific and clinical communities, as well as the population at large, to increase attention, awareness, and ultimately progress in the fight against pancreatic cancer,” Dr. Matrisian said.

The PCAN researchers used demographics and changes in the annual percentage of cancer incidence and deaths to estimate future cancer incidence and death rates. Increased numbers of older and minority populations will increase the population likely to be at greater risk for pancreatic cancer. Meanwhile, cancer death rates overall and incidence of other major cancers will decline because of better screening and prevention methods and lower prevalence of smoking and viral infections.

Dr. Matrisian said that historically, pancreatic cancer has been less studied, in part because of less funding and in part because the pancreas is located deep within the abdomen, where it is difficult to access and to visualize by imaging modalities. Furthermore, the dense stromal tissue surrounding and infiltrating many pancreatic tumors impedes both imaging and drug delivery.

PCAN is intensifying efforts to heighten awareness, raise funds for comprehensive private research, and advocate for dedicated federal research to advance early diagnostics, improve treatments, and increase chances of survival, with the goal of doubling pancreatic cancer survival by 2020, Dr. Matrisian said.

Pancreatic cancer breakthrough: Scientists turn cancer cells into normal cells


A new research study has shown that pancreatic cancer cells can be coaxed to revert back toward normal cells by introducing a protein called E47. E47 binds to specific DNA sequences and controls genes involved in growth and differentiation. The research provides hope for a new treatment approach for the more than 40,000 people who die from the disease each year in the United States.

“For the first time, we have shown that overexpression of a single gene can reduce the tumor-promoting potential of pancreatic adenocarcinoma cells and reprogram them toward their original cell type. Thus, cells retain a genetic memory which we hope to exploit,” said Pamela Itkin-Ansari, Ph.D., adjunct professor in the Development, Aging, and Regeneration Program at Sanford-Burnham and lead author of the study published today in the journal Pancreas.

E47 turns the clock back

The study, a collaborative effort between Sanford-Burnham, UC San Diego, where Itkin-Ansari holds a joint appointment, and Purdue University, generated human cell lines to make higher than normal levels of E47. The increased amount of E47 caused cells to stall in the G0/G1 growth phase, and differentiate back toward an acinar cell phenotype.

In vivo studies showed that when the reprogrammed cancer cells were introduced into mice, their ability to form tumors was greatly diminished compared to untreated adenocarcinoma cells.

“Presently, is treated with cytotoxic agents, yet the average survival for patients post-diagnosis is merely six months, and the improvements in therapies are measured in days,” said Andrew M. Lowy, M.D., professor of surgery at the UC San Diego Moores Cancer Center and co-chair of the National Cancer Institute’s Pancreatic Cancer Task Force. “The finding that we can differentiate these back to a non-threatening phenotype is encouraging. Indeed, there is a precedent for cell differentiation therapy in that the approach has been used to treat acute promyelocytic leukemia (APL) and some neuroblastomas successfully.”

“Our next step is to test primary patient-derived tumor tissue to determine whether E47 can produce similar results, potentially providing a novel therapeutic approach to combat this highly lethal disease,” said Itkin-Ansari. “Additionally, we are screening for molecules—potential drugs—that can induce overexpression of E47.”

Pancreatic adenocarcinoma

Pancreatic adenocarcinoma is the most common form of pancreatic cancer. It’s primarily caused by a mutation in the oncogene called Kras that causes the digestive enzyme-secreting cells () to differentiate into a destabilized duct-like cell type, which is cancerous. The disease is often called a “silent” cancer because it rarely shows early symptoms—it tends to be diagnosed at advanced stages when it causes weight loss, abdominal pain, and jaundice.