Reporter: Aviva Lev-Ari, PhD, RN
Aspirin Use, Tumor PIK3CA Mutation, and Colorectal-Cancer Survival
N Engl J Med 2012; 367:1596-1606 October 25, 2012DOI: 10.1056/NEJMoa1207756
Word Cloud By Danielle Smolyar
BACKGROUND
Regular use of aspirin after a diagnosis of colon cancer has been associated with a superior clinical outcome. Experimental evidence suggests that inhibition of prostaglandin-endoperoxide synthase 2 (PTGS2) (also known as cyclooxygenase-2) by aspirin down-regulates phosphatidylinositol 3-kinase (PI3K) signaling activity. We hypothesized that the effect of aspirin on survival and prognosis in patients with cancers characterized by mutated PIK3CA (the phosphatidylinositol-4,5-bisphosphonate 3-kinase, catalytic subunit alpha polypeptide gene) might differ from the effect among those with wild-type PIK3CA cancers.
METHODS
We obtained data on 964 patients with rectal or colon cancer from the Nurses’ Health Study and the Health Professionals Follow-up Study, including data on aspirin use after diagnosis and the presence or absence of PIK3CA mutation. We used a Cox proportional-hazards model to compute the multivariate hazard ratio for death. We examined tumor markers, including PTGS2, phosphorylated AKT,KRAS, BRAF, microsatellite instability, CpG island methylator phenotype, and methylation of long interspersed nucleotide element 1.
RESULTS
Among patients with mutated-PIK3CA colorectal cancers, regular use of aspirin after diagnosis was associated with superior colorectal cancer–specific survival (multivariate hazard ratio for cancer-related death, 0.18; 95% confidence interval [CI], 0.06 to 0.61; P<0.001 by the log-rank test) and overall survival (multivariate hazard ratio for death from any cause, 0.54; 95% CI, 0.31 to 0.94; P=0.01 by the log-rank test). In contrast, among patients with wild-type PIK3CA, regular use of aspirin after diagnosis was not associated with colorectal cancer–specific survival (multivariate hazard ratio, 0.96; 95% CI, 0.69 to 1.32; P=0.76 by the log-rank test; P=0.009 for interaction between aspirin and PIK3CA variables) or overall survival (multivariate hazard ratio, 0.94; 95% CI, 0.75 to 1.17; P=0.96 by the log-rank test; P=0.07 for interaction).
CONCLUSIONS
Regular use of aspirin after diagnosis was associated with longer survival among patients with mutated-PIK3CA colorectal cancer, but not among patients with wild-type PIK3CA cancer. The findings from this molecular pathological epidemiology study suggest that thePIK3CA mutation in colorectal cancer may serve as a predictive molecular biomarker for adjuvant aspirin therapy. (Funded by The National Institutes of Health and others.)
SOURCE:
Study Shows Aspirin Could Increase Survival in Colorectal Cancer Patients with PIK3CA Mutations
By mining epidemiological data from several long-term health studies and combining it with genomic data, a team led by the Dana-Farber Cancer Institute and Harvard Medical School has shown that colorectal cancer patients with PIK3CA mutations may benefit from treatment with aspirin, and that PIK3CA mutation status could serve as biomarker to predict response to aspirin treatment.
The study, published last month in the New England Journal of Medicine, evaluated data from 964 patients with colon or rectal cancer from the Nurses’ Health Study and the Health Professionals Follow-up Study. It found that patients with PIK3CA-mutated cancers who regularly took aspirin after their diagnosis had significantly longer survival, while those with wild-type cancers showed no benefit from aspirin treatment.
According to the researchers, led by Dana Farber’s Shuji Ogino, the results suggest that aspirin might be worth testing as an adjuvant treatment for the approximately 20 percent of colorectal cancer patients with PIK3CA mutations.
“What we conclude is that this PK3CA mutation can be a predictive biomarker and based on molecular testing, doctors could strongly or weakly recommend aspirin,” Ogino told PGx Reporter.
According to the group, numerous observational and other studies have suggested that aspirin might play a protective role in colorectal cancer. Aspirin is currently prescribed to some colorectal cancer patients, Ogino said, but so far there has been no way to predict which patients are likely to actually benefit from it.
Ogino said his team’s previous research found that levels of the enzyme PTGS2 could predict response to aspirin treatment, but the association didn’t reach statistical significance. And because of a lack of good standards for measuring PTGS2 using immunohistochemistry, the group wanted to search for a better, more objective marker.
According to the group, other experiments have suggested that as aspirin inhibits PTGS2 it also down-regulates PI3K signaling, which hinted that PIK3CA mutations could be a potential marker as well.
“Based on previous studies, we hypothesized that PIK3CA mutation may be a good marker for aspirin response,” Ogino said. Testing this hypothesis prospectively, he said, would have taken decades, but by using epidemiological data coupled with molecular data the group was able to find an answer much more quickly.
In the recent NEJM study, Ogino and his colleagues compared the survival of colorectal patients who reported that they regularly used aspirin after their diagnosis with those who didn’t, and further subdivided the group into those with PIK3CA mutations and those without.
The team studied samples from a subset of 964 patients from the two large longitudinal health studies for which the relevant aspirin use data was available, collecting specimens from the registries and using pyrosequencing to establish PIK3CA mutation status for each patient’s tumor. The group also recorded whether samples had BRAF or KRAS mutations.
The researchers found that patients with PIK3CA mutations who reported regular aspirin use had a significantly improved five-year survival rate — 97 percent — over those who didn’t take aspirin — 74 percent.
In contrast, patients without the mutation showed no difference in survival whether they took aspirin regularly or not.
Because the group had previously found that PTGS2 levels were also predictive of response to aspirin use, the researchers evaluated whether a combination of both markers could serve an even greater predictor. According to the study authors, the strongest effect of aspirin use was indeed in patients with both markers, though this finding did not have high statistical significance.
Because the study sampled patients treated before 2006, the group assumed that chemotherapy treatment was similar for the PIK3CA-mutated cases and the wild-type cases. According to the researchers, information on patients’ mutation status was not available to treating physicians at the time of the studies.
The team also distinguished between aspirin use before and after diagnosis, finding that pre-diagnosis use did not seem to influence the relationship between PIK3CA and post-diagnosis aspirin.
Ogino said that the group is pursuing avenues to validate the findings. Unfortunately, relatively few trials of aspirin treatment in colorectal cancer have been conducted.
One option, he said, would be to analyze data from a trial of celecoxib (Pfizer’s Celebrex), a similar drug to aspirin, instead. But it’s not an ideal solution. If the results reflect what the group found in its aspirin study it would shore up the aspirin finding. However, if the results do not match up it would be unclear what that might mean about the group’s original findings.
Potentially, the researchers could also use mouse models or cell lines, but this route has several downsides. Most important, Ogino said, is the fact that aspirin likely affects inflammation more than cancer cells themselves. “Cancer is not just the cancer cell, it’s a much more complicated system so you can’t assess it in the test tube, basically,” he said.
Molika Ashford is a GenomeWeb contributing editor and covers personalized medicine and molecular diagnostics. E-mail her here. |
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PUT IT IN CONTEXT OF CANCER CELL MOVEMENT
The contraction of skeletal muscle is triggered by nerve impulses, which stimulate the release of Ca2+ from the sarcoplasmic reticuluma specialized network of internal membranes, similar to the endoplasmic reticulum, that stores high concentrations of Ca2+ ions. The release of Ca2+ from the sarcoplasmic reticulum increases the concentration of Ca2+ in the cytosol from approximately 10-7 to 10-5 M. The increased Ca2+ concentration signals muscle contraction via the action of two accessory proteins bound to the actin filaments: tropomyosin and troponin (Figure 11.25). Tropomyosin is a fibrous protein that binds lengthwise along the groove of actin filaments. In striated muscle, each tropomyosin molecule is bound to troponin, which is a complex of three polypeptides: troponin C (Ca2+-binding), troponin I (inhibitory), and troponin T (tropomyosin-binding). When the concentration of Ca2+ is low, the complex of the troponins with tropomyosin blocks the interaction of actin and myosin, so the muscle does not contract. At high concentrations, Ca2+ binding to troponin C shifts the position of the complex, relieving this inhibition and allowing contraction to proceed.
Figure 11.25
Association of tropomyosin and troponins with actin filaments. (A) Tropomyosin binds lengthwise along actin filaments and, in striated muscle, is associated with a complex of three troponins: troponin I (TnI), troponin C (TnC), and troponin T (TnT). In (more ) Contractile Assemblies of Actin and Myosin in Nonmuscle Cells
Contractile assemblies of actin and myosin, resembling small-scale versions of muscle fibers, are present also in nonmuscle cells. As in muscle, the actin filaments in these contractile assemblies are interdigitated with bipolar filaments of myosin II, consisting of 15 to 20 myosin II molecules, which produce contraction by sliding the actin filaments relative to one another (Figure 11.26). The actin filaments in contractile bundles in nonmuscle cells are also associated with tropomyosin, which facilitates their interaction with myosin II, probably by competing with filamin for binding sites on actin.
Figure 11.26
Contractile assemblies in nonmuscle cells. Bipolar filaments of myosin II produce contraction by sliding actin filaments in opposite directions. Two examples of contractile assemblies in nonmuscle cells, stress fibers and adhesion belts, were discussed earlier with respect to attachment of the actin cytoskeleton to regions of cell-substrate and cell-cell contacts (see Figures 11.13 and 11.14). The contraction of stress fibers produces tension across the cell, allowing the cell to pull on a substrate (e.g., the extracellular matrix) to which it is anchored. The contraction of adhesion belts alters the shape of epithelial cell sheets: a process that is particularly important during embryonic development, when sheets of epithelial cells fold into structures such as tubes.
The most dramatic example of actin-myosin contraction in nonmuscle cells, however, is provided by cytokinesisthe division of a cell into two following mitosis (Figure 11.27). Toward the end of mitosis in animal cells, a contractile ring consisting of actin filaments and myosin II assembles just underneath the plasma membrane. Its contraction pulls the plasma membrane progressively inward, constricting the center of the cell and pinching it in two. Interestingly, the thickness of the contractile ring remains constant as it contracts, implying that actin filaments disassemble as contraction proceeds. The ring then disperses completely following cell division.
Figure 11.27
Cytokinesis. Following completion of mitosis (nuclear division), a contractile ring consisting of actin filaments and myosin II divides the cell in two.
http://www.ncbi.nlm.nih.gov/books/NBK9961/
This is good. I don’t recall seeing it in the original comment. I am very aware of the actin myosin troponin connection in heart and in skeletal muscle, and I did know about the nonmuscle work. I won’t deal with it now, and I have been working with Aviral now online for 2 hours.
I have had a considerable background from way back in atomic orbital theory, physical chemistry, organic chemistry, and the equilibrium necessary for cations and anions. Despite the calcium role in contraction, I would not discount hypomagnesemia in having a disease role because of the intracellular-extracellular connection. The description you pasted reminds me also of a lecture given a few years ago by the Nobel Laureate that year on the mechanism of cell division.
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