Hormone Replacement Therapy (HRT) & Breast Cancer
Stool DNA Testing & Cancer of the Colon & Rectum
HORMONE REPLACEMENT THERAPY (HRT) & BREAST CANCER
Hormone replacement therapy (HRT) came of age during the sexual revolution in the United States in the 1960s. During this revolution, premenopausal women not only finally gained control over their reproductive systems with the advent of oral contraceptives, but postmenopausal women could also effectively alleviate the symptoms of menopause by taking HRT pills. However, despite a recent avalanche of clinical research data linking the most commonly prescribed form of HRT with an increased risk of breast cancer, diehard supporters of HRT continue to cling to alternative explanations for the lock-step rise and fall of breast cancer cases relative to the number of HRT prescriptions filled in the United States (and around the world). While the cloak of obfuscation and overstated benefits that has obscured the risks of HRT finally began to be peeled away with the 2002 publication of the preliminary results of the enormous Women’s Health Initiative Study, entrenched proponents of HRT are not going down without a fight. Recently, persistent HRT advocates have attempted to link a modest and recent decrease in the incidence of screening mammograms with the recent and historical decline in the number of breast cancer cases diagnosed in the United States, despite highly compelling research evidence that breast cancer rates are falling as a direct consequence of declining HRT use by women. Now, a new study, just published in the New England Journal of Medicine, substantially adds to the findings of other recent studies in debunking this alternate hypothesis.
In this new study, the Women’s Health Initiative (WHI) study researchers have gone back and reviewed their data on the nearly 17,000 women who volunteered for this pivotal women’s health study (the average duration of follow-up in this prospective, randomized, placebo-controlled study has already exceeded 12 years, rendering it an exceedingly powerful clinical research study). In particular, the significant increase in breast cancer incidence that was observed among the WHI study women who had received HRT pills for an average of almost 6 years was then compared to the subsequent decline in breast cancer rates in this same group of women after the premature termination of the combination HRT portion of the WHI study in 2002.
Among the group of women randomized to receive HRT pills, the incidence of new breast cancer cases after 5.6 years of HRT was almost twice as high as was observed in the “control group” of women that received only placebo pills. However, within two years of discontinuing HRT, following the premature termination of the WHI study in 2002, the breast cancer rate rapidly declined in the original HRT group of women. During this phase of the WHI study, there was no significant difference in the incidence of screening mammograms between the two groups of women. Thus, the incidence of breast cancer rose dramatically over a 5 to 6 year period among women randomized to receive standard combination HRT, and then fell just as dramatically among this same group of women as fewer and fewer women in this group continued to use HRT. As this “experimental group” of women were confirmed to have utilized mammograms to the same degree as the “control group” of women did during this prolonged phase of the WHI study, the potential impact, if any, of declining mammogram rates on the incidence of breast cancer among these nearly 17,000 postmenopausal women is automatically eliminated with respect to the seminal findings of the WHI study.
The history of the dramatic rise of HRT after World War II, and its gradual and still ongoing decline, is a fascinating (and disturbing) story of hubris, bias, and ignorance; as well as the crass commercial exploitation of momentous cultural shifts in the United States (and around much of the world) for financial gain. Look for a new book on this unsettling medical drama from me in the coming year or two.
STOOL DNA TESTING & CANCER OF THE COLON & RECTUM
Depending upon your age and your risk profile for colorectal cancer, you may be advised to undergo colonoscopy every 5 to 10 years. Although there are several available options for colorectal cancer screening, colonoscopy remains the “gold standard” screening test, as it allows for evaluation of the entire colon and rectum. Unlike other methods of screening, colonoscopy also allows physicians to biopsy or remove suspicious lesions identified during the screening examination. Let’s face it, though, undergoing colonoscopy is no picnic. For most people (myself included), the “prep” is the worst part of the experience.
On the day before colonoscopy, powerful purgatives are used to flush out the colon. Although there are several different types of “bowel prep” solutions available, all of them result in some degree of abdominal cramps and nausea, and they all produce the same “end result.” Hours spent sitting on the toilet, with profuse diarrhea throughout the day, make for a miserable day, indeed. At the end of the prep day, most people feel rather spent and hungry from a day of purging and consuming only liquids. In most cases, colonoscopy is performed with intravenous sedation and, fortunately, most patients have little or no recall of the actual procedure.
While thousands of colonoscopies are safely performed every day, colonoscopy is an invasive procedure, and there is a very small (but not completely insignificant) risk of complications, including bleeding and bowel perforation.
Because of the negative aspects of colonoscopy, alternative colorectal cancer screening methods are always being evaluated. “Virtual colonoscopy,” using computed tomography (CT) scans, is still undergoing evaluation, but many experts have already noted that patients still have to purge their colons before CT-colonography, and any polyps or other abnormalities that are detected during CT-colonography will still require that a separate colonoscopy be performed. There is also the issue of being exposed to not inconsequential doses of radiation each time a patient undergoes CT-colonography.
Given the unpleasantness associated with conventional colonoscopy, studying the stool for signs of premalignant or malignant polyps or tumors is an attractive option. In fact, various tests that detect tiny amounts of shed blood in the stool have been used for decades as colorectal cancer screening tests. Unfortunately, fecal occult blood testing is not sensitive or specific enough to rely upon as a single screening method for cancers, or precancerous lesions, of the colon and rectum. (There are multiple non-cancer causes of occult blood loss into the stool, and not all precancerous polyps, or even small colon or rectal cancers, will consistently shed enough blood into the stool to be detected by fecal occult blood testing.)
Recently, a new approach to screening the stool for signs of precancerous and cancerous lesions has been developed. Unlike fecal occult blood testing, which detects a substance in the stool (e.g., traces of blood) that is not specific to cancer, the most recent generation of stool studies detect genetic material specific to malignant or premalignant cells that are also shed into the stool. Of particular interest, currently, are stool DNA studies. In this method of colorectal cancer screening, DNA is extracted from stool samples and, using a powerful DNA amplification test (polymerase chain reaction, or PCR), DNA mutations specific to cancer cells can often be detected. However, these stool DNA tests currently miss about half of all colorectal cancers, and they are largely incapable of detecting the precancerous polyps that can easily be detected and removed during colonoscopy. However, a new study, just published in the journal Gastroenterology, reveals a potentially important advance in stool DNA testing for colorectal cancer screening.
In this new study, PCR was combined with another test known as digital melt curve analysis. Adding digital melt curve analysis further increases the already exquisite sensitivity of PCR in detecting tiny traces of mutated DNA that are shed into the stool by colorectal cancers, and by many premalignant polyps as well. Using this approach in patients already diagnosed with colorectal cancer, and in whom specific cancer-related DNA mutations were known to be present, evidence of tumor DNA was identified in 90 percent of the stool samples that were tested with the new DNA test. In another group of patients known to have precancerous polyps (advanced adenomas) containing a specific cancer-associated DNA mutation called KRAS, this new method of stool DNA testing was able to detect the KRAS mutation in an impressive 75 percent of patients.
The results of this small pilot study are extremely impressive, and will likely lead to a new generation of stool DNA testing that will overcome many of the limitations associated with currently available stool DNA tests. As this study evaluated only a very small number of patients, however, it will be necessary to repeat this study with larger numbers of patients before stool DNA testing can be considered equivalent to screening colonoscopy. Until then, colonoscopy, in my opinion, remains the current gold standard for colorectal cancer screening. Perhaps one day, in the near future, however, colonoscopy will only be reserved for the approximately 20 to 25 percent of patients who have colorectal polyps or other neoplastic lesions (including cancer) at the time of their periodic colorectal cancer screening exams. Fortunately, I have another four years left before I have to repeat my next colonoscopy prep. Perhaps stool DNA testing will be a reasonable colorectal cancer screening alternative for me, and for millions of other patients, by then!
Disclaimer: As always, my advice to readers is to seek the advice of your physician before making any significant changes in medications, diet, or level of physical activity
is an oncologic surgeon, a professor
of surgery, a widely published author, and the
Physician-in-Chief for Surgical
Oncology at the Kaiser Permanente healthcare system in Orange County,
Robert A. Wascher, MD, FACS.
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