Cancer Screening—The Good, the Bad, and the Ugly

Before I dive into my personal perspective on cancer screening, I want to address the dire state of healthcare in our country. A recently published paper evaluated the best and worst countries in the world in terms of healthcare.

This study included an analysis of 71 performance measures across five domains. The United States ranked last overall, despite spending far more of its gross domestic product on health care, which includes a massive amount on cancer screening. The U.S. ranks last on access to care, administrative efficiency, equity, and health care outcomes, but second on measures of care process.^[1]

Chronic Disease in the United States: A Worsening Health and Economic Crisis

• The prevalence and cost of chronic disease in the United States is growing and will continue to grow, not just as a result of the Baby Boomer generation aging but also due to increased disease prevalence among children and younger adults.
• The prevalence of chronic disease varies greatly across the country with a higher concentration in the Mid-South region.
• People with chronic disease and their families face both direct and indirect costs: Direct costs primarily stem from longer and more frequent hospital visits and greater prescription drug use, while indirect costs arise from lost education and job opportunities.
• ·When including indirect costs associated with lost economic productivity, the total cost of chronic disease in the United States is $3.7 trillion each year, approximately 19.6 percent of the country’s gross domestic product.^[2]

While the risk of chronic disease is not growing among older adults, the incidence among older adults is, and this growth is not just occurring in this demographic.  A recent study comparing the prevalence of 17 chronic diseases among various age groups between 2005 and 2014 found increases in nearly every disease, including in the youngest groups in the study: 35-50 years old and 51-65 years old.[3]

Children have similarly suffered from increasing rates of chronic disease. Less than 2 percent of children in 1960 had a health condition severe enough to interfere with activities of daily life. Fifty years later, more than 8 percent of children have such a condition. Much of the increase is associated with greater prevalence of four types of conditions: asthma, obesity, mental health conditions, and neurodevelopmental disorders.^[4]

When considering the vulnerabilities of people with chronic disease, the indirect effects of social isolation are important to understand. Studies show that those who report frequent feelings of loneliness or who lack social connections suffer higher rates of morbidity and mortality, infection, depression, and cognitive decline.^[5]

What You Should Know about Cancer Screening

The goal of cancer screening is to reduce cancer mortality. I do not deny that cancer screenings reduce mortality in certain cases. However, this clearly is not true in all, or even most, situations. We only need to look at the effects of routine PSA (prostate specific antigen) screenings. In some cases, PSA screenings have found prostate cancer at an early stage, but in more cases, the screenings have led to many unnecessary biopsies, with the fear and worry that accompany such procedures. The result has too often been unnecessary or over treatment and undesirable long-term side effects.

I am not against cancer screening. But I want to share with you the truth regarding the risk-to-benefit and suggest some alternatives that are available. Here are some questions to ponder: Is the standard-of-care screening really the best and only option? Is the frequency of the test based on good scientific research? As people age, should we continue to do these screenings, especially since they are sometimes invasive, have risk, and don’t equate to much difference when it comes to reducing mortality rates? 

For example, I know many elderly men who tested positive for prostate cancer, and were treated with radiation and hormones. As a result, the treatments shortened their lives, and without a doubt, drastically reduced their quality-of-life. These men would have been better off never testing for prostate cancer. The reality is that most men die with prostate cancer not from prostate cancer; especially older men. However, it is true that there are some more aggressive types of cancer that can be serious.

My point is that there are limits to the effectiveness of today’s onslaught of recommended cancer screenings. I sometimes think that between all the screenings we are asked to do and all the vaccines that are now recommended, we would need to be at the doctor’s office numerous times a year.

One major problem with cancer screening that is not widely known is that screenings tend to miss the fastest growing cancers. These cancers have a brief window during which they are detectable by screening but are not yet clinically evident.

The accepted model of thinking is that effective screening requires not only earlier detection, but also that treatment initiated earlier is reliably better than treatment initiated later. Although this is often true for acute disease (such as cardiovascular emergencies, or infections), it may not be true for long-term chronic disease, especially when you consider the age of the patient. Detecting cancerous tumors that are a few millimeters smaller than those detected previously may make less difference than what was once believed, particularly as we learn that tumor biology is more relevant than size. These factors explain why the most favorable effects observed in randomized trials of screening tests result in a less than one-third reduction in cancer mortality.^[6],[7]

Mammograms: Questioning the Risk-to-Benefit Ratio

False alarms with mammograms are surprisingly common. There are as many as 600 false-positive results in a 10-year course of mammography,^[8] and some research suggests that mammograms (the older 2D, prior to the 3D scanners) can actually INCREASE your risk of breast cancer. This doesn’t mean to never do a mammogram. But it means that there are real risks associated with mammograms. I recommend evaluating whether or not mammograms are your best option, and if possible, to seek alternatives that may even be better, such as Elastography. If something looks suspicious, then an MRI can be used for further evaluation.

The New Current Guideline Recommendations

The new guidelines state that women should undergo a breast cancer risk assessment starting at age 25 years, and they emphasize annual mammography screening beginning at age 40 for those with average risk. This screening approach offers the greatest mortality reduction, according to available evidence.

An earlier start may be recommended for those with additional risk factors. The guidelines also recommend screening for women who are pregnant or breastfeeding. During pregnancy, the belly can be shielded, and the radiation is low dose and targeted. The guidelines note that it’s particularly important to keep up with screenings for women whose first pregnancy occurs at age 40 or older.

The guidelines also address evaluation of breast symptoms, such as a palpable lump, pain, or nipple discharge, and emphasize the need for prompt clinical and diagnostic evaluation, including imaging and biopsy when needed.^[9]

What You Should Know about Mammograms

The illustration above—although meant to be humorous—is why I don’t recommend routine mammograms, despite what you may hear from other medical sources. Mammograms expose your body to radiation that can be 1,000 times greater than that from a chest x-ray. This makes you unnecessarily vulnerable to further risks of radiation-induced cancer.

It is very debatable regarding the effect that mammograms have on saving lives. Research demonstrates that adding an annual mammogram to a careful physical examination of the breasts does not improve breast cancer survival rates over getting the examination alone. Approximately 30% of abnormalities identified on screening mammography represent an over-diagnosis and lead to over-treatment.^[10]

According to a 2013 Cochrane meta-analysis review study, screening with mammography uses X-ray imaging to find breast cancer before a lump can be felt. The goal is to treat cancer earlier, when a cure is more likely. “The review includes seven trials that involved 600,000 women in the age range 39 to 74 years who were randomly assigned to receive or not receive screening mammograms. The studies which provided the most reliable information showed that screening did not reduce breast cancer mortality. Studies that were potentially more biased (less carefully done) found that screening reduced breast cancer mortality. However, screening will result in some women getting a cancer diagnosis even though their cancer would not have led to death or sickness.

Currently, it is not possible to tell which women these are, and they are therefore likely to have breasts or lumps removed and to receive radiotherapy unnecessarily. If we assume that screening reduces breast cancer mortality by 15% after 13 years of follow-up and that over-diagnosis and over-treatment is at 30%, it means that for every 2000 women invited for screening throughout 10 years, one will avoid dying of breast cancer and 10 healthy women, who would not have been diagnosed if there had not been screening, will be treated unnecessarily. Furthermore, more than 200 women will experience important psychological distress including anxiety and uncertainty for years because of false positive findings.”^[11]

In 1980, Canadian investigators began a randomized trial of mammography and physical examination in almost 90,000 women aged 40-59 years, and they now report findings based on up to 25 years of follow-up. Each woman underwent an initial clinical breast exam and then was randomly assigned either to 5 annual mammograms or to no mammography.

The mean size of cancers diagnosed in the women undergoing mammography was 1.9 cm, significantly smaller than the mean of 2.1 cm in the no-mammogram group. However, the proportion of tumors that were node positive was similar in the 2 groups.

The 25-year cumulative mortality from breast cancer was almost identical among women in the mammography and no-mammography arms; these findings did not vary by age group.^[12]

With 15 years of follow-up, 666 cases of breast cancer were detected in the mammogram arm and 524 in the no-mammogram arm. The excess 142 cases of breast cancer in the mammography group represents over-diagnosis of tumors destined not to cause future problems.

This study’s findings on lack of efficacy of screening mammograms and over-diagnosis parallel those of other recent studies.^[13],[14]^,[15]^,[16] Screening mammograms are costly and are associated with high rates of false-positive findings.

Certainly, there is no direct evidence to support breast cancer screening in women older than 74 years.^[17] 

Natural History of Breast Cancers Detected in the Swedish Mammography Screening Program: A Cohort Study—Many Screen-detected Invasive Breast Cancers Regress Spontaneously

Because the cumulative incidence among controls did not reach that of the screened group, researchers in this study believe that many invasive breast cancers detected by repeated mammography screening do not persist to be detected by screening at the end of 6 years, suggesting that the natural course of many of the screen-detected invasive breast cancers is to spontaneously regress.^[18]

The risks of breast cancer screening in women ages 40 to 49 years includes more false positive recalls and biopsies as well as transient anxiety when compared to woman 50 years and older.^[19]

A recent study did find that mammography screening reduces the incidence rates of advanced and fatal breast cancers.^[20]

Here is the problem: The referenced study that was used to create the guidelines was determined from a weak analysis review conducted by US Preventive Services Task Force (USPSTF).^[21]  The methodology used by USPSTF to determine their finding that claims mammography screening saves lives is flawed, and is not supported by scientific support for mammography screening.^[22] Evaluation of breast cancer screening strategies must be based on the comparison of harms and benefits.^[23]

The most important parameters controlling patients’ total effective risk within breast screening are the screening commencement age and number of screens. The more times you are screened, the greater the risk.^[24]

Mammograms Lead to Increases in Mastectomies

One of the goals of mammograms is detecting breast cancer early enough to avoid needing a mastectomy. But a new Norwegian study suggests that mastectomy rates climb higher as more women undergo the screening test.

Using national cancer data for more than 35,000 women aged 40 to 79 who were diagnosed with early or invasive breast cancers, Researchers found a 31 percent increased risk of mastectomy in women invited to screening compared with a non-invited younger age group. The Norwegian breast cancer screening program began in 1996 in four counties, encompassing the country’s remaining 15 counties by 2004.

While scientists did not investigate why mastectomy rates climbed in screened groups, study author Pal Suhrke said the main reason is likely “cancer overdiagnosis,” or the detection and subsequent treatment of tumors that might grow very slowly and not pose much of a risk.^[25]

Now the big question: Is there a better and safe screening for breast cancer?  What I recommend is a combination of the following:

1)      Good self-exams

2)      Ultrasound Elastography, and if this detects anything,

3)      A breast MRI

Ultrasound Elastography detects breast lesions, showing statistical differences when differentiating benign and malignant lesions.^[26] 

Ultrasound Elastography appears to be better at characterizing questionable lesions. This decreases false-positive breast biopsy rates and enables earlier detection of breast cancer.^[27]

Cancer Screening Leads to Overdiagnosis

In the case of breast, prostate, skin, and thyroid cancer screening, patients are more likely to experience the harm of overdiagnosis than they are the benefit of screening, which is avoiding a cancer death.

A sustained rise in cancer incidence coupled with stable mortality (A) suggests overdiagnosis superimposed on stable true cancer occurrence. Rising early-stage cancer incidence coupled with stable late-stage incidence (B) also suggests overdiagnosis and that increased early cancer detection efforts have not produced the desired result: a decline in the rate at which individuals present with late-stage cancer. The fact is that early detection has failed to advance the time of diagnosis of those cancers destined to present at a late stage. If true cancer occurrence were changing, incidence and mortality would be expected to move in tandem, as would early and late-stage disease.^[28]

From the population perspective, the most consequential harms relate to the dynamics of screening: many individuals must be screened to potentially benefit a very few. For cancer screening in the general population (i.e., not targeting an extremely high-risk group, such as screening heavy smokers for lung cancer), roughly 1,000 people must be screened to avert 1 cancer death in 10 years. Therefore, questions about what happens to the other 999 individuals become relevant. However, the bigger problem is that many people with false-positive test results are not told that the test was wrong, but rather that something is wrong with them. These people are told that they have a lesion with cellular atypia or dysplasia, or they themselves are more vulnerable to develop cancer and thus require more frequent testing. Even the screening campaigns induce vulnerability—the fear of cancer—as a means to persuade people to get screened.^[29] Thus, cancer screening injects a sense of “dis”-ease into the population.

What are the advantages of an MRI over a mammogram?

MRIs (Magnetic Resonance Imaging) are a non-invasive imaging technology that produces three dimensional detailed anatomical images. It is often used for disease detection, diagnosis, and treatment monitoring.  MRI do not emit the ionizing radiation that is found in x-ray and CT imaging.

According to most studies, breast cancer screening using MRI two times a year is considered better than one mammogram per year to detect breast cancer early in young women who are at high risk of breast cancer.

Breast MRIs can detect tumors that mammograms may miss, but they also have the potential to mistakenly identify non-cancerous breast tissue as cancer, which can lead to a false-positive result. MRI may particularly be favorable because they have a higher resolution than mammograms and provide a more efficient means to screen dense breasts. A breast MRI has a sensitivity ranging from 81% to 100% in women with different risk profiles.[30]

A breast MRI is a technology that employs a magnetic field to build a picture of breast tissue by taking hundreds of photographs rapidly.  A breast MRI is the best screening test for breast cancer in women.

Breast MRIs can be expensive, and the cost isn’t always covered by health insurance.[31] Mammograms are far less expensive than MRI scans and are covered by insurance.^[32]

Misleading Feedback, Financial Incentives, and Distraction

I believe that medical care should be driven by patient needs, not surgeon needs (or now, system needs). We must recognize there is a price to be paid both financially and health-wise in testing. All tests incur emotional stress, and some require invasive procedures—for example, colonoscopies that require strong laxatives to clean out the GI tract, which destroys the gut microbiome.

“There is clear evidence that, in normal individuals, a high-volume polyethylene glycol bowel cleansing preparation has a long-lasting effect on the gut microbiota composition and homeostasis, in particular, with a decrease in the Lactobacillaceae abundance, a population of protective bacteria.” ^[33]

Cancer screening is typically motivated by a genuine belief in its value, but it has also become an important revenue stream for volume-driven medical care systems, with estimates of $40 to $80 billion per year.^[34] The importance of this revenue stream was highlighted during the COVID-19 lockdown, when after a substantial decline in screening occurred after the onset of the COVID-19 pandemic and other services and businesses remained closed, but screening was rapidly restored within a few months.^[35],[36]

Although cancer screening does make sense in selected high-risk individuals, such as CA-125 screening in woman who may be at high-risk for ovarian cancer, it doesn’t make sense in many other situations. Plus, there are often newer, better, cheaper and less invasive tests, such as a stool test called “Cologuard,” a specific blood test for colon cancer risk, and a urine test called “PCA-3” for prostate cancer risk which may even be more reliable than a biopsy for detecting prostate cancer.^[37],[38]  A biopsy takes many tissue samples and can miss cancer.

I do believe there is value in PSA screening, but with these rules: 1) if over 4, then get a free versus total PSA, ask for PAP (prostatic acid phosphatase), and a PCA-3 to begin with. The PSA should always be a marker that is compared to the specific individual. One man with a PSA of 6 is totally fine while another may have cancer, or even an aggressive form of prostate cancer.  I believe everyone should get a baseline and compare yourself to yourself.  Cancer blood marker interpretation is both an art and a science.

For colon cancer risk screening there is a  blood-based DNA test (liquid biopsy), called Epi proColon, which tests for an altered gene called SEPT9, and it is FDA approved. Epi proColon uses polymerase chain reaction technology to pick up methylation status of the Septin 9 tumor marker. Methylated Septin 9 is part of a family of tumor suppressor genes that circulate in the blood of some patients with colon cancer.^[39] However, it is also found in the blood of some patients with chronic gastritis and lung cancer and even pregnant women, the FDA said.^[40]

I believe general population screening, as currently practiced in the US, has become a huge distraction to our core work. Our focus needs to be on helping people improve their health, not on searching for disease.

References

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^[1] Eric C. Schneider et al., Mirror, Mirror 2021 — Reflecting Poorly: Health Care in the U.S. Compared to Other High-Income Countries

(Commonwealth Fund, Aug. 2021). https://doi.org/10.26099/01DV-H208

^[2] https://milkeninstitute.org/sites/default/files/reports-pdf/ChronicDiseases-HighRes-FINAL.pdf

[3] Atella, Vincenzo et al. “Trends in age-related disease burden and healthcare utilization.” Aging cell vol. 18,1 (2019): e12861. doi:10.1111/acel.12861

^[4] Perrin JM, Anderson LE, Van Cleave J. The rise in chronic conditions among infants, children, and youth can be met with continued health system innovations. Health Aff (Millwood). 2014 Dec;33(12):2099-105. doi: 10.1377/hlthaff.2014.0832. PMID: 25489027.

^[5] Cornwell, Erin York, and Linda J Waite. “Social disconnectedness, perceived isolation, and health among older adults.” Journal of health and social behavior vol. 50,1 (2009): 31-48. doi:10.1177/002214650905000103

^[6] Welch HG. Evidence on cancer screening efficacy in randomized trials & effectiveness in US practice. Accessed March 2, 2022. https://csph.brighamandwomens.org/wp-content/uploads/2021/12/Evidence-on-Cancer-Screening-Efficacy-in-Randomized-Trials-Effectiveness-in-United-States-Practice.pdf

^[7] Welch HG. Cancer Screening—The Good, the Bad, and the Ugly. JAMA Surg. 2022;157(6):467–468. doi:10.1001/jamasurg.2022.0669

^[8] Hubbard  RA, Kerlikowske  K, Flowers  CI, Yankaskas  BC, Zhu  W, Miglioretti  DL.  Cumulative probability of false-positive recall or biopsy recommendation after 10 years of screening mammography: a cohort study.   Ann Intern Med. 2011;155(8):481-492. doi:10.7326/0003-4819-155-8-201110180-00004

^[9] New NCCN Guidelines for Mammography: All Women Over 40, Medscape Oncology, Sharon Worcester, MA, July 29, 2022, https://www.medscape.com/viewarticle/978273?src=mkm_ret_220814_mscpmrk_BC_monthly&uac=45925HN&impID=4524130, from https://www.nccn.org/patientresources/patient-resources/guidelines-for-patients

^[10] Morris, Elizabeth et al. “Implications of Overdiagnosis: Impact on Screening Mammography Practices.” Population health management vol. 18 Suppl 1,Suppl 1 (2015): S3-11. doi:10.1089/pop.2015.29023.mor

^[11] Gøtzsche PC, Jørgensen K. Screening for breast cancer with mammography. Cochrane Database of Systematic Reviews 2013, Issue 6. Art. No.: CD001877. DOI: 10.1002/14651858.CD001877.pub5

^[12] Miller AB, Wall C, Baines CJ, Sun P, To T, Narod SA. Twenty five year follow-up breast cancer incidence and mortality of the Canadian National Breast Screening Study: randomized screening trial. BMJ. 2014;348:g366.

^[13] Kalager M, Adami H-O, Bretthauer M. Too much mammography. BMJ. 2014;348:g1403.

^[14] O’Donoghue C, Eklund M, Ozanne EM, Esserman LJ. Aggregate cost of mammography screening in the United States: comparison of current practice and advocated strategies. Ann Int Med. 2014;160:145-153.

^[15] Elmore JG, Gross CP. The cost of breast cancer screening in the United States: A picture is worth…a billion dollars? Ann Int Med. 2014;160:203-205.

^[16] Welch HG, Passow HJ. Quantifying the benefits and harms of screening mammography. JAMA Int Med. 2013 Dec 30.

^[17] Ilana B. Richman, MD , New Breast Cancer Screening Technologies in Older Women—Is It Time to Pump the Brakes?, JAMA Internal Medicine Published online January 14, 2019

^[18] Zahl PH, Gøtzsche PC, Mæhlen J. Natural history of breast cancers detected in the Swedish mammography screening programme: a cohort study. Lancet Oncol. 2011 Nov;12(12):1118-24. doi: 10.1016/S1470-2045(11)70250-9. Epub 2011 Oct 11. PMID: 21996169.

^[19] Grimm LJ, Avery CS, Hendrick E, Baker JA. Benefits and Risks of Mammography Screening in Women Ages 40 to 49 Years. J Prim Care Community Health. 2022 Jan-Dec;13:21501327211058322. doi: 10.1177/21501327211058322. PMID: 35068237; PMCID: PMC8796062.

^[20] “Mammography screening reduces the incidence rates of advanced and fatal breast cancers: Results in 549,091 women.” Stephen Duffy, László Tabár, Amy Ming-Fang Yen, Peter B. Dean, Robert A. Smith, Håkan Jonsson, Sven Törnberg, Sam Li-Sheng Chen, Sherry Yueh-Hsia Chiu, Jean Ching-Yuan Fann, May Mei-Sheng Ku, Wendy Yi-Ying Wu, Chen-Yang Hsu, Yu-Ching Chen, Gunilla Svane, Edward Azavedo, Helene Grundström, Per Sundén, Karin Leifland, Ewa Frodis, Joakim Ramos, Birgitta Epstein, Anders Åkerlund, Ann Sundbom, Pál Bordás, Hans Wallin, Leena Starck, Annika Björkgren, Stina Carlson, Irma Fredriksson, Johan Ahlgren, Daniel Öhman, Lars Holmberg, Tony Hsiu-Hsi Chen. CANCER; Published Online: May 11, 2020 (DOI: 10.1002/cncr.32859).

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^[22] Kopans DB. The 2009 US Preventive Services Task Force (USPSTF) guidelines are not supported by science: the scientific support for mammography screening. Radiol Clin North Am. 2010 Sep;48(5):843-57. doi: 10.1016/j.rcl.2010.06.005. PMID: 20868889.

^[23] Hubbard R, Kerlikowske K, Buist D, Yankaskas B. Evaluation of breast cancer screening strategies must be based on comparison of harms and benefits. AJR Am J Roentgenol. 2011 Oct;197(4):W793; author reply 794. doi: 10.2214/AJR.11.6791. PMID: 21940562.

^[24] M Ali RMK, England A, Mercer C, Tootell A, Walton L, Schaake W, Hogg P. Mathematical modelling of radiation-induced cancer risk from breast screening by mammography. Eur J Radiol. 2017 Nov;96:98-103. doi: 10.1016/j.ejrad.2017.10.003. Epub 2017 Oct 3. PMID: 29103483.

^[25] Pal Suhrke, doctoral candidate, department of pathology, Oslo University Hospital, Norway; Stephanie Bernik, M.D., chief, surgical oncology, Lenox Hill Hospital, New York City; Sept. 13, 2011 BMJ

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^[29] Woloshin  S, Schwartz  LM, Black  WC, Kramer  BS.  Cancer screening campaigns—getting past uninformative persuasion.   N Engl J Med. 2012;367(18):1677-1679. doi:10.1056/NEJMp1209407

[30] Mann RM, Kuhl CK, Moy L. Contrast-enhanced MRI for breast cancer screening. J Magn Reson Imaging. 2019;50(2):377-390. doi:10.1002/jmri.26654

[31] https://www.verywellhealth.com/difference-between-a-mammogram-and-a-breast-mri-430274

^[32] https://brooklynopenmri.com/breast-mri-vs-mammogram-which-is-better-for-breast-cancer-detection/

^[33] Drago L, Toscano M, De Grandi R, Casini V, Pace F. Persisting changes of intestinal microbiota after bowel lavage and colonoscopy. Eur J Gastroenterol Hepatol. 2016 May;28(5):532-7. doi: 10.1097/MEG.0000000000000581. PMID: 27015015.

^[34] Welch  HG. Estimating annual expenditures for cancer screening in the US. Accessed March 2, 2022. https://csph.brighamandwomens.org/wp-content/uploads/2021/12/Estimating-Annual-Expenditures-for-Cancer-Screening-in-the-United-States.pdf

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^[36] Mazer  B. When cancer screening stopped. September 5, 2021. Accessed March 2, 2022. https://www.theatlantic.com/health/archive/2021/09/when-cancer-screening-stopped/619994/

^[37] Roobol MJ, Schröder FH, van Leeuwen P, Wolters T, van den Bergh RC, van Leenders GJ, Hessels D. Performance of the prostate cancer antigen 3 (PCA3) gene and prostate-specific antigen in prescreened men: exploring the value of PCA3 for a first-line diagnostic test. Eur Urol. 2010 Oct;58(4):475-81. doi: 10.1016/j.eururo.2010.06.039. Epub 2010 Jul 9. PMID: 20637539.

^[38] Ficarra V, Novara G, Zattoni F. The role of the prostate cancer antigen 3 (PCA3) test for the diagnosis of prostate cancer in the era of opportunistic prostate-specific antigen screening. Eur Urol. 2010 Oct;58(4):482-4; discussion 484-5. doi: 10.1016/j.eururo.2010.07.025. Epub 2010 Jul 30. PMID: 20685032.

^[39] Epigenomics receives FDA approval for Epi proColon [news release]. Berlin, Germany: Epigenomics, Inc.; April 13, 2016. http://www.epigenomics.com/en/news-investors/news-media/press-releases/latest-news/article/epigenomics-erhaelt-fda-zulassung-fuer-epi-procolonR.html. Accessed April 24, 2016.

^[40] Epi proColon®: The Blood Test for Colorectal Cancer Screening. U.S. Food and Drug Administration website. http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/MedicalDevices/MedicalDevicesAdvisoryCommittee/MolecularandClinicalGeneticsPanel/UCM390239.pdf. Updated March 14, 2014. Accessed May 19, 2016.