As described in the November 1 issue of the New England Journal of Medicine, tumor cells shed DNA into body fluids including plasma and feces.  The current approach of biopsying tumors directly has several disadvantages.  First, some tumors, such as those in the brain and spinal cord, are difficult to biopsy safely.  Another important problem is sample error.  This means that the tiny biopsy may not be representative of the whole tumor.  This can be especially important when the tumor is heterogeneous or when there are multiple metastases.  Different metastases often give different DNA profiles. Finally, it is impractical to biopsy a tumor more than once.  Performing a " liquid biopsy" however, by examining the tumor's DNA found in plasma and other body fluids, potentially overcomes these difficulties.  Plasma and feces can be easily and safely obtained by drawing blood or collecting a bowel movement.  Because tumors are typically very vascular and "leaky," the DNA from the entire tumor will seep into the blood or stool thereby eliminating the error resulting from blindly examining the proverbial elephant.  Plasma and stool can also be collected consecutively from the same patient to look for changes in DNA profiles in response to surgery, radiation, or chemotherapy.  The authors believe this will be the most important application of cell-free DNA in the next few years.  For example, we physicians often worry that surgical removal of, for example, a breast cancer, may not have been curative.  We therefore recommend toxic "adjuvant" treatments to increase the likelihood of eradicating microscopic tumor implants too small to be detected by our current imaging technologies.  But what if the doctor could sample the same patient's plasma and show that the tumor DNA that was present before surgery was completely eliminated?  In this way, patients who were truly cured by surgery could be spared toxic radiation and chemotherapy whereas those with residual tumor DNA could be treated more aggressively and accurately. Patients could be tested quarterly for recurrence and, if positive, treated long before the recurrent tumors were large enough to be detected by PET imaging. Tumor antigens, such as CA 125 for ovarian cancer, are already used in this way but most tumors do not produce reliable antigens.

Cell-free stool DNA is the basis for the Cologuard® test that I recommend to some of my patients as a screening test for colon cancer. The test is FDA approved for patients over the age of 50 without a personal history of polyps or family history of colon cancer.  The test is safe, specific, and sensitive. Unfortunately, some private insurance plans would prefer to pay for a colonoscopy. In any event, Cologuard® is the first case where cell-free DNA has had a major impact on clinical practice.  

Patient's often ask me, "Is there a blood test for cancer." The current answer is no, with the possible exception of serum PSA for prostate cancer.  Will cell-free DNA finally give us a universal and simple blood test to detect cancers?  Here the authors are cautious because the test would have to have a very, very low false positive rate. Imagine the angst of a false positive test and the cost of the follow-up studies that would be required.  Therefore, this very promising technology will most likely find its greatest utility in patients already suspected of having a tumor, allowing oncologists to individualize care to maximize benefit and minimize harm.

The last two issues of this newsletter discussed the three recently published aspirin primary prevention trials published in the New England Journal of Medicine ( ARRIVE and ASPREE) and Lancet ( ASCEND).  I concluded that (1) aspirin is beneficial in patients of all ages known to have cardiovascular disease ( heart attack, stroke, TIA, stents, peripheral vascular disease, and/or high coronary calcium scores), (2) that healthy individuals between the ages of 50 and 70 and no bleeding history should follow the guidelines of the United States Prevention Task Force using the cardiovascular risk calculator available at the America Heart Association web site, and (3) that healthy individuals over 70 without cardiovascular disease should not take low dose aspirin. 

Now comes an interesting editorial published in the October 18 issue of the New England Journal of Medicine comparing the value of low dose aspirin to statins.  The author says, "...the results of these aspirin trials, which showed minimal benefits and consistent bleeding risks, should be considered alongside the results of contemporary statin trials.  In primary prevention trials (in patients with risk factors but no demonstrable cardiovascular disease), the use of statins was associated with a  25% decrease in the risk of major vascular events for every 1 mmol per liter (~40 mg/dL) decrease in low-density lipoprotein (LDL) cholesterol level.  This statistically certain benefit was associated with an enviable safety profile and was not associated with the bleeding complications seen with aspirin."  There you have it.  Statins win again.

Everyone loses bone mass with age, men and women alike.  Bone density is measured in the spine and hip using a simple low-dose Xray test called DEXA.  Osteoporosis is defined as bone density in either location that is 2.5 standard deviations less than the bone density of 18 year olds.  This is expressed as a " T-score." Women and men with a T-score of -2.5 or worse are recommended to take a bisphosphonate (e.g., alendronate ( Fosamax®), risedronate ( Actonel®), or zoledronic acid   ( Reclast®) to prevent hip and spine fractures.  This approach, proven in numerous controlled randomized trials (CRTs), misses the point that most fractures occur in women with osteopenia, that is, in women with T-scores between -1.0 and - 2.5.  You might therefore ask, "Why wait until the T-score is -2.5 to treat?".  The answer is that the famous Fracture Intervention Trial conducted by Merck with alendronate (Fosamax®) only showed benefit in those with a T-score of -2.5 or worse.

Now comes a new study, and accompanying editorial, published online in the October 1 issue of the New England Journal of Medicine, that is about to change this paradigm.  The study showed that women 65 and older, with T-scores in the osteopenic range (-1.0 to -2.5), had one third fewer hip and spine fractures and maintained stature, if they received zoledronic acid (Reclast®) intravenously every 18 months for four doses over a six year period.  The number of women needed to treat (NNT) to prevent one fracture was 15.  The study is important because it shows that senior women in the osteopenic category, especially those who are at increased risk of fracture (as measured by the FRAX calculator), shouldn't wait for osteoporosis to begin treatment with zoledronic acid.  Though the study was not designed to test for complications, no serious complications, including osteonecrosis of the jaw and atypical fracture of the femur, were observed.