MAMMOGRAPHY SCREENING AND RADIATION RISK

One of the major issues that has been raised about mammography screening is the concern that the radiation from mammography might cause breast cancers. I want to state this at the outset since some may still be concerned.

BOTTOMLINE FACT:

There is no measurablerisk from radiation to the breast from mammograms for women ages 40 and over.Even the extrapolated risk is much lower than the proven benefit.

THE ORIGINS OF THE CONCERN

The Health Insurance Plan of New York,randomized, controlled trial in the 1960’s, (HIP) demonstrated that screening for breast cancer could reduce deaths (1).  It was then suggested that it would not be possible to screen all the women in the U.S. In the 1970’s the Breast Cancer Detection Demonstration Project (BCDDP) was organized and ultimately showed that more than 250,000 women could be screened every year for four years, efficiently and effectively (2).  However, while the BCCDP was underway, John Bailar, greatly overestimating the risk, wrote that the radiation from mammography screening would cause as many cancers as might be cured (3).  Needless to say this raised a great deal of concern and the BCDDP ceased screening women in their forties.  For many years the concern was very high and was used to try to curtail screening for younger women.

FACTS

As the years passed, the issue was studied in increasing detail. It was debated as to whether or not there was a threshold dose and that there was no risk withlow doses of radiation, and that it was not until sufficient dose was received before radiation carcinogenesis would occur. Given the impossibility of, directly, measuring the effect at low dosesin humans, it was decided that a no threshold model would be used and that the effects of radiation causing cancers was most likely a linear model – risk went up directly with dose.  However, as the years passed and more data accrued from exposures such as from the survivors of the atomic bomb attacks in World War II; women who were treated with radiationfor postpartum mastitis in the 1940’s; and women who underwent numerous chest fluoroscopic examinations during pneumothorax treatment for tuberculosis, it became increasingly apparent that, as far as the breast is concerned, the risk from radiation is very much determined by the age at which breast tissues are exposed.  There is certainly risk to the breast in girls and teen age women, but this declines rapidly with increasing age.  For example, women who have mediastinal irradiation for the treatment of Hodgkin’s Disease while in theirteens and early twenties have a very high risk of, subsequently, developing breast cancer from the direct and scatter radiation received by the breasts with as many as 30% developing breast cancer by age 40 (4).  However, it is reassuring that women treated in the same way after the age of 30 had no excess risk of breast cancer.

THE UNDIFFERENTIATED BREAST MAY BE THEREASON FOR ANY RADIATION RISK

There is no exact proof as to why radiation risk drops rapidly with increasing age, but I suspect it is related to differentiation of the glandular tissues and the high concentration of stemcells prior to the differentiation of the lobules.  It is my understanding that it is very difficult to cause a differentiated cell to dedifferentiate and become a cancercell.  However, a stem cell that is undifferentiatedand “pluripotent” to begin with is more easily damaged and converted.  As we know, damage to the DNA of a cell canbe corrected by cellular repair mechanisms.  If the damage cannot be corrected the cell will likely under go apoptosis and eliminate itself.  At times, however, the damage may not be corrected,and the cell may not destroy itself, and it may continue to exist with compromised DNA.  Depending on what part of the genetic code is damaged, there may not be any major consequences. However, if DNA changes occur in critical portions of the code, that damage may be sufficient to convert the cell to acancer cell, or, with future additional damage or mutation that is also not corrected and also does not kill the cell, the accumulated damage may result in uncontrolled cell division and it becomes a cancer cell.

Although the breast begins to develop under the influence of pubertal hormones, the terminal duct lobular units (the glandular portions of the breast) remain undifferentiated for variable lengthsof time. A full-term pregnancy is one of the ways that “terminal differentiation” takes place since the breast has to be ready for lactation.  In nulliparous women,there is no way to know when differentiation takes place, but it is likely a more drawn out process over many years in the absence of a full-term pregnancy, with differentiation occurring at various ages simply with aging. 

Differentiation means that stem cells have produced “differentiated”, functioning cells that form breast tissues.  I suspect that with terminal differentiation,the concentration of stem cells drops. With fewer stem cells, exposure to a carcinogen would be less likely toresult in cancer initiation.   Datasuggest that differentiation is an important event in the risk of developing breast cancer.  A woman who has her first full term pregnancy by age 18 has about 1/3 the risk of, subsequently, developing breast cancer as a woman who has not had a full-term pregnancy by age 30 (5).  A full-term pregnancy leads to cellular differentiation and fewer stem cells.  Inmouse models when the mice are given a carcinogen before they have had a litter they have a very high risk of developing breast cancers.  However, the same carcinogen has little effect after the mouse has delivered a litter. These along with radiation risk declining with age suggest that breast cancer risk is likely related to the concentration of stem cells in the undifferentiated breast that are more susceptible to carcinogens.  With age and differentiation, the concentration of stem cells likely declines and along with it the risk from carcinogens like radiation.

THERE IS NO MEASURABLE RISK TO THE BREASTFROM RADIATION FOR WOMEN AGES 40 AND OVER

Regardless of the explanation, the dataclearly show that radiation risk for the breast declines with increasing age. If there is any risk to the breast from radiation for women age 40 and over, it is so small that it cannot be directly measured.  In the U.S. screening began in the mid 1980’s in large numbers. Given that there is a latency period of 8-10 years following exposure to a carcinogen and the subsequent development of a cancer, we would expect to have seen a major jump in the incidence of breast cancer by the late 1990’s.  Instead, there was a drop in incidence that began in 1999 that was due to the end of the prolonged prevalence screening period. In 1999 participation in screening plateaued and incidence returned toward the chronically (since at least 1940) increasing base line as expected.  There was no sudden increase that would have been expected from thee millions of mammograms that had been obtained over the preceding decade.

Numerous studies have been published that have tried to quantify the actual risk.  By the time a woman reaches the age of 40 the risk is so small it can not bemeasured directly. Consequently,investigators have extrapolated the risk among older women from the more measurable risk in younger women.  These have been very reassuring.  Even the most pessimistic analyses have shown that the extrapolated risk is much lower than the benefit from screening and early detection. Mettler et al showed that that risk is lower than even a 5% benefit from lives saved by screening (6).  Miglioretti et al estimated that if we screen 100,000 women ages 40-74, as many as 125 breast cancers might be induced from the radiation that might lead to 16 deaths, but the screening would save 968 lives (7).  Yaffe and Manprize came to similarconclusions (8). 

The important conclusion is that mammography screening women ages 40 and over has been proven to save tens of thousands of lives while the risk from the radiation is unmeasurably small and may well be nonexistent.

REFERENCES

1  Shapiro S. Evidence on Screening for Breast Cancer from a Randomized Trial.  Cancer. 1977;39:2772-278

2  Baker LH.Breast Cancer Detection Demonstration Project: five-year summary report. CACancer J Clin. 1982 Jul-Aug; 32(4):194-225

3  Bailar, JC.  Mammography: Acontrary view.  Ann Intern Med 197684:77-84.  

4  Bhatia S, Robison LL, Oberlin O, Greenberg M, Bunin G, Fossati-Bellani F,Meadows AT.  Breast Cancer and Other Second Neoplasms After Childhood Hodgkin's Disease.  J Engl J Med 1996;334:745-751.

5  MacMahon B, Cole P, Lin M, Lowe CR, Mirra AP, Ravinhar B.  Age at First Birth and Breast CancerRisk.  Bull World Health Organ 1970;43:209-221.

6  Mettler FA, Upton AC, Kelsey CA, Rosenberg RD, Linver MN.  Benefits versus Risks from Mammography:  A Critical Assessment.  Cancer 1996;77:903-909.

7  Miglioretti DL, Lange J, van den Broek JJ, Lee CI, van Ravesteyn NT,Ritley D, Kerlikowske K, Fenton JJ, Melnikow J, de Koning HJ, Hubbard RA.Radiation-Induced Breast Cancer Incidence and Mortality From DigitalMammography Screening: A Modeling Study. Ann Intern Med. 2016 Feb16;164(4):205-14.

8  Yaffe MJ, Mainprize JG. Risk of radiation-induced breast cancer from mammographic screening. Radiology. 2011 Jan;258(1):98-105.