Case Western Reserve University School of Medicine researchers published a study in The American Journal of Human Genetics identifying the hereditary components of colorectal cancer (CRC.) “Identification of Susceptibility Genes for Cancer in a Genome-wide Scan: Results from the Colon Neoplasia Sibling Study” is the first large linkage study of families with CRC and colon polyps in the country. Because only five percent of CRC cases are due to known gene defects, this NIH-funded study is designed to identify the remaining CRC-related susceptibility genes. The team built on a previous study which identified a specific region on chromosome 9q that harbors a CRC susceptibility gene. Upon review of a whole genome scan of all chromosome pairs in 194 families, the researchers were able to identify additional CRC gene regions on chromosomes 1p, 15q, and 17p.

While the overall Case Western Reserve University School of Medicine study looked at families with colon cancer and colon polyps, the study also analyzed families with different clusters of cancer, such as CRC with multiple polyps and CRC with breast cancer. These different phenotypes appeared to link to different chromosomal regions, which the study teams says supports the idea of multiple susceptibility genes causing different types of cancers. These links will be further investigated in the next phase of the study.

“The goal of our study is to identify the CRC genes in susceptible patients to better understand who may be prone to develop CRC and why,” said Georgia L. Wiesner, M.D., lead author of “Identification of Susceptibility Genes for Cancer in a Genome-wide Scan: Results from the Colon Neoplasia Sibling Study.” “This study is step towards future the of genetic CRC testing.”

The genome-wide scan used in this study will help physicians elucidate the genetic factors in CRC in the future. Once the genes are identified, physicians will be able to use these genetic markers to identify “at risk” patients and to develop better cancer screening strategies, such as colonoscopies well before standard screening begins at age 50. Currently, without new gene tests, family history is the only tool to determine a person’s risk for CRC. Knowing the exact gene will allow physicians to better take care of CRC patients and lead to earlier screening.

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According to research from a team of Mayo Clinic scientists, smoking puts older women at significant risk for loss of DNA repair proteins that are critical for defending against development of some colorectal cancers.

In a study being presented at the annual meeting of the American Association for Cancer Research (AACR), the researchers found that women who smoked were at increased risk of developing colorectal tumors that lacked some or all of four proteins, known as DNA mismatch repair (MMR) proteins. These proteins keep cells lining the colon and rectum healthy because they recognize and repair genetic damage as well as mistakes that occur during cell division.

Researchers believe that, in this study population, few if any of the four proteins were absent because of an inherited genetic alteration. “We think that smoking induces a condition within intestinal cells that does not allow MMR genes to express their associated proteins, and this loss leads to formation of tumors in some women.”

Mayo gastroenterologist, Paul Limburg, M.D. said, “Our findings suggest that tumors may form because cells can’t repair themselves from damage induced by smoking. Tobacco toxins appear to block the DNA repair genes from producing their beneficial proteins.”

“We are beginning to realise that there might be different risk factors for different subsets of colon and rectal cancers. Smoking is emerging as a potentially important, modifiable risk factor among postmenopausal women,” he says.

He added, “The findings also could have other clinical implications with respect to chemotherapy, as tumors that lack MMR proteins might respond differently to standard treatment regimens.”

The research team examined data from the 41,836-participant Iowa Women’s Health Study and selected those 1,421 women who developed colorectal cancer since the study began in 1986. They then worked with the Iowa Cancer Registry and pathology laboratories around the state to collect tumor specimens from these patients.

When the scientists examined colorectal cancers in female smokers with the perspective of MMR-deficient gene involvement, there was a strong association between smoking and MMR-negative status. For example, former smokers had a 61 percent increase in relative risk for MMR-negative colorectal cancer compared to never smokers, and current smokers were more than twice as likely to develop colorectal tumors with absent mismatch repair proteins.

Dr Limberg saus, “The association between smoking and MMR-negative colorectal cancer also steadily increased with the number of cigarettes a woman smoked per day. The relative risk for MMR-negative cancer increased 54 percent if a patient smoked 1–19 cigarettes daily, more than twofold for 20 cigarettes a day, and more than threefold for a woman who smoked more than 30 cigarettes daily.”

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Chemotherapy given both before and after surgery to remove liver metastases (secondary cancers) improves progression free survival over surgery alone in patients with metastatic colorectal cancer, concludes a study published recently in The Lancet. The phase III European Organization for Research and Treatment of Cancer (EORTC) study demonstrated that perioperative chemotherapy (i.e. that given before and after surgery) was compatible with major liver surgery.

Liver metastases are found in 40 to 50% of the nearly one million people diagnosed in the world each year with colorectal cancer. Despite advances in chemotherapy five year survival for metastatic colorectal cancer is less than 5%. In the subset of patients where surgery to remove liver metastases (resection) is possible, five year survival increases to 60 %. Recurrence after surgery in this group, however, is common. It has been suggested that the combination of chemotherapy and surgery can reduce the risk of relapse. The rationale for this is that preoperative chemotherapy allows surgery to be undertaken on tumours that have shrunk in size, while postoperative chemotherapy acts on any cancer cells remaining in the liver.

This multi-centre trial, which was led by Bernard Nordlinger, from the Hôpital Ambroise Paré ( Paris, France), and involved researchers from Europe, Australia and Hong Kong, set out to investigate whether combining perioperative chemotherapy with surgery could reduce the risk of relapse compared to surgery alone. The collaboration represents one of the few studies to have investigated combining chemotherapy with surgery in such patients, and is the first to assess the benefits of preoperative chemotherapy.

In the trial, 364 patients, with histologically proven colorectal cancer and up to four operable liver metastases, were randomised to receive surgery alone (n=182) or surgery plus the FOLFOX4 chemotherapy regimen with six cycles before and six cycles after (n=182). The FOLFOX4 regimen consisted of calcium folinate (leucovorin), followed by bolus injection of 5-fluorouracil and a 22 hour infusion of 5-fluorouracil on days one and two, and oxaliplatin on day one. Patients were recruited from 78 hospitals in 11 countries.

Upon further evaluation, 11 patients in each arm were found to be ineligible for inclusion so that in total 152 patients in the surgery alone group and 151 in the chemotherapy and surgery group underwent liver surgery.

In an intention to treat analysis results show that progression free survival does not differ significantly between the two groups (P=0.058 versus the required P=0.0434). However a second analysis, just including the patients who were able to undergo surgery, shows that the progression free survival at three years was 33.2 % in the surgery only group versus 42.4 % in the adjuvant chemotherapy group (HR 0.73, P=.025). This was statistically significant and represents an absolute increase in progression free survival of 9.2 %. Progression free survival is defined as the time until progression, recurrence or death. Overall survival is still being monitored.

The most common adverse events seen with preoperative chemotherapy included neutropenia, diarrhoea, stomatitis/pharyngitis and neurological toxicities. Similar side effects were seen following postoperative chemotherapy with the exception of stomatitis/pharyngitis. Reversible post operative complications (such as biliary fistula, hepatic failure, wound infection and urinary infection) occurred more frequently in patients who had received chemotherapy than the surgery only group (25 % versus 16%, p=0.04).

“We conclude that perioperative FOLFOX4 chemotherapy reduced the risk of events of progression free survival by a quarter and was compatible with major surgery,” writes Nordlinger and colleagues, adding that although the trial was restricted to patients with four or fewer metastases, the conclusions are likely to be valid for those at higher risk. Future trials, they add, should look at more intense chemotherapy or combinations with targeted agents.

In an accompanying editorial Scott Kopetz and Jean-Nicolas Vauthey, (University of Texas MD Andersen Cancer Centre, Houston, TX),write: “Despite the modest benefits on progression-free survival, this study clearly shows the advantage of preoperative FOLFOX to select the patients most likely to benefit from hepatic resection.”

The study, they add, confirms the importance of multidisciplinary care and the improved outcomes that can be achieved when the best of medical and surgical oncology are integrated.

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Regular monitoring with positron emission tomography (PET) scanning – which detects changes in the function of cells – achieves earlier detection of recurrences of colorectal cancer than conventional scanning that simply looks at the structure of body tissues, a prospective study has shown.

Colorectal cancer – cancer affecting the lower part of the digestive tract – is the second most common cause of cancer-related deaths in Western countries. Most people newly diagnosed with the disease undergo surgery to completely remove their tumour. However, approximately half of people who have curative surgery go on to develop recurrent disease. The median survival after surgery is two years. Adjuvant chemotherapy – anticancer drug treatment given just after surgery – improves the prognosis, but one-third of patients having this treatment still suffer a recurrence within two years after surgery.

Surgery to remove metastases in the liver or lung in people who have a recurrence of colorectal cancer improves survival so that 35-40% are alive after five years. This means that it is very important to follow up patients with colorectal cancer regularly to detect recurrence as early as possible so that tumour tissue can be removed and their chances of survival improved. Most people have regular clinical examinations and computed tomography (CT) scans, which provide detailed images of structures inside the body, to look for signs of recurrence.

French researchers carried out a study to see if functional positron emission tomography (PET) imaging – looking at the function of body cells by measuring their use of a radio-labelled isotope of glucose (18fluorodeoxyglucose, 18FDG) – could detect recurrences of colorectal cancer earlier than CT imaging. They randomly allocated 130 patients who had undergone curative surgery for colorectal cancer followed by chemotherapy to regular follow-up with conventional tests or with PET scans.

All the patients had six follow-up appointments, starting from the ninth month after their initial surgery and continuing to 24 months or their death. They had a physical examination, measurement of biological markers for cancer, an ultrasound scan every three months (replaced by abdominal CT scans after 9 and 15 months) and a chest X-ray every six months. Patients in the PET group also had 18FDG-PET scans after 9 and 15 months.

Results showed that recurrence occurred in 46 patients – 25 in the FDG-PET group and 21 in the group having conventional follow-up. Use of PET scans revealed unexpected tumours in a further three patients.

Recurrences were detected after a significantly shorter time with PET scanning (12.1 months, on average) compared with conventional follow-up (15.4 months, P=0.01). Recurrences in the PET group were also more frequently cured by surgery, with 10 patients with recurrence being cured, compared with only two patients in the group not having PET scans.

Professor Iradj Sobhani, Université Paris 12 et Hôpital Henri Mondor, Paris, France, and lead author of the study, commented: “We showed that FDG-PET is a valuable adjunct to conventional follow-up. Using this new follow-up strategy increased the rate of curative resection by allowing us to detect recurrences of colorectal cancer at an earlier stage.” He added: “Regular FDG-PET monitoring in the follow up of colorectal cancer patients may permit the earlier detection of recurrence. We would expect improved patient survival if such as follow-up programme was undertaken.”

PET scanners have now been developed that can detect smaller tumours than the machine used in the French study. The study authors noted that coupled PET and CT scans appears to provide more accurate diagnoses than using the techniques separately. They predicted that using combined PET-CT scans would make it easier to correctly determine the stage of a patient’s cancer, although more research is needed to confirm this.

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