By Laura Sussman

A select number of high-risk pancreatic cancer patients initially deemed inoperable are, in fact, eligible for surgery and have a chance for a cure, thanks to a treatment protocol pioneered at MD Anderson.

The protocol combines a more accurate reading of CT scans, the use of chemo-radiation upfront and an advanced surgical resection of the pancreas and removal and reconstruction of appropriate blood vessels.   Jason Fleming, M.D., associate professor in the Department of Surgical Oncology and the study's lead author, says that collaboration between surgeons, radiologists, medical oncologists is also paramount.

Adenocarcinoma of the pancreas is the most common and lethal type of the disease, with a five-year survival rate of just 5%. According to the American Cancer Society, an estimated 43,920 new cases of pancreatic cancer will be diagnosed in the United States in 2012, with approximately 37,390 deaths expected. Surgical removal of the pancreas, known as the Whipple procedure, is a patient's best chance for survival, yet, currently, just 20% of patients are eligible for the high risk procedure.

Published in the Journal of American College of Surgeons, the MD Anderson study enrolled 88 high-risk pancreatic cancer patients from 1990-2010. All were initially told at outside institutions that they were surgical candidates; however, upon opening, their tumors were deemed more extensive and, thus, inoperable. They then were referred to MD Anderson for care.

Of these 88 patients, 66 were able to complete the MD Anderson protocol regimen, culminating with the removal of their tumor.  In surgical patients, the median survival was 29.6 months, compared to 10.6 months and 5.1 months in those with locally advanced disease at their time of referral or those who developed metastatic disease before resection, respectively.
 
"This exciting news was that of the 88 patients, 60 percent could have their tumor successfully removed, even though they had had surgery before and it was deemed unresectable, or not removable," said Fleming. "Even more exciting to us is that the survival of those patients who can have surgery here is the same as our group of patients on whom we do surgery first."

Fleming discusses the significance of the findings here:

By Will Fitzgerald

During the next two decades, breast cancer diagnoses in older women are expected to increase by 57%. It's a reality that highlights the importance of understanding this demographic and the unique management decisions associated with their treatment.

New research led by Benjamin Smith, M.D., in the Department of Radiation Oncology, found that a clinical tool, or nomogram, demonstrates accuracy in predicting which women are likely to benefit from radiation therapy.  The tool compiles readily available clinical and pathological data including age, race, tumor size and estrogen receptor status.

The study, published in the Journal of Clinical Oncology, examined 16,092 women ages 66--79 who were treated with breast-conserving surgery.  The primary outcome was mastectomy-free survival (MFS) at five and 10 years. Overall, the five- and 10-year rates of MFS were 98.1% percent and 95.4% percent respectively.

"We thought it was relevant and interesting to look at the risk of mastectomy after initial treatment for breast cancer, see if radiation therapy made a difference and then develop a tool to individualize recommendations based on a person's risk profile," Smith said.

Individualizing Treatment

Beyond providing baseline estimates of MFS, the tool provides physicians with individual estimates for whom radiation therapy might, or might not be effective.

For example, a 75-year-old woman with a 1.5 cm ER-positive tumor and node-negative disease who underwent radiation therapy, yields an estimated 10-year MFS of 97%. However, if this same patient did not receive radiation therapy, the 10-year MFS rate would be 95%, suggesting radiation offers limited benefit.

Additional studies are needed to more accurately determine the risk of recurrence for certain subgroups of older populations.

"Although no nomogram is perfect, it's step forward to actually have a validated model based on the outcomes of 16,000 patients," Smith said.

Additional resources:

JCO study and podcast

MD Anderson news release

The protein Grb2, once considered merely a passive link between other proteins, acts as an on-off switch for a critical growth signaling pathway, MD Anderson scientists report this week in the journal Cell..

Grb2, pronounced "Grab2," binds to the fibroblast growth factor receptor (FGFR) to control normal signaling through the FGF pathway, a research team led by John Ladbury, Ph.D., professor in MD Anderson's Department of Biochemistry and Molecular Biology.

In addition to this basic science discovery, the team's findings provide a potential explanation for how genomic changes found in breast, bladder and gastric cancer and melanoma tumors might promote cancer development and progression.

In each case, the portion of the gene that encodes FGFR's internal signaling domain is abnormal, Grb2 binds to the receptor at that spot to control signaling to other proteins.

"If Grb2 can't bind to FGFR there, that could lead to the FGFR pathway being turned on constantly," Ladbury said.

Like "a car idling in neutral" but ready to go

As a receptor tyrosine kinase, FGFR has a docking station to receive growth factors on the cell's surface and an internal domain that relays growth factor signaling on to proteins in the cell by attaching phosphate groups to them.

A gene most commonly known as a tumor-suppressor appears to help breast cancer cells survive treatment by a common chemotherapy drug.

  

In the June 12 edition of Cancer Cell, MD Anderson researchers report that normal p53 thwarts the effects of doxorubicin while mutated versions of the gene improved the drug's effect. Doxorubicin is an anthracycline, a class of antibiotics used to treat a variety of cancers.

 

The p53 gene regulates the cell cycle. It's capable of stopping division when flaws in the cell are detected, summoning repair proteins to deal with DNA damage, or ordering the cell to kill itself (apoptosis) if the defects are beyond repair

.

"It's really important to understand the genetic defects a tumor cell has before we treat it," said lead author Guillermina Lozano, Ph.D., professor and chair of MD Anderson's Department of Genetics. "What we learned here is the complete opposite of what we expected. We thought tumors would respond better to treatment if the p53 gene were normal. But the opposite was true, and for a really interesting reason."

 

Normal p53 halted cell division after detecting DNA damage done by the drug. This inability to divide, called senescence, allowed the cells to survive.

 

These cells, Lozano and colleagues found, produce cell-signaling molecules called cytokines that stimulate adjacent cancer cells to grow, leading to relapse.

 

Mutant p53 cells do not arrest. Instead, they proceed through the cell cycle into cell division with broken chromosomes caused by the chemotherapy. "That's a signal for the cell to die," she said. "It can't go any farther."

 

Mice with normal p53 treated with doxorubicin had less tumor shrinkage, quicker relapse and no sign of cancer cell death. Those with mutated p53 had greater tumor regression and p53-independent cell death. The same effect was observed in human tumor cell lines.

 

By Jennifer Litton, M.D.

The Annual American Society of Clinical Oncology (ASCO) meeting will be discussing several new drugs in development. We have been investigating targeted therapies for many years, several with significant promise. These therapies work on a specific pathway that either speeds up cell division or lengthens the tumor cell survival.

Although we have had significant improvements in outcomes for our patients with these drugs, there are just too many of these pathways going on in the same tumor cell at the same time. 

It is important to note that even in this era of personalized medicine, we are not likely to find that one singular drug that will eradicate the disease. Instead, we will be looking at trying to simultaneously shut down the tumor from all directions. Chemotherapy, targeted therapies and what I hope will be one of the major game changers in this disease is the harnessing of the immune system.

We are hearing about new therapies such as Trastuzumab DM-1. This is an exciting therapy engineered to combine the immune system as the delivery of a lethal drug directly into the tumor cells, with minimal toxicity and improved results for patients. Also other stories include using a compound pd-1 which will help the T cells find the tumor and kill the tumor. 

As these tumor cells become more and more genetically abnormal, using the immune system may be even more important.