New USPSTF mammogram screening guidelines

 The US Preventive Services Task Force just published their final recommendations on breast cancer screening (see mammog uspstf recs 2024 JAMA2024 in dropbox, or doi:10.1001/jama.2024.5534)

 

Summary of USPSTF recommendations:

-- biennual screening mammogram for women aged 40 to 74 (grade B recommendation)

-- insufficient evidence to assess the balance of benefits and harms of screening mammography in women 75 years or older (grade I statement)

-- insufficient evidence to balance the benefits and harms of supplemental screening for breast cancer with breast ultrasound or MRI in women identified as having dense breasts on otherwise negative screening mammogram (grade I statement)

 

-- These recommendations apply to cisgender women (and includes transgender men and non-binary persons) at average risk of breast cancer, but also to those with some factors associated with increased risk (e.g. family history of breast cancer in first-degree relative, or having dense breasts)

    -- these recommendations basically are the same as the 2016 recommendations by the USPSTF, with the exception of lowering the age to start screening to 40yo, vs individualizing the decision for screening for earlier ages per the 2016 guidelines

-- these recommendations do not apply to those with a genetic marker or syndrome associated with a high risk of breast cancer (eg BRCA1 and BRCA2), a history of high dose radiation therapy to the chest at a young age, previous breast cancer, or a high-risk breast lesion on previous biopsies

-- both digital mammography and digital breast tomosynthesis ( “3D mammography”) are effective mammographic screening modalities

-- they also highlight the fact that there are significant disparities in the US regarding breast cancer mortality by race and ethnicity (though screening mammography is done actually more frequently in Black women, access to subsequent adequate care seems to be quite different and mortality rates are much higher in this group)

-- clinicians should use clinical judgment about whether to screen women 75 years or older or to use supplemental screening in women who have dense breasts and otherwise normal mammograms

 

Details:

-- benefits of early detection and treatment: the meta-analysis for the 2016 USPSTF screening recommendations found that screening was associated with a relative risk reduction of breast cancer mortality of 12%, RR 0.88 (0.73-1.00, 9 trials) for women age 39 to 49; 14% relative risk reduction RR 0.86 (0.68-0.97, 7 trials) for women age 50 to 59; 33%relative risk reduction, RR 0.67 (0.54-0.83, 5 trials) for women age 60 to 69: and a nonsignificant trend to a 20% relative risk reduction, RR 0.80 (0.51-1.28, 3 trials) for women age 70 to 74

    -- an update of three Swedish screening trials reported a 15% relative reduction in breast cancer mortality for women age 40-74, RR 0.85 (0.73-0.98), though Black women were underreported  overall in these trials

-- screening test: as mentioned above, both digital mammography and digital breast tomosynthesis (DBT, or “3-D mammography”) are effective mammographic screening modalities. But they do comment that the two dimensional DBT “must be accompanied by traditional digital mammography or synthetic digital mammography”

    -- studies reporting at least two consecutive rounds of screening have found in general no significant difference in breast cancer detection or in tumor characteristics between DBT and digital mammography, though there may be small increases in the positive predictive value of DBT

-- screening interval: they continue to support biennial screening, given the favorable trade-off between benefits and harms: modeling data suggests that the life-years gained or breast cancer deaths averted by a positive result supported biennial screening (there is a Finnish study on triennial screening finding similar mortality from incident breast cancer and all-cause mortality vs annual screening, with followup to age 52)

-- DCIS: ductal carcinoma in situ is a particularly complex issue with not a lot of useful data, though 25% of women with abnormal mammograms have DCIS diagnosed on biopsy (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3580892/):

    -- DCIS is considered to be a heterogenous ”noninvasive condition with abnormal cells in the breast duct lining with uncertainty regarding its prognostic significance” and with significant clinical variability

    -- There is significant inconsistency in the  diagnosis of DCIS by pathologists: https://europepmc.org/article/pmc/499493

    -- 3.3% of women diagnosed with DCIS die from it 20 years later: https://www.breastcancer.org/research-news/how-many-women-die-after-dcis-dx

    --  the USPSTF does notes that DCIS treatment “may include surgery, radiation, and endocrine treatment, intended to reduce the risk for future invasive breast cancer”

        -- my comments: it is pretty remarkable how little information we have on this rather prevalent condition. though a small minority of women die from this condition, many women do get quite aggressive treatment for this. It is pretty striking that over the last many decades we still do not have a sufficient information to develop more insight into this problem that could render more appropriate management…

-- disparities in breast cancer outcomes: they do note that there are large differences in breast cancer mortality (Black women have approximately 40% increased risk of breast cancer mortality, five-year age-adjusted mortality of 27.6 per 100,000 women versus 19.7 per 100,000 white women). And they do note that Black women have a higher incidence of at least one negative molecular marker (estrogen receptor, progesterone receptor, and HER-2 receptor) and are more likely to have triple-negative hormone receptor status, which is associated with worse outcomes and are less readily detected through screening. They also note that this is all likely to be from “environmental factors and social determinants of health, including racism”, as well as racial and economic segregation driven by discriminatory housing policies, exposures to toxic environment such as air pollution, industrial waste, and built environments that do not support health, have stressful life conditions, and have less access to high-quality health care.

    -- This disparity in breast cancer outcomes is quite striking given that recent data suggest that Black women have mammography screening somewhat more so than white women

    -- the main issue leading to the disparity in outcomes is access to care after a positive mammogram, and this is documented to be related to decreased real access to care

        -- a very recent article assessed racial/ethnic differences in breast cancer survival, also finding that, as compared to white women, those of several different races/ethnicities were more likely to decline surgery, decline chemotherapy, decline radiotherapy but were more likely to accept hormone therapy (see breast cancer minorities dec service utilization JAMA2024 in dropbox, or doi:10.1001/jamanetworkopen.2024.9449)

-- age boundaries for the recommendations:

    -- epidemiologic evidence has suggested that the incidence of invasive breast cancer for those 40 to 49 years old has increased an average of 2.0% annually between 2015 and 2019, a rate higher than previous years

    -- women >75yo: the mortality from breast cancer increases with increasing age, but there are no randomized controlled trials showing screening benefit in this age group. Modeling studies have suggested no benefit in screening those 75-84 years old.

    -- However, not mentioned here, is that prior mathematical modeling studies have suggested women with at least a 10 year life expectancy might well benefit

-- potential harms of screening: they do comment that there are many false positives leading to additional testing and invasive follow-up procedures; there is significant overdiagnosis and overtreatment of lesions that would not have led to health problems; and there is increased radiation exposure. They do not have further comments on radiation exposure, but see my commentary below.

 

Commentary:

-- breast cancer is the second most common cancer and second most common cause of death in US women. In 2023 there were an estimated 43,170 women who died of breast cancer.

-- breast cancer incidence increases with age and peaks in women age 70-74 (453.3 cases per 100K women), though it still remains high in those over 75 years old (409.9 cases per 100K women). And it is clear that younger women now comprise about 8-10% of cancer diagnoses, per the CDC, and that breast cancer diagnoses are increasing in women <50yo over the past 2 decades (increasing in those 40-49 from 2000-2015, but increasing more dramatically from 2015-2019 at 2.0%/year):

 

 

    – this graph is from the CDC

 

-- there are a few important issues not addressed in these recommendations:

    1. radiation exposure

        -- this is even more of an issue with the increasing number of mammograms and the attendant increase in ionizing radiation, per the new USPSTF recommendations

    -- there are few studies that assess the risk of radiation-induced cancer; many were based on cancers induced in survivors of the atomic bomb in Hiroshima and Nagasaki, including one done on breast cancer (see Radiat Res 1987;112:243–272):

        -- this study found that women who were under 10 years of age at the time of radiation exposure were at the highest risk of subsequently developing breast cancer as an adult. The data for older women was less clear. 

    -- there are modeling studies that suggests that repeated x-rays are likely associated with initiation of cancers. For example an evaluation of radiation exposure by performing multiple low-dose chest CTs (LDCTs) for smokers suggested that one in 2500 would develop cancer because of the radiation exposure

     -- I would like to add that these calculated numbers for LDCT screening leading to lung cancer are largely based on people with normal lungs and not on people with damaged lungs from smoking, where the likelihood of cancer seems to be quite a bit higher (e.g. those with COPD versus no COPD with the same amount of smoking exposure seem to have a three-fold increased risk of lung cancer). This observation fits with the "multiple-hit model of cancer", whereby multiple different potential carcinogenic factors significantly increase cancer risk

    -- and, this multiple-hit concept might well apply to women receiving lots of mammograms who are at higher risk (e.g. with prior biopsies with results suggesting they have higher risk of breast cancer in the future) or those who receive more radiation exposure (which may be the case in women with larger breasts, and dense breast tissue also absorbs significantly more radiation during a mammography versus fatty breast tissue), perhaps along with a known or unknown genetic predisposition, etc. And these women often receive even more ionizing radiation exposure if they have annual exams or more diagnostic mammograms. There is also a study suggesting that women with a history of mastitis and benign breast disease are at increased risk of breast cancer by radiation exposure (see https://gmodestmedblogs.blogspot.com/2022/05/mammograms-50-false-positive-rate-in-10.html for more information on this)

-- a pretty recent analysis was done on breast cancer induced by digital mammographic techniques (having a glandular radiation dose of 2.5 mGy of radiation), suggesting a 60% increased incidence over baseline for biennial screening in women age 50 to 74 (see mammog radiation inc cancer MedPrincPract2015 dropbox, or DOI: 10.1159/000442442), and presumably higher incidence if women 40-50 were involved (also, there will be a longer time lag in a 40 year old, since the cumulative effects of this earlier exposure will be present for longer)

    -- one major concern is that genetic susceptibility to breast cancer increases the adverse effect of ionizing radiation:  5-10% of all breast cancer cases are due to familial autosomal dominant effects (there are at least 20 susceptible genes that harbor intermediate- or high-risk mutations for breast cancer that have been identified). These women have increased carcinogenic effects from these genetic predispositions, presumably because the radiation leads to misrepaired DNA damage in the already compromised genome particularly from DNA double strand breaks.

        --also, some women have an uncommon “low-dose hypersensitivity to radiation” leading to excess susceptibility and higher cancer  risk

        -- and many of the women who develop breast cancer are unaware of their genetic higher risk

-- It may well be that radiation-induced cancer may be more of an issue for Black women who seem to get more mammograms than white women, who are therefore subjected to more ionizing radiation, but have less mammogram screening benefit related to issues that decrease access to subsequent care (see below)

 

    2. the increasing prevalence of breast cancer. why is this happening?  My guess is that much of this is from environmental exposures, in particular to estrogenic toxins.

        – for a list of xenoestrogens (endocrine disrupting chemicals that can mimic the effects of estrogen, which is a promoter of breast cancer : https://www.biocare.co.uk/news/xenoestrogens-and-environmental.html#:~:text=Plastics%3A%20Bisphenol%20A%20(BPA),to%20heat%20or%20acidic%20conditions. including:

        -- PFAS (Per- and poly-fluorinated alkyl substances), also known as the "forever chemicals", a large chemical family of over 10,000 highly persistent chemicals that don't occur in nature, and these have been found to be estrogen-receptor agonists (see https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10898820/ )

        -- BPAs (bisphenol A) has strong estrogenic effects by binding to estrogen receptors: https://www.biocare.co.uk/news/xenoestrogens-and-environmental.html#:~:text=Plastics%3A%20Bisphenol%20A%20(BPA),to%20heat%20or%20acidic%20conditions.

        -- PCBs (polychlorinated biphenyls) have weak estrogenic effects: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1480489/#:~:text=Polychlorinated%20biphenyls%20(PCBs)%20have%20been,of%20the%20female%20reproductive%20tract.

        -- microplastics are omnipresent in our society, and have been recently shown to increase the risk of cardiovascular events, perhaps related to their creating a chronic inflammatory state: https://gmodestmedblogs.blogspot.com/2024/03/plastics-too-many-and-too-bad-for-our.html

            -- most plastics also release estrogenic chemicals that potentially affect breast tissue (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3222987/ )

       -- the issue here is that industry is producing about 1500 new chemicals/year. many end up in our water supply, air, ground, and sometimes into our foods. Very few of them are rigorously tested prior to making it into our environment

-- one comment about MRIs of the breast: though they have a sensitivity of 90%, the specificity is 75% on average, but down to 39% in women at high-risk. So MRIs lead to lots of further invasive testing and increased anxiety

    -- there is often a big problem with MRIs: too much information. they seem to be excellent in finding "abnormalities", which may well be present but their clinical significance may be suboptimal. this has been found repeatedly in MRIs for low back pain, where there are several studies finding quite serious looking pathology in people with no history of back pain, and another study finding that getting an MRI can lead to more disability later on: https://gmodestmedblogs.blogspot.com/2021/12/low-back-pain-disability-worse-with.html

 

-- and a comment about racial/ethnic disparities and the increased breast cancer along racial/ethnic lines:

    -- it is certainly true that many non-white patients (and some white ones) distrust the health care system, and many of them either themselves or from reasonable understanding of others, have experienced being considered victims of research on health

    -- a blatant example of this is the followup of the Tuskegee Study (where the US Public Health Service conducted a study of the natural history of untreated syphilis from 1932-1972!!!!!); 40 years later Black men in Tuskegee still felt mistrust of the health care system, had decreased involvement with medical care, and increased mortality ( https://academic.oup.com/qje/article-abstract/133/1/407/4060075?redirectedFrom=fulltext )

    -- and there are lots of other examples (per my experience): community people in Boston in the 1960s and 1970s developed community health centers under their own control largely because community members felt that the city hospital was experimenting on them (this perception, which I found was quite accurate, required me to have extensive meetings with the health center board  where I was working at to get permission for medical residents to train at the health center)

    --or the many African-American women who migrated to Chicago in the "Great Migration" from the South who had had hysterectomies without their knowledge (many personal stories related to me when i was training in Chicago)

 

-- it is notable that the increase in breast cancer in young people has also been found for colon cancer and is associated with a parallel decrease in the age for recommended screening ( https://gmodestmedblogs.blogspot.com/2024/04/colon-cancers-earlier-onset.html ), reinforcing perhaps some similar etiologies for the earlier incidence of cancers (in particular, the role of environmental changes/exposures as being more globally carcinogenic)

 

-- here are some relevant prior blogs:

    --https://gmodestmedblogs.blogspot.com/2022/05/mammograms-50-false-positive-rate-in-10.html : the cumulative probability of false positive results after 10 years of annual mammography screening was in the 50% range. This blog also reviews the Nagasaki/Hiroshima data, as well as information on inaccuracies of radiologic mammogram interpretation

    --https://gmodestmedblogs.blogspot.com/2014/10/lung-cancer-screening.html which shows the USPSTF overreach in their recommendations to do LDCT screening of smokers, and that regular screening would engender one cancer death per 2500 screened

    --https://gmodestmedblogs.blogspot.com/2014/04/mammograms-again.html reviews an articles suggesting that the benefits of aggressive mammogram screening a much less than what it seems: for women in their 50s, breast cancer mortality may decrease from 3-32 of 10,000 women screened, with 6130 having false positive tests, 940 getting biopsies, and 30-137 with overdiagnosed breast cancers)

 

so, these new USPSTF guidelines on mammography reflect the increasing number of breast cancer diagnoses in young people over the past 2 decades, and especially over the past several years.

--as is obvious, breast cancer is a devastating problem for many women: huge morbidity, including psychological morbidity, and mortality. we do have an increasing array of medications to treat breast cancer, even pretty refractory cases, including lots of meds in clinical trials. and these can be very helpful. but the goal is clearly prevention and early diagnosis

-- the increased breast cancer along racial/ethnic lines brings up the issue of how we clinicians are talking with our patients: we really should be using motivational interviewing when discussing mammography results (and before then...) to assess what the real roadblocks are for seeking treatment for breast cancer in anyone declining treatment, which seems to be especially true for non-white patients

--mammography is an important took in early diagnosis of breast cancer, though there are important issues of overdiagnosis and false positive results (not so different from the issues of prostate cancer in men)

--but this increased and earlier incidence of breast cancer really does bring up the issue of why breast cancer is increasing, and why we need to address the issues that lead to breast cancer (ie, breast cancer prevention).  i think there are reasonable arguments that many environmental exposures are at least partially to blame. industrial chemical production/environmental protection should be integrated into a robust public health system to prevent the untoward effects of pollution on our health (and the health of the planet)

 

geoff

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