A blood test for a metastasis-associated protein demonstrated potential for early diagnosis of colorectal and gastric cancers and for identifying tumors destined to metastasize, German investigators reported.

Comparison of blood samples from cancer patients and cancer-free volunteers showed significantly higher levels of S100A4 mRNA in 100% of the tumor specimens (P<0.0001), Ulrike Stein, PhD, of Charite University in Berlin, said at the combined clinical congress of the European CanCer Organization and the European Society of Molecular Oncology (ECCO-ESMO).

The test also distinguished metastatic from nonmetastatic disease.

“More importantly, prospective analysis of the data showed that follow-up patients who later developed metastases showed higher S100A4 levels at initial blood analysis than those whose disease did not metastasize,” Stein said in a statement. “This means that in the future we might be able to identify those patients who are likely to develop metastases.”

• Explain to patients that a blood test has shown potential as a means of diagnosing colorectal and gastric cancer and identifying patients whose disease is likely to spread to other parts of the body.
• Note that the test is not yet available and requires validation in other studies.
• Note that this study was published as an abstract and presented at a conference. These data and conclusions should be considered preliminary until published in a peer-reviewed journal.

Previous studies had shown that the S100A4 gene promotes metastasis, and the presence of S100A4 mRNA has shown diagnostic and prognostic relevance for several types of tumors. However, a blood-based assay to detect S100A4 transcripts had not been developed.

So Stein and colleagues set out to develop one using reverse transcriptase PCR analysis to examine the diagnostic and prognostic potential of S100A4 in colorectal and gastric cancer.

They collected blood samples from 466 cancer patients, including 185 with colon cancer, 190 with rectal cancer, and 91 with gastric cancer.

Levels of S100A4 mRNA in the cancer patients were compared with those of 51 cancer-free volunteers.

The investigators found not only that S100A4 mRNA levels in the cancer patients exceeded those of the volunteers, but that S100A4 levels increased with cancer stage for all three types of cancer.

Moreover, patients with metastatic colon cancer had higher levels of S100A4 mRNA compared with patients who had nonmetastatic disease.

Patients who initially had nonmetastatic cancer that subsequently metastasized, Stein and colleagues found, had elevated levels of S100A4 mRNA in the initial blood samples as compared with those from patients who did not develop metastatic disease.

“We are hoping that, by enabling the identification of those patients whose disease is likely to progress more quickly, we will be able to treat them in the future accordingly by tailoring therapy to their individual needs,” said Stein.

The data on the diagnostic potential of the test are interesting but incomplete, said Richard Schilsky, MD, of the University of Chicago. Parameters of accuracy and utility, such as sensitivity, specificity, and reproducibility have not been characterized.

“All we know at this point is that people with three different kinds of cancer seem to have elevations of S100A4 levels in their blood,” Schilsky said in an interview. “It may not be specific for the three cancers, in which case the test would be far less useful.”

The investigators also did not indicate whether the test can distinguish between cancer and other types of gastrointestinal abnormalities, he added.

The test’s prognostic potential might be easier to establish, Schilsky continued. If S100A4 is associated with metastasis, he said, test results could be combined with other staging information after surgery to help determine a patient’s risk and possibly aid in decision-making about disease management.

Primary source: European CanCer Organization and the European Society of Molecular Oncology

Source reference:
Stein U, et al “S100A4 transcripts in blood of colon, rectal, and gastric cancer patients: development of a new blood-based assay for improved diagnosis and prognosis” ECCO 15/ESMO 34 2009; Abstract 13LBA.

Scientists have discovered nine new sites in the human genome that have variants that can increase a man’s risk of developing prostate cancer by three fold. Their findings were published in two papers in Nature Genetics* yesterday (Sunday).

In the first study, an international team of scientists led by Cancer Research UK funded researchers at The Institute of Cancer Research (ICR) and the University of Cambridge** analysed variations in the genomes of almost 38,000 men and found seven regions in the genome that increase the risk of developing prostate cancer. They are located at sites on chromosomes 2, 4, 8, 11 and 22.

One of the genes, NKX3.1, could be a useful as a new target for treating prostate cancer. It helps control how cells die and when damaged can be a key element in developing cancer.

Drugs called HDAC1 inhibitors, that play a similar role to this gene, are currently in clinical trials and this research could help doctors target this treatment to men with variations in the NKX3.1 gene.

Another gene, ITGA6, could also be a potential target for new drugs. It plays an important role in cell growth, movement and survival and when overactive it is associated with some prostate cancers.

Lead author Dr Ros Eeles, from the ICR, said: “Our study adds further compelling evidence that genetic factors can influence a man’s risk of developing prostate cancer. These results will help us to more accurately calculate the risk that a man could develop prostate cancer which will enable more targeted screening. Understanding more about these genes could also lead to the development of new treatments.”

The team examined the genetic differences in 19,879 men with prostate cancer and 18,761 healthy individuals - using data from 21 studies worldwide. This looked at differences in over 43,000 SNPs, pieces of DNA that vary between individuals. The team identified seven regions that were all linked to a man’s risk of developing prostate cancer.

This research takes the total number of regions of the human genome associated with an increased prostate cancer risk to over 20.

In the second paper, the scientists studied a region on chromosome 8 which has previously been identified as having an important link to prostate cancer risk. They found two new SNPs that each, independently, affect the risk of developing prostate cancer, bringing the total number in this region to eight.

Based on all the studies to date, the scientists estimate that one in 100 men carry most of the genetic variants and their lifetime risk of developing prostate cancer is one in five compared with the average of one in ten.

Joint lead author, Professor Doug Easton, director of Cancer Research UK’s Genetic Epidemiology Unit at the University of Cambridge added: “Prostate cancer has the greatest number of independent genes affecting risk of any cancer but we still understand very little about how it develops. This study provides new clues about the processes involved, which could be used to aid the development of new treatments in the future.”

Prostate cancer is the most common cancer in men in the UK. A quarter of all new cases of cancer diagnosed in men are prostate cancers. In 2006, more than 35,000 men in the UK were diagnosed with the disease. Around seven in ten newly diagnosed prostate cancer patients now survive beyond five years. In the 1970s, when the numbers of men detected with slow growing prostate cancers were lower, it was three in ten. Each year around 10,200 men in the UK die from prostate cancer.

Harpal Kumar, chief executive of Cancer Research UK, said: “This important research increases our knowledge of how some genes can affect men’s risk of developing prostate cancer. Thanks to international collaborations like this, funded by Cancer Research UK and others, we have been able to scan the DNA of thousands of men to discover more about the genes that affect prostate cancer risk. This is ground-breaking research that we hope will open up more avenues worldwide to diagnose, prevent and treat this disease better.”

Notes

*Eeles, R.A., et al. Identification of seven novel prostate cancer susceptibility loci through a genome-wide association study, Nature Genetics, 20 September 2009

Amin A., et al. Multiple loci associated with prostate cancer susceptibility on 8q24, Nature Genetics, 20 September 2009

Link to video

This research will also be presented at the NCRI Cancer Conference on Tuesday 6 October. To find out more about the 2009 NCRI Cancer Conference, visit: www.ncri.org.uk/ncriconference

** The international team of researchers involved in this research were based at The Institute of Cancer Research; Cancer Research UK Genetic Epidemiology Unit, University of Cambridge; The Cancer Council Victoria, Australia; University of Melbourne, Australia; University of Nottingham Medical School; University of Southern California/Norris Comprehensive Cancer Centre; University of Tampere; Tampere University Hospital; Cancer Research UK Cambridge Research Institute; University of Bristol; Fred Hutchinson Cancer Research Centre, University of Washington; National Institutes of Health; University of Southern California; Keck School of Medicine; Northern California Cancer Centre, Mayo Clinic, H. Lee Moffitt Cancer Centre, Queensland Institute of Medical Research, Australia; Queensland Institute of Medical Research, Australia; Australian Prostate Cancer Research Centre-Qld; Menzies Research Institute, Australia; Institut fur Humangenetik, Germany; Clinic of Obstetrics and Gynaecology Hannover Medical School, Germany; Center for Clinical Epidemiology and Biostastics and Abramson Cancer Center, University of Pennsylvania; University of Michigan Medical School, USA; University of Utah School of Medicine, USA; University Hospitals of Geneva, Switzerland; Institut Central des Hopitaux Valaisans, Switzerland; School of Medicine, University of Birmingham; Maastricht University Medical Centre, The Netherlands; Medical University - Sofia, Bulgaria; Second Military University Hospital, Shanghai; Institute of Cancer, Queen Mary, University of London; McGill University, Canada; Chulabhorn Cancer Research Centre, Thailand; Cancer Research Centre, University of Hawaii; Institute for Cancer Studies, University of Sheffield; Viertel Centre for Research in Cancer Control, Australia; University of Queensland, Australia.

Family history and prostate cancer risk

A family history of prostate cancer is one of the strongest known risk factors for this disease. It has been estimated that 5-10 per cent of all prostate cancer cases and 30-40 per cent of early-onset cases (men diagnosed under the age of 55 years) are caused by inherited susceptibility genes.

Risk increases two to three times for men with a first-degree relative diagnosed with prostate cancer. If the relative is less than 60 years old at diagnosis or more than one relative is affected (at any age), the individual’s risk is four times the average. These factors combine so that if more than one relative is affected by early-onset prostate cancer, the risk is increased by seven-fold.

A strong family history of breast cancer may also affect a man’s risk of prostate cancer, particularly if the family members were diagnosed under the age of 60. In particular, germline mutations in the breast cancer susceptibility genes, BRCA1 and BRCA2, can predispose men to prostate cancer.

Recently, genome-wide association studies have identified several genetic variants that each slightly increase prostate cancer risk. However, because such genetic variants are common in the population, they may contribute to a significant proportion of all prostate cancer cases. Current research in this area is likely to identify further variants in the next few years. Genetic profiling is being used to inform prostate screening and treatment.

Source
The Institute of Cancer Research

Cancer Research UK

Women given a more intensive ‘dose-dense’ regimen of chemotherapy survive longer and have a higher-rate of progression free survival, concludes an Article published Online First in an upcoming edition of The Lancet. The Article is written by Dr Noriyuki Katsumata, National Cancer Center Hospital, Tokyo, Japan, and colleagues.

Paclitaxel and carboplatin given every 3 weeks is currently considered standard first-line chemotherapy for advanced epithelial ovarian cancer. Paclitaxel and carboplatin have been combined with other drugs, given either concurrently or sequentially, in the hope of prolonging survival in women with advanced ovarian cancer, but the results of several randomised trials have been disappointing. Dose-dense weekly administration of paclitaxel is another strategy to enhance antitumour activity and prolong survival. In this study, the authors compared a conventional regimen of paclitaxel and carboplatin with a dose-dense weekly regimen in women with advanced ovarian cancer.

Patients with advanced epithelial ovarian cancer, fallopian tube cancer, or primary peritoneal cancer were eligible for this phase III randomised controlled trial at 85 centres in Japan. Patients given six cycles of either paclitaxel (180 mg/m²; 3-h intravenous infusion) plus carboplatin, given on day 1 of a 21-day cycle (conventional regimen; n=320), or dose-dense paclitaxel (80 mg/m²; 1-h intravenous infusion) given on days 1, 8, and 15, plus carboplatin given on day 1 of a 21-day cycle (dose-dense regimen; n=317). The primary endpoint was progression-free survival.

Median progression-free survival was longer in the dose-dense treatment group (28 months) than in the conventional treatment group (17 months). Overall survival at 3 years was also higher in the dose dense regimen group (72%) than in the conventional treatment group (65%). Expressed another way, women assigned to the dose-dense regimen had a 29% lower risk of disease progression and a 25% lower risk of death than those given the conventional regimen. 165 patients assigned to the dose-dense regimen and 117 assigned to the conventional regimen discontinued treatment early. Reasons for participant dropout were balanced between the groups, apart from withdrawal because of toxicity, which was higher in the dose-dense regimen group than in the conventional regimen group (n=113 vs n=69). Most patients in both groups experienced neutropenia (reduced white blood cell count). Severe anaemia was higher in the dose-dense treatment group (214 [69%]) than in the conventional treatment group (137 [44%]).

The authors say that the survival benefits shown in the dose-dense group are rare in women with advanced ovarian cancer. They conclude: “Dose-dense weekly paclitaxel plus carboplatin improved survival compared with the conventional regimen and represents a new treatment option in women with advanced epithelial ovarian cancer.”

In an accompanying Comment, Dr Michael A Bookman, Arizona Cancer Center, Tucson, AZ, USA, says that confirmatory trials are now underway regarding dose-dense regimens. He concludes: “The use of such dose-dense therapy should be decided on an individual basis together with other options for women with advanced-stage ovarian cancer.”

Link to article and comment

Source
The Lancet