COMMENTSON THE 2021 PLAN FOR THE US PREVENTIVE SERVICES TASK FORCE (USPSTF) REVIEW OFBREAST CANCER SCREENING GUIDELINES

THE USPSTF SCREENING GUIDELINES OVER TIME

1. In 2005 the USPSTF supported annual screening for all women  ages 40 and over (1).

2. In 2009 the USPSTF dropped support for screening women ages 40-49 and urged women ages 50-74 be screened every two years (2).

3. In 2016 the USPSTF advised that women ages 50-74 be screened every two years (3)despite the fact that the Task Force continued to admit that the most lives are saved by screening beginning at the age of 40. They stated “the USPSTF found adequate evidence that mammography screening reduces breast cancer mortality in women aged 40 to 74 years.” (4).

4. Apparently the USPSTF is, once again, preparing to review their guidelines for breast cancer screening.

AVOIDING THE ADVICE OF EXPERTS

The recent pandemic has demonstrated the tragic consequences that result from ignoring science, evidence, and the analysis and advice of experts while being guided by inexpert advice.  In a supposed effort to avoid biases from panel members who have a conflict of interest (COI), the United States Preventive Services Task Force (USPSTF) has prevented anyone with actual expertise in breast cancer screening and the issues involved, from serving on the Task Force Panel.  Consequently, the Panel members have been unable to, critically, sort through the available data and understand the validity or lack of validity of the material they have beenasked to review. 

This has also given “advisers” to the Panel extraordinary influence to “guide” an experientially and factually naive Panel.  In the past, the vast majority of“advisers” to the Task Force Panel reviewing breast cancer screening have been individuals who have expressed their opposition to screening and have clearly had great influence on the Panel.  Many of the advisers have been viewed as having no COI when, in fact, this is not true.  Without an obvious COI it is impossible to gain expertise in a field.  Experts, suchas I, who earn a living related to breast cancer screening, have an obvious and open COI. However, advisers who have received and continue to receive grant support for their research efforts areviewed as free of COI.  In fact, theirsis a far less obvious COI.  Granting agencies, including the National Cancer Institute (NCI), and Foundations have undeclared biases. When the work of agrantee supports the biases of the grantor, grants are likely to be renewed.  Grant or Foundation support isa far more insidious COI than those that are out in the open. 

The practice of excluding experts should stop.  COI’s should be detailed, but rather than being excluded, experts are critical for an accurate analysis of the data to provide the most factual and evidence-based advice.   Guidelines Panels, including the USPSTF, should have leading experts involved in their decisions and the public should be provided with “minority” reports should there be unresolvable disagreements.

FACTS：

Advantages:

1. The randomized, controlled trials (RCT) of breast cancer screening proved that screening and early detection of breast cancer reduces deaths for women ages 40-74 (the ages of thewomen who participated in the trials) (5). Confusion had been created in 1993 by the inappropriate use of subgroup analysis (6)to falsely claim no benefit for women ages 40-49.  The 1993 claims had also ignored the fact that an immediate benefit is not expected from a periodic screening program (7).  The NCI position was later refuted with longer follow-up (8)that showed a clear benefit for screening women ages 40-49 and thus benefit for all women (the RCT’s targeted average populations) ages 40-74.  Although it has been suggested that these trials are old, they provide the fundamental PROOF that early detection reduces deaths. 
   

2. Because of “non-compliance” and “contamination” the RCT’s have underestimated the benefit of early detection.  The results of these trials should be viewed as the lower level of the likely benefit.

3. The USPSTF should be aware that the Edinburgh Trial is no longer cited with the RCT’s because of an apparent imbalance in the socioeconomic factors of participants. 

4. The Canadian National Breast Screening Studies (CNBSS) should also have been dropped from guidelines analyses years ago. Not only are their results major outliers among the RCT’s,but numerous critical analyses over the years have challenged their validity(9,10,11,12,13,14,15,16,17,18,19,20,21,22,23).The trials were compromised by poor quality mammography (24,25),and their data compromised by the fact that they violated the fundamental requirements of RCT’s by having a nonblinded allocation process (26,27). This resulted in a statistically significant excess of women with advanced cancers being assigned to the screening arm of CNBSS1 (28,29).  It has been claimed that the CNBSS trials showed a major, 22% rate of “overdiagnosis”, when, in fact, their own data show that there was only a 4% difference in cancers diagnosed between the two arms (30).  The CNBSS results are compromised and unreliable and should not factor into the USPSTF review (31).

5. Numerous observational studies have validated the benefit of screening women starting at the age of 40 in the general population with reductions in deaths of as much as 40% or more(32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49).

6. In a review of the incidence of death among more than 500,000 women in Sweden there was some benefit from improvements in therapy, but those who participated in mammography screening had a 41% reduction in their risk of dying from breast cancer within 10 years compared to those who had not participated in screening (50])

7. There are NO DATA (ZERO) that show that any of the parameters of screening change abruptly at age 50 or any otherage (51).  The RCT’s proved mortality reduction for women ages 40-74.  The threshold for initiating  screening at the age of 50 is completely arbitrary with NO scientific support.  Grouping of data and averaging has falsely suggested a legitimate threshold when the data show that none exists.  The only reason to use the age of 50 as a threshold is based on individual and scientifically unsupportable biases byanalysts.

   
   

   In fact, allmajor groups including the USPSTF agree that the most lives are saved by annualscreening starting at the age of 40.

   
   

   There are more years of life lost to breast cancer among women ages 40-49 than for women ages50-59 (52).

   
   

8. Radiation risk for the breast from mammography (there is little exposure to any other susceptible organs) drops rapidly with increasing age so that by the age of 40 it is unmeasurable and maybe nonexistent.  Even the extrapolated risk is below even the smallest amount of benefit from screening (53,54).

9. The NCI/CISNET models all predict that the most lives are saved by annual screening starting at the age of 40 (55).

10. Despite specious arguments to the contrary, screening has been shown to reduce the rate of advanced cancers(see below) (56,57,58,59,60,61,62,63,64,65,66,67) that has been used as a surrogate for death since these are incurable cancers.

11. In the Harvard Hospitals 71% ofdeaths from breast cancer were among the 20% of women who were not participating in screening despite having access to modern therapies (68). Spencer et al had similar results (69).

12. The claim that the RCT's didnot reduce "all-cause mortality" is specious (70).  "All-cause mortality" is appropriate in treatment trials where everyone has breast cancer and most of the deaths will be due to breast cancer. You want to be certain that the treatment is not causing an unforeseen risk.  In radiation therapy trials this revealed the unexpected risk that radiation therapy damaged the coronary arteries.  In screening trials, however,most deaths will be due to other causes since breast cancer only accounts for 3% of deaths each year from "all causes".  If you reduce breast cancer deaths by 30% then this will reduce "all cause mortality" by 1%.  It would take a 2.5 million woman trial to prove that this major decrease in breast cancer deaths"significantly" reduces "all-cause mortality".  It would be more appropriate to look at"all-cause mortality" among women with breast cancer in the RCT's and this does show that screening reduces the rate of "all-causemortality" (71).

13. The CISNET models show that as many as 100,000 women now in their 30’s will die by waiting until the age of 50 and being screened every two years whose lives could be saved by annual screening starting at the age of 40 (72). Among just the women who are age 40 today, if they wait until the age of 50 tobe screened every two years as many as 13,770 will die whose lives could be saved by annual screening beginning at the age of 40 (73).

14. The claim of massive overdiagnosis has been manufactured by "guessing" that the incidence of breast cancer was not steadily increasing as screening was being introduced.  Since no one has ever seen a mammographically detected invasive breast cancer disappear on its own (the few"miracles" have all been clinically evident), and Arleo et al showed that none of almost 250 invasive cancers that were untreated did not regress or disappear (74),then waiting until age 50 and screening every two years will not reduce"overdiagnosis" if it even exists, because the cancers will still be there. 

15. Delaying screening will reduce recalls from screening (inappropriately called "false positives") for a few extra pictures or an ultrasound. The recall rate is approximately 10% (which is, approximately, the same recall rate as cervical cancer - Pap - testing) and a very small chance of having an imaging guided needle biopsy using local anesthesia with a fairly high yield of cancer. Approximately 2-4% of women screened will be advised to have an imaging guided needle biopsy and 20-40% of these lesions will prove to be malignant.

    
    

    There is no question that recalls make all of us anxious and recalls from screening are no exception, but, for most, the anxiety is short lived (75).   Given that the major "harm"("harm" is pejorative, it should be called "risk") from screening is the anxiety of being recalled, it is beyond paternal/maternalistic to advise women that it is preferable to let them die an avoidable death than to be made anxious by a recall!!?

    
    

16. Finally, it has been suggested that only high-risk women ages 40-49 should participate in screening.  Although high risk women are just that – at higher risk than the average risk – there are no RCT data to prove that screening only high-risk women will save any lives.  None of the RCT’s stratified by risk so,given that RCT’s are the only way to “prove” a benefit, there is no “proof”that screening only high-risk women will save any lives.  In addition, high-risk women account for approximately 25% of all women diagnosed with breast cancer each year so that screening only high-risk women will exclude 75% of the women who develop breast cancer (76,77).  At the present time it appears that all women are at risk and should be encouraged to participate in screening.  Based on the CISNET models (there has been no RCT comparing screening intervals) annual screening is estimated to provide the greatest reduction in deaths.  All women ages 40-74 should be encouraged to be screened every year.  High risk women may benefit (no proof) from additional screening with MRI or perhaps Ultrasound in between annual mammography.

    
    

    PROBLEMS WITH THE PLANNED USPSTF 2021REVIEW

    
    

17. The Task Force is not going to include the NCI/CISNET computer models to project the potential outcomes of various screening protocols.  Without these the Task Force will be guessing in their predictions.  It would appear that CISNET modeling has been dropped because the models all showed that the most lives are saved by annual screening beginning at the age of 40.  

18. Although a reduction inadvanced stage disease is a potentially useful “surrogate endpoint”, it is critical to remember that lives are lost among women diagnosed at all stages of breast cancer (78).  It has been shown that reducing the size of cancers within stages is also a major benefit from screening that reduces deaths (79,80,81).

19. A critical fact that has been,repeatedly, overlooked by analyses that denigrate the value of screening and(falsely) suggest massive “overdiagnosis”, is the false claim that the background incidence of breast cancer has not increased over time.  This has been the fundamental piece of misinformation that has been used to promote the false concepts of massive overdiagnosis and the false claim that there has not been a reduction in advanced cancers.

    
    

    The data clearly show that the baseline incidence of breast cancer has increased steadily by 1-1.3% per year dating back to at least 1940 (82),long before there was any screening which did not start until the mid 1980’s.  If the correct increasing baseline is used, not only is there no apparent “overdiagnosis” of invasivecancers, but it appears that there has been a major reduction in the incidence of invasive cancers (83).  Although unproven, this is likely due to the removal of Ductal Carcinoma In Situ (lesions almost exclusively detected by mammography) precluding the future development of invasive cancers.

    
    

    By using the correct baseline incidence and extrapolation it is also clear that there has been amajor reduction in the rate of advanced cancers.

CONCLUSION

1. The USPSTF should include experts in breast cancer screening.

2. The USPSTF should provide women with the facts based on science and evidence.

3. The USPSTF guidelines should not be based on the biased, subjective opinions of the Panel members.

REFERENCES

1 http://www.lumen.luc.edu/lumen/meded/hmps/pocketgd[1].pdf  “The U.S. Preventive Services Task Force(USPSTF) recommends screening mammography, with or without clinical breast examination (CBE), every 1-2 years for women aged 40 and older. Rating: B Recommendation.”

2 US Preventive Services Task Force. Screening for breast cancer: U.S. Preventive Services Task Force recommendation statement. Ann Intern Med. 2009 Nov 17;151(10):716-26, W-236. doi:10.7326/0003-4819-151-10-200911170-00008. Erratum in: Ann Intern Med. 2010 May18;152(10):688. Ann Intern Med. 2010 Feb 2;152(3):199-200.

3 Siu AL; U.S.Preventive Services Task Force. Screening for Breast Cancer: U.S. Preventive Services Task Force Recommendation Statement. Ann Intern Med. 2016 Feb16;164(4):279-96. doi: 10.7326/M15-2886. Epub 2016 Jan 12. PubMed PMID:26757170

4 Siu AL; U.S.Preventive Services Task Force. Screening for Breast Cancer: U.S. PreventiveServices Task Force Recommendation Statement. Ann Intern Med. 2016 Feb16;164(4):279-96. doi: 10.7326/M15-2886. Epub 2016 Jan 12. PubMed PMID:26757170

5 Smith RA, Duffy SW, Gabe R, Tabár L, Yen AM, Chen TH.The randomized trials of breast cancer screening: what have we learned? RadiolClin North Am 2004;42(5):793–806

6 Kopans DB, Halpern E, Hulka CA. Statistical Powerin Breast Cancer Screening Trials and Mortality Reduction Among Women 40-49with Particular Emphasis on The National Breast Screening Study of Canada.  Cancer 1994;74:1196-1203

7 Kopans DB.Screening for breast cancer and mortality reduction among women 40-49 years ofage. Cancer. 1994 Jul 1;74(1 Suppl):311-22.

8 Hendrick RE, Smith RA, Rutledge JH, SmartCR. Benefit of screening mammography in women ages 40-49: a new meta- analysisof randomized controlled trials.  Journalof the National Cancer Institute Monograph 22: 87-92, 1997.

9 KopansDB. Major failings of trial procedures and quality of screening fatally compromise the results of the Canadian National Breast Screening Studies. J MedScreen. 2021 Jan 17:969141320986186. doi: 10.1177/0969141320986186. Epub aheadof print. PMID: 33459171.

10 Kopans DB. The Canadian National Breast Screening Studies are compromised and their results are unreliable. They should not factor into decisions about breast cancer screening. Breast Cancer Res Treat. 2017 Aug;165(1):9-15.

11 Heywang-Köbrunner SH, SchreerI, Hacker A, Noftz MR, Katalinic A. Conclusions for mammography screening after 25-year follow-up of the Canadian National Breast Cancer Screening Study(CNBSS). Eur Radiol. 2016 Feb;26(2):342-50.

12 Tabár L, Yen AM, Wu WY, ChenSL, Chiu SY, Fann JC, Ku MM, Smith RA, Duffy SW, Chen TH. Insights from the breast cancer screening trials: how screening affects the natural history of breast cancer and implications for evaluating service screening programs.Breast J. 2015 Jan-Feb;21(1):13-20

13 http://www.mammographyed.com/news/NewsDetail.aspx?a=8076)  Last accessed 4/12/2015

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15 Bailar JC, MacMahon B,Randomization in the Canadian National Breast Screening Study: A Review forEvidence of Subversion.  Can Med Assoc J1997;156:193-199.

16 Kopans DB.  NBSS: Opportunity to Compromise the Process. Letter to the Editor.  Can MedAssoc J 1997;157:247.

17 Tarone RE.  The Excess of Patients with Advanced Breast Cancers in Young Women Screened with Mammography in the Canadian National Breast Screening Study.  Cancer 1995;75:997-1003.

18 Kopans DB, Halpern E, Hulka CA.Statistical Power in Breast Cancer Screening Trials and Mortality Reduction Among Women 40-49 with Particular Emphasis on The National Breast Screening Study of Canada.  Cancer 1994;74:1196-1203.

19 Burhenne LJ, Burhenne HJ. The Canadian National Breast Screening Study: a Canadian critique. AJR Am J Roentgenol. 1993 Oct;161(4):761-3.

20 Boyd NF, Jong RA, Yaffe MJ, Tritchler D, Lockwood G,Zylak CJ. A Critical Apraisal of the Canadian National Breast Cancer Screening Study.  Radiology 1993;189:661-663.