Breast cancer drug pushes colon cancer cells to their death

ScienceDaily (June 9, 2011) — 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.

See Also:Health & MedicineColon CancerLung CancerCancerBreast CancerBrain TumorLymphomaReferenceTumor suppressor geneMonoclonal antibody therapyMetastasisTumor

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

Folic acid given to mother rats protects offspring from colon cancer

ScienceDaily (May 26, 2011) — Folic acid supplements given to pregnant and breast-feeding rats reduced the rate of colon cancer in their offspring by 64 per cent, a new study has found.

See Also:Health & MedicineFolic AcidVitamin BNutritionVitaminColon CancerGastrointestinal ProblemsReferenceNutrition and pregnancyB vitaminsSpina bifidaVitamin

The research, led by Dr. Young-in Kim, a gastroenterologist at St. Michael's Hospital, adds to the growing but sometimes contradictory evidence that folic acid supplementation during pregnancy and lactation can increase or decrease the development or progression of some pediatric malignancies and common cancers in their offspring in adulthood.

For example, a separate study by Kim published in February found the daughters of rats who were given folic acid supplements before conception, during pregnancy and while breast-feeding have breast cancer rates twice as high as other rats who were not given the supplements. They also had more tumours and developed them at a faster rate.

Kim said these studies collectively suggest that folic acid may have drastically different effects on cancer development in different organs, that specific organs may have different needs for folate, its natural form, or metabolize it differently. He said more studies, including human studies, were needed.

Kim's new study, published in Gut, an international journal in gastroenterology, is the first to find that folic acid supplements at the level ingested by North American women of childbearing age "significantly protects against the development of colorectal cancer in the offspring."

Folate is known to help make DNA and help it replicate.

"It appears that giving folic acid during pregnancy and lactation reduces DNA damage and suppresses the proliferation of cells in the colon," Kim said. "It actually increases the stability of the DNA and this might be one of the mechanisms of how folic acid in utero may protect against colon cancer."

The amount of folic acid to which fetuses are exposed has increased dramatically in North America in the past decade. Natural folate is found in grains and dark, leafy vegetables. Women are routinely advised to take folic acid supplements before becoming pregnant and while pregnant to prevent neural tube birth defects such as spina bifida.

Since 1998, the Canadian and U.S. governments have required food manufacturers to add folic acid to white flour, enriched pasta and cornmeal products as a way of ensuring women receive enough of the B vitamin. In addition, up to 40 per cent of North Americans take folic acid supplements for possible but as yet unproven health benefits.

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New test targets Lynch syndrome, a risk factor for colon cancer

ScienceDaily (May 18, 2011) — Mayo Clinic has developed a screening procedure that could dramatically increase testing for Lynch syndrome, a hereditary genetic disorder that raises cancer risk, particularly for colorectal cancer. An estimated 3 percent of colon cancers can be attributed to Lynch syndrome. At least 80 percent of people with Lynch syndrome develop colorectal cancer, many of them before age 50.

See Also:Health & MedicineColon CancerPersonalized MedicineToday's HealthcareDiseases and ConditionsWounds and HealingBreast CancerReferenceColorectal cancerMammographyMetastasisBreast cancer

In the past, as few as 50 percent of patients who fit the profile for possible Lynch syndrome were tested before or after surgery. Now, a group of Mayo Clinic researchers has developed and tested a protocol that could raise the level of testing to nearly 90 percent, helping doctors make important decisions on the timing and delivery of care for patients with the disease. Their findings were presented at The American Society of Colon and Rectal Surgeons Annual Scientific Meeting, May 14-18, 2011 in Vancouver, British Columbia, Canada.

Mayo Clinic researchers in 2003 started testing all newly diagnosed colorectal cancers in patients under 50. Biopsies of the cancers were sent to pathologists, who conducted Microsatellite Instability (MSI) testing on them. MSI testing looks for certain mutations in genes that repair DNA by testing 10 different DNA markers for irregularities. Patients categorized in the "high" group for microsatellite instability were offered additional testing for Lynch syndrome and genetic counseling.

Over the five-year study, 210 of 258 newly diagnosed patients under age 50 who underwent colorectal cancer surgery at MCR had the MSI testing. Of those, 13 percent had MSI-H tumors. Overall, 88 percent of the high-risk group had tests, and the protocol caught 11 percent of MSI-H tumors that would have otherwise been missed.

"Probably the most significant result of this research is that it has stimulated our multidisciplinary team of geneticists, pathologists, gastroenterologists and surgeons to develop new clinical pathways that will direct patients at risk to providers experienced with management of Lynch Syndrome," says Eric Dozois, M.D. who has organized the multidisciplinary Young Onset Working Group and is the lead researcher on this project. This ensures appropriate evaluation and genetic and surgical counseling before critical treatment decisions are made, thus allowing patients and referring physicians to be fully informed regarding options for treatment, especially risks and benefits.

"The benefit of this testing to the patient and their family is huge," says research fellow Rajesh Pendlimari, M.B.B.S. "If they have Lynch syndrome and will, therefore, be more prone to getting cancer, they can get screened more regularly. Plus, with it being a hereditary condition, family members can also get tested." As a result of this testing, cancer may be caught earlier and physicians may be more proactive in treatment. The testing should be done before surgery, because a diagnosis may change the course of treatment. Testing after surgery also is beneficial; the knowledge gleaned can affect future care for patients and their families.

The study's other researchers are Noralane Lindor, M.D.; Stephen Thibodeau, Ph.D.; Thomas Smyrk, M.D.; David Larson, M.D.; Robert Cima, M.D.; Lisa Boardman, M.D.; Nancy You, M.D.; and Jennifer Wang, M.D.

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New treatment regimen shows clinical benefit in advanced colon cancer

ScienceDaily (May 21, 2011) — A new treatment regimen for patients with metastatic colon cancer appears to offer clinical benefit even when used after multiple other treatments have failed, say research physicians at Georgetown Lombardi Comprehensive Cancer Center, a part of Georgetown University Medical Center.

See Also:Health & MedicineBreast CancerColon CancerLung CancerCancerOvarian CancerLeukemiaReferenceMetastasisTumor suppressor geneTumorGlioma

The research team found that combining a PARP inhibitor with chemotherapy (temozolomide) offers significant benefit in patients who had no further treatment options. However, the study is small, and does not include a comparison arm, so further investigation is needed, they add. The study will be presented in an oral session on Saturday, June 4th, at the 2011 annual meeting of the American Society of Clinical Oncology in Chicago.

PARP, short for "poly (ADP-ribose) polymerase" is a key part of a cell's DNA repair apparatus, and is important for protecting our normal cells against DNA damage. However, cancer cells become resistant to chemotherapy in part by increasing PARP expression and thus rapidly repairing DNA damage intentionally caused by chemotherapy. PARP inhibitors are designed to overcome a cancer cell's ability to repair the damaged DNA. (They are showing promise in both breast and ovarian cancers, and are being studied in a variety of other cancer types).

In this clinical study, doctors administered a potent DNA-damaging chemotherapy, temozolomide, with a PARP inhibitor called ABT-888. The theory is that ABT-888 will diminish the ability of these cancer cells to fix the damage that was just inflicted by the temozolomide, pushing the cancer into a death spiral.

"This is a classic one-two punch: the chemotherapy damages the cancer cells and the PARP inhibitor prevents it from fixing itself, leaving the cell to die," says lead author, Michael Pishvaian, M.D., Ph.D., an assistant professor at Georgetown Lombardi.

This single-arm, phase II study enrolled 49 patients with metastatic disease who were not eligible for surgery and had exhausted all of the standard therapies currently used. Despite having advanced cancer, all study participants were still active at work or home. Researchers found the drug combination controlled cancer growth for nearly six months in 23 percent of the patients, with two patients having a significant reduction in their tumor burden (partial response).

Pishvaian explains, "The treatment was extremely well tolerated, so to have a period of six months with no tumor growth, but also no significant side effects was really meaningful for the patients."

In addition, researchers were able to collect samples of the patients' tumors for further molecular analysis. "By testing tissue samples and identifying their molecular fingerprints, perhaps we can identify which patient subgroups are most likely to respond to this new therapeutic combination," concludes Pishvaian.

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DNA repair system affects colon cancer recurrence and survival

ScienceDaily (May 20, 2011) — Colorectal cancer patients with defects in mismatch repair--one of the body's systems for repairing DNA damage--have lower recurrence rates and better survival rates than patients without such defects, according to a study published online May 19th in the Journal of the National Cancer Institute.

See Also:Health & MedicineColon CancerBirth DefectsGenesBrain TumorDiseases and ConditionsLung CancerReferenceBRCA1Tumor suppressor geneDNA repairBRCA2

About 15% of colorectal cancers are associated with mismatch repair defects. Some defects are caused by the inherited gene mutations found in Lynch syndrome and others occur by chance, or "sporadically." But it has never been clear whether mismatch repair defects are linked to cancer recurrence rates, time-to-recurrence and site of recurrence and whether such defects influence response to chemotherapy.

To explore these questions, Frank A. Sinicrope, M.D., of the Mayo Clinic in Rochester, Minn., and colleagues analyzed data from more than 2,000 clinical trial patients who had been treated after surgery with chemotherapy that included 5-fluorouracil (5-FU), a standard drug used in colorectal cancer. All patients had stage II or III colon cancer.

The patients with defective mismatch repair had lower rates of tumor recurrence, longer remissions, fewer metastases, and better survival rates compared to those without the defects. Both overall survival and disease-free survival were improved.

Whether mismatch repair status influences response to 5-FU therapy has been a subject of some debate. In this study treatment with 5-FU reduced recurrence rates in stage III, regardless of mismatch repair status, but not stage II patients.

The researchers also compared the effects of 5-FU-based therapy in patients thought to have inherited mismatch repair defects versus those whose defects occurred sporadically. They suggest that 5-FU appeared to reduce recurrences only in those with inherited defects.

"In conclusion," they write, "our data demonstrate that patients with defective mismatch repair colon cancers have a statistically significant reduction in their rates of tumor recurrence, a delayed time to recurrence, and better survival rates" than those without the defects. They note that the difference between inherited and sporadic tumors, though a preliminary finding, warrants further study.

In an accompanying editorial, Sabine Tejpar,M.D., Ph.D., of University Hospital Gasthuisberg, Leuven, Belgium, and colleagues note that the influence of mismatch repair defects on patients' prognosis and response to 5-FU has long been a contentious issue. They say that this study, with its large number of samples, provides "valuable information about the prognostic and certainly the predictive role" of mismatch repair defects. The editorialists conclude that it will be important to validate whether patients should have their mismatch repair defects identified as hereditary or sporadic before deciding on chemotherapy with 5-FU.

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