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P-53 BOOSTING DRUGS COULD BE DANGEROUS TO CANCER PATIENTS

The genome guardian's dimmer switch: Regulating p53 is a matter of life or death

June 30th, 2011 in Genetics 

 

Scientists at the Salk Institute for Biological Studies have found clues to the functioning of an important damage response protein in cells. The protein, p53, can cause cells to stop dividing or even to commit suicide when they show signs of DNA damage, and it is responsible for much of the tissue destruction that follows exposure to ionizing radiation or DNA-damaging drugs such as the ones commonly used for cancer therapy. The new finding shows that a short segment on p53 is needed to fine-tune the protein's activity in blood-forming stem cells and their progeny after they incur DNA damage.

"It's like a dimmer switch, or rheostat, that helps control the level of p53 activity in a critical stem cell population and the offspring they generate," says Geoffrey M. Wahl, professor in the Salk Institute's Gene Expression Laboratory, and senior author of the study, which appears online in the journal Genes & Development on July 1, 2011. "In principle, controlling this switch with drugs could reduce the unwanted effects from DNA-damaging chemotherapy or radiation treatment, allowing higher doses to be used."

The protein p53 is an important tumor suppressor because it can destroy or halt the growth of cells that develop potential cancer-causing DNA mutations. But as Wahl's lab and others have shown over the past several years, p53 has much broader importance in the life and death of cells. "It's critical for determining whether a cell survives stress and continues to function in a variety of situations," says Wahl.

One problem with p53 is that it apparently evolved to protect the integrity of the genome for future generations, rather than to prolong the lives of individual cells or animals. From the point of view of an animal, p53 sometimes goes too far in killing cells or suppressing growth. Experiments in mice have suggested that even modest reductions in p53's activity greatly increases survival after exposure to radiation, without raising the long-term cancer risk to unacceptable levels.

Scientists therefore are eager to find out how cells naturally regulate p53, so that they can target these mechanisms with drugs. One clue uncovered by recent studies is that regulatory molecules can alter p53 activity by chemically modifying some key amino acids. In the current study, Wahl and colleagues set out to illuminate the function of a stretch of regulatory amino acids at one end of the protein by creating "designer" mice with other amino acids in this region, thereby rendering it inoperative.

The mutant mice had somewhat higher p53 activity than normal mice, at least in some tissues. Based on other studies, Wahl's team expected the mutants to age faster. To their surprise, however, the mutant mice lived about as long as ordinary, "wild type" mice. A second surprise came when Wahl's team exposed the mice to ionizing radiation, of the sort that nuclear power plants may emit. While all the normal mice survived, half the mutant mice died within four weeks.

To understand why the mutant mice died so readily, Vivian Wang, a postdoc in Wahl's lab, collaborated with the Salk veterinarian, Mat Leblanc, and hematologists at UCSD and noted that the irradiated mutant mouse hearts became enlarged and pale, as if they had been starved of oxygen. "Eventually, we found the reason for this," Wahl explains. "We found that irradiation and the ensuing p53 response significantly damaged the blood-forming cells of their bone marrow, but other parts of their bodies seemed quite normal. We followed up these studies with stem cell transplantation experiments to show the mutant p53 really affected the stem cells and their descendents that make the blood."

These results led the team to conclude that the loss of function of p53's normal "dimmer-switch" segment had allowed the protein to become too active in the hematopoietic stem cells of the mutant mice, arresting the stem cells' proliferation and preventing them from replacing the blood cells lost to irradiation. "If the stem cells and their descendants are arrested for too long, they can't recover fast enough, and the mice eventually die of the effects of insufficient oxygenation of critical tissues," Wahl says.

The team then studied how p53 activation could cause these cells to arrest for too long. Using sophisticated new techniques, they found that p53 lacking its "dimmer switch" turned on too much of a gene called p21, which acts as a brake to halt cells from dividing. "To confirm the significance of that finding, we created mice that expressed the mutant p53, but had only one instead of the normal two copies of p21," Wahl says. "This reduced p21 levels after irradiation. Remarkably, this was enough to significantly reduce the mortality of the 'dimmerless' p53 mice. They were much less sensitive to radiation when they just had one less copy of p21."

The study underscores the importance of an evolutionarily conserved regulatory segment of p53 and the importance of p53 activity in the response to conditions that produce DNA damage. "Our study indicates that the amount of damaged DNA caused by radiation or toxins, isn't the sole determinant of life or death," says Wahl. "The extent to which p53 is also very important."

One implication of this research is that drugs to lower p53 levels, or to reduce its transcription of other growth-stopping genes such as p21, might be used temporarily to reduce unwanted tissue damage from DNA-altering drugs or radiation. Another implication is that p53-boosting drugs, which are currently being tested in cancer patients, could have dangerous side effects if used in combination with other drugs that cause DNA damage. "Our mouse model suggests that if you use a p53-activating agent, the last thing you should do is combine it with a general DNA-damaging chemotherapy or radiotherapy," Wahl says.

Provided by Salk Institute

 

"The genome guardian's dimmer switch: Regulating p53 is a matter of life or death." June 30th, 2011. http://medicalxpress.com/news/2011-06-genome-guardian-dimmer-p53-life.html

 

CHANGING CHEMO MAKES NO DIFFERENCE IN ADENOCARCINOMA

Chemo Changes Fail to Improve Surgical Outcomes in Rectal Cancer

Elsevier Global Medical News. 2011 Jun 29, R Hyer

 

CHICAGO (EGMN) - An effort to bolster standard preoperative chemoradiotherapy with capecitabine and oxaliplatin failed to improve surgical outcomes in a four-armed, phase III clinical study of 1,608 patients with stage II and III rectal adenocarcinoma.

Results were similar whether the preoperative regimen contained capecitabine (Xeloda) or continuous venous infusion (CVI) 5-fluorouracil (5-FU); the addition of oxaliplatin (Eloxatin) increased toxicity without changing outcomes, regardless of which regimen was used.

"For the surgical outcome analysis, administration of capecitabine with preoperative radiotherapy achieved rates similar to CVI 5-FU for surgical down-staging, sphincter-saving surgery, and [pathological] complete response," said Dr. Mark S. Roh, who presenting the results of the NSABP (National Surgical Adjuvant Breast and Bowel Project) R-04 trial at the annual meeting of the American Society of Clinical Oncology.

"Addition of oxaliplatin did not improve outcomes and added significant toxicity," added Dr. Roh, chairman of surgery at M.D. Anderson Cancer Center Orlando.

The current standard of care for T3-4 rectal cancer is preoperative chemoradiotherapy with CVI 5-FU. It has a distant relapse rate of 24%-30%, and compliance is suboptimal, he said. The trial was initiated, therefore, in the hope that more effective systemic chemotherapy would improve compliance, decrease the locoregional tumor relapse rate, and increase survival.

"The thought was that giving more effective systemic therapy up front perhaps would decrease the distant relapse rate," said Dr. Roh.

Evaluation of these end points is yet to come, with the final assessments of locoregional tumor relapse and disease-free and overall survival rates to be presented in 2013.

NSABP R-04 was activated in 2004 as a two-arm noninferiority study comparing CVI 5-FU with oral capecitabine, in both cases delivered with preoperative radiotherapy. With the Food and Drug Administration's approval of oxaliplatin, the trial was amended in 2005 to include it, and the design was changed to a 2 x 2 factorial with the oxaliplatin comparison looking for superiority. During radiation therapy, 5-FU and capecitabine were reduced from 7 to 5 days each week. The trial was closed in August 2010.

All four groups received 4,600 cGy plus 540-1,080 cGy radiation. Chemotherapy dosages were 5-FU (CVI 225 mg/m² on 5 days per week for 5-6 weeks) in group 1; the same dosage of 5-FU plus oxaliplatin (50 mg/m² once weekly for 5 weeks) in group 2; oral capecitabine (825 mg/m² twice daily on 5 days per week for 5-6 weeks) in group 3; and same dose of capecitabine plus oxaliplatin (50 mg/m² once weekly for 5 weeks) in group 4.

More than half of the patients were stage II. About two-thirds of the population were men. At randomization, sphincter-sparing surgery was the intent in about three-quarters of the cases.

The only significant difference between arms of the study was that oxaliplatin increased grade 3/4 diarrhea (15.4% vs. 6.6% without oxaliplatin; P =.0001).

Surgical down-staging rates were similar in comparisons of 5-FU vs. capecitabine (20.7% and 23%, respectively) and oxaliplatin vs. no oxaliplatin (19.2% and 23%, respectively).

Nor was there any difference in sphincter-saving surgery rates by treatment (61.7% with 5-FU and 62.5% with capecitabine; 60.4% with oxaliplatin and 63.6% without oxaliplatin).

And there was no statistically significant difference in R-04 node positivity among the various treatment groups. The rates were about 70% with no positive nodes and about 90% with 0-3 positive nodes regardless of treatment?

Surgical complication rates also did not differ significantly among the groups; the rate of any complication was 34.92% with 5-FU, 37% with 5-FU plus oxaliplatin, 36.89% with capecitabine, and 40.2% with capecitabine plus oxaliplatin.

For pathological complete response, outcomes also were similar at 22.2% with capecitabine and 18.8% with 5-FU; they were 20.9% with oxaliplatin, and 19.1% without.

Discussant Dr. Robert Glynne-Jones of the Mount Vernon Centre for Cancer Treatment in Northwood, England, praised the study and its 2 x 2 factorial design as "a very nice study, very large numbers." He said the design allowed investigators to look at individual components and "see which is doing the work." He also said that this study would not change his clinical practice.

Dr. Roh stated that he had no relevant relationships to disclose. Dr. Glynne-Jones disclosed research funding from Roche.

 

CANCER CELLS MORPH INTO STEM CELLS

New Clues to How Cancer Spreads

ScienceDaily (June 28, 2011) — Cancer cells circulating in the blood carry newly identified proteins that could be screened to improve prognostic tests and suggest targets for therapies, report scientists at the Duke Cancer Institute.

Building on current technologies that detect tumor cells circulating in blood, the Duke team was able to characterize these cells in a new way, illuminating how they may escape from the originating tumors and move to other locations in the body.

The circulating tumor cmoponents include proteins normally seen when embryonic stem cells begin to specialize and move through the body to develop organs such as the heart, bones and skin, the Duke scientists reported this month in the journal Molecular Cancer Research.

The discovery may enhance the accuracy of blood tests that detect circulating cancer cells, giving doctors better information to gauge how a patient's disease is responding or progressing.

"By developing a better blood test based on our findings, we may be able to identify molecular targets for therapy tailored to an individual patient's cancer," said Andrew J. Armstrong, M.D., ScM, assistant professor of medicine at Duke and lead author of the study.

The Duke team isolated tumor cells from blood samples of 57 patients, including 41 men with advanced prostate cancer and 16 women with metastatic breast cancer.

In the tumor cells of more than 80 percent of the prostate cancer patients and 75 percent of those with breast cancer, the researchers detected a group of proteins normally seen during embryonic development when stem cells begin to assume distinct roles.

As stem cells morph to build tissue and organs, they switch back and forth in what is known as epithelial-mesenchymal transition (EMT) and it's opposite, mesencymal-epithelial transition (MET). Cancer cells have that same ability, changing from an epithelial cell similar to the organs from which they arose, to a mesenchymal or connective tissue-like cell. This EMT may underlie much of the treatment resistance and ability of cancer cells to spread.

Current FDA-approved blood tests that detect circulating tumor cells flag molecules associated with epithelial transitions; however, the Duke team found additional markers associated with mesenchymal origins, adding new targets that could be used to enhance the usefulness and sensitivity of the tests.

"Cancer is a hijacking of that normal embryonic stem cell process," Armstrong said. "It reactivates this silent program that is turned off in adult cells, allowing tumor cells to move throughout the body and become resistant to therapy."

Armstrong said the involvement of EMT/MET processes in tumor growth is a relatively new finding that is gaining acceptance among cancer scientists. The discovery by the Duke team adds strong evidence that the EMT/MET processes are underway when a patient's cancer is spreading.

"In my opinion this work presents some of the most compelling data for the existence of epithelial-mesenchymal transitions in human cancer," said Mariano A. Garcia-Blanco, professor of medicine, molecular genetics and microbiology, and senior author in the work.

"This work should pave the way for studies to understand the mechanisms underlying these transitions in humans and their importance in disease progression and therapy," said Garcia-Blanco, who is also director of the Duke Center for RNA Biology.

The Duke team additionally noted that tumor cells appear to be most dangerous when they can easily transition between EMT and MET in a stem cell-like phase of changability that enables them to grow, spread and resist treatment.

That finding could provide new opportunities for novel therapies that target these morphing mechanisms.

"This is not just for a biomarker, it's a direction to take therapies as well," Armstrong said. "It's a new horizon."

In addition to Armstrong and Garcia-Blanco, study authors include Matthew S. Marengo; Sebastian Oltean; Gabor Kemeny; Rhonda L. Bitting; James Turnbull; Christina I. Herold; Paul K. Marcom; and Daniel George.

The study was funded with grants from the National Institutes of Health; the Department of Defense Prostate Cancer Research Program; the Prostate Cancer Foundation; the American Cancer Society; and the Duke Cancer Institute.

Armstrong, Oltean, George and Garcia-Blanco have a patent application for the biological process used for detecting the blood markers.

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The above story is reprinted (with editorial adaptations by ScienceDaily staff) from materials provided by Duke University Medical Center.

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Journal Reference:

1. A. J. Armstrong, M. S. Marengo, S. Oltean, G. Kemeny, R. Bitting, J. Turnbull, C. I. Herold, P. K. Marcom, D. George, M. Garcia-Blanco. Circulating Tumor Cells from Patients with Advanced Prostate and Breast Cancer Display Both Epithelial and Mesenchymal Markers. Molecular Cancer Research, 2011; DOI: 10.1158/1541-7786.MCR-10-0490

 

POLYP DETECTION DEPENDS ON TIME OF DAY!

Multiple Factors Influence Detection of Colorectal Adenomas

Elsevier Global Medical News. 2011 Jun 6, C Helwick

 

CHICAGO (EGMN) - Several modifiable technical factors can influence detection of colorectal adenomas, as can lifestyle factors, based on data from a large study conducted in the United Kingdom.

The findings came from the National Health Service (NHS) Bowel Cancer Screening Program, the largest study to examine the effects of patient and physician factors on adenoma detection during colonoscopy. The colonoscopies in this study were done to follow-up on positive fecal occult blood test (FOBT) results, said Dr. Tom J. Lee of Newcastle (U.K.) University, who presented the data at the annual Digestive Disease Week.

"Many factors affect the chance of an adenoma being detected," he said, "including patient factors, both modifiable and nonmodifiable, and colonoscopy factors, which are usually technical."

The NHS program offers a colonoscopy to any person aged 60-74 years who has a positive FOBT result. "It is a unique opportunity to study the interplay of factors that influence adenoma detection," Dr. Lee said.

From 2006 to 2009, fecal occult blood tests were returned by 2,269,983 persons (mean age 66 years; 60% male), and 2% of these were positive. The total number of colonoscopies (performed by 177 experienced endoscopists at 50 screening centers) was 36,460, of which 31,088 were included in this analysis. Of the patients who underwent colonoscopy, 14,423 (46%) had at least one adenoma.

Data were collected on cecal intubation, rectal retroversion, mean withdrawal time for the endoscopist, quality of bowel prep, use of the antispasmodic hyoscine butylbromide, start time of the procedure, and sedation use. Patient factors included gender, age, smoking and alcohol status, and geographic area.

Adverse lifestyle can negate protection for women

In the multivariate analysis, risk for adenomas was significantly associated with male gender, older age, current or previous smoking, and current alcohol use.

Men were more likely than women to have adenomas, and poor lifestyle habits elevated the risk further beyond that from gender alone. Among patients who did not drink or smoke, 45% of men had one or more adenomas, compared with 32% of women.

In men, this rate rose progressively according to alcohol and smoking status, exceeding 60% for men who reported current smoking and alcohol intake, Dr. Lee said. The same pattern held true for women; those reporting current alcohol intake and cigarette use had a 43% risk of having an adenoma.

All the associations were highly significant for the detection of any adenomas, advanced adenomas, and right-sided adenomas at a P value less than .001.

"Female smokers who drink had a significantly higher risk than men who did not smoke or drink. We found that adverse lifestyle factors can overcome gender protection from adenomas in females," Dr. Lee reported. "This stresses the importance of lifestyle factors in the development of adenomas."

In addition, older age was a significant factor, as was geographic area, even after adjustment for other factors. "There was a significant variation in risk depending on where the procedure was done," he said.

Technical factors linked to detection rate

The technical or procedural factors that were significantly associated with detection of adenomas were cecal intubation, longer withdrawal time, higher-quality bowel preparation, use of an intravenous antispasmodic, earlier procedure start time, and greater colonoscopist experience, Dr. Lee reported.

Similar results were found for the effect of these factors on detection of advanced adenomas and right-sided adenomas.

Procedures in which the cecum was reached had a threefold greater likelihood of detecting adenomas overall (P less than .001), and a more than fivefold greater likelihood in the right colon (P less than .001). A mean withdrawal time for the endoscopist greater than or equal to 10 minutes increased the detection rate by 10% overall and by 28% in the right colon (P less than .001). Bowel prep that was adequate or better was associated with an almost 40% increased chance for detection (P less than .001) and the use of hyoscine was associated with a 30% increase (P less than .001), although it is possible that hyoscine use is "an indicator of a good colonoscopist," Dr. Lee suggested.

The association with the time of day offers "fascinating insight into colonoscopists' behavior," he added. As the day progressed from 8 a.m. to noon, there was no change in cecal intubation, bowel prep, or withdrawal times, but adenoma detection diminished from nearly 48% to 45%. Adenoma detection rates rose again until 3 p.m., then dropped back to around 45%, creating a "biphasic" pattern, he noted.

"Interestingly, procedures in which rectal retroversion was performed were not associated with increased detection of one or more adenomas and did not increase the detection of rectal adenomas," he added. There was also no association with sedation.

Dr. Lee acknowledged the study's limitations: it was not a randomized controlled trial, certain risk factors (family history, NSAID use) were not accounted for, and the scoring tools were also not validated, especially for bowel prep quality.

"Our study probably raises more questions than it answers," he acknowledged. Further study of geographical variations, time of day variations, and nontechnical colonoscopy factors should be performed, he suggested. Meanwhile, at least one current recommendation can be emphasized: that colonoscope withdrawal time should be at least 10 minutes, he said.

Dr. Lee had no relevant financial disclosures.

 

RADIOTHERAPY FOR COLON CANCER

Efficacy and Safety of Intraoperative Radiotherapy in Colorectal Cancer: A Systematic Review

Cancer Lett. 2011 Jul 28;306(2):121-133, P Cantero-Muñoz, MA Urién, A Ruano-Ravina

TAKE-HOME MESSAGE

This analysis of the role of intraoperative radiotherapy added to conventional treatment showed that the technique reduces the rate of local recurrence and does not increase treatment-related toxicity in patients with colorectal cancer.

Abstract

Intraoperative radiotherapy (IORT) has been proposed as an encouraging treatment for colorectal cancer. The aim of this study is to assess the efficacy and safety of IORT for this cancer through a systematic review. Studies located in electronic databases were selected according to established criteria, read and analysed and the results extracted by two independent reviewers. Fifteen studies met the selection criteria. Five-to-six-year local control (LC) was over 80% and 5-year overall survival (OS) was close to 65%. For recurrences, the 5-year overall survival was 30%. The main acute complications were gastrointestinal. Adding IORT to conventional treatment reduces the incidence of local recurrences within the radiation area over 10%. IORT is a safe technique as it does not increase toxicity associated with conventional treatment.

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TREATMENT OUTCOMES FOR APPENDIX CANCER

Systemic Chemotherapy and Surgical Cytoreduction for Poorly Differentiated and Signet Ring Cell Adenocarcinomas of the Appendix

Ann Oncol. 2011 Jun 8;[Epub Ahead of Print], CH Lieu, LA Lambert, RA Wolff, C Eng, N Zhang, S Wen, S Rafeeq, M Taggart, K Fournier, R Royal, P Mansfield, MJ Overman

TAKE-HOME MESSAGE

This single-center retrospective study found that systemic chemotherapy is a viable option for treating metastatic poorly differentiated and signet ring cell adenocarcinomas of the appendix and that complete cytoreduction correlates with improved survival.

SUMMARY

OncologySTAT Editorial Team

Appendiceal adenocarcinomas are a rare and histologically diverse group of cancers; patient prognosis varies significantly by tumor biology. Most of these tumors are slow growing and do not develop extraperitoneal metastases, and the standard treatment is complete cytoreductive surgery (CRS), followed by hyperthermic intraperitoneal chemotherapy. Tumors with poorly differentiated or signet ring cell histology, however, tend to be more aggressive, with studies suggesting worse outcomes for patients with these tumor histologies. As treatment response in patients with poorly differentiated and/or signet ring cell tumor histology has not been evaluated, Lieu et al conducted a single-center retrospective study to examine the effects of CRS and systemic chemotherapy on survival in this subset of patients with appendiceal adenocarcinoma.

The study included patients who were treated for appendiceal adenocarcinoma at MD Anderson Cancer Center (Houston, TX) between September 1992 and January 2010 and who were identified as having either poor tumor differentiation or signet ring cell histology. Study patients (n = 142; median age, 52 years) were histologically grouped for analysis into those with poorly differentiated adenocarcinomas with/without focal signet ring cells (n = 114 [80%]), those with signet ring cell adenocarcinomas (n = 19 [13%]), and those with well- or moderately differentiated adenocarcinomas with focal signet ring cells (n = 9 [6%]). Patients’ medical records were reviewed for patient and tumor characteristics, treatment history, treatment response, laboratory tumor markers, disease progression, and survival. Patients with peritoneal metastases who underwent CRS were divided into those with no visible remaining disease following CRS (complete cytoreduction score of 0 [CC-0]) and those with visible remaining disease ≤ 2.5 mm (CC-1). For systemic chemotherapy evaluation, patients had to have visible radiographic disease prior to chemotherapy, to receive at least one cycle of chemotherapy, and to undergo follow-up radiographic evaluation; only patients with radiographic improvement were considered to have a response to chemotherapy.

Study endpoints were progression-free survival (PFS), relapse-free survival (RFS), and overall survival (OS) by Kaplan–Meier method. OS for the overall study population was calculated from date of diagnosis to death. For the chemotherapy and CRS subgroups, PFS and OS were calculated from the date of initial chemotherapy and the date of CRS, respectively.

Median follow-up was 4.5 years. All patients with metastatic disease at presentation (n = 123) had peritoneal disease; 12 (10%) also had extraperitoneal disease. Of patients with metastatic disease, 78 underwent first-line systemic chemotherapy with radiographic follow-up; the overall radiographic response rate was 44%. In the chemotherapy cohort, median PFS was 6.9 months (95% CI, 5.3–9.2), and median OS was 1.7 years (95% CI, 1.4–2.3). In a multivariate analysis of this subset, achieving a chemotherapy response correlated with improved PFS (hazard ratio [HR], 0.49; 95% CI, 0.27–0.89; P = .02), and achieving a complete CRS correlated with improved OS (HR, 0.26; 95% CI, 0.10–0.66; P = .004).

Of patients with metastatic disease, 26 had complete CRS (15 with CC-0; 11 with CC-1). In the CRS cohort, median RFS after resection was 1.2 years (95% CI, 1.05–7.08), and median OS was 4.2 years (95% CI > 2.55). In a multivariate analysis of this cohort, achieving a CC-0 resection correlated with both improved RFS (HR, 0.07; 95% CI, 0.01–0.53; P = .01) and improved OS (HR, 0.02; 95% CI, 0–0.37; P = .01).

This single-center retrospective study suggests that systemic chemotherapy is a viable treatment option for patients with metastatic poorly differentiated and/or signet ring cell appendiceal adenocarcinoma. In addition, CRS may offer survival benefits for those patients in whom complete CRS (no visible remaining disease) is considered feasible.

 

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MARKER FOUND FOR HEREDITARY COLON CANCER

Hereditary colon cancer syndrome marked by abnormally dense blood vessel growth in mouth

June 23rd, 2011 in Cancer 

 

A team led by Johns Hopkins researchers has found that a hereditary colon cancer syndrome, familial adenomatous polyposis (FAP), is associated with abnormally dense blood vessel growth in the skin lining the mouth.

The finding, reported in the June issue of Familial Cancer, could lead to a quick screening test for FAP, which is normally diagnosed with expensive DNA tests and colonoscopies, and sometimes goes unnoticed until cancer develops.

"This higher blood vessel density in the mouth may reflect an abnormal state of cells lining the digestive tract – including the oral cavity – that predisposes people to colorectal cancer and precancerous polyps," says Francis M. Giardiello, M.D., Johns G. Rangos Sr. Professor of Medicine at Johns Hopkins and director of Hopkins' Hereditary Colorectal Cancer Program.

People who have even one copy of the mutant gene that causes FAP develop hundreds of precancerous colorectal polyps, also known as adenomas, in their teens. Most have their colons removed after diagnosis to avoid what would otherwise be a near-100 percent risk of colon cancer by middle age.

In 2003, Italian researchers reported that a similar genetic condition, hereditary non-polyposis colorectal cancer (HNPCC), was linked to a greater complexity of blood vessels in the oral mucosa – the skin that lines the mouth. Daniel L. Edelstein, a senior research program coordinator at Johns Hopkins University School of Medicine, says he read the Italian report and brought it to Giardiello's attention.

Edelstein also contacted Jessica C. Ramella-Roman, an expert on bio-optics systems at The Catholic University of America. "She developed a cameralike device that enabled a direct and relatively automated measurement of this vascular density in the lining of the mouth," he says.

Using Ramella-Roman's device and associated image-analysis software, the researchers scanned a two-centimeter-square patch of oral mucosa inside the lower lip of 33 patients with FAP. All 33 were enrolled in the Johns Hopkins Hereditary Colorectal Cancer Registry. The team also scanned a similar tissue sample of 50 control subjects who were matched for age and other variables but had no personal or family history of colorectal cancer or adenoma(s). Each subject was screened to determine the density of visible blood vessels in their lower lip – a measure they called the "oral mucosal vascular density (OMVD)."

"The OMVD measures were significantly higher in FAP patients than in healthy controls," says Giardiello. "About 90 percent of FAP patients in this sample had OMVD values above a certain threshold, and about 90 percent of controls were below that threshold, so in principle, we could use that threshold for screening purposes." Differences in the OMVD results were unrelated to age or gender, according to the researchers.

To further investigate the technique's screening potential, the researchers gave the OMVD test to five of Giardiello's patients who had multiple polyps but no detectable mutation for FAP or HNPCC on genetic tests. "They might have other, unknown gene mutations predisposing them to polyp formation, or they might have FAP or HNPCC mutations that somehow weren't picked up in the tests," said Giardiello.

All five of these patients had OMVD scores above the high-risk threshold. "The results suggest that this high-OMVD condition may be an alternative marker for colon cancer risk, even when we can't find a gene mutation," Giardiello says.

Tumors typically promote the spread of new blood vessels in their vicinity to maintain their high growth rates. FAP mutations also boost the production of factors that increase new-vessel growth in the colon and other tissues. That could explain why people with FAP have higher vascular densities in their mouths, says Giardiello.

"While there seems to be a reason why FAP patients have this denser vessel growth, I don't yet have a plausible explanation for how HNPCC gene mutations could cause this overgrowth," says Giardiello. "It's something that we'd like to investigate further."

Provided by Johns Hopkins Medical Institutions

 

"Hereditary colon cancer syndrome marked by abnormally dense blood vessel growth in mouth." June 23rd, 2011. http://medicalxpress.com/news/2011-06-hereditary-colon-cancer-syndrome-abnormally.html

 

MARRIAGE IS EARLY WARNING SYSTEM FOR COLON CANCER

Marriage improves odds of surviving colon cancer

June 21st, 2011 in Cancer 

 

(Medical Xpress) -- A new study shows that being married boosts survival odds for both men and women with colon cancer at every stage of the disease.

Married patients had a 14 percent lower risk of death according to researchers at Penn State’s College of Medicine and Brigham Young University. That estimate is based on analysis of 127,753 patient records.

Similar to studies of other types of cancers, the researchers did find that married people were diagnosed at earlier stages of colon cancer and sought more aggressive treatment. The researchers took those and other factors into account before calculating the benefit of marriage on survival odds.

“Controlling for the stage that the cancer was detected is key,” said Sven Wilson, a study coauthor and professor at Brigham Young University. “Without that, it’s hard to know whether the analysis is just picking up a diagnosis effect.”

Colon cancer is the fourth most common type of cancer in the United States for both men and women. Curiously, the marriage benefit seen in the new study was nearly identical for both men and women.

So what’s driving the different survival rates? Marriage is a self-selected group, and Wilson is careful to note that the selection process makes it difficult to sort out the root cause. One intuitive idea is that spouses serve as an important informal caregiver during a critical time, and that extra support may translate into better disease management and, hence, better outcomes.

The journal Cancer Epidemiology published the new study online in advance of its print publication. Penn State’s Li Wang is the lead author. BYU graduate Chris Hollenbeak, who is now a faculty member at Penn State’s College of Medicine, is also a coauthor on the study.

Provided by Brigham Young University

 

"Marriage improves odds of surviving colon cancer." June 21st, 2011. http://medicalxpress.com/news/2011-06-marriage-odds-surviving-colon-cancer.html

 

METASTATIC COLON CANCER INHIBITED BY DRUG FROM TAPEWORM

Tapeworm drug inhibits colon cancer metastasis

June 17th, 2011 in Cancer 

A compound that for about 60 years has been used as a drug against tapeworm infection is also apparently effective against colon cancer metastasis, as studies using mice have now shown. The compound silences a gene that triggers the formation of metastases in colon cancer. Professor Ulrike Stein (Experimental and Clinical Research Center, a joint cooperation between the Charité Medical Faculty and the Max Delbrück Center for Molecular Medicine, (MDC)) and her research group made this discovery in collaboration with Professor Robert H. Shoemaker of the National Cancer Institute (NCI) in Frederick, Maryland. Plans are already underway with Professor Peter M. Schlag (Charite Comprehensive Cancer Center) to conduct a clinical trial.

Colon cancer is one of the most common tumor diseases in Western countries. In Germany alone, there are approximated 73 000 new cases of the disease every year. Despite surgery, chemotherapy and radiation therapy, only about half of the affected patients are cured.

The reason is that around 20 percent of the colon cancer patients already have metastases at diagnosis and in about one third of the patients, metastasis occurs despite successful initial treatment. Of these patients with metastatic colon cancer, the five-year survival rate is only about 10 percent. By contrast, for nonmetastatic colon cancer patients the survival rate is 90 percent.

Scientists have known for several years that the gene S100A4/metastasin can initiate colon cancer metastasis. Five years ago Professor Stein, working together with Professor Schlag and Professor Walter Birchmeier (MDC), showed how this gene is regulated. They found that the beta-catenin gene, when mutant, activates this S100A4/metastasin gene, thus triggering colon cancer metastasis. Beta-catenin normally regulates cellular adhesion.

The scientists looked for compounds that block the expression of the metastasin gene. They screened 1280 compounds and found what they were looking for: niclosamide, a drug until now approved for use to treat intestinal parasite infections from tapeworms.

Surprisingly, the researchers discovered that niclosamide inhibits the beta catenin-driven expression of the S100A4/metastasin gene, both in the cell culture and in mice. The animals had fewer metastases. Next, the researchers want to conduct clinical trials to find out whether the compound is also effective in patients with metastasizing colon cancer.

More information: Journal of the National Cancer Institute, Vol. 103, No. 12, June 17, 2011.

Provided by Helmholtz Association of German Research Centres

 

"Tapeworm drug inhibits colon cancer metastasis." June 17th, 2011. http://medicalxpress.com/news/2011-06-tapeworm-drug-inhibits-colon-cancer.html

 

COMBO TREATMENT GETS COLON CANCER VICTIMS NEARLY 4 YEARS

Cetuximab Plus Irinotecan, Fluorouracil, and Leucovorin As First-Line Treatment for Metastatic Colorectal Cancer: Updated Analysis of Overall Survival According to Tumor KRAS and BRAF Mutation Status

J Clin Oncol. 2011 Apr 18;[Epub Ahead of Print], E Van Cutsem, CH Köhne, I Láng, G Folprecht, MP Nowacki, S Cascinu, I Shchepotin, J Maurel, D Cunningham, S Tejpar, M Schlichting, Zubel A, I Celik, P Rougier, F Ciardiello

TAKE-HOME MESSAGE

In post-hoc analysis of the phase III CRYSTAL study, KRAS wild-type status was associated with improved outcomes in response to cetuximab plus FOLFIRI compared with FOLFIRI alone, while BRAF mutations were associated with poorer outcomes.

SUMMARY

OncologySTAT Editorial Team

Cetuximab is a monoclonal antibody targeting the epidermal growth factor receptor (EGFR). In phase III studies, cetuximab has been shown to improve outcomes when added to standard chemotherapy for treatment of metastatic colorectal cancer. The Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) study showed reductions in risk of progression and tumor response in patients who received cetuximab in addition to a chemotherapy regimen of irinotecan, infusional fluorouracil, and leucovorin (FOLFIRI). In particular, the benefits of cetuximab appeared to be limited to patients whose tumors were wild-type at the KRAS gene. This study is an updated analysis of the CRYSTAL study that evaluates outcomes after a longer follow-up time and in a larger number of patients evaluated for KRAS status. In addition, the significance of the BRAF gene, which is a downstream effector of KRAS was evaluated.

This was a retrospective subgroup analysis of KRAS mutation status in patients enrolled in an open-label, randomized, multicenter, phase III study of cetuximab plus FOLFIRI or FOLFIRI alone as first-line treatment for metastatic colorectal cancer.

The intention to treat (ITT) population comprised 1198 patients who were randomly assigned to receive cetuximab plus FOLFIRI (n=599) or FOLFIRI alone (n=599). The original analysis of KRAS evaluated 540 patients; this study extended the analysis to a total of 1063 patients (89%), with a median follow-up time of 46.8 months for the cetuximab plus FOLFIRI group and 46.2 months for the FOLFIRI alone group. A total of 487 patients (81%) died in the cetuximab plus FOLFIRI group, compared with 502 (84%) in the FOLFIRI alone group. Addition of cetuximab improved overall survival time (19.9 months vs 18.6 months; hazard ratio [HR], 0.878; 95% confidence interval [CI], 0.774 to 0995; P =.0419). Tumor tissue in 397 of 1063 patients (37%) had mutations in KRAS codons 12 or 13. More patients had KRAS mutations in the cetuximab plus FOLFIRI group than in the FOLFIRI alone group (40% vs 34%).

Among patients whose tumors were wild-type for KRAS, cetuximab plus FOLFIRI resulted in significantly reduced risk of disease progression (median progression free survival [PFS], 9.9 vs 8.4 months; HR, 0.96, P= .0012), significantly improved overall survival (23.5 vs 20.0 months; HR, 0.796; P = .0093), and significantly increased odds of response (best overall response rate 57.3% vs 39.7%; odds ratio, 2.069; P <.001) compared with FOLFIRI alone. Among patients with wild-type KRAS, those in the cetuximab plus FOLFIRI group who developed early acne-like rash had significantly prolonged survival time compared with those who did not develop early acne-like rash (26.4 vs 19.1 months).

Among patients with mutations in KRAS, the addition of cetuximab did not improve PFS, overall survival, or best overall response. KRAS mutations were associated with worse overall survival in both treatment groups compared with wild-type. Treatment effect and KRAS mutation status were associated with significant interaction effects for PFS (P =.0028), overall survival (P =.0463), and best overall response (P =.0005).

A total of 60 of 999 (6%) tumor samples evaluated for both BRAF and KRAS had BRAF V600E mutations. All but 1 patient with BRAF were wild-type for KRAS. Patients who were wild-type for both genes who received cetuximab plus FOLFIRI had significantly reduced risk of disease progression (HR, 0.637; P =.0037) and significantly increased odds of response (odds ratio, 2.175; P <.001) compared with FOLFIRI alone, but overall survival no longer differed significantly between treatment groups. BRAF mutation status was not associated with a significant treatment interaction effect, but was associated with worse outcomes in both treatment groups. KRAS mutation status was not associated with differences in safety outcomes.

 

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HEATED CHEMO BEING EVALUATED

Colon cancer 'chemobath' evaluated

June 10th, 2011 in Cancer 

(Medical Xpress) -- As part of a multicenter clinical trial, surgical oncologists at UC San Diego Moores Cancer Center are comparing the effectiveness of standard chemotherapy to a tri-modality approach to halt advanced colon cancers. The objective is to determine if there is a difference in survival rates between patients who receive intravenous (IV) anti-cancer drugs or a combination of IV drugs in addition to surgery and a procedure called hyperthermic intraperitoneal chemotherapy, more commonly known as HIPEC or "chemobath."

“This will be the most comprehensive study to date to examine an aggressive approach to treating colon cancers that have spread to the abdominal lining,” said Dr. Andrew Lowy, chief of surgical oncology at Moores Cancer Center. “The study will also compare quality of life, cancer progression by cell subtype, toxicity levels and the reaction of the tumor cellsto intervention.”

The 5-year research study, funded by the National Cancer Institute, will recruit 360 colon cancer patients. Based on significant experience with the chemobath, Moores Cancer Center was selected as one of only 10 national sites to initially enroll patients. In this randomized trial, all patients will receive the best available drugs; however, one group will also undergo surgery combined with both direct- and IV-drug delivery. When treated with chemotherapy alone, patients with peritoneal metastases have an average life expectancy of 12 to 15 months.

“Colorectal cancer that has spread to the abdominal surface is extremely difficult to eradicate with surgery alone,” said Lowy. “A tiny tumor hidden in the anatomy or just a few remaining cancer cells can later spread to other areas. We hope to show that optimal treatment must be not only immediate but multidisciplinary.”

The surgical arm of the clinical trial consists of two parts. In the first part, called cytoreductive surgery, surgeons inspect the entire abdominal cavity to remove all visible signs of malignancy. Once all suspicious growths are removed, the patient is prepared for the HIPEC or chemobath.

During the chemobath, drugs are circulated throughout the abdomen via catheters that form a circuit. The fluid containing the chemotherapy is continuously heated to 106 to 107 degrees and washed over the internal organs. After 90 minutes, the solution is removed. The exposure of the tumor cell to the drug can be as much as 75-fold that which can be administered intravenously.

Traditionally, patients are administered chemotherapy by IV, but this approach is ineffective in obliterating tumors that are unattached to the bloodstream because the drug cannot reach the tumor cells. With the chemobath, the heated chemotherapy drug is poured directly into the abdomen. The combination of direct contact and heat make the tumor cells more susceptible to chemotherapy.

According to Lowy, while this approach is logical and its efficacy has been suggested by many small studies, its widespread adoption as a standard therapy requires testing in a study where patients are randomized to receive the current standard (IV chemotherapy only) or the proposed new standard (IV chemotherapy + surgery + HIPEC).

Patients who are enrolled to the IV chemotherapy arm may receive surgery and HIPEC if their disease is not responsive to their chemotherapy treatment.

Provided by University of California - San Diego

 

"Colon cancer 'chemobath' evaluated." June 10th, 2011. http://medicalxpress.com/news/2011-06-colon-cancer-chemobath.html

 

NEW ABDOMINAL CANCER EARLY DETECTION TEST

Simple test could hold key to early diagnosis of cancers

June 9th, 2011 in Cancer 

 

Cancers of the gut, stomach and pancreas could be detected much sooner with a simple urine test, research suggests.

Researchers at the University of Edinburgh have identified key proteins in the urine of patients with advanced cancers.

The findings could help the detection of these cancers in people who have not yet started to show symptoms of the disease.

This would enable patients to be diagnosed much earlier, leading to improved survival rates.

Only around 10 per cent of patients with these cancers – known as cancers of the upper gastrointestinal tract – are still alive five years after diagnosis.

This is because such cancers, which tend to be aggressive, are often diagnosed at an advanced stage.

Dr Holger Husi, of the University of Edinburgh's Tissue Injury and Repair Group, said: "The aim of this work is to enable these cancers to be diagnosed much earlier. This would help us to treat the cancer before it has a chance to spread. The majority of these cancers are currently diagnosed late where no surgery is possible due to its advanced stage. Earlier diagnosis would mean that curative surgery or chemotherapy would be possible for more patients."

The research, published in the journal Proteomics-Clinical Applications, compared urine samples from patients with upper gastrointestinal cancers with urine samples from people who were cancer-free.

Scientists analysed the samples to identify thousands of proteins. They then identified six particular proteins, which were present in 98 per cent of the cancer cases but absent in almost 90 per cent of samples from patients without cancer.

The researchers then narrowed molecules down to the two proteins – S100A6 and S1009 – most likely to appear in samples from patients with cancer but be absent from the other samples.

The scientists now intend to see whether people with early stage cancers, which have not yet been diagnosed, have the same levels of proteins present.

This would involve analysing samples from at least 1,000 volunteers and tracking the participants over a number of years to identify those who are then later diagnosed with upper gastrointestinal cancers.

Provided by University of Edinburgh

 

"Simple test could hold key to early diagnosis of cancers." June 9th, 2011. http://medicalxpress.com/news/2011-06-simple-key-early-diagnosis-cancers.html

 

1-2 PUNCH KILLS COLON CANCER CELLS

Breast cancer drug pushes colon cancer cells to their death

June 8th, 2011 in Cancer 

 

A new treatment for colon cancer that combines a chemotherapy agent approved to treat breast cancer and a cancer-fighting antibody is ready for clinical trials, according to Penn State College of Medicine researchers.

More than 150,000 cases of colorectal cancer are diagnosed each year, and about 50,000 people die from colorectal cancer yearly. Currently there are limited chemotherapy treatments for colorectal cancer with little that has been in the pipeline in recent years.

Wafik S. El-Deiry, M.D. Ph.D., American Cancer Society Research Professor and Rose Dunlap Professor and chief of hematology/oncology, and his team have tested lapatinib, a targeted chemotherapy agent currently approved for breast cancer treatment, in a new combination with artificial antibodies that mimic a natural cancer-fighting protein produced in the human body. The monoclonal antibodies mapatumumab and lexatumumab act similarly to TRAIL -- tumor necrosis factor [TNF]-related apoptosis-inducing ligand -- a naturally occurring molecule in the body that tells a cell it is time to die. TRAIL sets a process in motion that targets and shuts down tumor cells and keeps them from spreading.

"These are therapeutic antibodies that are manufactured very efficiently, and given to patients," said El-Deiry, who is also the associate director for translational research, CancerInstitute.

The TRAIL receptors -- death receptors -- on the cancer cells respond to TRAIL by dying. The artificial antibodies act as surrogates of TRAIL by activating the same signaling pathway resulting in tumor cell death.

The monoclonal antibodies have an advantage over TRAIL because they remain active in the body for a longer period of time. TRAIL receptor antibodies last for less than 30 minutes, while the artificial monoclonal antibodies last for about nine days. Although the antibodies can act similarly to TRAIL, they do not completely substitute for TRAIL and ultimately which one gets used in what situation is still being tested in clinical trials. But for the purpose of these new advances either one works.

Lapatinib increases the amount of "death receptor" protein available for TRAIL to do its job -- killing off cancerous cells -- El-Deiry and his colleagues report in this week's issue ofScience Translational Medicine.

The researchers tested the lapatinib and monoclonal antibody combination in mice. Separately, the two treatments did not increase tumor cell suppression -- but when the drugs were administered together, the researcher found that cell death escalated.

"We have discovered a mechanistic basis for combining these drugs that says one drug upregulates the receptor for the other drug, and maybe now when we combine these two drugs we'll get an even better synergy between them," said El-Deiry. "I think that's probably the most exciting result, to be able to provide a molecular rationale for a new treatment combination for difficult-to-treat advanced colorectal cancers."

The Food and Drug Administration approved lapatinib in 2007 for use as a breast cancer chemotherapy. It blocks two specific types of proteins located on tumor cell surfaces from causing tumors to grow. These proteins are a potent way that tumors are signaled to grow -- and if the proteins are blocked, there is one less mechanism for tumors to proliferate. However, in the treatment El-Deiry has proposed, lapatinib would be used off-label by increasing a different tumor cell death-inducing protein to help colon cancer patients.

Provided by Pennsylvania State University

 

"Breast cancer drug pushes colon cancer cells to their death." June 8th, 2011. http://medicalxpress.com/news/2011-06-breast-cancer-drug-colon-cells.html

 

XELODA, ERBITUX USELESS IN FIGHTING COLON CANCER

Many patients with advanced cancers get treatments that won't help

June 7th, 2011 in Cancer 

 

A study of more than 1,000 patients with colon cancer that had spread to distant sites found that one in eight was treated with at least one drug regimen that was not recommended. Those patients were exposed to significant risk without proven benefits, at an estimated cost—just for the drugs—of more than $2 million.

The study, presented June 7, 2011, by University of Chicago researchers at the American Society for Clinical Oncology's annual meeting in Chicago, focused on three chemotherapy regimens that were not supported by evidence from prior clinical studies or clinical practice guidelines. One treatment was rated "insufficient data to support," one had been "shown to be ineffective," and one was supported by "no data, nor is there a compelling rationale."

"Patients with advanced cancers that do not respond to standard therapies should either be looking for clinical trials, where there is a chance for a benefit, or should have been thinking about shifting toward palliative care," said study author Jonas De Souza, M.D., a hematology/oncology fellow at the University of Chicago. "Patients should not face the risks, discomforts and costs of aggressive and often quite toxic chemotherapy with treatment regimens that did not provide a benefit in previous studies."

Under an agreement with UnitedHealthcare, a health benefits business, the researchers used de-identified medical and pharmaceutical claims data in the collaborative project. They examined claims from 7,642 colon cancer cases treated between January 2007 and June 2010, including 1,041 who developed metastatic disease. Of those 1,041 patients, 140 (13%) received treatments that were not supported by the evidence from clinical studies. Many of them received multiple cycles of non-beneficial chemotherapy.

The researchers focused on three chemotherapy regimens with specific recommendations against their use in the National Comprehensive Cancer Network (NCCN) guidelines. The regimen with insufficient data involved bevacizumab (trade name Avastin) used after the patient had progressed on a combination of that drug and chemotherapy. The treatment shown to be "ineffective" was capecitabine (trade name Xeloda) after progression on the same class of drugs. The regimen with no compelling rationale was panitumumab or cetuximab (trade name Erbitux) after progression on similar drugs.

The 140 patients received 869 cycles of chemotherapy. Some received two or more unproven treatments. 

• Ninety-one of those patients went through 632 intravenous cycles of bevacizumab, at an estimated cost of $1.3 million. Potential side effects include hypertension, heightened risk of bleeding and bowel perforation. 
• Fifty-nine patients received 218 non-evidence-based cycles of capecitabine, at a cost of more than $600,000. This drug, taken orally, can cause diarrhea, nausea, vomiting, fatigue, rash and swelling of the hands or feet. 
• Six patients underwent 19 cycles of panitumumab, at a cost of almost $70,000. This drug can trigger itching, dermatitis and rash.

"We did not study why these physicians and patients turned to unproven therapies," said co-author Caleb Alexander, M.D., associate professor of medicine at the University of Chicago. "I suspect that both patients and care providers, when facing life-threatening disease with limited options, are more willing to step outside guidelines."

 

"There could also be financial implications," he added. "A physician who has run out of options may be hesitant to send a patient to a center that has access to greater resources but may be far away."

The researchers emphasized, however, that as the costs of cancer care continue to rise, the impetus to base treatment decisions on solid evidence can only increase. "It's important to get the right medicines to the right patients," said Alexander.

"DeSouza's research highlights the importance of evidence-based treatment for cancer patients," said Lee Newcomer, M.D., UnitedHealthcare's senior vice president, oncology. "Expert oncology opinions tell us that the extra therapies that these patients received potentially exposed these patients to unnecessary side effects. We should be relieving symptoms and not causing new ones, even as we try to address the underlying disease."

Provided by University of Chicago Medical Center

 

"Many patients with advanced cancers get treatments that won't help." June 7th, 2011. http://medicalxpress.com/news/2011-06-patients-advanced-cancers-treatments-wont.html